US 20150250733A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0250733 A1 ODID (43) Pub. Date: Sep. 10, 2015
(54) ORAL DRUG DELIVERY FORMULATIONS A63L/38 (2006.01) A63/67 (2006.01) (71) Applicant: Isa ODIDI, Toronto (CA) (52) U.S. Cl. CPC ...... A61K 9/2846 (2013.01); A61 K3I/138 (72) Inventor: Isa ODIDI, Toronto (CA) (2013.01); A61 K3I/485 (2013.01); A61 K 31/167 (2013.01); A61K 31/437 (2013.01); (21) Appl. No.: 14/685,214 A6 IK3I/197 (2013.01); A61 K3I/I37 (2013.01); A61 K9/2086 (2013.01) (22) Filed: Apr. 13, 2015 (57) ABSTRACT Related U.S. Application Data In an aspect, a formulation is provided that comprises at least (63) Continuation of application No. PCT/CA2013/ one active Substance and at least one coat comprising Eudragit E (dimethylaminoethyl methacrylate copolymer), 000610, filed on Jun. 28, 2013. wherein the formulation is free of any active substance exter (60) Provisional application No. 61/714,182, filed on Oct. nal to the coat. The formulation is effective in preventing 15, 2012. significant dose dumping in alcoholic/non-alcoholic bever age(s). In another aspect, a formulation is provided that com Publication Classification prises a loading dose having at least one active Substance, wherein the release of the at least one active substance shows (51) Int. Cl. a Point Of Divergence (POD), in a dissolution profile, with A6 IK 9/28 (2006.01) the loading dose representing a point in a timeline where the A6 IK3I/485 (2006.01) history of the dissolution or release rate changes from an A6 IK9/20 (2006.01) onset of action to another set of points in the timeline repre A6 IK3I/437 (2006.01) sented by a controlled release. The formulation may be used A 6LX3/97 (2006.01) for releasing up to about 55% of a total dose as a loading dose A6 IK3I/37 (2006.01) in order to manage pain. Patent Application Publication Sep. 10, 2015 Sheet 1 of 15 US 2015/025.0733 A1
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ORAL DRUG DELVERY FORMULATIONS freezing and cutting to obtain finely divided powders, gran ules or coarse particles in order to instantaneously obtain the RELATED APPLICATIONS benefit of the total active ingredient present in the slow or 0001. This application is a continuation U.S. Application delayed release formulation by releasing or dumping all the under 35 U.S.C. S365 of International Patent Application No. active ingredient at once in the presence of a liquid milieu. PCT/CA2013/000610, filed on Jun. 28, 2013, which claims Products containing active ingredients that will produce an priority to U.S. Provisional Patent Application No. 61/714, emotional, psychological, euphoric, depressive or generally 182 filed on Oct. 15, 2012, the disclosures of each of which psychedelic experiences are particularly Vulnerable. are incorporated by reference herein in their entirety. 0007 As an example of this practice, is the well-docu mented abuse of modified release, delayed release, controlled FIELD OF THE INVENTION release or extended release medicinal opioid formulations. This has almost become a way of life to a rapidly growing 0002 The present invention relates to drug delivery for segment of the world population, especially in the United mulations, in particular, oral drug delivery formulations, uses States and Canada, so much so that, the abuse of opioid thereof and methods of making same. products by perturbation or tampering, is now a growing public health concern in the United States and Canada. BACKGROUND Tampering or perturbation of modified release, delayed 0003 Modified release, delayed release, controlled release, controlled release or extended release solid formula release or extended release formulations, in particular Solid tions of opioid analgesic taught in prior art and currently oral formulations, are often presented as compressed or commercialized, occur via heating, microwaving, freezing formed dosage units (as opposed to fine discrete particles or and/or perturbation or pulverization or crushing or grinding granules) with well-appointed physical geometries which or milling or cutting into one or more sizes ranging from very may be expressed internally as matrices and externally as fine to coarse particles, granules or spheres thereby making it round or shaped tablets, capsules, rods or beads. These geom available for instantaneous wetting and thus easy to be abused etries help present a physical form and barrier to quick or by the parenteral, nasal or oral route. Another route of abuse sudden entry of fluids to the micro environments within these is by chewing or licking. systems when these formulations are brought in contact with 0008. Yet another route of abuse which has become of a liquid milieu. When compromised, quick and Sudden expo serious concern is Snorting of fine powder obtained from sure to fluids results in rapid loss of modified release, delayed crushed opioid formulation or the oral ingestion of finely release, controlled release or extended release properties. crushed extended release oral formulation in order to instan 0004. It is well known that with modified release, delayed taneously obtain the benefit of the total opioid present in the release, controlled release or extended release formulations, slow release formulation. the release of active ingredient depends on certain physico 0009 Currently, many formulations and methods cur chemical properties of the retarding/gelling agents and or rently taught can be compromised and destroyed leading to polymeric and non-polymeric agents used to construct the the loss of controlled release effects and complete release or formulations. However, it is also well known that in order for dose dumping of its opioid content and the rising incidence of these types of formulations to act in accordance with their opioid abuse. The increase in opioid abuse is particularly properties (such as retard the release of active ingredients in a evident among young people. In light of this, the Food and controlled and or predictable manner), all the Ingredients Drug Administration (FDA) in the United States has encour must be brought into close proximity by compaction. The aged the development of novel interventions to prevent this presentation of these formulations as an Intact matrix (with a abuse, while recognizing the importance of maintaining the Solid physical geometry), whether formed or compressed, availability of these important drug products for the millions guarantees this close proximity which in turn provides a of patients who suffer from chronic pain. Numerous stake conducive environment for the active ingredient release retar holders have also recommended the development of tamper dation mechanism to kick in effectively. resistant formulations ever since the first reports of extensive 0005. There has always been the concern that patients may tampering of a commercially available extended release for be, inadvertently, administered crushed, modified release, mulation of Oxycodone surfaced. delayed release, controlled release or extended release for 0010 Unfortunately, to the best of our knowledge, suc mulations despite the very clear direction in product literature cessful new formulations have been elusive or non-existent. inserts or prescription labels/instructions not to crush the Particularly elusive are formulations which do not show com tablets before use. There have been reports of patients mis plete loss or which show none or insignificant loss in con takenly Sub-dividing or crushing and ingesting these tablets trolled release properties when heated, microwaved, freezed despite instructions not to do so, and Suffering serious adverse and/or perturbed, pulverized or crushed or ground or milled effects as a result. or cut Into one or more sizes ranging from very fine to coarse 0006. A major issue of great concern; however, is that the particles, granules or spheres. Others that are equally elusive need for a solid physical geometry for modified release, are Successful new formulations that do not instantaneously delayed release, controlled release or extended release for release all or significant amounts of active content when mulations to operate effectively is now being exploited by heated, microwaved, freezed and/or pulverized or crushed or unscrupulous individuals to tamper with or perturb these ground or milled or cut into one or more sizes ranging from types of modified release, delayed release, controlled release very fine to coarse particles, granules or spheres. Also elusive or extended release formulations in order to rapidly release are successful or effective new formulations which do not the active ingredients contained in them. The perturbation or release significant amounts or all of its active content over a tampering involves one or a combination of crushing, milling, short period of time when heated, microwaved, freezed and/ pulverizing, grinding, flattening, heating, microwaving, or pulverized or crushed or ground or milled or cut into one or US 2015/025.0733 A1 Sep. 10, 2015 more sizes ranging from very fine to coarse particles, granules and antagonist are interdispersed and are not isolated from or spheres; formulations with a loading dose having quick each other in two distinct layers. onset of action and Sustained action that are effective and do 0016 U.S. Pat. No. 7,955,619 is directed to an abuse resis not release significant amounts or all of its active content over tant oral pharmaceutical composition, comprising: a barrier a short period of time when heated, microwaved, freezed layer, comprising a first polymer; a diffusion layer compris and/or pulverized or crushed or ground or milled or cut into ing a second polymer, Substantially covering the barrier layer, one or more sizes ranging from very fine to coarse particles, wherein the diffusion layer is bonded to the barrier layer and granules or spheres; and formulations with a loading dose comprises a drug that is Substantially homogeneously distrib having quick onset of action and Sustained action that are uted within the second polymer and diffuses from the diffu effective and do not dose dump in the presence of alcohol (i.e. sion layer within the gastrointestinal (GI) tract; and option alcoholic beverage). ally an expansion layer comprising an expandable polymer, 0011 Attempts have been made in the past to control the wherein the expansion layer is substantially covered by the abuse potential associated with opioid analgesics. Parenteral barrier layer. Methods of making the same and methods of dose of opioid analgesics are more potent as compared to the using the same are also provided. same dose administered orally. Therefore, drug abuse is often (0017 U.S. Pat. No. 3,980,766 is directed to the incorpo carried out by the extraction of the opioid from the formula ration of an ingestible solid, which causes a rapid increase in tion, and the Subsequent injection of the opioid (using any Viscosity (gelling) upon concentration of an aqueous Solution “suitable' vehicle for injection) in order to achieve a “high.” thereof. Attempts to curtail abuse have therefore typically centered on (0018 U.S. Pat. No. 4,070,494 is directed to the incorpo the inclusion in the oral formulation of an opioid antagonist ration of a non-toxic, water gellable material in an amount which is not orally active but which will substantially block Sufficient to render the drug resistant to aqueous extraction, the analgesic effects of the opioid if one attempts to dissolve thus retarding the release of the drug Substance. the opioid and administer it parenterally. 00.19 U.S. Pat. No. 6,309.668 is directed to a tablet for oral 0012 U.S. Pat. No. 3,254,088 is directed to the prepara administration containing two or more layers comprising one tion of naloxone and its activity as a narcotic antagonist. U.S. or more drugs and one or more gelling agents within separate Pat. No. 3,493,657 is directed to the combination of morphine layers of the tablet. The examples in this patent all describe and naloxone as a composition for parenteral use “which has conventional immediate release formulations and the result a strong analgesic, as well as antagonistic effect, without the ing tablets form a gel when combined with the volume of occurrence of undesired or dangerous side effects.” A New water necessary to dissolve the drug; this formulation thus York Times article appearing in a Jul. 14, 1970 issue reduces the extractability of the drug from the tablet. described the oral administration of naloxone to narcotic 0020. Although these compositions may preclude abuse addicts as a method of treatment. The oral administration of by injections, this approach would fail to prevent abuse by naloxone (in high doses) "makes it impossible for the addict crushing and Swallowing or Snorting the formulation. It to experience a high no matter how much heroin he uses.” should also be noted that reduction of extractability was only 0013 The combination of pentazocine and naloxone has reported in small volumes of water. been utilized in tablets available in the United States, com 0021 U.S. Pat. Nos. 6,277,384, 6,375,957 and 6,475,494 mercially available as Talwin R) from Sanofi-Winthrop. Tal are directed to oral formulations including a combination of win R) contains pentazocine hydrochloride equivalent to 50 an orally active opioid agonist and an orally active opioid mg base and naloxone hydrochloride equivalent to 0.5 mg antagonist in a ratio that, when delivered orally, is analgesi base. Taiwin R is indicated for the relief of moderate to severe cally effective but that is aversive in a physically dependent pain. The amount of naloxone present in this combination has subject. While such a formulation may be successful in deter no action when taken orally, and will not interfere with the ring abuse, it also has the potential to produce adverse effects pharmacologic action of pentazocine. However, this amount in legitimate patients. of naloxone given by injection has profound antagonistic (0022 U.S. Patent Application Publication No. 2007/ action to narcotic analgesics. Thus, the inclusion of naloxone 0066537 is directed to an abuse resistant opioid wherein the is intended to curb a form of abuse of oral pentazocine, which opioid is bound to niacin, biotin or peptide. U.S. Patent Appli occurs when the formulation is solubilized and injected. cation Publication No. 2006/0104909 is directed to a phar Therefore, this dosage has lower potential for parenteral maceutical composition comprising an opioid and a tamper abuse than previous oral pentazocine formulations. However, resistant matrix comprising one or more tenacious cross it is still Subject to patient misuse and abuse by the oral route, linked polymers that are capable of bonding with the opioid for example, by the patient taking multiple doses at once. such that the opioid is substantially incapable of immediate release from the polymer. U.S. Patent Application Publication 0014 U.S. Pat. No. 6,627,635 is directed to a method of No. 2005/0281748 is directed to an opioid bound to a lipid or preventing abuse of opioid formulations wherein an analge fatty acid to produce an abuse resistant drug. U.S. Pat. No. sically effective amount of an orally active opioid agonist is 7,943,173 is directed to a pharmaceutical composition com combined with an opioid antagonist into an oral formulation. prising from 10 to 40 mg of oxycodone or a pharmaceutically 0015 U.S. Pat. No. 6,696,088 is directed to a tamper acceptable salt thereof and 0.65 to 0.90 mg naloxone or a resistant oral opioid agonist formulations comprising (i) an pharmaceutically acceptable salt thereof. U.S. Pat. No. 7,914, opioidagonist in releasable form and (ii) a sequestered opioid 818 is directed to oral formulations, comprising (i) a thera antagonist which is Substantially not released when the for peutically effective amount of an opioidagonist; (ii) an opioid mulation is administered intact, Such that the ratio of the antagonist in releasable form; and (iii) a sequestered opioid amount of antagonist released from said formulation after antagonist which is not released when the formulation is tampering to the amount of the antagonist released from the administered intact. U.S. Pat. No. 7,201.920 is directed to intact formulation is about 4:1 or greater, wherein the agonist therapeutic pharmaceutical compositions comprising a mix US 2015/025.0733 A1 Sep. 10, 2015 ture including (a) at least one specific opioid analgesic (b) gel tablets. In other words, current formulations/compositions forming polyethylene oxide; (c) at least one specific disinte have resulted in less effective and, therefore, less optimal grant; and (d) a nasal tissue irritant, wherein the composition treatment of pain in the management of moderate to severe functions such that less than about 50% of the total amount of pain when a continuous, around-the-clock opioid analgesic is opioid analgesic in the composition is recovered when about needed for an extended period of time. 490 mg. of the composition is contacted with 15 ml of water. 0026. For these reasons, there is still a need for a stable U.S. Pat. No. 7,842,307 is directed to an oral formulation drug delivery system that can be reproducibly manufactured, comprising a therapeutically effective amount of an opioid provide adequate and timely drug release, and yet reduce the analgesic, an opioid antagonist and one or more pharmaceu potential for abuse?tampering. tically acceptable excipients. U.S. Pat. Nos. 7,842.307 and 7.201.920 do not, however, solve the problem of solubiliza SUMMARY tion and significant drug release seen when crushed. 0027. In accordance with one aspect, there is provided a 0023 U.S. Pat. No. 7,674,799 is directed to an oral formu formulation comprising: at least one primary active Sub lation comprising particles having from about 5 mg to about stance; and at least one coat comprising Eudragit E (dimethy 320 mg oxycodone hydrochloride active pharmaceutical laminoethyl methacrylate copolymer), wherein the formula ingredient. The particles are coated with an amount of hydro tion is free of any active Substance external to said at least one phobic material effective to provide a sustained release. U.S. COat. Pat. No. 6,488.963 is directed to a non-film controlled release 0028. In accordance with another aspect, onset of action of pharmaceutical formulation comprising an effective amount said at least one primary active Substance is potentiated by the of a therapeutic compound and a high molecular weight poly presence of a loading dose comprising said at least one pri (ethylene oxide). U.S. Pat. No. 7,776,314 is directed to a mary active Substance. In another aspect, the release of said at parenteral abuse-proofed solid formulation for oral adminis least one primary active substance shows a Point Of Diver tration, comprising, in addition to one or more active ingre gence (POD), in a dissolution profile, with the loading dose dients with potential for abuse selected from the group con representing a point in a timeline where the history of the sisting of opiates, opioids, tranquilizers, stimulants and dissolution or release rate changes from an onset of action to narcotics, at least one viscosity-increasing agent. U.S. Pat. another set of points in the timeline represented by a con No. 8,114,383 is directed to a thermoformed formulation trolled release. In another aspect, prior to the POD, there is no comprising: i) one or more active ingredients with abuse significant controlled release. In another aspect, the formula potential (A) selected from the group consisting of opiates tion further comprises at least one secondary active sub and opioids, ii) optionally physiologically acceptable auxil stance, wherein the formulation has a quick onset of action of iary substances (B), iii) at least 30% by weight of polyalky said at least one primary active Substance followed by a lene oxide (C) having a molecular weight of 1-15 million controlled release of at least one secondary active Substance, according to rheological measurements, and iv) optionally at or vice versa, wherein said at least one primary active Sub least one wax (D), wherein the formulation has a breaking stance and said at least one secondary active substance are the strength of at least 500 N and wherein the active ingredient same or different. In another aspect, the formulation further with abuse potential (A) is present in a controlled release comprises at least one secondary active Substance, wherein matrix of component (C). said at least one primary active Substance in the loading dose 0024 Despite all the above attempts in the prior art to is released at a higher rate in comparison to another dose address, the problem of improper administration of medica having said at least one secondary active Substance, wherein tions and their use in a non-indicated or non-prescribed man said at least one primary active Substance and said at least one ner resulting in abuse, drug overdose, addiction, Suboptimal secondary active Substance are the same or different. In efficacy or death and the problems of dose dumping in the another aspect, the formulation further comprises a core, presence of alcohol and tampering of Solid formulations by wherein said at least one primary active substance is incor way of heating, microwaving, freezing and/or perturbation, porated into the core, external to the core, or a combination pulverizing or crushing or grinding or milling or cutting them thereof. In another aspect, the formulation further comprises into one or more sizes ranging from very fine to coarse par a maintenance dose having at least one secondary active ticles, granules or spheres leading to a faster release of the Substance, wherein said at least one secondary active Sub active content or all of its content, the problem persists. This stance is the same or different than said at least one primary is partly because of design faults in the formulations or com active Substance. In another aspect, the maintenance dose positions and addicts coming up with creative ways to beat the comprises said at least one secondary active Substance in a anti-tampering mechanism or patients and healthcare practi controlled release matrix. In another aspect, the formulation tioners not adhering to instructions not to crush or sub-divide comprises at least one layer of said at least one loading dose Such systems. At present, the problem is escalating at an and at least one layer of said at least one maintenance dose. In alarming rate with devastating financial, health and social another aspect, said at least one layer of said at least one consequences. loading dose covers at least a portion of said at least one layer 0025 Moreover, the aforementioned formulation/compo of said at least one maintenance dose or vice versa, forming a sition design shortcomings have resulted in inadequacies in layered formulation. In another aspect, said at least one coat the treatment of severe to moderate pain using opioid anal Surrounds said layered formulation. In another aspect, the gesics. With current formulations, it may take from 1 to 4 formulation further comprises a core having said at least one hours before the patient experiences adequate pain relief. The maintenance dose and at least one coat comprising said at design of abuse?tamper resistant formulations and composi least one loading dose. In another aspect, the formulation tions has compromised timely delivery of onset of pain relief further comprises at least one coat comprising at least one in the quest to impart tamper resistance on opioid formula maintenance dose, which said at least one maintenance dose tions and prevent their abuse by way of very hard to crush in the core is the same or different than said maintenance dose US 2015/025.0733 A1 Sep. 10, 2015
in said at least one coat. In another aspect, the core further hydrophobic polymers. In another aspect, the hydrophobic comprises said at least one loading dose and/or said at least polymers are selected from Eudragit RL, Eudragit NE, one coat of said loading dose further comprises said at least Eudragit RS and/or Eudragit NM. In another aspect, the at one maintenance dose, which said at least one loading dose in least one excipient comprises polyethylene oxide and the core is the same or different than said loading dose in said Eudragit RL. In another aspect, the formulation further com at least one coat. In another aspect, said at least one coat prises at least one Swellable material in Such an amount that comprising said at least one loading dose significantly covers dissolution of the pulverized/milled formulation in alcoholic said core. In another aspect, the formulation further com and/or non-alcoholic beverages causes the formulation to prises a core, wherein said at least one loading dose and said agglomerate, the amount of Swellable material ranges from at least one maintenance dose are external to the core. In about 15 wt % to about 90 wt % of the maintenance dose another aspect, said at least one coat comprising the Eudragit and/or loading dose. In another aspect, the formulation is E further comprises at least one active Substance, wherein objectionable to chewing, sucking, licking and/or holding in said at least one active Substance and said at least one primary the mouth. In another aspect, the formulation further com active Substance are the same or different. In another aspect, prises a bittering agent and/or irritant. In another aspect, the said at least one coat controls the release of said at least one formulation is an oral formulation. In another aspect, the primary active Substance. In another aspect, release of any formulation is a solid unit form. In another aspect, the Surface active substance in the formulation is activated by a pH area covered by the Eudragit E in said at least one coat is dependent mechanism, ion-exchange dependent mechanism, greater than 5 mg/cm. In another aspect, the surface area bacterial flora/enzymes dependent mechanism, or a combi covered by the Eudragit E in the coat is greater than 10 nation thereof. In another aspect, the pH for the pH dependent mg/cm. In another aspect, the surface area covered by the mechanism is at most about 5. In another aspect, the ion Eudragit E in the coat is greater than 20 mg/cm. In another exchange mechanism is controlled by at least one ion-ex aspect, the surface area covered by the Eudragit E in the coat change resin. In another aspect, said at least one ion-exchange is from about 5 mg/cm to about 100 mg/cm. In another resin is selected from Cholestyramine, Colestipol, Sodium aspect, the surface area covered by the Eudragit E in the coat polystyrene sulfonate, Polacrilex resin, and/or Polacrilin is from about 10 mg/cm to about 100 mg/cm. In another potassium. In another aspect, the bacterial flora/enzymes aspect, the surface area covered by the Eudragit E in the coat dependent mechanism is controlled by at least one polymer is from about 20 mg/cm to about 100 mg/cn2. In another reactive to intestinal bacterial flora/enzymes. In another aspect, the formulation is capable of withstanding about a 350 aspect, said at least polymer is selected from polysaccharides N force. In another aspect, the formulation is effective in Such as guar gum, inulin, chondrotin Sulphate, alginates, and/ preventing significant dose dumping in any beverage. In or dextran. In another aspect, the Eudragit E comprises another aspect, the formulation further comprises at least one Eudragit E 100TM. In another aspect, up to about 55% of the acid to facilitate release of any active Substance in the formu total dose is released as a loading dose to manage pain. In lation. In another aspect, the formulation further comprises at another aspect, the loading dose is released within about 60 least one organic acid to facilitate release of any active Sub minutes of ingestion. In another aspect, the formulation is stance in the formulation, wherein at least one of said at least configured such that when the formulation is administered in one loading dose, said at least one maintenance dose, or said a physically compromised form to a subject, the rate of at least one coat comprises said at least one organic acid. In release of said at least one primary active Substance in the another aspect, at least one of said at least one loading dose loading dose is substantially the same or lower than the rate of and said at least one coat comprises said at least one organic release of said at least one primary active Substance in the acid and the wt.% ratio of the organic acid to said at least one loading dose when the formulation is administered in an primary active substance is from about 1:100 to about 100:1. Intact form. In another aspect, when the formulation is pull In another aspect, said at least one loading dose comprises Verized/milled and added to an alcoholic and/or non-alco from about 1 wt % to about 15 wt % by weight of said at least holic beverage, the rate of release of said at least one primary one organic acid based on the weight of the loading dose. In active Substance in the loading dose is Substantially the same another aspect, said at least one maintenance dose comprises or lower than the rate of release of said at least one primary from about 1 wt % to about 10 wt % by weight of said at least active Substance in the loading dose when the formulation is one organic acid based on the weight of the maintenance dose. administered in an intact form. In another aspect, the bever In another aspect, said at least one coat comprises from about age is an alcoholic beverage. In another aspect, the formula 5 wt % to about 100 wt % by weight of said at least one tion comprises at least one excipient, wherein dissolution of organic acid based on the weight of said at least one coat. In the pulverized/milled formulation in alcoholic and/or non another aspect, the formulation further comprises an over alcoholic beverages causes the formulation to agglomerate. coat, wherein the overcoat comprises said at least one organic In another aspect, the at least one excipient comprises at least acid and at least one polymer. In another aspect, the amount of one Sweliable material in Such an amount that dissolution of said at least one organic acid is from about 5 wt % to less than the pulverized/milled formulation in alcoholic and/or non about 100 wt % of the overcoat. In another aspect, said alcoholic beverages causes the formulation to agglomerate. organic acid is selected from lactic acid, phosphoric acid, In another aspect, said at least one Swellable material is at citric acid, malic acid, fumaric acid, Stearic acid, tartaric acid, least one pH independent polymer. In another aspect, said at benzoic acid, or combinations thereof. In another aspect, said least one swellable material is selected from carbomers, poly at least one primary active Substance is an addictive Sub ethylene oxides or hydrophilic polymers that are lightly stance. In another aspect, the addictive Substance is an opiod cross-linked. Such cross-links being formed by covalent or agonist and/or a narcotic analgesic. ionic bonds, which interact with water and aqueous biological 0029. In accordance with another aspect, there is provided fluids and Swell or expand to some equilibrium state. In a formulation comprising: a loading dose having at least one another aspect, said at least one Swellable material comprises primary active substance, wherein the release of said at least US 2015/025.0733 A1 Sep. 10, 2015 one primary active substance shows a Point Of Divergence ion-exchange resin. In another aspect, said at least one ion (POD), in a dissolution profile, with the loading dose repre exchange resin is selected from Cholestyramine, Colestipol, senting a point in a timeline where the history of the dissolu Sodium polystyrene sulfonate, Polacrilex resin, and/or Polac tion or release rate changes from an onset of action to another rilin potassium. In another aspect, the bacterial flora/enzymes set of points in the timeline represented by a controlled dependent mechanism is controlled by at least one polymer release. reactive to intestinal bacterial flora/enzymes. In another 0030. In another aspect, the onset of action is a quick onset aspect, said at least polymer is selected from polysaccharides of action. In another aspect, the loading dose represents an Such as guar gum, inulin, chondrotin Sulphate, alginates, and/ active Substance that is released at a higher rate in comparison or dextran. In another aspect, the formulation comprises at to another dose of an active Substance in the same formula least one excipient, wherein dissolution of the pulverized/ tion, wherein said at least one primary active Substance and milled formulation in alcoholic and/or non-alcoholic bever said active substance are the same or different. In another ages causes the formulation to agglomerate. In another aspect, a greater amount of said at least one primary active aspect, the at least one excipient comprises at least one Substance is released in a certain time interval in comparison swellable material in such an amount that dissolution of the to another dose of an active substance in the formulation that pulverized/milled formulation in alcoholic and/or non-alco is released in a similar time interval, wherein said at least one holic beverages causes the formulation to agglomerate. In primary active Substance and said active Substance are the another aspect, said at least one Swellable material is at least same or different. In another aspect, the formulation further one pH independent polymer. In another aspect, said at least comprises at least one secondary active Substance, wherein one swellable material is selected from carbomers, polyeth the formulation has the onset of action of said at least one ylene oxides or hydrophilic polymers that are lightly cross primary active substance followed by the controlled release of at least one secondary active Substance, or vice versa, linked. Such cross-links being formed by covalent or ionic wherein said at least one primary active substance and said at bonds, which interact with water and aqueous biological flu least one secondary active Substance are the same or different. ids and Swell or expand to Some equilibrium state. In another In another aspect, prior to the POD, there is no significant aspect, said at least one Swellable material comprises hydro controlled release. In another aspect, the formulation further phobic polymers. In another aspect, the hydrophobic poly comprising a core, wherein said at least one primary active mers are selected from Eudragit RL, Eudragit NE, Eudragit Substance is incorporated into the core, external to the core, or RS and/or Eudragit NM. In another aspect, the at least one a combination thereof. In another aspect, the formulation excipient comprises polyethylene oxide and Eudragit RL. In further comprises a maintenance dose having at least one another aspect, the formulation further comprises at least one secondary active Substance, wherein said at least one second Sweliable material in such an amount that dissolution of the ary active Substance is the same or different than said at least pulverized/milled formulation in alcoholic and/or non-alco one primary active Substance. In another aspect, the mainte holic beverages causes the formulation to agglomerate, the nance dose comprises said at least one secondary active Sub amount of swellable material ranges from about 15 wt % to stance in a controlled release matrix. In another aspect, the about 90 wt % of the maintenance dose and/or loading dose. formulation comprises at least one layer of said at least one In another aspect, the formulation further comprises at least loading dose and at least one layer of said at least one main one acid to facilitate release of any active Substance in the tenance dose. In another aspect, said at least one layer of said formulation. In another aspect, the formulation further com at least one loading dose covers at least a portion of said at prises at least one organic acid to facilitate release of any least one layer of said at least one maintenance dose or vice active Substance in the formulation, wherein at least one of Versa, forming a layered formulation. In another aspect, at said at least one loading dose or said at least one maintenance least one coat Surrounds said layered formulation. In another dose comprises said at least one organic acid. In another aspect, the formulation further comprises a core having said aspect, said at least one loading dose comprises from about 1 at least one maintenance dose and at least one coat comprising wt % to about 15 wt % by weight of said at least one organic said at least one loading dose. In another aspect, the formu acid based on the weight of the loading dose. In another lation further comprises at least one coat comprising at least aspect, said at least one maintenance dose comprises from one maintenance dose, which said at least one maintenance about 1 wt % to about 10 wt % by weight of said at least one dose in the core is the same or different than said maintenance organic acid based on the weight of the maintenance dose. In dose in said at least one coat. In another aspect, the core another aspect, said at least one loading dose comprises said further comprises said at least one loading dose and/or said at at least one organic acid. In another aspect, the formulation least one coat of said loading dose further comprises said at further comprises an overcoat, wherein the overcoat com least one maintenance dose, which said at least one loading prises said at least one organic acid and at least one polymer. dose in the core is the same or different than said loading dose In another aspect, the amount of said at least one organic acid in said at least one coat. In another aspect, said at least one is from about 5 wt % to less than about 100 wt % of the coat comprising said at least one loading dose significantly overcoat. In another aspect, said organic acid is selected from covers said core. In another aspect, the formulation further lactic acid, phosphoric acid, citric acid, malic acid, fumaric comprises a core, wherein said at least one loading dose and acid, Stearic acid, tartaric acid, benzoic acid, or combinations said at least one maintenance dose are external to the core. In thereof. In another aspect, said at least one primary active another aspect, the release of any active Substance is activated Substance is an addictive Substance. In another aspect, the by a pH dependent mechanism, ion-exchange dependent addictive Substance is an opiod agonist and/or a narcotic mechanism, bacterial flora/enzymes dependent mechanism, analgesic. In another aspect, up to about 55% of the total dose or a combination thereof. In another aspect, the pH for the pH is released as a loading dose to manage pain. In another dependent mechanism is at most about 5. In another aspect, aspect, the loading dose is released within about 60 minutes the ion-exchange mechanism is controlled by at least one of ingestion. US 2015/025.0733 A1 Sep. 10, 2015
0031. In accordance with yet another aspect, there is pro timeline where the history of the dissolution or release rate vided a formulation comprising: at least one primary active changes from an onset of action to another set of points in the Substance; and at least one excipient, wherein dissolution of timeline represented by a controlled release. In another the intact and or pulverized/milled formulation in alcoholic aspect, prior to the POD, there is no significant controlled and/or non-alcoholic beverages causes the formulation to release. In another aspect, the formulation further comprises agglomerate. at least one secondary active Substance, wherein the formu 0032. In another aspect, the at least one excipient com lation has a quick onset of action of said at least one primary prises at least one Swellable material in Such an amount that active substance followed by a controlled release of at least dissolution of the pulverized/milled formulation in alcoholic one secondary active Substance, or vice versa, wherein said at and/or non-alcoholic beverages causes the formulation to least one primary active Substance and said at least one sec agglomerate. In another aspect, said at least one Swellable ondary active Substance are the same or different. In another material is at least one pH independent polymer. In another aspect, the formulation further comprises at least one second aspect, said at least one Swellable material is selected from ary active Substance, wherein said at least one primary active carbomers, polyethylene oxides or hydrophilic polymers that Substance in the loading dose is released at a higher rate in are lightly cross-linked. Such cross-links being formed by comparisonto another dose having said at least one secondary covalent or ionic bonds, which interact with water and aque active Substance, wherein said at least one primary active ous biological fluids and Swell or expand to some equilibrium Substance and said at least one secondary active Substance are state. In another aspect, said at least one Swellable material the same or different. In another aspect, the formulation fur comprises hydrophobic polymers. In another aspect, the ther comprises a core, wherein said at least one primary active hydrophobic polymers are selected from Eudragit RL, Substance is incorporated into the core, external to the core, or Eudragit NE, Eudragit RS and/or Eudragit NM. In another a combination thereof. In another aspect, the formulation aspect, the at least one excipient comprises polyethylene further comprises a maintenance dose having at least one oxide and Eudragit RL. In another aspect, the formulation secondary active Substance, wherein said at least one second further comprises at least one organic acid to facilitate release ary active Substance is the same or different than said at least of any active Substance in the formulation. In another aspect, one primary active Substance. In another aspect, the mainte the formulation further comprises an overcoat, wherein the nance dose comprises said at least one secondary active Sub overcoat comprises said at least one organic acid and at least stance in a controlled release matrix. In another aspect, the one polymer. In another aspect, the amount of said at least one formulation comprises at least one layer of said at least one organic acid is from about 50 wt % to about 90 wt % of the loading dose and at least one layer of said at least one main overcoat. In another aspect, said organic acid is selected from tenance dose. In another aspect, said at least one layer of said lactic acid, phosphoric acid, citric acid, malic acid, fumaric at least one loading dose covers at least a portion of said at acid, Stearic acid, tartaric acid, benzoic acid, or combinations least one layer of said at least one maintenance dose or vice thereof. In another aspect, said at least one primary active Versa, forming a layered formulation. In another aspect, said Substance is an addictive Substance. In another aspect, the at least one coat that comprises said Eudragit E and said at addictive Substance is an opiod agonist and/or a narcotic least one coat that comprises said at least one acid Surrounds analgesic. said layered formulation in any order. In another aspect, the 0033. In accordance with another aspect, there is provided formulation further comprises a core having said at least one a formulation comprising: at least one primary active Sub maintenance dose and at least one coat comprising said at stance; at least one coat comprising Eudragit E(dimethylami least one loading dose. In another aspect, the formulation noethyl methacrylate copolymer); and at least one coat com further comprises at least one coat comprising at least one prising at least one acid to facilitate release of any active maintenance dose, which said at least one maintenance dose Substance in the formulation. in the core is the same or different than said maintenance dose 0034. In another aspect, a wt % ratio of said at least one in said at least one coat. In another aspect, the core further acid to said at least one primary active Substance is from about comprises said at least one loading dose and/or said at least 1:100 to about 100:1. In another aspect, said at least one coat one coat of said loading dose further comprises said at least that comprises said Eudragit E further comprises at least one one maintenance dose, which said at least one loading dose in acid. In another aspect, said at least one coat that comprises the core is the same or different than said loading dose in said said at least one acid is an overcoat. In another aspect, said at at least one coat. In another aspect, said at least one coat least one coat comprising at least one acid comprises from comprising said at least one loading dose significantly covers about 5 wt % to about 100 wt % by weight of said at least one said core. In another aspect, the formulation further com organic acid based on the weight of said at least one coat. In prises a core, wherein said at least one loading dose and said another aspect, the overcoat comprises said at least one acid at least one maintenance dose are external to the core. In and at least one polymer. In another aspect, said at least one another aspect, said at least one coat that comprises said acid is at least one organic acid. In another aspect, said Eudragit E and/or said at least one coat that comprises said at organic acid is selected from lactic acid, phosphoric acid, least one acid further comprises at least one active Substance, citric acid, malic acid, fumaric acid, Stearic acid, tartaric acid, wherein said at least one active Substance and said at least one benzoic acid, or combinations thereof. In another aspect, the primary active Substance are the same or different. In another formulation is a controlled release formulation. In another aspect, said at least one coat that comprises said Eudragit E. aspect, onset of action of said at least one primary active controls the release of said at least one primary active Sub Substance is potentiated by the presence of a loading dose stance. In another aspect, release of any active Substance in comprising said at least one primary active Substance. In the formulation is activated by a pH dependent mechanism, another aspect, the release of said at least one primary active ion-exchange dependent mechanism, bacterial flora/enzymes substance shows a Point Of Divergence (POD), in a dissolu dependent mechanism, or a combination thereof. In another tion profile, with the loading dose representing a point in a aspect, the Eudragit E comprises Eudragit E 100TM. In US 2015/025.0733 A1 Sep. 10, 2015
another aspect, up to about 55% of the total dose is released as another aspect, the temperature for heating the formulation is a loading dose to manage pain. In another aspect, the loading about 540°C. In another aspect, less than about 20% of the dose is released within about 60 minutes of ingestion. In dose is released after microwaving for about 2 minutes and another aspect, the formulation is configured such that when thereafter, exposing the microwaved formulation to aqueous the formulation is administered in a physically compromised media. form to a subject, the rate of release of said at least one 0036. In another aspect, there is provided use of the for primary active Substance in the loading dose is substantially mulation for releasing up to about 55% of the total dose as a the same or lower than the rate of release of said at least one loading dose to manage an ailment. In another aspect, use of primary active Substance in the loading dose when the formu a controlled release narcotic analgesic having a loading dose lation is administered in an intact form. In another aspect, for treatment of an ailment. In another aspect, the ailment is when the formulation is intact and or pulverized/milled and pain. In another aspect, the loading dose is released within added to an alcoholic and/or non-alcoholic beverage, the rate about 60 minutes of ingestion. of release of said at least one primary active Substance in the 0037. In another aspect, there is provided a method of loading dose is substantially the same or lower than the rate of managing an ailment comprising administering the formula release of said at least one primary active Substance in the tion for releasing up to about 55% of the total dose as a loading dose when the formulation is administered in an loading dose to manage the ailment. In another aspect, a intact form. In another aspect, the beverage is an alcoholic method for treatment of an ailment comprising administering beverage. In another aspect, the formulation comprises at an oral controlled release formulation for releasing up to least one excipient, wherein dissolution of the intact and or about 55% of the total dose as a loading dose, wherein the pulverized/milled formulation in alcoholic and/or non-alco loading dose comprises at least one active Substance. In holic beverages causes the formulation to agglomerate. In another aspect, a method for treatment of an ailment compris another aspect, the at least one excipient comprises at least ing administering an oral controlled release formulation for one Sweliable material in Such an amount that dissolution of releasing up to about 55% of the total dose as a loading dose, the intact and or pulverized/milled formulation in alcoholic wherein the loading dose comprises at least one active Sub and/or non-alcoholic beverages causes the formulation to stance. In another aspect, the ailment is pain. agglomerate. In another aspect, said at least one Swellable 0038. In another aspect, there is provided an oral con material is selected from Eudragit RL, Eudragit NE, Eudragit trolled release formulation for treatment of an ailment releas RS and/or Eudragit NM. In another aspect, the at least one ing up to about 55% of the total dose as a loading dose to treat excipient comprises polyethylene oxide and Eudragit RL. In the ailment, wherein the loading dose comprises at least one another aspect, the formulation is objectionable to chewing, active Substance. In another aspect, there is provided a for Sucking, licking and/or holding in the mouth. In another mulation comprising at least one maintenance dose and at aspect, the formulation further comprises a bittering agent least one loading dose in at least one unit formulation for and/or irritant. In another aspect, the formulation is an oral treatment of an ailment. In another aspect, the ailment is pain. formulation. In another aspect, the formulation is a solid unit 0039. In other aspects: form. In another aspect, the Surface area covered by the 1. (Claim 1) A formulation comprising: Eudragit E in said at least one coat is greater than 5 mg/cm. 0040 at least one primary active substance; and In another aspect, the surface area covered by the Eudragit E 0041 at least one coat comprising Eudragit E (dimethy in the coat is from about 5 mg/cm to about 100 mg/cm. In laminoethyl methacrylate copolymer), another aspect, the formulation is capable of withstanding 0042 wherein the formulation is free of any active sub about a 350 N force. In another aspect, the formulation is stance external to said at least one coat. effective in preventing significant dose dumping in any bev 2. The formulation according to claim 1, wherein onset of erage. In another aspect, said at least one primary active action of said at least one primary active Substance is poten Substance is an addictive Substance. In another aspect, the tiated by the presence of a loading dose comprising said at addictive Substance is an opiod agonist and/or a narcotic least one primary active Substance. analgesic. In another aspect, the loading dose is made from 3. The formulation according to claim 2, wherein the release hot melt extrusion. In another aspect, at least one of the of said at least one primary active substance shows a Point Of components used in the maintenance dose and/or the loading Divergence (POD), in a dissolution profile, with the loading dose are made from hot melt extrusion. In another aspect, the dose representing a point in a timeline where the history of the maintenance dose and/or the loading dose are made from hot dissolution or release rate changes from an onset of action to melt extrusion. In another aspect, an extruded component another set of points in the timeline represented by a con from the hot melt extrusion is extruded and cut into a desired trolled release. shape and/or is extruded, ground and pressed. In another 4. The formulation according to claim 3, wherein prior to the aspect, the particle size of the components of the formulation POD, there is no significant controlled release. is less than about 1000 microns. In another aspect, the surface 5. The formulation according to claim 2, wherein the formu area of the components is between 0.5 and 10000 m/g or lation further comprises at least one secondary active Sub higher. In another aspect, the formulation does not dose dump stance, wherein the formulation has a quick onset of action of in the presence of alcohol. said at least one primary active Substance followed by a 0035. In another aspect, less than about 30% by weight of controlled release of at least one secondary active Substance, the dose is released as a vapor for inhalation when the formu or vice versa, wherein said at least one primary active Sub lation is subjected to heat. In another aspect, less than about stance and said at least one secondary active substance are the 10% by weight of the dose is released as a vapor for inhalation same or different. when the formulation is Subjected to heat. In another aspect, 6. The formulation according to claim 2, wherein the formu the formulation is milled prior to heating. In another aspect, lation further comprises at least one secondary active Sub heating is achieved with an open flame or otherheat source. In stance, wherein said at least one primary active Substance in US 2015/025.0733 A1 Sep. 10, 2015
the loading dose is released at a higher rate in comparison to 22. The formulation according to claim 20, wherein the ion another dose having said at least one secondary active Sub exchange mechanism is controlled by at least one ion-ex stance, wherein said at least one primary active Substance and change resin. said at least one secondary active Substance are the same or 23. The formulation according to claim 22, wherein said at different. least one ion-exchange resin is selected from 7. The formulation according to any one of claims 1 to 6 Cholestyramine, Colestipol, Sodium polystyrene Sulfonate, further comprising a core, wherein said at least one primary Polacrilex resin, and/or Polacrilin potassium. active Substance is incorporated into the core, external to the 24. The formulation according to claim 20 wherein the bac core, or a combination thereof. terial flora/enzymes dependent mechanism is controlled by at 8. The formulation according to claim 2, wherein the formu least one polymer reactive to intestinal bacterial florafen lation further comprises a maintenance dose having at least Zymes. one secondary active Substance, wherein said at least one 25. The formulation according to claim 24 wherein said at secondary active Substance is the same or different than said least polymer is selected from polysaccharides such as guar at least one primary active Substance. gum, inulin, chondrotin Sulphate, alginates, and/or dextran. 9. The formulation according to claim 8, wherein the main 26. The formulation according to any one of claims 1 to 25, tenance dose comprises said at least one secondary active wherein the Eudragit E comprises Eudragit E 100TM. Substance in a controlled release matrix. 27. The formulation according to claim 1, wherein up to about 10. The formulation according to claim 8 or 9, wherein the 55% of the total dose is released as a loading dose to manage formulation comprises at least one layer of said at least one pain. loading dose and at least one layer of said at least one main 28. The formulation according to claim 27 wherein the load tenance dose. ing dose is released within about 60 minutes of ingestion. 11. The formulation according to claim 10 wherein said at 29. The formulation according to claim 2, wherein the for least one layer of said at least one loading dose covers at least mulation is configured Such that when the formulation is a portion of said at least one layer of said at least one main administered in a physically compromised form to a Subject, tenance dose or vice versa, forming a layered formulation. the rate of release of said at least one primary active Substance 12. The formulation according to claim 11, wherein said at in the loading dose is Substantially the same or lower than the least one coat Surrounds said layered formulation. rate of release of said at least one primary active Substance in 13. The formulation according to claim 8 or 9 further com the loading dose when the formulation is administered in an prises a core having said at least one maintenance dose and at intact form. least one coat comprising said at least one loading dose. 30. The formulation according to claim 2, wherein when the 14. The formulation according to claim 13 further comprises formulation is pulverized/milled and added to an alcoholic at least one coat comprising at least one maintenance dose, and/or non-alcoholic beverage, the rate of release of said at which said at least one maintenance dose in the core is the least one primary active Substance in the loading dose is same or different than said maintenance dose in said at least substantially the same or lower than the rate of release of said One COat. at least one primary active Substance in the loading dose when the formulation is administered in an intact form. 15. The formulation according to claim 13 or 14, wherein the 31. The formulation according to claim 30 wherein the bev core further comprises said at least one loading dose and/or erage is an alcoholic beverage. said at least one coat of said loading dose further comprises 32. The formulation according to any one of claims 1 to 28, said at least one maintenance dose, which said at least one wherein the formulation comprises at least one excipient, loading dose in the core is the same or different than said wherein dissolution of the pulverized/milled formulation in loading dose in said at least one coat. alcoholic and/or non-alcoholic beverages causes the formu 16. The formulation according to claim 13, wherein said at lation to agglomerate. least one coat comprising said at least one loading dose sig 33. The formulation according to claim 32 wherein the at least nificantly covers said core. one excipient comprises at least one Swellable material in 17. The formulation according to claim 8 or 9 further com such an amount that dissolution of the pulverized/milled for prises a core, wherein said at least one loading dose and said mulation in alcoholic and/or non-alcoholic beverages causes at least one maintenance dose are external to the core. the formulation to agglomerate. 18. The formulation according to any one of claims 1 to 17, 34. The formulation according to claim 33 wherein said at wherein said at least one coat comprising the Eudragit E least one swellable material is at least one pH independent further comprises at least one active Substance, wherein said polymer. at least one active Substance and said at least one primary 35. The formulation according to claim 33 wherein said at active substance are the same or different. least one swellable material is selected from carbomers, poly 19. The formulation according to claim 1, wherein said at ethylene oxides or hydrophilic polymers that are lightly least one coat controls the release of said at least one primary cross-linked, Such cross-links being formed by covalent or active Substance. ionic bonds, which interact with water and aqueous biological 20. The formulation according to claim 19, wherein release of fluids and Swell or expand to some equilibrium state. any active Substance in the formulation is activated by a pH 36. The formulation according to claim 35 wherein said at dependent mechanism, ion-exchange dependent mechanism, least one swellable material comprises hydrophobic poly bacterial flora/enzymes dependent mechanism, or a combi CS. nation thereof. 37. The formulation according to claim 36 wherein the hydro 21. The formulation according to claim 20, wherein the pH phobic polymers are selected from Eudragit RL, Eudragit for the pH dependent mechanism is at most about 5. NE, Eudragit RS and/or Eudragit NM. US 2015/025.0733 A1 Sep. 10, 2015
38. The formulation according to claim 37 wherein the at least 57. The formulation according to any one of claims 53 to 56, one excipient comprises polyethylene oxide and Eudragit RL. wherein said at least one coat comprises from about 5 wt.% to 39. The formulation according to claim 8 further comprises at about 100 wt % by weight of said at least one organic acid least one Swellable material in Such an amount that dissolu based on the weight of said at least one coat. tion of the pulverized/milled formulation in alcoholic and/or 58. The formulation according to any one of claims 54 to 57 non-alcoholic beverages causes the formulation to agglom further comprises an overcoat, wherein the overcoat com erate, the amount of swellable material ranges from about 15 prises said at least one organic acid and at least one polymer. wt % to about 90 wt % of the maintenance dose and/or loading 59. The formulation according to claim 58 wherein the dose. amount of said at least one organic acid is from about 5 wt % 40. The formulation according to any one of claims 1 to 39, to less than about 100 wt % of the overcoat. wherein the formulation is objectionable to chewing, Suck 60. The formulation according to any one of claims 52 to 59. ing, licking and/or holding in the mouth. wherein said organic acid is selected from lactic acid, phos 41. The formulation according to claim 39 further comprises phoric acid, citric acid, malic acid, fumaric acid, Stearic acid, a bittering agent and/or irritant tartaric acid, benzoic acid, or combinations thereof. 42. The formulation according to any one of claims 1 to 40, 61. The formulation according to any one of claims 1 to 60, wherein the formulation is an oral formulation. wherein said at least one primary active Substance is an addic 43. The formulation according to any one of claims 1 to 42, tive Substance. wherein the formulation is a solid unit form. 62. The formulation according to claim 61 wherein the addic 44. The formulation according to any one of claims 1 to 43. tive Substance is an opiod agonist and/or a narcotic analgesic. wherein the surface area covered by the Eudragit E in said at least one coat is greater than 5 mg/cm. 63. (Claim 63) A formulation comprising: 45. The formulation according to claim 43 wherein the sur 0043 a loading dose having at least one primary active face area covered by the Eudragit E in the coat is greater than Substance, wherein the release of said at least one primary 10 mg/cm. active substance shows a Point Of Divergence (POD), in a 46. The formulation according to claim 43 wherein the sur dissolution profile, with the loading dose representing a point face area covered by the Eudragit E in the coat is greater than in a timeline where the history of the dissolution or release 20 mg/cm. rate changes from an onset of action to another set of points in 47. The formulation according to claim 43 wherein the sur the timeline represented by a controlled release. face area covered by the Eudragit E in the coat is from about 64. The formulation according to claim 63 wherein the onset 5 mg/cm to about 100 mg/cm. of action is a quick onset of action. 48. The formulation according to claim 43 wherein the sur 65. The formulation according to claim 63 wherein the load face area covered by the Eudragit E in the coat is from about ing dose represents an active Substance that is released at a 10 mg/cm to about 100 mg/cm. higher rate in comparison to another dose of an active Sub 49. The formulation according to claim 43 wherein the sur stance in the same formulation, wherein said at least one face area covered by the Eudragit E in the coat is from about primary active Substance and said active Substance are the 20 mg/cm to about 100 mg/cm. same or different. 50. The formulation according to any one of claims 1 to 49, 66. The formulation according to claim 63 wherein a greater wherein the formulation is capable of withstanding about a amount of said at least one primary active Substance is 350 N force. released in a certain time interval in comparison to another 51. The formulation according to any one of claims 1 to 50, dose of an active substance in the formulation that is released wherein the formulation is effective in preventing significant in a similar time interval, wherein said at least one primary dose dumping in any beverage. active Substance and said active Substance are the same or 52. The formulation according to any one of claims 1 to 50 different. further comprises at least one acid to facilitate release of any 67. The formulation according to claim 63 or 64, wherein the active Substance in the formulation. formulation further comprises at least one secondary active 53. The formulation according to claim 8 further comprises at substance, wherein the formulation has the onset of action of least one organic acid to facilitate release of any active Sub said at least one primary active substance followed by the stance in the formulation, wherein at least one of said at least controlled release of at least one secondary active Substance, one loading dose, said at least one maintenance dose, or said or vice versa, wherein said at least one primary active Sub at least one coat comprises said at least one organic acid. stance and said at least one secondary active substance are the 54. The formulation according to claim 53 wherein at least same or different. one of said at least one loading dose and said at least one coat 68. The formulation according to any one of claims 63 to 67, comprises said at least one organic acid and the wt % ratio of wherein prior to the POD, there is no significant controlled the organic acid to said at least one primary active Substance release. is from about 1:100 to about 100:1. 69. The formulation according to any one of claims 63 to 68 55. The formulation according to claim 53 or 54, wherein said further comprising a core, wherein said at least one primary at least one loading dose comprises from about 1 wt % to active Substance is incorporated into the core, external to the about 15 wt % by weight of said at least one organic acid core, or a combination thereof. based on the weight of the loading dose. 70. The formulation according to claim 63 wherein the for 56. The formulation according to any one of claims 53 to 55, mulation further comprises a maintenance dose having at wherein said at least one maintenance dose comprises from least one secondary active Substance, wherein said at least one about 1 wt % to about 10 wt % by weight of said at least one secondary active Substance is the same or different than said organic acid based on the weight of the maintenance dose. at least one primary active Substance. US 2015/025.0733 A1 Sep. 10, 2015
71. The formulation according to claim 70 wherein the main 88. The formulation according to claim 87 wherein said at tenance dose comprises said at least one secondary active least one Sweliable material is at least one pH independent Substance in a controlled release matrix. polymer. 72. The formulation according to claim 70 or 71, wherein the 89. The formulation according to claim 87 wherein said at formulation comprises at least one layer of said at least one least one swellable material is selected from carbomers, poly loading dose and at least one layer of said at least one main ethylene oxides or hydrophilic polymers that are lightly tenance dose. cross-linked, Such cross-links being formed by covalent or 73. The formulation according to claim 72 wherein said at ionic bonds, which interact with water and aqueous biological least one layer of said at least one loading dose covers at least fluids and Swell or expand to some equilibrium state. a portion of said at least one layer of said at least one main 90. The formulation according to claim 87 wherein said at tenance dose or vice versa, forming a layered formulation. least one swellable material comprises hydrophobic poly 74. The formulation according to claim 73 wherein at least CS. one coat Surrounds said layered formulation. 91. The formulation according to claim 90 wherein the hydro 75. The formulation according to claim 70 or 71 further phobic polymers are selected from Eudragit RL, Eudragit comprises a core having said at least one maintenance dose NE, Eudragit RS and/or Eudragit NM. and at least one coat comprising said at least one loading dose. 92. The formulation according to claim 87 wherein the at least 76. The formulation according to claim 75 further comprises one excipient comprises polyethylene oxide and Eudragit RL. at least one coat comprising at least one maintenance dose, 93. The formulation according to claim 70 further comprises which said at least one maintenance dose in the core is the at least one Swelable material in Such an amount that disso same or different than said maintenance dose in said at least lution of the pulverized/milled formulation in alcoholic and/ One COat. or non-alcoholic beverages causes the formulation to agglom 77. The formulation according to claim 75 or 76, wherein the erate, the amount of swellable material ranges from about 15 core further comprises said at least one loading dose and/or wt % to about 90 wt % of the maintenance dose and/or loading said at least one coat of said loading dose further comprises dose. said at least one maintenance dose, which said at least one 94. The formulation according to any one of claims 63 to 93 loading dose in the core is the same or different than said further comprises at least one acid to facilitate release of any loading dose in said at least one coat. active Substance in the formulation. 78. The formulation according to claim 75, wherein said at 95. The formulation according to claim 70 further comprises least one coat comprising said at least one loading dose sig at least one organic acid to facilitate release of any active nificantly covers said core. Substance in the formulation, wherein at least one of said at 79. The formulation according to claim 70 or 71 further least one loading dose or said at least one maintenance dose comprises a core, wherein said at least one loading dose and comprises said at least one organic acid. said at least one maintenance dose are external to the core. 96. The formulation according to claim 95 wherein said at 80. The formulation according to any one of claims 63 to 79, least one loading dose comprises from about 1 wt % to about wherein the release of any active substance is activated by a 15 wt % by weight of said at least one organic acid based on pH dependent mechanism, ion-exchange dependent mecha the weight of the loading dose. nism, bacterial flora/enzymes dependent mechanism, or a 97. The formulation according to claim 95 or 96, wherein said combination thereof. at least one maintenance dose comprises from about 1 wt % to 81. The formulation according to claim 80 wherein the pH for about 10 wt % by weight of said at least one organic acid the pH dependent mechanism is at most about 5. based on the weight of the maintenance dose. 82. The formulation according to claim 80 wherein the ion 98. The formulation according to claim 95 or 96, wherein said exchange mechanism is controlled by at least one ion-ex at least one loading dose comprises said at least one organic change resin. acid. 83. The formulation according to claim 82 wherein said at 99. The formulation according to any one of claims 94 to 97 least one ion-exchange resin is selected from further comprises an overcoat, wherein the overcoat com Cholestyramine, Colestipol. Sodium polystyrene sulfonate, prises said at least one organic acid and at least one polymer. Polacnlex resin, and/or Polacrilin potassium. 100. The formulation according to claim 99 wherein the 84. The formulation according to claim 80 wherein the bac amount of said at least one organic acid is from about 5 wt % terial flora/enzymes dependent mechanism is controlled by at to less than about 100 wt % of the overcoat. least one polymer reactive to intestinal bacterial florafen 101. The formulation according to any one of claims 94 to Zymes. 100, wherein said organic acid is selected from lactic acid, 85. The formulation according to claim 84 wherein said at phosphoric acid, citric acid, malic acid, fumaric acid, Stearic least polymer is selected from polysaccharides such as guar acid, tartaric acid, benzoic acid, or combinations thereof. gum, inulin, chondrotin Sulphate, alginates, and/or dextran. 102. The formulation according to any one of claims 63 to 86. The formulation according to any one of claims 63 to 85, 101, wherein said at least one primary active substance is an wherein the formulation comprises at least one excipient, addictive substance. wherein dissolution of the pulverized/milled formulation in 103. The formulation according to claim 102, wherein the alcoholic and/or non-alcoholic beverages causes the formu addictive Substance is an opiod agonist and/or a narcotic lation to agglomerate. analgesic. 87. The formulation according to claim 86 wherein the at least 104. The formulation according to any one of claims 63 to one excipient comprises at least one Swellable material in 103, wherein up to about 55% of the total dose is released as such an amount that dissolution of the pulverized/milled for a loading dose to manage pain. mulation in alcoholic and/or non-alcoholic beverages causes 105. The formulation according to claim 104, wherein the the formulation to agglomerate. loading dose is released within about 60 minutes of ingestion. US 2015/025.0733 A1 Sep. 10, 2015
106. (Claim 106) A formulation comprising: 123. The formulation according to claim 122, wherein said at 0044 at least one primary active substance; and least one coat comprising at least one acid comprises from 0045 at least one excipient, wherein dissolution of the about 5 wt % to about 100 wt % by weight of said at least one intact and or pulverized/milled formulation in alcoholic and/ organic acid based on the weight of said at least one coat. or non-alcoholic beverages causes the formulation to agglom 124. The formulation according to claim 122, wherein the erate. overcoat comprises said at least one acid and at least one 107. The formulation according to claim 106, wherein the at polymer. least one excipient comprises at least one Swellable material 125. The formulation according to any one of claims 119 to in such an amount that dissolution of the pulverized/milled 124, wherein said at least one acid is at least one organic acid. formulation in alcoholic and/or non-alcoholic beverages 126. The formulation according to claim 125, wherein said causes the formulation to agglomerate. organic acid is selected from lactic acid, phosphoric acid, 108. The formulation according to claim 106, wherein said at citric acid, malic acid, fumaric acid, Stearic acid, tartaric acid, least one swellable material is at least one pH independent benzoic acid, or combinations thereof. polymer. 127. The formulation according to any one of claims 119 to 109. The formulation according to claim 106, wherein said at 128, wherein the formulation is a controlled release formula least one swellable material is selected from carbomers, poly tion. ethylene oxides or hydrophilic polymers that are lightly 128. The formulation according to any one of claims 119 to cross-linked. Such cross-links being formed by covalent or 126, wherein onset of action of said at least one primary active ionic bonds, which interact with water and aqueous biological Substance is potentiated by the presence of a loading dose fluids and Swell or expand to some equilibrium state. comprising said at least one primary active Substance. 110. The formulation according to claim 106, wherein said at 129. The formulation according to claim 128, wherein the least one swellable material comprises hydrophobic poly release of said at least one primary active Substance shows a CS. Point Of Divergence (POD), in a dissolution profile, with the 111. The formulation according to claim 110, wherein the loading dose representing a point in a timeline where the hydrophobic polymers are selected from Eudragit RL, history of the dissolution or release rate changes from an Eudragit NE, Eudragit RS and/or Eudragit NM. onset of action to another set of points in the timeline repre 112. The formulation according to claim 107, wherein the at sented by a controlled release. least one excipient comprises polyethylene oxide and 130. The formulation according to claim 129, wherein prior to Eudragit RL. the POD, there is no significant controlled release. 113. The formulation according to any one of claims 106 to 131. The formulation according to claim 128, wherein the 112 further comprises at least one organic acid to facilitate formulation further comprises at least one secondary active release of any active Substance in the formulation. Substance, wherein the formulation has a quick onset of 114. The formulation according to claim 113 further com action of said at least one primary active Substance followed prises an overcoat, wherein the overcoat comprises said at by a controlled release of at least one secondary active Sub least one organic acid and at least one polymer. stance, or vice versa, wherein said at least one primary active 115. The formulation according to claim 114, wherein the Substance and said at least one secondary active Substance are amount of said at least one organic acid is from about 50 wt % the same or different. to about 90 wt % of the overcoat. 132. The formulation according to claim 128, wherein the 116. The formulation according to any one of claims 113 to formulation further comprises at least one secondary active 115, wherein said organic acid is selected from lactic acid, Substance, wherein said at least one primary active Substance phosphoric acid, citric acid, malic acid, fumaric acid, Stearic in the loading dose is released at a higher rate in comparison acid, tartaric acid, benzoic acid, or combinations thereof. to another dose having said at least one secondary active 117. The formulation according to any one of claims 106 to Substance, wherein said at least one primary active Substance 116, wherein said at least one primary active Substance is an and said at least one secondary active Substance are the same addictive substance. or different. 118. The formulation according to claim 117, wherein the 133. The formulation according to any one of claims 119 to addictive Substance is an oplod agonist and/or a narcotic 132 further comprising a core, wherein said at least one analgesic. primary active Substance is incorporated into the core, exter 119. (Claim 119) A formulation comprising: nal to the core, or a combination thereof. 0046 at least one primary active substance; 134. The formulation according to claim 128, wherein the 0047 at least one coat comprising Eudragit E (dimethy formulation further comprises a maintenance dose having at laminoethyl methacrylate copolymer); and least one secondary active Substance, wherein said at least one 0.048 at least one coat comprising at least one acid to secondary active Substance is the same or different than said facilitate release of any active Substance in the formulation. at least one primary active Substance. 120. The formulation according to claim 119, wherein a wt % 135. The formulation according to claim 134, wherein the ratio of said at least one acid to said at least one primary active maintenance dose comprises said at least one secondary substance is from about 1:100 to about 100:1. active Substance in a controlled release matrix. 121. The formulation according to claim 119 or 120, wherein 136. The formulation according to claim 134 or 135, wherein said at least one coat that comprises said Eudragit E further the formulation comprises at least one layer of said at least comprises at least one acid. one loading dose and at least one layer of said at least one 122. The formulation according to any one of claims 119 to maintenance dose. 121, wherein said at least one coat that comprises said at least 137. The formulation according to claim 136, wherein said at one acid is an overcoat. least one layer of said at least one loading dose covers at least US 2015/025.0733 A1 Sep. 10, 2015
a portion of said at least one layer of said at least one main 152. The formulation according to claim 151, wherein the tenance dose or vice versa, forming a layered formulation. beverage is an alcoholic beverage. 138. The formulation according to claim 137, wherein said at 153. The formulation according to any one of claims 119 to least one coat that comprises said Eudragit E and said at least 152, wherein the formulation comprises at least one excipi one coat that comprises said at least one acid Surrounds said ent, wherein dissolution of the intact and or pulverized/milled layered formulation in any order. formulation in alcoholic and/or non-alcoholic beverages 139. The formulation according to claim 134 or 135 further causes the formulation to agglomerate. comprises a core having said at least one maintenance dose 154. The formulation according to claim 153, wherein the at and at least one coat comprising said at least one loading dose. least one excipient comprises at least one Swellable material 140. The formulation according to claim 139 further com in Such an amount that dissolution of the intact and or pulver prises at least one coat comprising at least one maintenance ized/milled formulation in alcoholic and/or non-alcoholic dose, which said at least one maintenance dose in the core is beverages causes the formulation to agglomerate. the same or different than said maintenance dose in said at 155. The formulation according to claim 154, wherein said at least one coat. least one swellable material is selected from Eudragit RL, 141. The formulation according to claim 139 or 140, wherein Eudragit NE, Eudragit RS and/or Eudragit NM. the core further comprises said at least one loading dose 156. The formulation according to claim 154, wherein the at and/or said at least one coat of said loading dose further least one excipient comprises polyethylene oxide and comprises said at least one maintenance dose, which said at Eudragit RL. least one loading dose in the core is the same or different than 157. The formulation according to any one of claims 119 to said loading dose in said at least one coat. 156, wherein the formulation is objectionable to chewing, 142. The formulation according to claim 139, wherein said at Sucking, licking and/or holding in the mouth. least one coat comprising said at least one loading dose sig 158. The formulation according to claim 157 further com nificantly covers said core. prises a bittering agent and/or irritant. 143. The formulation according to claim 139 or 140 further 159. The formulation according to any one of claims 119 to comprises a core, wherein said at least one loading dose and 158, wherein the formulation is an oral formulation. said at least one maintenance dose are external to the core. 160. The formulation according to any one of claims 119 to 144. The formulation according to any one of claims 119 to 159, wherein the formulation is a solid unit form. 143, wherein said at least one coat that comprises said Eudragit E and/or said at least one coat that comprises said at 161. The formulation according to any one of claims 119 to least one acid further comprises at least one active Substance, 160, wherein the surface area covered by the Eudragit E in wherein said at least one active Substance and said at least one said at least one coat is greater than 5 mg/cm. primary active substance are the same or different. 162. The formulation according to claim 161, wherein the 145. The formulation according to claim 119, wherein said at surface area covered by the Eudragit E in the coat is from least one coat that comprises said Eudragit E. controls the about 5 mg/cm to about 100 mg/cm. release of said at least one primary active Substance. 163. The formulation according to any one of claims 119 to 146. The formulation according to claim 145, wherein release 162, wherein the formulation is capable of withstanding of any active substance in the formulation is activated by a pH about a 350 N force. dependent mechanism, ion-exchange dependent mechanism, 164. The formulation according to any one of claims 119 to bacterial flora/enzymes dependent mechanism, or a combi 163, wherein the formulation is effective in preventing sig nation thereof. nificant dose dumping in any beverage. 147. The formulation according to any one of claims 119 to 165. The formulation according to any one of claims 119 to 146, wherein the Eudragit E comprises Eudragit E 100TM. 164, wherein said at least one primary active substance is an 148. The formulation according to claim 119, wherein up to addictive substance. about 55% of the total dose is released as a loading dose to 166. The formulation according to claim 165, wherein the manage pain. addictive Substance is an opiod agonist and/or a narcotic 149. The formulation according to claim 148, wherein the analgesic. loading dose is released within about 60 minutes of ingestion. 167. The formulation according to any one of claims 2.63 and 150. The formulation according to claim 128, wherein the 128, wherein the loading dose is made from hot melt extru formulation is configured such that when the formulation is Sion. administered in a physically compromised form to a subject, 168. The formulation according to any one of claims 1 to 167, the rate of release of said at least one primary active Substance wherein at least one of the components used in the mainte in the loading dose is Substantially the same or lower than the nance dose and/or the loading dose are made from hot melt rate of release of said at least one primary active Substance in extrusion. the loading dose when the formulation is administered in an 169. The formulation according to claim 168, wherein the intact form. maintenance dose and/or the loading dose are made from hot 151. The formulation according to claim 128, wherein when melt extrusion. the formulation is intact and or pulverized/milled and added 170. The formulation according to any one of claims 167 to to an alcoholic and/or non-alcoholic beverage, the rate of 169, wherein an extruded component from the hot melt extru release of said at least one primary active Substance in the sion is extruded and cut into a desired shape and/or is loading dose is substantially the same or lower than the rate of extruded, ground and pressed. release of said at least one primary active Substance in the 171. The formulation according to any one of claims 1 to 170, loading dose when the formulation is administered in an wherein the particle size of the components of the formula intact form. tion is less than about 1000 microns. US 2015/025.0733 A1 Sep. 10, 2015
172. The formulation according to any one of claims 1 to 171, detailed description and the specific examples while indicat wherein the surface area of the components is between 0.5 ing embodiments of the invention are given by way of illus and 10000 m/g or higher. tration only, since various changes and modifications within 173. The formulation according to any one of claims 1 to 172, the spirit and scope of the invention will become apparent to wherein the formulation does not dose dump in the presence those skilled in the art from the detailed description. of alcohol. 174. The formulation according to any one of claims 1 to 172, BRIEF DESCRIPTION OF THE DRAWINGS wherein less than about 30% by weight of the dose is released as a vapor for inhalation 0050 Embodiments of the present invention will now be when the formulation is subjected to heat. described, by way of example only, with reference to the 175. The formulation according to claim 174, wherein less attached Figures. than about 10% by weight of the dose is released as a vapor for inhalation when the formulation is subjected to heat. 0051 FIG. 1 shows the effect of subjecting the tablet of 176. The formulation according to claim 174 or 175, wherein Example 7 to a 350 Newton force using a Vankel VK200 the formulation is milled prior to heating. Tablet Hardness Tester; 177. The formulation according to any one of claims 174 to 0.052 FIG. 2 shows the effect of subjecting a commer 176, wherein heating is achieved with an open flame or other cially available Oxycodone extended release tablet to a 350 heat Source. Newton force using a Vankel VK200 Tablet Hardness Tester. 178. The formulation according to any one of claims 174 to 0053 FIG.3 shows a pulverized/milled tablet of Example 177, wherein the temperature for heating the formulation is 7 compared to the pulverized/milled tablet of the commer about 540° C. cially available Oxycodone extended release tablet shown in 179. The formulation according to any one of claims 1 to 172, FIG. 2: wherein less than about 20% of the dose is released after microwaving for about 2 0054 FIG. 4 shows the effect of subjecting the pulverized/ minutes and thereafter, exposing the microwaved formulation milled Oxycodone tablet of Example 7 to moisture or aque to aqueous media. ous media; 180. Use of the formulation according to any one of claims 1 0055 FIG. 5A shows a mean dissolution profile of an to 179 for releasing up to about 55% of the total dose as a example of the commercially available Oxycodone extended loading dose to manage an ailment. release tablet in comparison to the Oxycodone tablets of 181. Use of a controlled release narcotic analgesic having a Example 7 in acidic media; loading dose for treatment of an ailment. 0056 FIG. 5B shows a mean dissolution profile of an 182. The use according to claim 180 or 181, wherein the example of the commercially available Oxymorphone ailment is pain. extended release tablet in comparison to the Oxymorphone 183. The use according to any one of claims 180 to 182, tablets of Example 5 in acidic media: wherein the loading dose is released within about 60 minutes 0057 FIG. 6 shows an embodiment of the mechanism of of ingestion. action of certain examples of the tablets described herein; 184. A method of managing an ailment comprising adminis tering the formulation according to any one of claims 1 to 175 0.058 FIG. 7 shows a mean dissolution profile of an for releasing up to about 55% of the total dose as a loading example of the commercially available Oxycodone extended dose to manage the ailment. release tablet in comparison to the Oxycodone tablet of 185. (Claim 185) A method for treatment of an ailment com Example 7 in acidic media; prising administering an oral controlled release formulation 0059 FIG. 8 shows a mean dissolution profile of Oxyc for releasing up to about 55% of the total dose as a loading odone tablets of Example 7 in media of varying pH: dose, wherein the loading dose comprises at least one active 0060 FIG.9 shows a mean dissolution profile of Oxymor Substance. phone tablets of Example 5 in alcoholic media: 186. (Claim 186) A method for treatment of an ailment com prising administering an oral controlled release formulation 0061 FIG. 10 shows a mean dissolution profile of Oxyc for releasing up to about 55% of the total dose as a loading odone tablets of Example 7 in alcoholic media; dose, wherein the loading dose comprises at least one active 0062 FIG. 11 shows a pulverized/milled Oxycodone tab Substance. lets of Example 7 compared to the pulverized/milled tablet of 187. The method according to any one of claims 184 to 186, the commercially available Oxycodone extended release tab wherein the ailment is pain. let in Coca-ColaTM: 188. (Claim 188) An oral controlled release formulation for 0063 FIG. 12 shows a pulverized/milled Oxycodone tab treatment of an ailment releasing up to about 55% of the total lets of Example 7 compared to the pulverized/milled tablet of dose as a loading dose to treat the ailment, wherein the load the commercially available Oxycodone extended release tab ing dose comprises at least one active Substance. let in water; 189. (Claim 189) A formulation comprising at least one main tenance dose and at least one loading dose in at least one unit 0064 FIG. 13 shows a mean dissolution of Oxycodone formulation for treatment of an ailment. tablets of Example 29 in water; and 190. The formulation according to claim 188 or 189, wherein 0065 FIG. 14 shows a mean dissolution profile of Oxyc the ailment is pain. odone tablets of the Examples described herein compared to 0049 Other features and advantages of the present inven the commercially available Oxycodone HCl extended release tion will become apparent from the following detailed tablets, microwaved for 2 minutes in 0.1N HCl or in 40% description. It should be understood, however, that the Ethanol and 0.1N HC1. US 2015/025.0733 A1 Sep. 10, 2015 14
DETAILED DESCRIPTION OF CERTAIN dimethylamino-4-phenyl-4-trans-carbethoxy-delta-cyclo EMBODIMENTS hexene, 3-dimethylamino-0-(4-methoxyphenylcarbamoyl)- propiophenone oxime, (-)B-2'-hydroxy-2,9-dimethyl-5- Definitions phenyl-6,7-benzomorphan. (-)2'-hydroxy-2-(3-methyl-2- 0066. The terms “formulation' and "composition” may be butenyl)-9-methyl-5-phenyl-6,7-benzomorphan, used interchangeably. pirinitramide, (-)C.-5,9-diethyl-2'-hydroxy-2-methyl-6,7- 0067. The term “active ingredient” or “active substance” benzomorphan, ethyl-1-(2-dimethylaminoethyl)-4,5,6,7-tet means any compound which has biological, chemical, or rahydro-3-methyl-4-oxo-6-phenylindole-2-carboxylate, physiological utility including, without limitation, active 1-Benzoylmethyl-2,3-dimethyl-3-(m-hydroxyphenyl)-pip pharmaceutical ingredient, drug, naturally occurring com eridine, N-allyl-7C.-(1-(R)-hydroxy-1-methylbutyl)-6,14 pound, nucleic acid compound, peptide compound, biolog endo-ethanotetrahydron ororipavine, (-)2'-hydroxy-2-me ics, nutraceutical, agricultural or nutritional ingredient or thyl-6,7-benzomorphan, noracylmethadol, phenoperidine, synthetic drug, Including addictive Substances Such as opiod C-d1-methadol, B-d1-methadol, C-1-methadol, B-d1-acetyl agonists or narcotic analgesics. methadol, C-1-acetylmethadol and B-1-acetylmethadol and 0068. The terms “primary” and “secondary' used in con pharmaceutically acceptable salts thereof, Stereolsomers junction with “active Ingredient' were used to assist simply thereof, ethers thereof, esters thereof, and mixtures thereof for antecedent purposes and are not meant to imply the level and their prodrugs in each case. of importance of the active ingredient. 0073. Furthermore, in certain embodiments, the formula 0069. The term “addictive substance” means any com tions described herein may be particular suitable for prevent pound upon which a user may develop a psychic or physical ing abuse of a pharmaceutical active ingredient selected from dependence, including, without limitation, any active ingre the group consisting of opiates, opioids, tranquilizers, typi dient or active substance as defined herein that may have this cally benzodiazepines, barbiturates, stimulants and other nar property. cotics and their prodrugs in each case. The formulations may 0070. Many interchangeable terms are commonly used to be particularly Suitable for preventing abuse of an opiate, describe the psychic or physical dependence of people upon opioid, tranquilizer or another narcotic selected from the compounds. The term addiction is most commonly used group consisting of N-1-2-(4-ethyl-5-oxo-2-tetrazolin-1- when talking about the strong analgesics or opioid agonist or yl)ethyl-4-methoxymethyl-4-piperid-yl)propionanilide (al abuse-able Substances. The strong analgesics or opioid ago fentanil), 5,5-diallylbarbituric acid (allobarbital), allylprod nist or abuse-able substances, in contrast to the weaker agents ine, alphaprodine, 8-chloro-1-methyl-6-phenyl-4H-1.2.4 Such as aspirin, acetaminophen, and the like, are employed in triazolo 4.3-a 1,4-benzodiazepine (alprazolam), the relief of more severe pain. They usually produce a 2-diethylaminopropiophenone (amfepramone), (t)-O-me euphoric effect when crushed and Swallowed, snorted and thyl-phenethylamine (amphetamine), 2-C.-methylphenethy “shoot parenterally. When taken as oral controlled release lamino)-2-phenylacetonitrile (amphetaminil), 5-ethyl-5-iso composition intact there is usually no significant euphoria. pentylbarbituric acid (amobarbital), anileridine, apocodeine, 0071. Addictive substances also include drugs most com 5,5-diethybarbituric acid (barbital), benzylmorphine, bezit monly employed for illicit purposes (to bring about a “high”. ramide, 7-bromo-5-(2-pyridyl)-1H-1,4-benzodiazepine-2 euphoria, excitement, stupor, sleep deprivation etc..) Such as (3H)-one (bromazepam), 2-bromo-4-(2-chlorophenyl)-9- the barbiturates, lysergic acid diethylamide (LSD), mesca methyl-6H-thieno 3.2-f 1.2.4 triazolo-4.3-a 1.4 line, marijuana (tetrahydrocannabinol), heroin, and the like, diazepine (brotizolam), 17-cyclopropylmethyl-4,5C.-epoxy the central nervous system stimulants (the amphetamines and 7C(S)-1-hydroxy-1.2.2-trimethyl-propyl-6-methoxy-6, 14 the like) sedative, hypnotics and some of the major and minor endo-ethanomorphinane-3-ol (buprenorphine), 5-butyl-5- tranquilizers (the promazines, meprobamate, the diazepines, ethylbarbituric acid (butobarbital), butorphanol, (7-chloro-1, and the like). 3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4- 0072 Examples of some of the opiod agonists or narcotic benzodiazepine-3-yl)-dimethylcarbamate (camazepam), analgesics contemplated for use in this invention include (1S,2S)-2-amino-1-phenyl-1-propanol (cathine/D-norpseu alfentanil, allylprodine, alphaprodine, anileridine, benzyl doephedrine), 7-chloro-N-methyl-5-phenyl-3H-1,4-benzo morphine, bezitramide, buprenorphine, butorphanol, clonita diazepine-2-ylamine-4-oxide (chlorodiazepoxide), 7-chloro Zene, codeine, desomorphine, dextromoramide, dezocine, 1-methyl-5-phenyl-1H-1,5-benzodiazepine-2.4(3H,5H)- diampromide, diamorphone, dihydrocodeine, dihydromor dione (clobazam), 5-(2-chlorophenyl)-7-nitro-1H-1,4- phine, dimenoxadol, dimepheptanol, dimethylthiambutene, benzodiazepine-2(3H)-one (clonazepam), clonitaZene, dioxaphetylbutyrate, diplpanone, eptazocine, ethoheptazine, 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiaz ethylmethylthiambutene, ethylmorphine, etonitaZene, etor epine-3-carboxylic acid (clorazepate), 5-(2-chlorophenyl)-7- phine, dihydroetorphine, fentanyl hydrocodone, hydromor ethyl-1-methyl-1H-thieno 2,3-e 1,4-diazepine-2(3H)-one phone, hydroxypethidine, isomethadone, ketobemidone, (clotiazepam), 10-chloro-11b-(2-chlorophenyl)-2,3,7,11b levorphanol, levophenacylmorphan, lofentanil, meperidine, tetrahydrooxazolo 3,2-d1.4benzodiazepine-6(5H)-one meptazinol, metazocine, methadone, metopon, morphine, (cloxazolam), (-)-methyl-3?-benzoyloxy-2-3(1C.(H.5- myrophine, narceline, nicomorphine, norlevorphanol, CH)-tropancarboxylate (cocaine), 4.5-O-epoxy-3-methoxy normethadone, nalorphine, nalbuphene, normorphine, norpi 17-methyl-7-morphinene-6-O-ol (codeine), 5-(1-cyclohex panone, opium, oxycodone, oxymorphone, papaveretum, enyl)-5-ethylbarbituric acid (cyclobarbital), cyclorphan, pentazocine, phenadoxone, phenomorphan, phenazocine, cyprenorphine, 7-chloro-5-(2-chlorophenyl)-1H-1,4-benzo phenoperidine, piminodine, piritramide, propheptazine, diazepine-2(3H)-one (delorazepam), desomorphine, dextro promedol, properidine, propoxyphene, Sufentanil, tramadol, moramide, (+)-(1-benzyl-3-dimethylamino-2-methyl-1-phe tilidine, alphaprodine, dextroporpoxyphene, propiram, pro nylpropyl)propionate (dextropropoxyphen), dezocine, fadol, phenampromide, thiambutene, pholcodeine, 3-trans diampromide, diamorphone, 7-chloro-1-methyl-5-phenyl
US 2015/025.0733 A1 Sep. 10, 2015 nomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2- NM30D, EudragitTMRS 100, EudragitTM RSPO, EudragitTM hydroxy-4-methoxy-benzoic acid 3-(2- RS 30 D, and EudragitTM RS 12.5. dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, I0083. The terms “low”, “small' or “fine” particle size are (RR-SS)-2-hydroxy-5-nitro-benzoic acid 3-(2-dimethylami interchangeable and refer to sizes lower than 1500 microns. nomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2', I0084. The terms “large”, “high” or “big” surface area with 4'-difluoro-3-hydroxy-biphenyl-4-carboxylic acid 3-(2-dim respect to Surface area of the active ingredients or excipients ethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester and as a population of particles, powder, crystals, granules etc. are for corresponding stereoisomeric compounds, the corre interchangeable and refer to surface areas up to 10000m/g or sponding derivatives thereof in each case, in particular esters higher. or ethers, and the physiologically acceptable compounds thereof in each case, in particular the salts and Solvates I0085. The term “coat may be variously characterized as a thereof, and their prodrugs in each case. The compounds coating, layer, membrane, film, shell, capsule, or the like, and (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)- may substantially or completely surround or envelope. phenol, (1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluo I0086. The term “controlled release' may be variously robenzyloxy)-1-(m-methoxyphen-yl)cyclohexanol or the characterized by “sustained release”, “sustained action'. Stereoisomeric compounds thereof or the physiologically “extended release”, “modified release”, “pulsed release'. acceptable compounds thereof, in particular the hydrochlo “delayed release”, “targeted release”, “site specific release'. rides thereof, the derivatives thereof, such as esters or ethers, and “timed release', which are used interchangeably in this and processes for the production thereof are known, for application and are defined for purposes of the present inven example, from EP-A-693475 or EP-A-780369. tion as the time of release, the extent of release, the rate of 0074 The formulations herein may also contain other release, the site of release and/or release of an active ingredi active ingredients. These include, amongst others and for ent from a formulation at such a rate that when a dose of the example, opioid antagonists (such as naloxone), aspirin, active ingredient is administered in the Sustained release, phenacetin, caffeine, acetaminophen, antihistamines, homa extended release, pulsed release, timed release, delayed tropine methylbromide, phenyltoloxamine citrate, barbitu release or controlled-release formulation, concentrations rates, or the like, or multiple combinations thereof. (levels) of the active ingredient are maintained within a 0075 Formulations herein may also comprise narcotic desired range but below toxic levels over a selected period of analgesics in combination with non-narcotic analgesics, anti time. In the case of in vivo administration, concentrations tussive preparations which contain narcotic or narcotic-like (levels) of the active ingredient could be measured in blood or cough Suppressants such as codeine, dihydrocodeinone, phol plasma, for example. When administered in vivo the sus codeine, and the like. Other products comprising a narcotic or tained release, extended release, pulsed release, timed narcotic-like composition for use as an antispasmodic in the release, delayed release or controlled-release formulation gastrointestinal tract, Such as Camphorated Opium Tincture, allows for a timely onset of action and useful plasma concen U.S.P., Opium Tincture, U.S.P., Opium extract, N.F., and the tration of an active Ingredient to be maintained for longer than like. in the case of immediate-release forms. 0076 Any desired amounts of the active substance may be I0087. The term “polymeric coating or “polymeric coat” used in the formulation described herein. means any coating, which is formed from materials such as 0077. The term “ailment” is understood to be any physical resins, pharmaceutical polymers or from materials formed by or mental disorder or physical or mental disease; acute or polymerization of one or more monomers to form linear or chronic. branched or cross-linked macromolecules. 0078. The term “maintenance dose' is referred to as the I0088. The term “functional coating as used herein is amount of active Substance required to keep a desired mean defined to mean a coating that affects the rate of release steady-state concentration. For example, it is the amount of in-vitro or in-vivo of the active drug(s). active Substance administered to maintain a desired level of 0089. The term “non-functional coat is defined to mean a the substance in the blood. coating that does not substantially affect the rate of release 0079. The term “loading dose” is defined as a dose of in-vitro or in-vivo of the active drug, but can enhance the active Substance, often larger than Subsequent doses, admin chemical, biological, physical stability characteristics, or the istered for the purpose of establishing a therapeutic level of physical appearance of the modified release dosage form. the active Substance. (0090. The term “onset time” or “onset of action” repre 0080. The term “Eudragit E is referred to as a pH depen sents latency, that is, the time required for the drug to reach dent polymer and may be any dimethylaminoethyl methacry minimum effective concentration or the time required for the late copolymers. Examples include, but are not limited to, drug to begin to elicit its action. It may also represent the time Eudragit ETM and Eudragit E 100TM. for complete release of the drug (e.g. loading dose). A “quick I0081. The term “Eudragit RL is referred to as a pH inde onset of action” represents a short period of time, for pendent polymer and may be any poly(ethyl acrylate-co example, about 1 hour or less, for the drug to reach minimum methyl methacrylate-co-trimethylammonrroethyl methacry effective concentration. late chloride. Examples include, but are not limited to, 0091. The terms “non-enteric polymer and “pH indepen Eudragit RLTM, Eudragit RL 100TM, EudragitTM RL PO, dent polymer are here understood to refer to a polymer EudragitTM RL 30 D, and EudragitTM RL 12.5. which is non-enteric, i.e., which is not more soluble in non I0082. The terms “Eudragit NE”, “Eudragit RS' and acidic media than in acidic media. The terms “non-enteric “Eudragit NM are referred to as pH independent polymers polymer and “pH independent polymer therefore encom and may be any neutral copolymer based on ethyl acrylate and pass polymers which are equally soluble in acidic, and neutral methyl methacrylate. Examples include, but are not limited or basic media. The terms “non-enteric polymer and “pH to, EudragitTMNE 30 D, EudragitTMNE 40D, and EudragitTM independent polymer may additionally encompass poly US 2015/025.0733 A1 Sep. 10, 2015
mers which are more soluble inacidic media than in neutral or (e.g., ethyl alcohol), carbonated beverages and/or water itself. basic media and/or Swellable in non-acidic media. The formulation thus, can provide a deterrent to common 0092. The term “bittering agent includes a compound methods of improper administration, including intravenous used to impart a bitter taste, bitter flavor, etc. injection of the drug dissolved in solvent, and nasal or oral 0093. The term “irritant includes a compound used to administration of the crushed formulation, as the drug will not impart an irritating or burning sensation. be immediately and rapidly released from the formulation and in Some cases the actual amount of drug release can be Oral Drug Delivery Formulations. Uses Thereofand Methods decreased as compared to an intact formulation. This is dem of Making Same onstrated in the example shown in FIGS. 3 and 4. 0094 Oral drug delivery formulations, uses thereof and 0100 FIG.3 shows a comparison of the pulverized formu methods of making same are provided in order to reduce the lation of Example 7 and the pulverized formulation of a potential for abuse, misuse or improper administration of an commercially available formulation, wherein Example 7 is addictive substance or any active Substance. directed to a maintenance dose core, containing polyethylene 0095. The formulations disclosed herein are reasonably oxide and Eudragit RL, which is then coated with a loading resistant to perturbation or abuse?tampering and conse dose, followed by a coating of a pod-like envelope compris quences thereof. FIGS. 1 and 2, for example, shows the effect ing Eudragit E. The pulverized formulation of Example 7. of subjecting one embodiment of a tablet described herein to when combined with an aqueous solution, forms an agglom a 350 Newton force in comparison to the effect of subjecting erated mixture as shown in FIG. 4 that prevents improper a commercially available Oxycodone extended release tablet administration, including intravenous injection of the drug, to the same force. The embodiment shows a higher breaking and nasal or oral administration of the crushed formulation, as strength as compared to the commercially available Oxyc the drug will not be immediately and rapidly released from odone tablet. In most embodiments, the formulations have a the formulation and, in this case, the actual amount of drug higher breaking strength as compared to conventional com released is decreased as compared to an intact formulation. mercially available tablets, wherein the high strength is as a The combination of, for example, polyethylene oxide and result of an external coat. The external coat makes the formu Eudragit RL, in the formulation cause agglomeration when lation resistant to perturbation. The external coat may be any combined with an aqueous solution. Suitable shape, including, but not limited to, cylindrical-like, 0101 Certain formulations described herein may become cube-like, disc-like, a pod-like envelope or cocoon. objectionable and/or difficult to ingest, administer intrave 0096. In general, the formulations provide the necessary nously, and/or snort/inhale, for example, and as noted above amount of a drug to the patient over a period of time in order with respect to Example 7, in view of the inclusion of excipi to accomplish the pharmaceutical effect (Such as timely and ents such as polyethylene oxide and Eudragit RL. In general, adequate pain relief, inducing sleep, control of blood pressure the formulation may have at least one excipient that com and blood Sugar levels, etc.), while decreasing or eliminating prises a Swellable material. Such as a pH independent poly the problem of improper administration of medications and mer, that agglomerates in an aqueous solution Such as, for their use in a non-indicated or non-prescribed manner result example, an alcoholic and/or non-alcoholic beverage. The ing in abuse, drug overdose, addiction, Suboptimal efficacy or swellable material may be selected from swellable hydro death. philic polymers such as cellulose polymers and their deriva 0097. In other aspects, the formulation comprises a load tives (such as for example, hydroxyethylcellulose, hydrox ing dose having at least one active substance, wherein the ypropylcellulose, carboxymethylcellulose, release of the active substance shows a Point Of Divergence hydroxypropylmethylcellulose, and microcrystaline cellu (POD), in a dissolution profile, with the loading dose repre lose), polysaccharides and their derivatives, polyalkylene senting a point in a timeline where the history of the dissolu oxides, polyethylene glycols, chitosan, poly(vinyl alcohol), tion or release rate changes from an onset of action to another Xanthan gum, maleic anhydride copolymers, poly(vinyl pyr set of points in the timeline represented by a controlled rolidone), starch and Starch-based polymers, poly(2-ethyl-2- release. oxazoline), poly(ethyleneimine), polyurethane hydrogels, gums, alginates, lectins, carbopol and combinations thereof. Perturbation or Tamper Deterrent Formulations Other specific examples include carbomers, polyethylene oxide or hydrophilic polymers that are lightly cross-linked, 0098. In certain embodiments, the formulation may Such cross-links being formed by covalent or ionic bond, reduce the potential for abuse of one or more active sub which interact with water and aqueous biological fluids and stances upon heating, microwaving, freezing and/or pertur Swell or expand to Some equilibrium state. The amount of bation or disruption of the internal and external physical swellable material may range from about 15 wt % to about 90 geometries of the formulation. wt % of the core or layer/coat or from about 40 wt % to about 0099. The perturbation or tamper deterrent formulation 90 wt % of the core or layer/coat, typically, from about 50 wt described herein may retard, or at least not increase, signifi % to about 80 wt % or from about 70 wt % to about 80 wt %. cantly, the instantaneous release or rate of release of the drug Combinations of swellable materials may be used. In particu Substance from a formulation when the physical integrity of lar, combinations of at least one pH independent Eudragit the formulation containing the drug is compromised and the polymer and another swellable polymer. The Eudragit poly resulting formulation is Subsequently Snorted, injected, or mer may range from about 1 wt % to about 30 wt % of the core swallowed. The composition is “physically compromised or layer/coat, typically, from about 1 wt % to about 10 wt % when it is in a form other than an intact form. This can be or from about 3 wt % to about 6 wt %. Examples of the achieved by various means such as by heating, microwaving, Eudragit polymers used are Eudragit RL, Eudragit NE, freezing, chewing, chopping, grinding, crushing, or placing Eudragit RS and Eudragit NM. Specific examples include, into aqueous solvents, such as those containing an alcohol but are not to be limited to, Eudragit RLTM, Eudragit RL US 2015/025.0733 A1 Sep. 10, 2015
100TM, EUDRAGITTM RL PO, EUDRAGITTM RL 30 D, 0106. In embodiments, the loading dose releases the active EUDRAGITTM RL 12.5, EUDRAGITTM NE 30 D, Substance more than one times the rate of release of any EUDRAGITTM NE 40 D, and EUDRAGITTM NM 30 D, Subsequent dose of active Substance. The loading dose estab EUDRAGITTM RS 100 EUDRAGIT RS PO, EUDRAGITTM lishes a therapeutic level of the active substance in a short RS 30 D, and EUDRAGITTM RS 12.5. Such formulations time interval. Such formulations defined herein, permit thera may be objectionable to ingest, administer intravenously, peutic treatment without the potential for abuse thereof. and/or short/inhale on perturbation, pulverizing, crushing, 0107. In a specific embodiment, the formula comprises i) grinding, milling, cutting or chewing into sizes that may at least one active Substance, wherein release of the active range from very fine to coarse particles, granules or spheres. Substance, onset of action, is potentiated by the presence of a Such embodiments are not objectionable to ingest when taken loading dose of the active Substance and ii) at least one coat intact. ing for controlling the release of the loading dose, wherein at 0102 The formulation may have at least one excipient that least one of the coating(s) comprises Eudragit E(dimethy comprises a Swellable material, which includes pH indepen laminoethyl methacrylate copolymer) and, optionally, dent polymer(s), in any component of the formulation, how excludes any active Substance. In another embodiment, the ever, typically, they are included in at least one of the drug amount of Eudragit E in the coat makes the formulation more coat, drug layer, or drug core. difficult to be inadvertently subdivided, crushed or abused via crushing to instantaneously or significantly release its active 0103. Therefore, in certain embodiments, the formula ingredient as compared to known commercial products. In a tions are formed Such that an addictive Substance comprised therein is not easily soluble and immediately available upon further embodiment, the formulation comprises at least one crushing and attempting to dissolve it for intravenous injec primary active Substance and at least one coat that comprises tion or to obtain access to the total drug immediately upon Eudragit E, wherein the formulation is free of any active oral ingestion of the crushed formulation. In general, a for Substance external to the coat. mulation may comprise at least one active Substance; and at 0108. In certain embodiments, when the formulation is at least one excipient, wherein dissolution of the pulverized/ least one of perturbed, pulverized or crushed or ground or milled formulation in alcoholic and/or non-alcoholic bever milled or cut into one or more sizes ranging from very fine to ages causes the formulation to agglomerate. coarse particles, granules or spheres and mixed with from about 10 ml to about 1000 ml aqueous solution will not lead 0104. The formulations described herein can be more to at least one of solubilisation, significant, rapid and/or objectionable and/or resistant to perturbation and conse instantaneous drug release and/or release of most of the drug quences thereof, when presented as an intact dosage form in about the first hour. In other embodiments, even if the and/or when heated, burned, microwaved, frozen, perturbed, mixture was mixed under low to moderate to high agitation or pulverized or crushed or ground or milled or cut into one or speed of mixing will not lead to at least one of solubilisation, more sizes ranging from very fine to coarse particles, granules significant, rapid and/or instantaneous drug release and/or or spheres. The formulations described herein, with or with release of most of the drug in about the first hour. out a loading dose, may demonstrate non or insignificant loss in controlled release properties or does not result in instanta 0109 The aqueous solution may be any suitable aqueous neous or rapid release of active content when heated, burned, beverage for consumption Such as alcoholic and/or non-alco microwaved, frozen, perturbed, pulverized or crushed or holic beverages. ground or milled or cut into one or more sizes ranging from 0110. In other embodiments, the formulation having a very fine to coarse particles, granules or spheres as compared loading dose which when the formulation is at least one of to when presented as an intact dosage form. perturbed, pulverized or crushed or ground or milled or cut 0105 For example, the formulation comprises a loading into one or more sizes ranging from very fine to coarse par dose. The formulation, which in spite of the presence of a ticles, granules or spheres and mixed with from about 1 ml to loading dose, is more difficult to be subdivided, crushed or about 1000 ml aqueous solution under low to moderate to abused via crushing to instantaneously or significantly high agitation or speed of mixing, only from about 1 to about release its active ingredient as compared to known commer 30% of the loading dose is extracted and/or released in 10 cial products. The formulation may also comprise a loading minutes. dose, which assures a quick onset of action and a Sustained 0111. In another embodiment, the formulation having a action via timely release of the loading dose and adequately loading dose which when the formulation is at least one of controlled maintenance dose thereby providing effective pain perturbed, pulverized or crushed or ground or milled or cut relief as compared to known commercial products. These into one or more sizes ranging from very fine to coarse par types of formulations may resist abuse or unintended misuse ticles, granules or spheres and mixed with from about 10 ml without compromising therapeutic effectiveness. A formula to about 1000 ml aqueous solution under low to moderate to tion having a loading dose, as used herein, represents an high agitation or speed of mixing, only from about 1 to about active Substance that is released at a higher rate in comparison 30% of the loading dose is extracted and/or released in about to another dose of the active Substance in the same formula 10 minutes to about 60 minutes; typically about 10, about 20, tion. In other words, in the formulation, a greater amount of about 30 or about 60 minutes. the active Substance is released in a certain time interval in 0112. In a further embodiment, the formulation when per comparison to, for example, another dose of the active Sub turbed, pulverized or crushed or ground or milled or cut into stance in the formulation that is released in a similar time one or more sizes ranging from very fine to coarse particles, interval. For example, in an embodiment, 50% by weight of granules or spheres and mixed with from about greater than the active substance in the formulation is released in 1 hour; about 10 ml to about 1000 ml alcoholic or non-alcoholic however, in the following hour, only 10% by weight of the beverages under low to moderate to high agitation or speed of active Substance is released. mixing only from about 1 to about 30% is extracted and/or US 2015/025.0733 A1 Sep. 10, 2015
released in about 10 minutes to about 60 minutes, typically and/or pH dependent. For example, the formulation, which in about 10, about 20, about 30 or about 60 minutes. the presence of gastric fluid up to a pH of about 5.0 will 0113. In another aspect, the formulation when perturbed, release a loading dose having a greater magnitude than in pulverized or crushed or ground or milled or cut into one or gastric fluid of a pH above about 5.0 more sizes ranging from very fine to coarse particles, granules or spheres and mixed with from about greater than about 10 0.120. The formulation, in which the presence of gastric ml to about 1000 ml aqueous solution under low to moderate fluid or aqueous media that is less acidic to alkaline pH, to high agitation or speed of mixing only from about 1 to trigger the release of a lesser amount of a loading dose. An about 40% is extracted and/or released in about 2 to about 5 optimum amount of a loading dose is released in the presence hours. The aqueous Solution may be alcoholic or non-alco of acidic liquid media. In typical embodiments, the amount of holic beverages. active ingredient(s) is released in the first hour or in less than 0114. In another embodiment, the formulation comprises four hours from time zero of a release cycle or profile, in-vitro one or more active ingredients with a particle size less than and/or in-vivo. about 2000 microns and materials selected from release I0121 The formulations may be directed to a dosage form retarding agents, gelling agents, polymers, co-polymers, containing a matrix or non-matrix core incorporating one or cross-linked polymers and non-cross linked polymers in an more active ingredients, excipients, and release controlling amount and ratio which is sufficient to prevent the compro agent(s). The core may be surrounded by a coat of one or more mising or significant and or complete loss of integrity of the active ingredients, followed by another coat which is soluble controlled release mechanism of the composition when in liquid media with a pH less than about 5.0 but insoluble in burned, microwaved, heated, frozen, perturbed, pulverized or a pH above about 5.0 wherein the dosage form does not result crushed or grind or milled or cut into one or more sizes in instantaneous or rapid release of active content when ranging from very fine to coarse particles, granules or spheres heated, burned, microwaved, frozen, perturbed, pulverized or and placed in contact with from about 10 ml to about 1000 ml crushed or ground or milled or cut into one or more sizes of gastrointestinal (GI) fluids, simulated GI fluids, aqueous ranging from very fine to coarse particles, granules or spheres Solution, alcoholic or non-alcoholic beverages. as compared to when presented as an intact dosage. 0115 Accordingly, in certain embodiments, there is pro 0.122. In certain embodiments, the formulation has active vided a formulation with a loading dose that can be effectively pharmaceutical ingredient(s) and/or excipients and/or release employed to reduce the problems of dose dumping of one or controlling agents with low particle size and higher Surface more active Substances. The formulation may have a loading area. The formulation is capable of higher rates of release in dose that can be effectively employed to reduce the potential liquid media with a pH of less than about 5.0 than in liquid for abuse of one or more active Substances upon heating, microwaving, freezing and/or perturbation or disruption of media with a pH above about 5.0. the internal and external physical geometries of a delivery I0123. The formulation has one or more release cycles. The formulation. rate of release of the loading dose is higher than the rate of 0116. In another embodiment, a formulation has active release of the maintenance doses. In typical embodiments, the pharmaceutical ingredient(s) and/or inactive ingredient(s) formulation, which on perturbation or pulverizing or crushing having a large Surface area that can be effectively employed to or grinding or milling or cutting or chewing into one or more control the release of one or more active Substances in a sizes ranging from very fine to coarse particles, granules or formulation or prevent the instantaneous release of most of spheres will not result in the dose dumping of the active the dose in the formulations upon perturbation or disruption ingredient or instantaneous release of all of its dose. of the internal and external physical geometries of the said 0.124. In other embodiments, the formulation has one or formulation of composition. Examples of perturbation or dis more active Substances in a pharmaceutically effective ruption can include heating, microwaving, and/or freezing. amount, wherein the formulation is configured Such that 0117 Formulations with active pharmaceutical ingredient when the intact formulation is brought into contact with a (s) and/or inactive Ingredient(s) having a large surface area solution having a pH below 5, not more than about 55% of the can be effectively employed to reduce the problems of dose amount of drug is released in 1 hour and not less than about dumping of one or more active Substance. 30% is released in pH 1-2 in 1 hour. The rate of drug release is lower at a pH greater than about 5 than at a pH lower than pH Dependent, Ion Exchange Dependent or Intestinal about 5. In other embodiments, the formulation has a higher Bacterial Flora or Enzymes Dependent Formulations rate of release and/or higher loading dose released in acidic 0118. In embodiments, the formulations contain a loading media than in basic media. dose Surrounded by one or more coats in which drug release, 0.125. In certain embodiments of the formulations, drug onset of action, Sustained action and effectiveness is potenti release, onset of action, Sustained action and effectiveness is ated by the presence of a loading dose, which is triggered potentiated by the presence of a loading dose, which is trig when the coat(s) is activated by a pH dependent mechanism, gered or activated by a pH dependent mechanism, ion an ion exchange mechanism or intestinal bacterial flora or exchange dependent mechanism or intestinal bacterial flora/ enzymes. Examples are shown in FIGS. 5, 7, and 8 which enzymes dependent mechanism or a combination thereof. show pH dependency on dose dumping, wherein the formu Drug release shows a clearly defined Point Of Divergence lations (Examples 5 and 7) are directed to a maintenance dose (POD), in the dissolution profile or drug release time lines, core, which is then coated with a loading dose, followed by a with the loading dose representing a point in a timeline where coating of a pod-like envelope comprising Eudragit E. the history of the dissolution or drug release rate begins to 0119 The rate and extent of release of a loading dose in change from a quick onset of action to another set of points in Such embodiments is ion exchange dependent, dependent on the timeline represented by a Sustained action and provision intestinal bacterial flora, dependent on intestinal enzymes, of a maintenance dose. See, for example, FIG. 6. Prior to the US 2015/025.0733 A1 Sep. 10, 2015 20
POD, there is no history of a timeline of sustained action. weight of the dose is released as a vapor. The formulation may Certain formulations can have a sustained action followed by be milled prior to heating and the heating can be achieved, for a quick onset of action. example, with an open flame or other heat Source. Tempera 0126. In the various embodiments described throughout tures may be less than or equal to about 540°C. the description, the formulations may have a loading dose, for 0.130. The formulation can comprise an active substance in example, the formula comprises i) at least one active Sub a pharmaceutically effective amount, wherein the formula stance, wherein release of the active Substance, onset of tion is configured Such that when it is contacted with an action, is potentiated by the presence of a loading dose of the alcohol or consumed with an alcoholic beverage, the rate of active Substance and ii) at least one coating for controlling the active substance is released from the formulation within a release of the loading dose, wherein at least one of the coating time period selected from the group consisting of about 0.5 (s) comprises Eudragit E, which, optionally, excludes any hours, about 1 hour, about 2 hours, about 4 hours and about 8 active substance. In a further embodiment, the formulation hours and the release is Substantially the same or lower, comprises at least one primary active Substance and at least typically less than about 40%, more typically less than about one coat that comprises Eudragit E, wherein the formulation 30%, and most typically less than about 20%, than the rate of is free of any active substance external to the coat. The surface drug released when the formulation is administered with a area coverage by Eudragit E in the coat is at least about 5 non-alcoholic solution. mg/cm, more typically, at least about 10 mg/cm, and even I0131 The formulation can comprise an active substance in more typically, at least about 20 mg/cm. For example, the a pharmaceutically effective amount wherein the formulation Eudragit E may be present in an amount of from about 5 is configured Such that when it is contacted with an alcohol or mg/cm to about 100 mg/cm; typically, about 10 mg/cm to consumed with an alcoholic beverage, there is a lag time about 100 mg/cm and even more typically, about 10 mg/cm whereby the active substance is released in at least about 1 to about 100 mg/cm. The amount of Eudragit E in the coat hour. may be from about 5 wt % to about 80 wt % of said at least one of said at least one coating, typically, about 30 wt % to about 0.132. In another aspect, the formulation provides 60 wt %, or more typically, 40 wt % to about 60 wt %. The adequate and timely drug release and yet is less amenable to Eudragit E is used in Such an amount to prevent dose dumping the effects of perturbation, tampering, and/or abuse and does of the active ingredient(s), typically, in alcohol. In contrast, not significantly dose dump in the presence of alcohol. the formulations may not have a loading dose. Instead, the I0133. In embodiments, the formulation has a loading dose formulation may comprise at least one active ingredient as a of active Substance(s) and inactive Substance(s) with a high controlled release dose, for example, and coating(s), whereby Surface area. Eudragit E may be part of at least one of the coats. The I0134. In another embodiment, there is provided a con Eudragit E may have similar surface area coverage as trolled release formulation with a loading dose that is resis described above. In an embodiment, the formulation may be tant to being easily Sub-divided, resistant to abuse, and/or directed to a dosage form containing a matrix or non-matrix resistant to tampering. The loading dose of the formulation is core optionally incorporating one or more active ingredients, shielded from dose dumping in alcohol or common beverages excipients, and release controlling agent(s). The core may be used by addicts and/or inadvertent instantaneous release of Surrounded by a coat of one or more active ingredients, fol significant or all of the active ingredient when microwaved, lowed by another coat that includes Eudragit E, in which the burned, heated, perturbed, pulverized or crushed or ground or active ingredient(s) is released when the Eudragit E coat is milled or cut into one or more sizes ranging from very fine to activated by a pH dependent mechanism, an ion exchange coarse particles, granules or spheres. See, for example, FIGS. mechanism or intestinal bacterial flora or enzymes. 11 and 12, wherein the formulation (Example 7) is directed to Formulations in the Presence of Alcoholic and/or Non-Alco a maintenance dose core, which is then coated with a loading holic Beverages dose, followed by a coating of a pod-like envelope compris 0127 Certain formulations, in the presence of alcohol, ing Eudragit E. See also FIG. 14, which shows a mean disso release similar or lesser amounts at a similar or lesser rate lution profile of Oxycodone tablets of the Examples when compared to being in the presence of acidic or aqueous described herein compared to the commercially available solutions. See for example, FIGS.9 and 10 which show less or Oxycodone HCl extended release tablets, microwaved for 2 no dose dumping in the presence of alcohol, wherein the minutes in 0.1N HCl or in 40% Ethanol and 0.1N HCl, which formulations (Examples 5 and 7) are directed to a mainte indicates that the dissolution is not perturbed by microwav nance dose core, which is then coated with a loading dose, ing. In certain embodiments, less than about 20% of the dose followed by a coating of a pod-like envelope comprising in the formulation is released after microwaving for about 2 Eudragit E. minutes and thereafter, exposing the microwaved formulation 0128. The formulation may have perturbation or tamper to aqueous media. resistant properties, prevent the instantaneous release of the I0135) In accordance with yet another aspect, a modified active ingredient(s) upon heating/evaporation, microwaving, release, delayed release, controlled release or extended freezing and/or or upon perturbation, pulverizing, crushing, release formulation and method in which the physicochemi grinding, milling or cutting them into one or more sizes cal nature of the composition helps to prevent significant dose ranging from very fine to coarse particles, granules or spheres dumping in the presence of alcohol and also discourage and there is less or no dose dumping of one or more active abuse. Substances in the presence of alcohol. 0.136. A formulation incorporating an active substance 0129. In certain embodiments, and as shown in Example with Small particle size and large Surface area and the choice 42, less than about 30% by weight of the dose is released as a of a suitable polymer makes it harder for dose dumping of an vapor for inhalation when the formulation is subjected to addictive Substance in the presence of alcohol or during co heat. In other embodiments, even less than about 10% by ingestion of alcohol. US 2015/025.0733 A1 Sep. 10, 2015
0.137 The formulations may comprise any active ingredi 7.5% by weight, and most typically, between about 1 and ent, especially medications that are Subject to abuse due to the about 5% by weight of the formulation but not more than 50 presence of active ingredients that can produce an emotional, mg/kg body weight daily intake. psychological, euphoric, depressive or generally psychedelic experience. More specifically, it may pertain to medicaments Administration whose unintended or improper administration may lead to 0143. The formulation may be administered in-vivo oral, abuse, drug overdose, Suboptimal efficacy or death; medica vaginal, anal, ocular, Subcutaneous, intramuscular adminis ments used to manage pain, medicaments used to reduce or tration or for implantation. The composition may also be used eliminate anxiety attack (psychotherapeutic drugs), medica for in vitro or ex vivo delivery of an addictive substance. It ments that are used as stimulants and sleeping pills, cardio may be targeted at specific sites in the gastrointestinal tractor vascular agents, antidiabetics, acid labile drugs and in general to specific organs. It may be applied occularly and transder medicaments whose intended effects may be compromised if mally in a pouch or patch. It is evident that the physical State the intact dosage form is heated, burned, microwaved, frozen, of the formulation and the particular method of application perturbed, pulverized or crushed or ground or milled or cut may vary accordingly. into one or more sizes ranging from very fine to coarse par ticles, granules or spheres. 0144. The formulation may reduce the potential for improper administration or use of drugs but which, when Formulations Objectionable to Chewing, Sucking, Licking administered as directed, is capable of delivering a therapeu and/or Holding in the Mouth tically effective dose. In particular, the formulation addresses 0138 A bittering agent may optionally be present in the the need for a drug product, which, compared to conventional formulations to make the compromised formulation objec formulations, decreases the intensity, quality, frequency and tionable to chewing, sucking, licking and/or holding in the rate of occurrence of the "euphoria' and other untoward mouth. The pharmaceutically acceptable bittering agents effect, which can occur with improper administration. used may be denatonium benzoate, denatonium, saccharide 0145. In yet another embodiment, the formulation, despite esters such as saccharide Sucrose octaacetate, naringin, phe the presence of a loading dose, reduces the potential for nylglucopyranose, benzyl glucopyranose, tetramethylglu improper administration or use of drugs but which, when cose and glucose pentaacetate, or quassin. The most typical is administered as directed, is capable of delivering in a timely Sucrose octaacetate. With the inclusion of a bittering agent in fashion, a therapeutically effective dose. In particular, the a formulation, when the formulation is tampered with, the formulation addresses the need for a drug product, which, bittering agent imparts a discomforting quality to the abuser compared to conventional formulations, decreases the inten to typically discourage the inhalation or oral administration sity, quality, frequency and rate of occurrence of the "eupho of the tampered formulation, and typically to prevent the ria' and other untoward effect, which can occur with abuse of the formulation. improper administration. 0139 Suitable bittering compositions may include bitter ing agents or analogues thereof in a concentration 20 to 1000 Various Formulations ppm, typically 10 to 500 ppm and most typically 5 to 100 ppm in the finished product. 0146 In one embodiment, the formulation comprises: one 0140. In an embodiment, the formulation comprises a core or more of a modified release, delayed release, controlled containing one or more active Substance(s) with or without a release and/or extended release drug core referred to as the bittering agent, Surrounded by a film optionally containing maintenance dose; Surrounded first by one or more layers of one or more active Substance(s) embedded in a functional or active Substance(s) embedded in a non-functional coat; fol non-functional coat or coat matrix and further Surrounded by lowed by one or more layers of functional coat. a functional or non-functional coat or coat matrix. The coat or 0.147. In certain embodiments, some or all of the loading coat matrix can be applied by spraying or dry coating or dose of the formulation is incorporated into and/or onto the encapsulation or by a combination of these methods. core of the formulation. In other embodiments, the loading 0141. In certain embodiments, the formulation is objec dose is separated from the maintenance dose; the loading tionable to chewing, sucking, licking and/or holding in the dose is only incorporated in the maintenance dose; or the mouth for more than about 1 minute; for more than about 5 maintenance dose is only present in the core. The formulation minutes, or for more than about 10 minutes. In another may have the loading dose incorporated in the maintenance embodiment, the formulation is objectionable to chewing, dose in addition to a separate loading dose external to the Sucking, licking and/or holding in the mouth for less than maintenance dose. about 10 minutes but greater than about 30 seconds. More 0.148. The formulation may have one or more loading over, in similar embodiments, the formulation will not permit doses. release or will not release a significant amount of the active 0149. In a further embodiment, the formulation, which ingredient(s) in the pH environment of the mouth. when taken intact as intended, has a core and one or more 0142. An irritant may be present in the formulations. With active substance(s) layers internal or external to the core the inclusion of an irritant (e.g., capsaicin) in the formulation, which may contribute to the loading dose. The formulation, when the formulation is tampered with, the capsaicin imparts which when taken intact as intended, the core may contribute a burning or discomforting quality to the abuser to typically to the maintenance dose and one or more active substance(s) discourage the inhalation, injection, or oral administration of layers internal or external to the core contributes to the load the tampered formulation, and typically to prevent the abuse ing dose. of the formulation. Suitable capsaicin compositions include 0150. In the various formulations, the loading dose is capsaicin (trans 8-methyl-N-Vanillyl-6-noneamide) or ana released in one or more time intervals. logues thereof in a concentration between about 0.0012.5% 0151. The formulation may comprise one or more active and 50% by weight, typically between about 1 and about Substance(s) in a pharmaceutically effective amount, wherein US 2015/025.0733 A1 Sep. 10, 2015 22 the formulation is configured such that when the formulation in the art, liquid, semi-solid or solid, and may be homog is administered in physically compromised form to a subject, enously or non-homogenously dispersed in the core. the rate of active Substance(s) released from the composition, 0159. The formulation can be a solid unit formulation such within a time period selected from the group consisting of as, and without being limited thereto, a tablet, granules, about 0.5 hours, about 1 hour, about 2 hours, about 4 hours spheres, particles, beads, capsules or microcapsules. In and about 8 hours, is substantially the same or lower than the another embodiment, the formulation optionally has a load rate of active substance(s) released when the formulation is ing dose Surrounded by a protecting coat that has a high administered in an intact form. Surface area and is pH dependent, ion-exchange dependent, 0152 The formulation may comprise one or more active and/or bacterial flora/enzyme dependent. Substance(s) in a pharmaceutically effective amount, wherein 0160. It will be understood that the formulations may not the formulation is configured such that when the formulation be limited to addictive substances, and may also be useful in is administered in physically compromised form to a subject, formulations of any active ingredient or Substance. the rate of active Substance(s) released from the composition, 0.161 Several embodiments of the formulations are pro within a time period selected from the group consisting of vided: about 0.5 hours, about 1 hour, about 2 hours, about 4 hours 0162. In an embodiment, there is provided a formulation and about 8 hours, is Substantially the same or lower, typically that is effectively employed to control the release of one or less than 20%, more typically less than 30%, and most typi more active Substances or prevent the instantaneous release of cally less than 40%, than the amount of active substance(s) the entire dose in the formulation upon perturbation or dis released when the pharmaceutical composition is adminis ruption of the intemal and/or external physical geometries of tered in an intact form. the formulation. 0153. The formulation may comprise one or more active 0163. In a further aspect, the loading dose of the formula Substance(s) in a pharmaceutically effective amount, wherein tion is incorporated into at least one of the 1) core, 2) external the formulation is configured such that when the formulation to the core and 3) both 1 and 2. is administered in an intact form, at least 50% of the amount 0164. The formulation may have a modified release, ofactive substance(s) is released after about 8 hours and when delayed release, controlled release or extended release for the formulation is administered in a physically compromised mulation and in which the physicochemical nature of the form at most about 55%, typically at most about 50%, more formulation is used to reduce the potential and consequences typically at most about 30%, of the amount of active sub (drug overdose, addiction, Suboptimal efficacy, and/or death) stance(s) is released in about 1 hour. of improper administration of medications and their use in a 0154 The formulation may comprise one or more active non-indicated or non-prescribed manner. Substance(s) in a pharmaceutically effective amount, wherein 0.165. In one embodiment, a formulation comprises: i) a the formulation is configured such that when the formulation core comprising one or more active Substances in a matrix and is administered in an intact form, at least 80% of the amount ii) Substantially Surrounded by a coat comprising one or more of active substance(s) is released after about 1 hour and when of the same or different active substances in a functional or the formulation is administered in a physically compromised non-functional coat form at most about 70% of the amount of active substance(s) 0166 In another embodiment, a formulation comprises: i) is released in about 1 hour. a core comprising one or more active Substances in a modified 0155. In yet another embodiment, the formulation is release, delayed release, controlled release or extended designed Such that in the treatment of severe to moderate pain release matrix and ii) Substantially Surrounded by a coat com using opioid analgesics timely delivery of onset of pain relief prising one or more of the same or different active Substance and adequate pain relief is experienced by the patient from in a functional or non-functional coat. about 30, about 60, about 120, about 180 or about 240 min 0167. In accordance with yet another embodiment, a for utes. In another embodiment, the formulation is designed mulation comprises: i) a core comprising one or more active Such that the formulation or composition can be administered Substances in a modified release, delayed release, controlled every 8 hours to 12 hours to every 24 hours. release or extended release matrix, ii) Substantially Sur 0156. In certain formulations, the active substance(s) and/ rounded by a coat comprising one or more of the same or or inactive Substance(s) used in the formulation have a fine, different active Substances in a non-functional coat, and iii) Small or low particle size and large, high or big surface area. further substantially surrounded by a functional coat. Accordingly, the particle size is less than 1500 Microns, (0168. In accordance with another embodiment, a formu typically less than 1000 microns and more typically less than lation comprises: i) a core comprising one or more active 400 microns. Substances in a modified release, delayed release, controlled 0157. In certain formulations, the loading dose is applied release or extended release matrix, ii) Substantially Sur as a coat around the core of the formulation or composition. rounded by a coat comprising one or more of the same or 0158. The formulation may have one or more of an imme different active Substances in a functional or non-functional diate release, modified release, delayed release, controlled coat, and iii) optionally Surrounded by a functional or non release or extended release drug core: Surrounded first by one functional coat. or more layers of drug embedded in a non-functional coat (0169. In accordance with another embodiment, a formu followed by one or more layers of functional coat. The active lation comprises: i) a core comprising one or more active Substance may be, without limitation, an opioid agonist, a Substances in a modified release, delayed release, controlled narcotic analgesic, barbiturates, central nervous system release or extended release matrix, ii) Substantially Sur stimulants, tranquilizers, antihypertensive, antidiabetics, rounded by a coat comprising one or more of the same or and/or antiepileptics. Prior to incorporation within the core or different active Substances in a non-functional coat, and iii) coat, the active Substance may be in any suitable form known further substantially surrounded by a functional coat that is US 2015/025.0733 A1 Sep. 10, 2015
soluble in gastric fluid up to a pH of about 5 and below but 0177. In accordance with other embodiment, there is pro swellable and permeable above a pH of about 5. vided a formulation whereby one or more active substances 0170. In accordance with still another embodiment, a for are released in a pulsatile manner or in specific sites in the mulation comprises: i) a core comprising one or more active gastrointestinal tract (GIT). Substances with or without a bittering agent in a modified 0.178 Inyet another embodiment, the formulation also has release, delayed release, controlled release or extended use in other non-medical applications in which the release of release matrix, ii) Substantially surrounded by a coat com a Substance is desired into an environment, which eventually prising one or more of the same or different active substances comes into contact with fluids. For example, in agriculture, in a non-functional coat, and iii) further Substantially Sur Such formulations may be used, for instance, in conjunction rounded by a functional coat that is soluble in gastric fluid up with fertilizers, wherein the active ingredient(s) is not to a pH of about 5 but insoluble above a pH of about 5.0. released until contacted with specific fluid(s). 0171 In accordance with still another embodiment, a for 0179. In another embodiment, there is provided a formu mulation comprises: i) a core comprising one or more active lation with a loading dose that can be effectively employed to Substances with or without a bittering agent, and ii) Substan control the release of one or more active Substances in a tially surrounded by a coat comprising one or more of the formulation or prevent the instantaneous release of most of same or different active substances in a non-functional coat, the dose in the formulations upon perturbation or disruption and iii) further substantially surrounded by a functional coat of the internal and external physical geometries of the formu that is soluble in gastric fluid up to a pH of about 5 but lation. insoluble above a pH of about 5.0. 0180. An immediate release, delayed release, modified 0172. In accordance with still another embodiment, a for release, extended release, pulsed release, Sustained release or mulation comprises: i) a core comprising one or more active controlled release profile provided by the formulations dis Substances and a bittering agentina modified release, delayed closed herein may be advantageously used in the formulation release, controlled release or extended release matrix, ii) sub of any active ingredient. stantially surrounded by a coat comprising one or more of the 0181. A formulation may comprise a core with one or same or different active substances in a non-functional coat, more release retarding agent, controlled release agent, gelling and iii) further substantially surrounded by a functional coat agent, polymeric agents and one or more fillers in a pharma that is soluble in gastric fluid up to a pH of about 5 but ceutically suitable vehicle, and optionally materials selected swellable and permeable above a pH of about 5.0. from disintegrants, compression aids, lubricants, humectants, 0173. In accordance with still another embodiment, a for surfactants, emulsifiers, plasticizers, anti-oxidants and stabi mulation comprises: i) a core comprising one or more active lizers. Substances and a bittering agentina modified release, delayed 0182. A formulation may be formulated such that physi release, controlled release or extended release matrix, ii) sub cochemical properties reduces or prevents dose dumping of stantially surrounded by a coat comprising one or more of the addictive substances in the presence of alcohol, and discour same or different active substances in a non-functional coat, ages drug abuse by mode of crushing, milling or grinding the and iii) further substantially surrounded by a functional coat. formulation to powder or heating the formulation to vapor 0.174. In accordance with still another aspect, the formu and Snorting or inhalation by the nasal route or dissolving to lation comprises: i) a core comprising one or more active abuse via the parenteral route. Substances and a bittering agentina modified release, delayed 0183. A formulation may comprise a core surrounded by a release, controlled release or extended release matrix, and ii) polymeric coat, a plastic coat or elastic coat and the like. Substantially Surrounded by a coat comprising one or more of 0184. Where a formulation of the present invention com the same or different active Substances in a functional or prises more than one coat, a first coat Substantially Surrounds non-functional coat. or envelops a core, a second coat Substantially Surrounds or 0175. In embodiments of the formulations described envelopes the first coat, and so forth. Coats may take the form above, at least one of the functional or non-functional coats and composition of any known compatible controlled-release applied is from about 1 mg/cm to about 100 mg/cm; typi coat, for example a pH sensitive coat, ion exchange resin coat cally, from about 10 mg/cm to about 100 mg/cm. The outer (Cholestyramine, Colestipol, Sodium polystyrene Sulfonate, most coat is typically 10 mg/cm to about 100 mg/cnm, or 15 Polacrilex resin, Polacrilin potassium), intestinal bacteria mg/cm to about 55 mg/cm, or 10 mg/cm to about 40 flora or enzyme reactive polymer (Such as a polysaccharide mg/cm, or 40 mg/cm to about 80 mg/cm, or 80 mg/cm to based coat) a water repellant coat, or an aqueous solvent about 100 mg/cnm. The substance used in the outer most based coat, or a water-soluble coat. coat typically comprises Eudragit E. However, any suitable 0185. In embodiments, the coating thickness is below polymer may be used that provides pH dependency, ion 1000 mg/cm, typically below 200 mg/cm and more typi exchange dependency, and/or bacterial flora/enzyme depen cally below 100 mg/cm. dency and remains substantially intact when about a 350 N 0186 The formulations described herein may release up to force is applied. about 55% of the total dose as a loading dose to manage pain. 0176). In embodiments of the formulations described In certain embodiments, up to about 55% of the total dose is above, the active Substance may be present in any desirable released as a loading dose within about 60 minutes of inges amount. With respect to a maintenance dose, the amount may tion. range from about 1% to about 20% w/w; about 1% to about 0187. The formulation described herein may also include 10% w/w; or about 2% to about 7% w/w. With respect to a acid(s) in the coat(s), including an overcoat; layer(s); and/or loading dose, the amount may range from about 1% to about core of the formulation. Acids such as inorganic and organic 30% w/w; about 1% to about 10% w/w; about 15% to about acids may be used. Examples include, but are not limited 30% w/w; or about 1% to about 5% w/w. The substance used thereto, hydrochloric acid, Sulfuric acid, nitric acid, lactic in the outer most coat typically comprises Eudragit E. acid, phosphoric acid, citric acid, malic acid, fumaric acid, US 2015/025.0733 A1 Sep. 10, 2015 24
Stearic acid, tartaric acid, boric acid, borax, and benzoic acid. design of the physical geometry of the formulation polymeric The amount of acid(s) may be present in the formulation in coats, for example, without limitation, through the choice of any suitable amount. In some embodiments, the wt % ratio of particle size and Surface area, types of polymers used, the acid(s) to drug (e.g. in the loading dose and/or maintenance presence or absence of a loading dose, the order in which they dose) in the formulation is from about 1000:1 to about are deposited, the ratios of the loading dose to maintenance 1:1000; about 500:1 to about 1:500; or about 1:100 to about dose, the ratios of the polymers in the mix and the nature of 100:1. These ranges, and any ranges mentioned herein, are their interaction. The controlled-release profile can also be understood to include any incremental ranges and single modified by a variety of factors relating to the delivery for amounts encompassed by these ranges. In more specific mulation and the route of administration. For example, the embodiments, the wt % ratio of acid(s) to loading dose in the Sustained-release period and profile will vary depending upon formulation is from about 1:100 to about 100:1. In typical the loading dose concentration, solubility of the active ingre embodiments, the acid(s) are organic acids 1:50 to 50:1. In dient, the rate of clearance of the active ingredient from the Some embodiments, the loading dose may comprise from intended site of administration, the size and Surface area of about 1 wt % to about 1000 wt %; from about 1 wt % to about the particle, the amount of the active ingredient initially 500 wt %; from about 1 wt % to about 300 wt %; from about present in the core, the presence of other compounds within 1 wt % to about 200 wt %; from about 1 wt % to about 100 wt the core that affect the rate of release of the active ingredient, %; from about 1 wt % to about 50 wt %; from about 1 wt % to the permeability of the polymeric coating(s) to the active about 30 wt %; from about 1 wt % to about 20 wt %; or from pharmaceutical ingredient, and the rate of degradation of the about 1 wt % to about 15 wt % of the acid(s) based on the polymeric coating(s), as well as other factors. weight of the loading dose, whether it be a coat, layer and/or 0190. Release control may be effected or optimized core. In other embodiments, the maintenance dose may com through the loading dose, types of polymers used, the number prise from about 1 wt.% to about 1000 wt %; from about 1 wt of polymeric coats, the order in which they are deposited, the % to about 500 wt %; from about 1 wt % to about 300 wt %: from about 1 wt % to about 200 wt %; from about 1 wt % to width of polymeric coats and Surface area covered, the ratios about 100 wt %; from about 1 wt % to about 50 wt %; from of the polymers in the mix and the nature of their interaction. about 1 wt % to about 20 wt %; or from about 1 wt % to about 0191 Incorporating a pharmaceutical drug, that is an 15 wt % of the acid(s) based on the weight of the maintenance addictive substance as described, in the formulation herein dose, whether it be a coat, layer and/or core. The amount of may be useful for (1) reducing at least one mode of abuse, for acid, typically organic acid(s), may be present in any coat in example, the illicit use by Snorting/inhalation, parenteral any Suitable amount. In some embodiments, the amount of administration, or crushing and oral ingestion of formulations acid may be from about 5 wt % to less than about 100 wt %, intended for oral administration; (2) reducing dose dumping from about 50 wt % to about 90 wt %, from about 50 wt % to in the presence of alcohol; or (3) timed or extended release about 80 wt %, or from about 60 wt % to about 80 wt % by compositions and/or formulations which despite its physical weight of the coat. In still other embodiments, the coat com geometry being compromised maintains some or nearly all of prising Eudragit E may comprise from about 1 wt % to about its integrity sufficiently to perform controlled release func 30 wt %, typically from about wt % to about 25 wt % by tions during transit in the GIT and (4) potentiation of drug weight of the acid(s) based on the weight of the coat. Some effect due to its ability to deliver quick onset of action fol organic acid(s) that may particularly be used, for example, lowed by Sustained action, thus leading to a more effective and without being limited thereto, lactic acid, phosphoric drug delivery formulation. acid, citric acid, malic acid, fumaric acid, Stearic acid, tartaric 0.192 The formulations may comprise additives such as acid, and benzoic acid. Such acids modify the pH of the macro Polyethylene Oxide polymers, Polyethylene glycol poly and micro environment to facilitate release of the active sub mers, Cellulose ethers polymers, Cellulose esters polymers, stance. The formulations may have an overcoat comprising at homo- and copolymers of acrylic acid cross-linked with a least one acid, typically, at least one organic acid. Typically, polyalkenyl polyether, Poly(meth)acrylates, homopolyers Such coats comprise at least one acid and a polymer compo (e.g., polymers of acrylic acid crosslinked with allyl Sucrose sition Such as, but not limited to, Opadry. The amount of acid, or allyl pentaerythritol), copolymers (e.g., polymers of typically organic acid(s), may be present in the overcoat in acrylic acid and C10-C30 alkyl acrylate crosslinked with allyl any Suitable amount. In certain embodiments, the amount of pentaerythritol), interpolymers (e.g., a homopolymer or acid may be from about 5 wt % to less than about 100 wt %, copolymer that contains a block copolymer of polyethylene from about 50 wt % to about 90 wt %, typically from about 50 glycol and a long chain alkyl acid ester), disintegrants, ion wt % to about 80 wt %, or more typically from about 60 wt % exchange resins, polymers reactive to intestinal bacterial flora to about 80 wt % by weight of the overcoat. Examples 21 to 40 (e.g., polysaccharides Such as guar gum, inulin obtained from show specific overcoat examples and FIG. 13 shows the dis plant or chitosan and chondrotin Sulphate obtained from ani solution data for Example 29. mals oralginates from algae or dextran from microbial origin) 0188 Other formulations may simply comprise at least and pharmaceutical resins. one primary active Substance, at least one coat comprising 0193 In some formulations, the core and/or the coat may Eudragit E (dimethylaminoethyl methacrylate copolymer), contain ingredients that, when combined with an aqueous and at least one coat comprising at least one acid to facilitate Solution, will agglomerate to prevent abuse. Such combina release of any active Substance in the formulation. tions of ingredients include swellable materials such as PEO 0189 The release profile following crushing of the intact and Eudragit RL (or other non-enteric compounds). In gen formulation and the controlled release profile of the intact eral, a formulation may comprise at least one active Sub composition may be modified on the basis of many factors stance; and at least one excipient, wherein dissolution of the pertaining to the formulation, particle size and Surface area of pulverized/milled formulation in alcoholic and/or non-alco the active pharmaceutical ingredient and polymers used, holic beverages causes the formulation to agglomerate. US 2015/025.0733 A1 Sep. 10, 2015
0194 In some formulations, the core and/or the coat may 0198 Further examples of additives that may be used in contain a disintegrant. the formulation of the invention include, but are not limited 0.195 Any one of these materials may be present in the to, ethyl lactate, phthalates such as dimethyl phthalate formulation or composition in about from 0% to 99% by (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), weight, typically from about 1% to 90% by weight and more dioctyl phthalate, glycol ethers such as ethylene glycol typically from 5% to 85%. The typical material is Polyethyl diethyl ether, propylene glycol monomethyl ether, PPG-2 ene Oxide polymers and acrylic polymers and or their related myristyl ether propionate, ethylene glycol monoethyl ether, compounds. diethylene glycol monoethyl ether, propylene glycol monot 0196. The formulations may optionally comprise a phar ertiary butyl ether, dipropylene glycol monomethyl ether, maceutically acceptable nasal irritant such as Capsicum oleo N-methyl-2-pyrrolldone, 2 pyrrolidone, isopropyl myristate, resin. A nasal irritant can produce nasal irritation and annoy isopropyl palmitate, octyl palmitate, dimethylacetamide, pro ance feeling when the composition is brought in contact with pylene glycol, propylene glycol monocaprylate, propylene the nasal membrane. The irritant agent is not in amounts glycol caprylate/caprate, propylene glycol monolaurate, gly Sufficient to precipitate allergic type reactions or immune cofurol, linoleic acid, linoeoyl macrogol-6 glycerides, oleic response upon snorting. U.S. Pat. No. 7,157,103 suggests the acid, oleic acid esters such as glyceryl dioleate, ethyl oleate, use of various irritants in preparing pharmaceutical formula benzoic acid, oleoyl macrogol-6 glycerides, esters such as tions including, for example, capsaicin, a capsaicin analog ethylbenzoate, benzylbenzoate, Sucrose esters. Sucrose with similar type properties as capsaicin, and the like. Some acetate isobutyrate, esters of lactic acid, esters of oleic acid, capsaicin analogues orderivatives include for example, resin sebacates such as dimethyl sebacate, diethyl sebacate, dibutyl iferatoxin, tinyatoxin, heptanoylisobutylamide, heptanoyl sebacate, dipropylene glycol methyl ether acetate (DPM guaiacylamide, other isobutylamides or guaiacylamides, acetate), propylene carbonate, propylene glycol laurate, pro dihydrocapsaicin, homoVanilyl octylester, nonanoylvanilly pylene glycol caprylate/caprate, gamma butyrolactone, medium chain fatty acid triglycerides, glycerol and PEG lainide, or other compounds of the class known as Vaniloids. esters of acids and fatty acids, PEG-6 glycerol mono oleate, Resiniferatoxin is described, for example, in U.S. Pat. No. PEG-6 glycerollinoleate. PEG-8 glycerollinoleate, caprylic 5,290,816, and U.S. Pat. No. 4,812,446 describes capsaicin acid esters such as caprylocapryl macrogol-8 glycerides, analogs and methods for their preparation. PEG-4 glyceryl caprylate/caprate, PEG-8 glyceryl caprylate/ 0197) Some examples of controlled release agents that caprate, polyglyceryl-3-oleate, polyglyceryl-6-dioleate, may be used in the formulation of the invention include natu polyglyceryl-3-SoStearate, polyglyceryl polyoleate, decag rally occurring or synthetic, anionic or nonionic, hydropho lyceryl tetraoleate and glyceryl triacetate, glyceryl bic, hydrophilic rubbers, polymers, starch derivatives, cellu monooleate, glyceryl monolinoleate, dimethylformamide, lose derivatives, polysaccharides, carbomer, reseins, acrylics, dimethylsulfoxide, tetrahydrofuran, caprolactam, decylm proteins, vinyl-pyrrolidone-vinyl-acetate-copolymers, galac ethylsutfoxide, and 1-dodecylazacycloheptan-2-one. tomannan and galactomannan derivatives, carrageenans and the like. Specific examples are acacia, tragacanth, Xanthan 0199 The formulation may also contain self-emulsifying gum, locust bean gum, guar-gum, karayagum, pectin, arginic or Surface active agents with varying hydrophilic lipophilic acid, polyethylene oxide, polyethylene glycol, propylene gly balance (HLB) values such as polyoxyethylene castor oil, col arginate, hydroxypropyl methylcellulose, methylcellu polyoxyethylene hydrogenated castor oil, polyoxyethylene lose, hydroxypropyl cellulose, hydroxyethyl cellulose, car Sorbitan fatty acid esters, polyoxyethylene alkyl esters, poly boxymethylcellulose Sodium, polyvinylpyrrolidone, oxyethylene alkyl ethers, polyoxyethylene glycerol esters, carboxyvinyl polymer, sodium polyacrylate, a starch, sodium Sorbitan fatty acid esters, and sodium lauryl Sulphate. carboxymethyl starch, albumin, dextrin, dextran Sulfate, agar, 0200 Examples of antioxidants that may be used in the gelatin, casein, Sodium casein, pullulan, polyvinyl alcohol, formulation is selected from ascorbic acid, fumaric acid, deacetylated chitosan, polyethyoxazoline, poloxamers, eth malic acid, a tocopherol, ascorbic acid palmitate, butylated ylcellulose, chitin, chitosan, cellulose esters, aminoalkyl hydroxyanisole, propyl gallate, Sodium ascobate, and Sodium methacrylate polymer, anionic polymers of methacrylic acid metabisulfite or other suitable antioxidants and stabilizers. and methacrylates, copolymers of acrylate and methacrylates 0201 Examples of plasticizers that may be used in the with quaternary ammonium groups, ethylacrylate methyl formulation include adipate, aZelate, enzoate, citrate, Stear methacrylate copolymers with a neutral ester group, poly ate, isoebucate, sebacate, triethyl citrate, tri-n-butyl citrate, methacrylates, Surfactants, aliphatic polyesters, Zein, polyvi acetyl tri-n-butyl citrate, citric acid esters, and those nyl acetate, polyvinyl chloride, and the like. Further examples described in the Encyclopedia of Polymer Science and Tech of pharmaceutically acceptable acrylic polymers that may nology, Vol. 10 (1969), published by John Wiley & Sons. The also be used include, but are not limited to, acrylic acid and typical plasticizers are triacetin, acetylated monoglyceride, methacrylic acid copolymers, methyl methacrylate copoly acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, mers, ethoxyethyl methacrylates, cyanoethyl methacrylate, diethyloxalate, diethylmalate, diethylphthalate, diethylfuma aminoalkyl methacrylate copolymer, poly(acrylic acid), poly rate, dibutylsuccinate, diethylmalonate, dioctylphthalate, (methacrylic acid), methacrylic acid alkylamide copolyer, dibutylsebacate, triethylcitrate, tributylcitrate, glyceroltribu poly(methyl methacrylate), poly(methyl methacrylate) tyrate, polyethylene glycol, glycerol, vegetable and mineral copolymer, polyacrylamide, aminoalkyl methacrylate oils and the like. Depending on the particular plasticizer, copolymer, poly(methacrylic acid anhydride), and glycidyl amounts of from 0 to about 25%, and typically about 0.1% to methacrylate copolymers. Additionally, the acrylic polymers about 20% of the plasticizer can be used. The addition of may be cationic, anionic, or non-ionic polymers and may be plasticizer should be approached with caution. In certain acrylates, methacrylates, formed of methacrylic acid or meth compositions it is better not to use plasticizers. acrylic acid esters. The polymers may also be pH independent 0202) Examples of other additives that may be used as part or pH dependent. of the formulations of the invention include, but are not lim US 2015/025.0733 A1 Sep. 10, 2015 26 ited to disintegrants, carbohydrates, Sugars, Sucrose, Sorbitol, synthetic, anionic or nonlonic, polyethylene oxide, hydro mannitol, Zinc salts, tannic acid salts; salts of acids and bases philic rubbers, starch derivatives, cellulose derivatives, pro Such as Sodium and potassium phosphates, sodium and potas teins, and the like. Specific non-limiting examples are poly sium hydroxide, Sodium and potassium carbonates and bicar ethylene oxide and or its derivatives, gelatin, such as bonates; acids such as hydrochloric acid, Sulfuric acid, nitric alginates, pectins, carrageenans, or Xanthan; cellulose deriva acid, lactic acid, phosphoric acid, citric acid, malic acid, tives, such as methyl cellulose, hydroxypropylcellulose, fumaric acid, Stearic acid, tartaric acid, boric acid, borax, and hydroxyethylceflulose, hydroxypropyl methylcellulose, or benzoic acid. Sodium carboxymethylcellulose; starch and starch deriva 0203 Organic acid(s) may particularly be used, for tives such as a starch or sodium carboxymethyl starch; galac example, lactic acid, phosphoric acid, citric acid, malic acid, tomannan and galactomannan derivatives; polyvinylpyrroli fumaric acid, Stearic acid, tartaric acid, and benzoic acid. done, polyvinyl alcohol, polyvinyl acetate and the like, vinyl Such acids modify the pH of the macro and micro environ pyrrolidone-vinyl-acetate-copolymers, acacia, tragacanth, ment to facilitate release of the active substance. The acid(s) Xanthan gum, locust bean gum, guar-gum, karayagum, pec may be included in the coat(s), including the overcoat, layer tin, arginic acid, polyethylene oxide, Carbomer, polyethylene (s), and/or core of the formulation. glycols, polypropylene glycols, carboxyvinyl polymer, 0204 Materials such as the alkali metal chlorides, ammo Sodium polyacrylate, albumin, dextrin, dextran Sulfate, agar, nium chloride, and chlorides of Ba, Mg, Ca, Cu, Fe and Al; gelatin, casein, Sodium casein, pullulan, deacetylated chito alkali or alkaline earth Solutions of acetates, nitrates, phos san, polyethyoxazoline, polyethylene oxide, poloxamers and phates, and hydroxides may be used in this formulation the like. Of these, typical ones are polyethylene oxide, Hygroscopic or aqueous materials may be used but with hydroxyethyl cellulose, hydroxypropyl methylcellulose, caution. Limited quantities may be incorporated in certain methylcellulose, hydroxypropyl cellulose, carbomer, poly compositions. ethylene glycol, poloxamers, starch derivatives and polyvi 0205 Water insoluble organosoluble polymers may be nylpyrrolidone. Water-soluble gel forming polymers can be used in the formulation, which may be any polymers which used either singly or in combinations of two or more. are insoluble in water, are capable of being homogenously 0208 Polymeric coats may also be comprised of hydro dissolved or dispersed in an organosolvent, and can typically phobic or water repellant material Such as oils, fats, waxes, retard the release of active ingredients. By the term “water higher alcohols; pH sensitive polymers; enteric polymers; or insoluble' is intended not susceptible to being dissolved (in any other polymer, component or material known to be useful water). Specific examples of water insoluble organosoluble for preparing a controlled release coating. polymers are, cellulose ether, cellulose ester, or cellulose The polymers used in the formulation may be pH insensitive ether-ester e.g., ethyl cellulose, acetyl cellulose, and nitrocel or pH sensitive. lulose. Other water insoluble organosoluble polymers that 0209 For a delivery formulation designed to be orally can be used include acrylic and/or methacrylic ester poly administered to the digestive tract, polymers that are known mers, polymers or copolymers of acrylate or methacrylate to be orally ingestible can be used and include, for example, polyvinyl esters, polyvinyl acetates, polyacrylic acid esters, polyvinyl alcohol, hydroxypropyl methyl cellulose, and other and butadiene styrene copolymers, and the like. Typical water cellulose-based polymers. Other known polymers useful for insoluble polymers are, ethylcellulose, cellulose acetate, enteral delivery include polymer materials, which preferen polymethacrylates and aminoalkyl methacrylate copolymer. tially dissolve or disintegrate at different points in the diges 0206. In further specific examples, the acrylic polymer, tive tract. Such polymers include, for example, the known includes, but is not limited to, acrylic acid and methacrylic acrylic and/or methacrylic acid-based polymers, which are acid copolymers, methyl methacrytate copolymers, ethoxy soluble in intestinal fluids, e.g. the EudragitTM series of com ethyl methacrylates, cyanoethyl methacrylate, aminoalkyl mercially available polymers. Examples of these include methacrylate copolymer, poly(acrylic add), poly(methacrylic Eudragit ETM, such as Eudragit E 100T, which preferentially acid), methacrylic acid alkylamide copolyer, poly(methyl dissolves in the more acid pH of the stomach, or enteric methacrylate), poly(methyl methacrylate) copolymer, poly polymers such as Eudragit LTM and/or Eudragit STMwhich acrylamide, aminoalkyl methacrylate copolymer, poly(meth preferentially dissolve in the more alkaline pH of the intes acrylic acid anhydride), and glycidyl methacrylate copoly tine, or polymers which dissolve slowly, e.g. a predetermined mers. Additionally, the acrylic polymers may be cationic, rate in the digestive tract, such as Eudragit RLTM, e.g. anionic, or non-ionic polymers and may be acrylates, meth Eudragit RL 100TM, and/or Eudragit RSTM e.g. Eudragit acrylates, formed of methacrylic acid or methacrylic acid R100TM, and/or blends of such EudragitTM polymers. esters. The water insoluble polymers can be used either singly 0210 Polymeric coats may also be comprised of ion or in combinations of two or more. exchange resins and or polymers reactive to intestinal bacte 0207 Water-soluble gel forming polymers, which may be rial flora (e.g., polysaccharides Such as guar gum, inulin used in the formulation, may be any polymers, which are obtained from plant or chitosan and chondrotin Sulphate soluble in water, are capable of being homogenously dis obtained from animals or alginates from algae or dextran Solved or dispersed in an organosolvent, and can typically from microbial origin) retard the release of active ingredients. Typically, the water 0211 Hydrophobic or water repellant material that may be soluble gel-forming polymer is capable of hydrating quickly present is chosen from oil and fats, waxes, higher fatty acids, and forming strong, viscous gels. By the term “water-soluble' fatty acid esters, higher alcohols, hydrocarbons, and metal is intended susceptible of being dissolved (in water). Suitable salts of higher fatty acids. Specific examples of oils and fats water-soluble gel forming polymers include those which can include plant oils, e.g. cacao butter, palm oil, Japan wax form hydrocolloid or can form a strong, viscous gel through (wood wax), coconut oil, etc.; animal oils, e.g. beef tallow, which an active ingredient is released via diffusion or wicking lard, horse fat, mutton tallow, etc.; hydrogenated oils of ani or erosion or Swelling. They include naturally occurring or mal origin, e.g. hydrogenated fish oil, hydrogenated whale US 2015/025.0733 A1 Sep. 10, 2015 27 oil, hydrogenated beef tallow, etc.; hydrogenated oils of plant The formulation or composition may be used for treatment of origin, e.g. hydrogenated rape seed oil, hydrogenated castor a patient, for example, an animal and more particularly, a oil, hydrogenated coconut oil, hydrogenated soybean oil, etc.; mammal. By mammal, is meant any member of the class of and the like. Of these hydrogenated oils are typical as an oil Mammalia that is characterized by being a vertebrate having component of the present invention. hair and mammary glands. Examples include, without limi Specific examples of waxes that may be present include plant tation, dog, cat, rabbit, horse, pig, goat, cow, and human waxes, e.g. camauba wax, candelilla wax, bayberry wax, being. The formulation or composition of the present inven auricurry wax, espalt wax, etc.; animal waxes, e.g. bees wax, tion may be administered to any animal patient or mammalian breached bees wax, insect wax, spermaceti, shellac, lanolin, patient that is in need of treatment with a site specific, timed, etc.; and the like. Of these typical ones are camauba wax, pulsed, chronotherapeutic, extended, or controlled release of white beeswax and yellow beeswax. an active Ingredient. In one example, a delivery formulation 0212 Paraffin, petrolatum, microcrystalline wax, and the of the present invention is used for treating a horse, a dog or like, are given as specific examples of hydrocarbons, with a cat. In another example, a delivery formulation of the typical hydrocarbons being paraffin and microcrystalline present invention is used for treating a human being. Wax. 0220. A medical condition or dose dumping may be pre Given as examples of higher fatty acids are caprilic acid, vented or treated by administering to a patient a formulation undecanoic acid, lauric acid, tridecanic acid, myristic acid, or composition comprisingatherapeutically effective amount pentadecanoic acid, palmitic acid, malgaric acid, Stearic acid, of an addictive Substance with quick onset and Sustained nonadecanic acid, arachic acid, heneicosanic acid, behenic action of relief. acid, tricosanic acid, lignoceric acid, pentacosanic acid, 0221. In certain examples of methods of preparing or cerotic acid, heptacosanic acid, montanic acid, nonacosanic using the said formulation or composition, the administration acid, melissic acid, hentriacontanic acid, dotriacontanic acid, in man or animal may be internal. Such as oral or parenteral. and the like. Of these, preferable are myristic acid, palmitic Such internal parenteral administration includes but is not acid, Stearic acid, and behenic acid. limited to intravascular, intramuscular, Subcutaneous, intrad 0213 Specific examples of higher alcohols are lauryl alco ermal, implantation, and intracavitary routes of administra hol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, tion, as well as application to the external Surface of an inter cetyl alcohol, heptadecyl alcohol, Stearyl alcohol, nonadecyl nal bodily organ, Such as during a Surgical or laparoscopic alcohol, arachyl alcohol, behenyl alcohol, camaubic alcohol, procedure. The administration may be topical, including corianyl alcohol, ceryl alcohol, and myricyl alcohol. Particu administration to the skin or to a mucosal surface, including larly preferable alcohols are cetyl alcohol, stearyl alcohol, the oral, vaginal, rectal Surfaces, or to the Surface of the eye. 0222. The formulation may also be in the form of a solid. and the like. The means and area of application will depend on the par 0214 Specific examples of esters are fatty acid esters, e.g. ticular condition that is being treated. The formulation may be myristyl palmitate, Stearyl Stearate, myristyl myristate, behe dispensed using any Suitable formulation and/or dispensing nyl behenate, ceryl lignocerate, lacceryl cerotate, lacceryl formulation. For example, it may be taken orally, implanted, laccerate, etc.; glycerine fatty acid esters, e.g. lauric or as a depot. It may be targeted at specific sites in the monoglyceride, myristic monoglyceride, Stearic monoglyc gastrointestinal tract (GU) or to specific organs. As another eride, behenic monoglyceride, oleic monoglyceride, oleic example, the formulation may also be applied transdermally steeric diglyceride, lauric diglyceride, myristic diglyceride, in a pouch or patch. Stearic diglyceride, lauric triglyceride, myristic triglyceride, 0223 Solid particles may be prepared by conventional Stearic triglyceride, acetylistearic glyceride, hydoxy Stearic techniques. They may be milled to required size or Surface triglyceride, etc.; and the like. Glycerine fatty acid esters are area where necessary. The typical technique is by dry or wet more typical. granulation or hot melt extrusion or roller compaction of an 0215 Specific examples of metal salts of higher fatty acid active Substance, controlled release agent(s) and excipients are calcium Stearate, magnesium Stearate, aluminum Stearate, Such as solubilizing agents, emulsifying agents, Suspending Zinc Stearate, Zinc palmitate, Zinc myristate, magnesium agents, fillers, compression agents, stabilizers, pH altering myristate, and the like, with preferable higher fatty acid salts agents, buffers, lubricants, disintegrants and glidants. being calcium Stearate and magnesium Stearate. 0224 Fillers, such as lactose, and compression agents 0216 A polymeric coating composition may also contain Such as microcrystalline cellulose, lubricants such as magne other additives Such as disintegrants and additives normally sium Stearate and glidants such silicone dioxide may, in cer found in coatings used in the pharmaceutical art such as tain examples, be included in the core. The core onto which plasticizers, anti-tacking agents such as talc and coloring the coating is applied contains the active component. The core agents. may be a tablet, capsule, caplet, pellet, spherical or irregular 0217 Coloring agents are added for elegance and aesthet in shape. The core may be made up of multiple layers by press ics or to differentiate products and may be chosen, for coating or Solution coating. The core may contain a loading example, from metal oxide pigments or Aluminum Lake dose. dyes. 0225. In certain examples, swellable polymeric materials 0218. A coating composition may include an anti-tacking Such as hydrogels that Swell and expand significantly are agent Such as talc. Other examples of Suitable anti-tacking included in the core. agent are glycerol monostearate, calcium Stearate, colloidal 0226 Excipients may be homogenously mixed with an silicon dioxide, glycerin, magnesium Stearate, and aluminum active ingredient in a core particle. Excipients may be Stearate. selected from antiadherents, binders, diluents, emulsifying 0219. The compositions are typically formulated to be agents, Suspending agents, compression agents, extrusion compatible and result in stable products. agents, pH altering agents, buffers, glidants, lubricants, solu US 2015/025.0733 A1 Sep. 10, 2015 28 bilizers, wetting agents, Surfactants, penetration enhancers, capsules. Dibasic calcium phosphate is another popular tablet pigments, colorants, flavoring agents, Sweeteners, antioxi filler. A range of vegetable fats and oils can be used in soft dants, acidulants, stabilizers, antimicrobial preservatives and gelatin capsules. binders. 0232 Other examples of fillers include: lactose, sucrose, 0227 Extrusion agents include, for example, Copolyvi glucose, mannitol, Sorbitol, and, calcium carbonate. Fillers/ done; copovidone; VPNAc copolymer 60/40: copolymer of diluents are typically selected from microcrystalline cellulose, 1-vinyl-2-pyrrolidone and vinyl acetate in a ratio of 6:4 by plant cellulose, calcium phosphate, mannitol, Sorbitol. Xyli mass, Kollidon VA 64/Fine, Kollidon SR, Kollidon 12/17P. tol, glucitol, ducitol, inositiol, arabinitol, arabitol, galactitol, Kollidon 25, Kollidon 30/90, Soluplus (graft copolymer of iditol, allitol, fructose, Sorbose, glucose, Xylose, trehalose, polyethylene glycol, polyvinyl caprolactam and polyvinylac allose, dextrose, altrose, gulose, idose, galactose, talose, etate, Cremaphor RH 40. ribose, arabinose, Xylose, lyxose. Sucrose, maltose, lactose, 0228. Excipients are biologically inert ingredients, which lactulose, fucose, rhamnose, melezitose, maltotriose, and enhance the therapeutic effect. The filler or diluent (e.g. lac raffinose. Typical Sugars include mannitol, lactose. Sucrose, tose or Sorbitol) is a bulking agent, providing a quantity of Sorbitol, trehalose, glucose. material, which can accurately be formed into a tablet. The 0233 Glidants are used to improve the flowability of the binders and adhesives (e.g. methyl cellulose or gelatin) hold powder or granules or both. Some examples of glidant(s) are the ingredients together so that they form a tablet and hold silicon dioxide, Starch, calcium silicate, Cabosil, Syloid, and together. Lubricants (e.g. magnesium Stearate or calcium silicon dioxide aerogels. Typically, silicon dioxide is used. stearate) are added to improve powder flow so that the die fills 0234 Lubricants prevent ingredients from clumping accurately; they also reduce the friction between the tablet together and from Sticking to the tablet punches or capsule and the machine so that the process progresses Smoothly and filling machine. Lubricants also ensure that tablet formation uniformly. and injection can occur with low friction between the solid 0229. Anti-adherents are used to reduce the adhesion and die wall. Some examples of lubricant(s) are alkali stear between the powder (granules) and the punch faces and thus ates such as magnesium Stearate, calcium Stearate, Zinc Stear prevent tablet Sticking to the punches. ate, polyethylene glycol, adipic acid, hydrogenated vegetable oils, sodium chloride, Sterotex, glycerol monostearate, talc, 0230 Binders hold the ingredients in a tablet together. polyethylene glycol, Sodium benzoate, sodium lauryl Sulfate, Binders ensure that tablets and granules can be formed with magnesium lauryl Sulfate, Sodium Stearyl fumarate, light required mechanical strength. Binders may be selected from mineral oil and the like may be employed. Waxy fatty acid starches, Sugars, and cellulose or modified cellulose Such as esters, such as glyceryl behenate, sold as “Compritol’ prod hydroxypropyl cellulose, lactose, or Sugar alcohols like Xyli ucts, can be used. Other useful commercial lubricants include tol, sorbitol or maltitol. Solution binders are dissolved in a “Stear-O-Wet” and “Myvatex TL. Common minerals like Solvent (for example water or alcohol and used in wet granu talc or silica, and fats, e.g. Vegetable Stearin, glycerol lation processes. Examples of Solution binders are gelatin, monostearate, magnesium Stearate or Stearic acid are typi cellulose, cellulose derivatives, polyvinyl pyrrolidone, cally used lubricants. starch, Sucrose and polyethylene glycol. Dry binders are 0235 Sorbents are used for moisture proofing by limited added to a powder blend, either after a wet granulation step, or fluid Sorbing (taking up of a liquid or a gas either by adsorp as part of a direct powder compression. Examples of dry tion or by absorption) in a dry state. binders are cellulose, methyl cellulose, polyvinyl pyrroli done, polyethylene glycol. A commonly used binder or com 0236 Surfactants, wetting agents and solubilisers such as pression agent is microcrystalline cellulose. Microcrystalline glycerol monostearate, cetostearyl alcohol, cetomacrogol and powdered cellulose products are sold under the trade emulsifying wax, Sorbitan esters, polyoxyethylene alkyl names AviceITM PH (FMC Corporation, Philadelphia, Pa.) ethers (e.g., macrogol ethers such as cetomacrogol 1000), and Solka FlocTM (Penwest Company, Patterson N.Y.). polyoxyethlylene castor oil derivatives, polyoxyethylene Sor Microcrystalline cellulose may be used in various techniques bitan fatty acid esters (e.g., TWEENTM), polyoxyethylene Such as direct compression, dry granulation, wet granulation, Stearates, sodium dodecylsulfate, Tyloxapol (a nonionic liq or extrusion-spheronization. uid polymer of the alkyl aryl polyether alcohol type, also known as Superinone or triton) is another useful solubilisers. 0231 Compression agents are materials that may be com Most of these solubilisers, wetting agents and Surfactants are pacted. Compression agents may be added to increase the known pharmaceutical excipients and are described in detail overall hardness of a core particle. Compression agents have in the Handbook of Pharmaceutical Excipients, published inherently high compactibility due to properties of plastic jointly by the American Pharmaceutical Association and The deformation and limited elastic recovery. Non-limiting Pharmaceutical Society of Great Britain (The Pharmaceutical examples of materials that find use as compression agents are Press, 1986). microcrystalline cellulose, silicified microcrystalline cellu Typical wetting agents include tyloxapol, poloxamers such as lose (for example ProsolviM produced by JRS Pharma), oxi PLURONICTM F68, F127, and F108, which are block copoly dized polyethylene, calcium hydrogen phosphate dehydrate, mers of ethylene oxide and propylene oxide, and polyxam dextrate, or Sugar. ines such as TETRONICTM 908 (also known as POLOXAM Fillers or diluents are added for bulk to fill out the size of a INETM 908), which is a tetrafunctional block copolymer tablet or capsule, making it practical to produce and conve derived from sequential addition of propylene oxide and eth nient for the consumer to use. Fillers/diluents are typically ylene oxide to ethylenediamine (available from BASF), dex inert, compatible with the other components of the formula tran, lecithin, dialkylesters of sodium SulfoSuccinic acid Such tion, non-hygroscopic, soluble, relatively cheap, compact as AEROSOLTM OT, which is a dioctyl ester of sodium sul ible, and typically tasteless or pleasant tasting. Plant cellulose foSuccinic acid (available from American Cyanimid), (pure plant filler) is a popular filler in tablets or hard gelatin DUPONOLTMP, which is a sodium lauryl sulfate (available US 2015/025.0733 A1 Sep. 10, 2015 29 from DuPont), TRITONTM X-200, which is an alkyl aryl Swell in water and retain a significant fraction of water within polyether sulfonate (available from Rohm and Haas), its structure, and when cross-linked they will not dissolve in TWEENTM20 and TWEEN' 80, which are polyoxyethylene the water. Swellable polymers can swell or expand to a very sorbitan fatty acid esters (available from ICI Specialty high degree, exhibiting a 2 to 50 fold volume increase. Spe Chemicals), Carbowax3550 and 934, which are polyethylene cific examples of hydrophilic polymeric materials include glycols (available from Union Carbide), Crodesta F-110, poly(hydroxyalkyl methacrylate), poly(N-vinyl-2-pyrroli which is a mixture of Sucrose Stearate and Sucrose distearate, done), anionic and cationic hydrogels, polyelectrolyte com and Crodesta SL-40 (both available from Croda Inc.), and plexes, poly(vinyl alcohol) having a low acetate residual and SA90HCO, which is CgFI-CH (CON(CH)CH, cross-linked with glyoxal, formaldehyde, or glutaraldehyde, (CHOH) CFH). methyl cellulose cross-linked with dialdehyde, a mixture of 0237 Wetting agents which have been found to be particu cross-linked agar and carboxymethyl cellulose, a water larly useful, include Tetronic 908, the Tweens, Pluronic F-68 insoluble, water-swellable copolymer produced by forming a and polyvinylpyrrolidone. Other useful wetting agents dispersion of finely divided copolymer of maleic anhydride include decanoyl-N-methylglucamide; n-decyl-B-D-glu with styrene, ethylene, propylene, butylene, or isobutylene copyranoside; n-decyl-B-D-maltopyranoside; n-dodecyl-B- cross-linked with from 0.001 to about 0.5 moles of a polyun D-glucopyranoside; n-dodecyl-B-D-maltoside; heptanoyl-N- saturated cross-linking agent per mole of maleic anhydride in methylglucamide; n-heptyl-B-D-glucopyranoside; n-heptyl the copolymer, water-swellable polymers of N-vinyl lactams, B-D-thioglucoside; n-hexyl-B-D-glucopyranoside; cross-linked polyethylene oxides, and the like. Other nonanoyl-N-methylglucamide; n-octyl-B-D-glucopyrano examples of swellable materials include hydrogels exhibiting side; octanoyl-N-methylglucamide; n-octyl-B-D-glucopyra a cross-linking of 0.05 to 60%, hydrophilic hydrogels known noside; and octyl-3-D-thioglucopyranoside. Another typical as Carbopol acidic carboxy polymer, CyanamerTM polyacry wetting agent is p-isononylphenoxypoly(glycidol), also lamides, cross-linked water-swellable indene-maleic anhy known as Olin-10G or Surfactant 10-G (commercially avail dride polymers, Good-riteTM polyacrylic acid, starch graft able as 10G from Olin Chemicals). Two or more wetting copolymers, Aqua-KeepsTM acrylate polymer, diester cross agents can be used in combination. linked polyglucan, and the like. Methods for testing swellable 0238. The pharmaceutical formulation or formulation materials with regards to polymer imbibition pressure and may further include a pegylated excipient. Such pegylated hydrogel-water interface interaction are described in U.S. excipients include, but are not limited to, pegylated phospho Pat. No. 4,327,725. lipids, pegylated proteins, pegylated peptides, pegylated Sug 0242. In a certain example, the formulation may be coated ars, pegylated polysaccharides, pegylated block-co-polymers with salt forming, and/or ion exchanging resin, and/or a non with one of the blocks being PEG, and pegylated hydrophobic disintegrating and/or non-semi-permeable coat. Materials compounds such as pegylated cholesterol. Representative useful for forming the non-disintegrating non-semi-perme examples of pegylated phospholipids include 1,2-diacyl 1-sn able coat are ethylcellulose, polymethylmethacrylates, meth gycero-3-phosphoethanolamine-N-Poly(ethylene glycol) acrylic acid copolymers and mixtures thereof. 2000(“PEG 2000 PE) and 1,2-diacyl-sn-glycero-3-phos 0243 In yet another embodiment, the formulation is phoethanolamine-N-Poly(ethylene glycol) 5000 (“PEG coated with a non-disintegrating semipermeable coat. Mate 5000 PE), where the acyl group is selected, for example, rials useful for forming the non-disintegrating semiperme from dimyristoyl, dipalmitoyl, distearoyl, diolcoyl, and able coat are cellulose esters, cellulose diesters, cellulose 1-palmitoyl-2-oleoyl. triesters, cellulose ethers, cellulose ester-ether, cellulose acy 0239. Additional excipients may be included in the formu late, cellulose diacylate, cellulose triacylate, cellulose lation of the present invention. Further examples of excipients acetate, cellulose diacetate, cellulose triacetate, cellulose can include pigments, colorants, flavoring agents, preserva acetate propionate, and cellulose acetate butyrate. Other Suit tives and Sweetners. Flavors and colors are added to improve able polymers are described in U.S. Pat. Nos. 3,845,770, the taste or appearance of a formulation. Some typical pre 3,916,899, 4,008,719, 4,036,228 and 4,612,008. The most servatives used in pharmaceutical formulations are antioxi typical non-disintegrating semipermeable coating material is dants such as vitaminA, Vitamin E. Vitamin C, and selenium, cellulose acetate comprising an acetyl content of 39.3 to amino acids such as cysteine and methionine, citric acid and 40.3%, commercially available from Eastman Fine Chemi Sodium citrate, or synthetic preservatives such as methyl cals. paraben and propyl paraben. Sweeteners are added to make 0244. In an alternative embodiment, the non-disintegrat the ingredients more palatable, especially in chewable tablets ing semipermeable or non-disintegrating non-semi-perme Such as antacid or liquids like cough syrup. Sugar may be used able coat can be formed from the above-described polymers to disguise unpleasant tastes or smells. While for addictive and materials that will form pores or channels in the coat. The Substances bittering agents may be added make the adminis pore forming agents or channeling agents dissolve on contact tration of a non-intact form objectionable. with fluid and form passages through which fluid and active 0240. One skilled in the art can select appropriate exci pharmaceutical ingredient(s) can move through the coat. The plents for use in the formulation of the present invention. pore forming agent or channeling agent can be a water 0241 The formulation may comprise an excipient that is a soluble material or an enteric material. Some general Swellable material Such as a hydrogel in amounts that can examples of pore forming agents or channeling agents are swell and expand. Examples of Swellable materials include water soluble materials such as cellulose ethers, polyethylene polyethylene oxide, hydrophilic polymers that are lightly glycols or microcrystalline cellulose. Some further examples cross-linked. Such cross-links being formed by covalent or of pore forming agents or channeling agents are sodium chlo ionic bond, which interact with water and aqueous biological ride, potassium chloride, lactose, Sucrose, Sorbitol, mannitol, fluids and Swell or expand to some equilibrium state. polyethylene glycol (PEG), for example PEG 600, polyvinyl Swellable materials such as hydrogels exhibit the ability to pyrolidone, propylene glycol, hydroxypropyl cellulose, US 2015/025.0733 A1 Sep. 10, 2015 30 hydroxypropyl methycellulose, hydroxypropyl methycellu significantly affected by the rotation speed of the basket or lose phthalate, cellulose acetate phthalate, polyvinyl alco paddle in the speed range from about 50 rpm to about 100 rpm hols, methacrylic acid copolymers and mixtures thereof. at least in the first hour. 0245. The active pharmaceutical ingredient(s) that are 0262 Item 15 is the formulation according to items 1 to 11 water-soluble or that are soluble under intestinal conditions wherein dissolution using a USP dissolution tester is not may also be used to create pores in the coat. significantly affected by the rotation speed of the basket or 0246 The pore forming agent comprises approximately 0 paddle in the speed range from about 50 rpm to about 75 rpm to about 75% of the total weight of the coating, most typically at least in the first hour. about 0.5% to about 25% of the total weight of the coating. 0263 Item 16 is the formulation according to items 1 to 11 The pore-forming agent dissolves or leaches from the coat to wherein there is less or no dose dumping during dissolution form pores in the coat for the fluid to enter the core and using a USP dissolution tester with basket or paddle assembly dissolve the active ingredient. in alcoholic media. 0247. As used herein the term pore includes an aperture, 0264. Item 17 is the formulation according to items 1 to 11 orifice, bore, channel, hole, a discrete area of weakness or as wherein there is less or no dose dumping during dissolution created by soluble or leachable materials. using a USP dissolution tester with basket or paddle assembly 0248 Certain general illustrative examples of the formu at 50 or 100 rpm in about 1% to about 10% alcoholic media. lation or formulations and their uses may be helpful in under 0265 Item 18 is the formulation according to items 1 to 11 standing the present invention and are itemized as follows: wherein there is no dose dumping during dissolution using a 0249. Item 1 is the formulation, which provides Zero order USP dissolution tester with basket or paddle assembly at 50 or release: first order or pseudo-first order release of active sub 100 rpm in about 10% to about 20% alcoholic media. stance content after a loading dose has been released. 0266 Item 19 is the formulation according to items 1 to 11 0250 Item 2 is the formulation which releases less than wherein there is no dose dumping during dissolution using a 60% of active substance in 1 hour using USP basket dissolu USP dissolution tester with basket or paddle assembly at 50 or tion apparatus at 100 rpm. 100 rpm in about 20% to about 30% alcoholic media. 0251 Item 3 is the formulation which releases between 0267 Item 20 is the formulation according to items 1 to 11 30% to 40% of active substance in 1 hour using USP basket wherein there is no dose dumping during dissolution using a dissolution apparatus 100 rpm. USP dissolution tester with basket or paddle assembly at 50 or 0252) Item 4 is the formulation which releases between 100 rpm in about 30% to about 40% alcoholic media. 20% to 30% of active substance in 1 hour using USP basket 0268 Item 21 is the formulation according to items 1 to 11 dissolution apparatus at 100 rpm. wherein there is no dose dumping during dissolution using a 0253 Item 5 is the formulation which provides pulsed USP dissolution tester with basket or paddle assembly at 50 or delivery. 100 rpm in about about 40% to about 50% alcoholic media. 0254. Item 6 is the formulation which provides chrono 0269. Item 22 is the formulation according to items 1 to 11 therapeutic delivery. wherein there is no dose dumping during dissolution using a 0255 Item 7 is the formulation comprising an active sub USP dissolution tester with basket or paddle assembly at 50 or stance and one or more materials selected from the group 100 rpm in about 50% to about 70% alcoholic media. polyethylene oxide, disintegrant, acrylic polymer, for pre 0270 Item 23 is the formulation containing one or mixture venting dose dumping in the presence of alcohol and which of medicaments used to manage pain, medicaments used to makes it difficult for drug abuse. reduce or eliminate anxiety attack (psychotherapeutic drugs), 0256 Item 8 is the formulation comprising active sub medicaments that are used as stimulants and sleeping pills, stances with Small particle size or large Surface area and one cardiovascular agents, antidiabetics, acid labile drugs and in or more materials selected from the group polyethylene general medicaments (whose intended effects may be com oxide, disintegrant, acrylic polymer, for preventing dose promised if the intact formulation is heated, burned, micro dumping in the presence of alcohol and or which makes it waved, frozen, perturbed, pulverized or crushed or ground or difficult for drug abuse. milled or cut into one or a mixture of sizes ranging from very 0257 Item 9 is the formulation according to items 1 to 8 fine to coarse particles, granules or spheres) which provides which is presented as tablet, pellet, bead, microsphere, nano Zero order release; first order or pseudo-first order release of particle or granules drug content after a loading dose has been released. 0258 Item 10 is the formulation according to items 1 to 9 0271 Item 24 is the formulation according to items 1 to 11 for pediatric, adult or geriatric use. Item 11 is the formulation and 23 wherein it is enveloped in a coat. The coat may be a according to items 1 to 10 for use as an implant or Subcuta pod-like structure or cocoon. neous application. 0272. Item 25 is the formulation according to item 24 0259. Item 12 is the formulation according to items 1 to 11 wherein the pod-like structure or cocoon is made from acrylic wherein dissolution using a USP dissolution tester is not polymer and/or polysaccharide and/or ion exchange resin. significantly affected by the rotation speed of the basket or 0273 Item 26 is the formulation according to item 24 paddle in the speed range from about 25 rpm to about 150 rpm wherein the pod-like structure or cocoon is made from an at least in the first hour. acrylic polymer and/or polysaccharide and/or ion exchange 0260 Item 13 is the formulation according to items 1 to 11 resin and other pharmaceutically acceptable polymer. wherein dissolution using a USP dissolution tester is not 0274) Item 27 is the formulation according to item 24 significantly affected by the rotation speed of the basket or wherein the pod like structure or cocoon is made from acrylic paddle in the speed range from about 50 rpm to about 150 rpm polymer which dissolves by salt formation at acid pH. at least in the first hour. 0275 Item 28 is the formulation according to item 27 0261) Item 14 is the formulation according to items 1 to 11 wherein the loading dose is released after the coat (e.g. pod wherein dissolution using a USP dissolution tester is not like structure or cocoon) dissolves. US 2015/025.0733 A1 Sep. 10, 2015
0276 Item 29 is the formulation according to item 24 capsulation techniques, by milling and compression tech wherein multiple peak plasma concentrations are observed on niques or other Suitable known techniques. In certain oral administration. examples, different types of coats may be applied to the formulation. Method of Making the Formulations 0285. In certain examples, the particle size of solid mate 0277. The formulations can be made by any known meth rials is less than about 1000 microns. In certain other ods. For example, the core can be made by blending and direct examples, the particle size of solid materials is less than about compression without wet granulation; by hot melt extrusion; 500, 200. 100, or 50 microns and the formulation maintains by hot melt granulation; by roll compaction, slugging or a very Intimate and close proximity to the polymers and homo chilsonator, and/or by extrusion spheronization. The loading geneity especially when crushed. In certain further, examples dose or any coating may be press coated onto at least a portion the Solid particles are Sufficiently small and have large Surface of the core as a separate layer(s). area Such that they are in very intimate and close proximity 0278. In some embodiments, the loading dose is applied and homogeneity with one another. These types of formula by spraying coating, dry coating, press coating, encapsula tions may resist abuse or inadvertent misuse. tion, or by a combination of these methods. 0286. In certain examples, capsules, for example, soft or 0279. In a specific example, a polymeric coating is pre hard capsules, envelop the formulations. While both soft and pared by adding polymers, plasticizer, and anti-tacking agent hard capsules may be used, hard capsules may be particularly to an organosolvent or aqueous system and mixed until useful. In certain examples, the capsule is made by applying homogenously dissolved or dispersed using a low or high a polymeric coat of material that result in a plastic or elastic shear mixer. The coating may be applied to a core using shell in any shape (e.g. pod-like envelope). It could also be a standard coating methodology. hard gelatin capsule or is made of a metal or alloy of metals, 0280. In a certain embodiment, there is provided a method cellulose ether, vegetable or animal origin. for making a loading dose for a formulation, which comprises 0287. One skilled in the art will also know that capsules hot melt extruding a loading dose, wherein the loading dose made from materials other than gelatin may be used. For comprises at least one active Substance and at least one excipi example, U.S. Patent Application Publication No. 2006/ ent; and incorporating the loading dose in the formulation. 0099246 pertains to a non-gelatin soft capsule system having Hot melt extrusion is advantageous when utilizing insoluble a predominantly starch and gelling carrageenan based shell. material/components. Carrageenan is a collective term for polysaccharidesprepared 0281. The formulations described herein may contain one by alkaline extraction (and modification) from red seaweed or more active substance, or specifically one or more opioid (Rhodophycae), mostly of genus Chondrus, Eucheuma, agonist or narcotic analgesic or abuse-able Substances, may Gigartina and Iridaea. Different seaweeds produce different be made by any method wherein the particle size or surface carrageenans. Carrageenan consists of alternating 3-linked area of active ingredient and/or inactive ingredient, quantity B-D-galactopyranose and 4-linked-O-D-galactopyranose or ratio and type of loading dose, controlled release agents, units. Most, if not all, of the galactose units are substituted external coat(s) and excipients is optimum to form a formu with sulfate ester groups. In another example, US Patent lation with quick onset of action and Sustained action there Applin. Pub. No. 2006/0004193 (Muller) published Jan. 5, after while still capable of abuse resistant properties when 2006 relates to a tough-elastic material based on starch, which crushed. on the one hand has high impact toughness at low humidity, 0282 Typically, the entire quantity of the core formulation and on the other hand still has a high modulus of elasticity at is dry mixed and homogeneously blended, and made into a high humidity and has a high elongation capacity in a broad Solid unit (e.g. tablet, bead, compressed granules formed into range of humidity and on account of its property profile is any shape, etc.). Thereafter, the loading dose or a portion of it Suited to use as edible film and for the packaging of active is applied directly on the core by press coating as a layer, for ingredients, as well as high-quality Substitution of gelatin in example, on top of one side of the unit or Solution coating, the area of soft and hard capsules. As another example, PCT Surrounding or almost completely surrounding the tablet A Publication WO 01/37817 describes a soft capsule based on cold process under room temperature conditions is typical, thermoplastic starch (TPS) with high softener content. As however solid substances may be heated to their liquid state another example, U.S. Patent Application Publication No. prior to incorporation, using such methods as hot melt extru 2005/0196436 relates to a method of producing a film-form Sion. ing blend of different acyl gellan gums with starch having 0283 Alternatively, the formulation may be processed in a similar textural and functional properties compared to gela jacketed vessel, which allows precise control of the process tin. As another example, U.S. Patent Application Publication ing temperature. Other pharmaceutically acceptable addi No. 2007/0077293 (Park) published Apr. 5, 2007 relates to a tives, such as those described above, may be incorporated film-forming composition for hard capsules, comprising before, after, or during the addition of controlled release 7-12% by weight of starch, 1-6% by weight of a plasticizer, agents or narcotic analgesics. Wet granulation can also be 0.7-3% by weight of agelling agent, and 79-91.3% by weight used. of water. As another example, U.S. Patent Application Pub 0284. The solid particles may be of a size and/surface area lication No. 2006/0153909 relates to hard capsules made of a Such that the active ingredient maintains very intimate and base material containing a cellulose derivative including, for close proximity to the polymers and homogeneity. The Solid example, one or more of hydroxypropyl methylcellulose, particles may take any convenient form, including, for methylcellulose, hydroxypropyl cellulose, hydroxyethyl cel example, granules, spheroids, pellets, microspheres, nano lulose, hydroxypropyl methylcellulose phthalate, hydrox spheres, microcapsules, or crystals and can be prepared by ypropyl methylcellulose acetate Succinate, carmelose, car wet or dry granulation, by extrusion spheronization, by hot boxymethylethyl cellulose, cellulose acetate phthalate, and melt extrusion, by powder or Solution layering, by microen ethylcellulose. Also, additives Such as a gelling agent, a gel US 2015/025.0733 A1 Sep. 10, 2015 32 ling aid, a colorant, a plasticizer, an emulsifier, a dispersant, -continued and a preservative may be added to the capsule base material. As yet another example, U.S. Patent Application Publication Ingredients % Wiw No. 2005/0186268 describes a hard capsule made mainly of a Microcrystalline cellulose 14.00 polymer or copolymer obtained by polymerizing or copoly Eudragit RL S.OO merizing at least one polymerizable vinyl monomer in the Magnesium Stearate 1.OO presence of polyvinyl alcohol and/or a derivative thereof. Still many other examples exist, as will be recognized by the skilled person. Formula for Loading Dose 0288. In certain examples, a controlled release formula tion may be in combination with a non-controlled release 0293 formulation containing opioid antagonist and/or immediate release non-narcotic analgesics or other pharmaceutically active Substances or filled into a capsule or dispensing formu Ingredients % Wiw lation with non-controlled release composition containing Propranolol S.OO opioid antagonist and/or immediate release non-narcotic (particle size 400 microns) analgesics or other pharmaceutically active Substances. Lactose 6O.OO Hydroxypropyl methyl 4.OO 0289. In certain examples, dissolution using a USP disso cellulose lution tester is not significantly different by the rotation speed Pregelatinized starch S.OO of the basket or paddle in the speed range from about 25 rpm Microcrystalline cellulose 2O.OO to about 150 rpm, or at about 50 rpm and about 100 rpm or at Magnesium Stearate 1.OO about 50 rpm and about 75 rpm or at about 100 rpm and about 150 rpm. The rotation speed does not interact with or com promise the integrity of the formulation and release mecha Formula for the Pod-like Envelope nism, particularly in the first hour. Formulations that meet these requirements perform consistently in the gastrointesti 0294 nal tract without fear of collapse or disintegration. These are typically not perturbed, crushed or damaged by gastrointes tinal tract content, resident time or motility. Ingredients % Wiw 0290 When introducing elements disclosed herein, the Eudragit E 52.63 articles “a”, “an', “the’, and "said are intended to mean that Talc 22.10 Magnesium Stearate 3.23 there may be one or more of the elements. Titanium dioxide 1894 0291. The above disclosure generally describes the Polyethylene glycol 6000 3.10 present invention. A more complete understanding can be Water qs obtained by reference to the following specific Examples. Isopropyl alcohol qs These Examples are described solely for purposes of illustra Acetone tion and are not intended to limit the scope of the invention. Changes in form and Substitution of equivalents are contem plated as circumstances may suggest or render expedient Processing Techniques Although specific terms have been employed herein, Such 0295 Step 1a. Preparation of Granules for the Mainte terms are intended in a descriptive sense and not for purposes nance Dose: of limitation. 0296 All the ingredients with the exception of the mag nesium Stearate from the maintenance dose formula were EXAMPLES charged into a high shear granulator and dry mixed for less Example 1 than 10 minutes. The dry mixed granules were discharged into a Paterson Kelly V-Blender. The magnesium stearate was then added to the V-Blender. The granules were blended for Propranolol Sustained Action (SA) 80 mg Tablets less than 10 minutes. (80 mg Tablets Contain 70 mg Maintenance Dose and 10 mg Step 1b. Preparation of Granules for the Loading Dose: Loading Dose) 0297 All the ingredients with exception of the magnesium Stearate and pregelatinized starch from the loading dose for Formula for Maintenance Dose mula were charged into a high shear granulator and dry mixed for less than 10 minutes. The dry mixed granules were dis 0292 charged into a Paterson Kelly V-Blender. The magnesium Stearate and pregelatinized Starch were then added to the V-Blender. The granules were blended for less than 10 min Ingredients % Wiw utes. Propranolol 2O.OO Step 2. Preparation of a bi-layer tablet containing mainte (particle size 400 microns) nance dose and loading dose: The first layer is made from the Polyethylene Oxide 4S.OO granules prepared in Step 1a, and the second layer is made (particle size <600 microns) from granules prepared in Step 1b. A double rotary press was Lactose 1O.OO set-up to produce a bi-layer tablet (The Karnavati UNIK IFC Pregelatinized starch S.OO double rotary and double layer tablet press was used). Gran ules from Step 1a were charged into a first feed hopper and US 2015/025.0733 A1 Sep. 10, 2015
granules from Step 1b were charged into a second feed hopper -continued and the bi-layer tablet was produced from the double rotary press. Ingredients % Wiw Pregelatinized starch S.OO Step 3 Preparation of a Coating Suspension of the Ingredients Microcrystalline cellulose 2O.OO of the Pod-Like Envelope Applied to the Bi-Layer Tablet: Magnesium Stearate 1.OO 0298 (I) Isopropyl alcohol was added into a stainless steel vessel followed by Eudragit E, titanium dioxide, talc and Formula for the Pod-Like Envelope magnesium Stearate, step-by-step, while stirring vigorously 0302) with a high shear mixer until all ingredients were finely dis persed in a Suspension. (II) Polyethylene glycol was dis solved in water. (III) The polyethylene glycol water mixture Ingredients % Wiw was added to the Eudragit E Suspension while stirring using a Eudragit E 74SO high shear mixer. Citric Acid 25.50 Step 4. Application of the Coating Suspension from Step 3 to Water qs Form a Pod-Like Envelope Surrounding the Bi-Layer Tablet from Step 2: 0299 Tablets from step 2 were charged into a rotating Processing Techniques drum of a side vented automated Tablet coater (Rama Cota (0303 Step 1a. Preparation of Granules for the Mainte Tablet Film Coater was used). The suspension from Step 3 nance Dose: was applied to the tablets obtained from Step 2, using a 0304 All the ingredients with exception of the magnesium peristaltic pump and spray gun. The Suspension was dried as Stearate from the maintenance dose formula were charged a film onto the tablets, using heated air drawn through the into a high shear granulator and dry mixed for less than 10 tablet bed from an inlet fan. A sufficient amount of the sus minutes. The dry mixed materials were discharged into a Roll pension was applied to form about 20 mg/cm to about 30 Compactor and the materials were forced between two mg/cm of the coat surrounding the bi-layer tablet. counter rotating rolls in the Roll Compactor in order to form flakes or compacts. The compacts were granulated to reduce Example 2 their size to uniform particle size distribution by passing them through a size reduction mill fitted with rotating blades and a perforated screen. The granules were discharged into a Pater Hydromorphone Sustained Action (SA) 8 mg Tablets son Kelly V-Blender. The magnesium stearate was added to the granules in the V-Blender and blend for less than 10 (8 mg Tablets Contain 7 mg Maintenance Dose and 1 mg minutes. Loading Dose) Step 1b. Preparation of Granules for the Loading Dose: 0305 All the ingredients, with the exception of the mag Formula for Maintenance Dose nesium Stearate and pregelatinized Starch, from the loading dose formula were discharged into a high shear granulator 0300 and dry mixed for less than 10 minutes. The dry mixed mate rials were discharged into a Roll Compactor and the materials Ingredients % Wiw were forced between the two counter rotating rolls in the Roll Compactorin order to form flakes or compacts. The compacts Hydromorphone 2.OO (particle size 600 microns) were granulated to reduce their size to uniform particle size Polyethylene Oxide 40.OO distribution by passing them through a size reduction mill (particle size <600 fitted with rotating blades and perforated screen. The granules microns) were discharged into a Paterson Kelly V-Blender. The mag Lactose 28.00 Pregelatinized starch S.OO nesium Stearate and pregelatinized starch were added to the Microcrystalline cellulose 14.00 granules in the V-Blender and blended for less than 10 min Eudragit RL S.OO utes. Carbomer S.OO Step 2. Preparation of a bi-layer tablet containing mainte Magnesium Stearate 1.OO nance dose and loading dose: The first layer is made from the granules prepared in Step 1a, and the second layer is made from granules prepared in Step 1b. A double rotary press was Formula for Loading Dose set-up to produce a bi-layer tablet (The Karnavati UNIK IFC double rotary and double layer tablet press was used). Gran 0301 ules from Step 1a were charged into a first feed hopper and granules from Step 1b were charged into a second feed hopper and the bi-layer tablet was produced from the double rotary Ingredients % Wiw press. Hydromorphone 1.OO Step 3. Preparation of a Coating Suspension of the (particle size 600 microns) Ingredients of the Pod-Like Envelope Applied to the Bi-Layer Lactose 6S.OO Hydroxypropyl methyl 4.OO Tablet: cellulose 0306 (I) Water was added into a stainless steel vessel and Eudragit E was gradually added while stirring with a high US 2015/025.0733 A1 Sep. 10, 2015 34 shear mixer with controlled speed, sufficient to prevent sedi Processing Techniques mentation and lump formation. (II) The citric acid portion was added until a clear Solution is obtained. Step 1. Preparation of Granules for the Maintenance Dose: Step 4. Application of Coating Suspension from Step 3 to Form a Pod-Like Envelope Surrounding the Bi-Layer Tablet 0311 All the ingredients with the exception of the mag from Step 2: nesium Stearate from the maintenance dose formula were 0307 Tablets from step 2 were charged into a rotating charged into a high shear granulator and dry mixed for less drum of a side vented automated Tablet coater (Rama Cota than 10 minutes. The dry mixed granules were discharged Tablet Film Coater was used). The suspension from Step 3 was applied to the tablets obtained from Step 2, using a into a Paterson Kelly V-Blender. The magnesium stearate was peristaltic pump and spray gun. The Suspension was dried as then added to the V-Blender. The granules were blended for a film onto the tablets, using heated air drawn through the less than 10 minutes. tablet bed from an inlet fan. A sufficient amount of the sus pension was applied to form about 10 mg/cm to about 20 Step 2. Preparation of Tablets Containing Maintenance Dose: mg/cm of the coat surrounding the bi-layer tablet. 0312. A rotary press was set-up to produce tablets (The Example 3 Hata rotary tablet press was used). Granules from Step 1 were discharged into the feed hopper and compressed to form Morphine Sustained Action (SA) 30 mg Tablets tablets. (30 mg Tablets Contain 25 mg Maintenance Dose and 5 mg Step 3. Preparation of a Coating Suspension of the Loading Dose) Ingredients for the Loading Dose was Applied to the Tablet: Formula for Maintenance Dose 0313 (I) Water was added into a stainless steel vessel. (II) Opadry was added while stirring with a propeller mixer until 0308 all ingredients are finely dispersed in a Suspension. (III) Mor phine and Capsicum oleoresin was added to the Opadry water mixture while stirring using a propeller mixer. Ingredients % ww Step 4. Application of the Coating Suspension from Step 3 to Morphine (particle S.OO size 1000 microns) Form Part of the Loading Dose Surrounding the Tablet from Polyethylene Oxide 7O.OO Step 2: (particle size 1000 microns) 0314 Tablets from step 2 were charged into a rotating Crospovidone 2.OO drum of a side vented automated Tablet coater (Rama Cota Microcrystalline cellulose S.OO Tablet Film Coater was used). The suspension from Step 3 Eudragit RL S.OO was applied to the tablets obtained from Step 2, using a Capsicum oleoresin S.OO peristaltic pump and spray gun. The Suspension was dried as Magnesium Stearate 1.OO a film onto the tablets, using heated air drawn through the tablet bed from an inlet fan. The suspension is applied to form a coat Surrounding the tablet. Formula for Loading Dose Step 5. Preparation of a Coating Suspension of the Ingredi 0309 ents for a Pod-Like Envelope was Applied to the Coated Tablet from Step 4: 0315 (I) Water was added to a stainless steel vessel, fol Ingredients % Wiw lowed by Sodium lauryl Sulfate and Stearic acid, step-by-step, Opadry 83.OO while stirring vigorously with a high shear mixer until all Capsicum oleoresin 3.35 ingredients are dissolved. (II) Eudragit E was added step-by Morphine 16.65 step while stirring vigorously with a high shear mixer until all Water qS ingredients were dissolved. (III) Talc was added while stirring using a high shear mixer until finely dispersed in the solution. Step 6. Application of the Coating Suspension from Step 5 to Formula for the Pod-Like Envelope Form a Pod-Like Envelope Surrounding the Coated Tablet 0310 from Step 4: 0316 Tablets from Step 4 were charged into the rotating drum of a side vented automated Tablet coater (Rama Cota Ingredients % Wiw Tablet Film Coater was used). The suspension from Step 5 Eudragit E (milled) 59.29 was applied to the tablets obtained from Step 4, using a Sodium Laurylsulfate 5.93 peristaltic pump and spray gun. The Suspension was dried as Stearic acid (milled) 8.89 Talc 25.89 a film onto the tablets, using heated air drawn through the Water qS tablet bed from an inlet fan. A sufficient amount of the sus pension was applied to form about 40 mg/cm to about 50 mg/cm of the coat surrounding the coated tablet. US 2015/025.0733 A1 Sep. 10, 2015
Example 4 Step 1b. Preparation of Granules for the Loading Dose: 0322 All the ingredients with the exception of the stearic Codeine Sustained Action (SA) 30 mg Tablets acid from the loading dose formula were charged into a high shear granulator and dry mixed for less than 10 minutes. The (30 mg Tablets Contain 26 mg Maintenance Dose and 5 mg dry mixed granules were discharged into a Paterson Kelly Loading Dose) V-Blender. The stearic acid was then added to the V-Blender. The granules were blended for less than 10 minutes. Formula for Maintenance Dose Step 2. Preparation of a Bi-Layer Tablet Containing 0317 Maintenance Dose and Loading Dose: 0323. The first layer is made from the granules prepared in Step 1a, and the second layer is made from granules prepared Ingredients % Wiw in Step 1b. A double rotary press was set-up to produce a Codeine S.OO bi-layer tablet (The Karnavati UNIK I FC double rotary and (particle size 600 microns) Polyethylene Oxide 40.OO double layer tablet press was used). Granules from Step 1 a (particle size <600 were charged into a first feed hopper and granules from Step microns) 1b were charged into a second feed hopper and the bi-layer Lactose 2S.OO tablet was produced from the double rotary press. Pre-gelatinized starch S.OO Microcrystalline cellulose 19.00 Eudragit RL S.OO Step 3. Preparation of Coating Suspension of the Ingredients Magnesium Stearate 1.OO for a Pod-Like Envelope was Applied on the Bi-Layer Tablet: 0324 (I) Isopropyl alcohol was added into a stainless steel vessel followed by Eudragit E, titanium dioxide, talc and Formula for Loading Dose magnesium Stearate, step-by-step, while stirring vigorously with a high shear mixer until all ingredients were finely dis 0318 persed in a Suspension. (II) Polyethylene glycol was dis solved in water. (III) The polyethylene glycol water mixture was added to the Eudragit E suspension while stirring using a Ingredients % Wiw high shear mixer. Codeine 2.50 Step 4. Application of Coating Suspension from Step 3 to (particle size 600 microns) Form a Pod-Like Envelope Surrounding the Bi-Layer Tablet Lactose 37.OO Hydroxypropyl 2.OO from Step 2: methylcellulose 0325 Tablets from step 2 were charged into a rotating Crospovidone 7.50 drum of a side vented automated Tablet coater (Rama Cota Microcrystalline cellulose 24.50 Tablet Film Coater was used). The suspension from Step 3 Stearic acid 1...SO was applied to the tablets obtained from Step 2, using a peristaltic pump and spray gun. The Suspension was dried as a film onto the tablets, using heated air drawn through the Formula for the Pod-Like Envelope tablet bed from an inlet fan. A sufficient amount of the sus pension was applied to form about 20 mg/cm to about 30 0319 mg/cm of the coat surrounding the bi-layer tablet. Example 6 Ingredients % Wiw Eudragit E 52.63 Oxymorphone Sustained Action (SA) Tablets Talc 22.10 Magnesium Stearate 3.23 Titanium dioxide 1894 (30 mg Tablets Contain 25 mg Maintenance Dose and 5 mg Polyethylene glycol 6000 3.10 Loading Dose) Water qS Isopropyl alcohol qS Formula for Maintenance Dose 0326 Processing Techniques Ingredients % Wiw 0320 Step 1a. Preparation of Granules for the Mainte nance Dose: Oxymorphone S.OO Polyethylene Oxide 76.OO 0321 All the ingredients with the exception of the mag Lactose 6.OO nesium Stearate from the maintenance dose formula were Crospovidone 2.OO charged into a high shear granulator and dry mixed for less Microcrystalline cellulose S.OO Eudragit RL S.OO than 10 minutes. The dry mixed granules were discharged Sucrose Octaacetate OSO into a Paterson Kelly V-Blender. The magnesium stearate was Magnesium Stearate OSO then added to the V-Blender. The granules were blended for less than 10 minutes. US 2015/025.0733 A1 Sep. 10, 2015 36
Formula for Loading Dose Step 5. Preparation of a Coating Suspension of the Ingredients for a Pod-Like Envelope: 0327 0333 (I) Water was added into a stainless steel vessel followed by sodium lauryl sulfate and stearic acid, step-by Ingredients % Wiw step, while stirring vigorously with a high shear mixer until Opadry 83.OO all ingredients are dissolved. (II) Eudragit E was added, step Sucrose Octaacetate O.34 by-step, while stirring vigorously with a high shear mixer Oxymorphone 16.65 until all ingredients were dissolved. (III) Talc and simethi Water qS cone was added while stirring using a high shear mixer until finely dispersed in the solution. Step 6. Application of the Coating Suspension from Step 5 to Form a Pod-Like Envelope Surrounding the Coated Tablet Formula for the Pod Like Envelope from Step 4: 0328 0334 Tablets from step 4 were charged into the rotating drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 5 Ingredients % Wiw was applied to the tablets obtained from Step 4, using a peristaltic pump and spray gun. The Suspension was dried as Eudragit E 59.29 Sodium Laurylsulfate 5.93 a film onto the tablets, using heated air drawn through the Stearic acid 8.89 tablet bed from an inlet fan. A sufficient amount of the sus Talc 20.75 pension was applied to form about 45 mg/cm to about 80 Simethicone 17.09 mg/cm of the coat Surrounding the coated tablet. Water qS 0335 Representative results are shown in FIGS.5b and 9. Example 6 Processing Techniques Oxycodone and Acetaminophen Sustained Action Step 1. Preparation of Granules for the Maintenance Dose: (SA) 30/325 mg Tablets 0329. All the ingredients with the exception of the mag (30/325 mg Tablets Contain 25 mg Maintenance Dose and 5 nesium Stearate from the maintenance dose formula were mg Loading Dose of Oxycodone and 325 mg of charged into a high shear granulator and dry mixed for less Acetaminophen) than 10 minutes. The dry mixed granules were discharged into a Paterson Kelly V-Blender. The magnesium stearate was Formula for Maintenance Dose then added to the V-Blender. The granules were blended for 0336 less than 10 minutes.
Step 2. Preparation of Tablets Containing Maintenance Dose: Ingredients % Wiw 0330. A rotary press was set-up to produce tablets (The Oxycodone 6.25 (particle size <400 Hata rotary tablet press was used). Granules from Step 1 were microns) discharged into the feed hopper and compressed to form Polyethylene Oxide 90.00 tablets. (particle size <400 microns) Lactose Anhydrous DT 5.25 Step 3. Preparation of Coating Suspension of the Ingredients Crospovidone 2.00 for the Loading Dose was Applied on the Tablet: Eudragit RL S.OO Magnesium stearate OSO 0331 Begin by: (I) Water was added into a stainless steel vessel. (II) Opadry was added while stirring with a propeller mixer until all ingredients are finely dispersed in a suspen Sion. (III) Oxymorphone and Sucrose octacetate was added to Formula for Loading Dose the Opadry water mixture while stirring using a propeller 0337 mixer. Step 4. Application of a Coating Suspension from Step 3 to Form Part of the Loading Dose Surrounding the Tablet from Ingredients % Wiw Step 2: Oxycodone (particle size 1.25 <400 microns) 0332 Tablets from step 2 were charged into a rotating Acetaminophen (particle 81.25 drum of a side vented automated Tablet coater (Rama Cota size <400 microns) Tablet Film Coater was used). The suspension from Step 3 Hydroxypropyl 4.OO methylcellulose was applied to the tablets obtained from Step 2, using a Crospovidone S.OO peristaltic pump and spray gun. The Suspension was dried as Microcrystalline cellulose 7.50 a film onto the tablets, using heated air drawn through the Stearic Acid 1.OO tablet bed from an inlet fan. The suspension was applied to form a coat Surrounding the tablet. US 2015/025.0733 A1 Sep. 10, 2015 37
Formula for the Pod-Like Envelope pension was applied to form about 100 mg/cm of the coat surrounding the bi-layer tablet. 0338 Example 7 Ingredients % Wiw Eudragit E 59.29 Oxycodone Sustained Action (SA) 40 mg Tablets Sodium Laurylsulfate 5.93 Stearic acid 8.89 Talc 20.75 (40 mg Tablets Contain 35 mg Maintenance Dose and 5 mg Simethicone 17.09 Water qS Loading Dose)
Formula for Maintenance Dose Processing Techniques (0345 0339 Step 1a. Preparation of Granules for the Mainte nance Dose: 0340 All the ingredients with the exception of the mag Ingredients % Wiw nesium Stearate from the maintenance dose formula were Oxycodone (particle size S.OO charged into a high shear granulator and dry mixed for less <400 microns) than 10 minutes. The dry mixed granules were discharged Polyethylene Oxide 76.OO (particle size <400 into a Paterson Kelly V-Blender. The magnesium stearate was microns) then added to the V-Blender. The granules were blended for Lactose 6.OO less than 10 minutes. Crospovidone 2.OO Step 1b. Preparation of Granules for the Loading Dose: Microcrystalline cellulose S.OO Eudragit RL S.OO 0341 All the ingredients with the exception of the stearic Sucrose Octaacetate OSO acid from the loading dose formula were charged into a high Magnesium Stearate OSO shear granulator and dry mixed for less than 10 minutes. The dry mixed granules were discharged into a Paterson Kelly V-Blender. The stearic acid was then added to the V-Blender. The granules were blended for less than 10 minutes. Formula for Loading Dose Step 2. Preparation of a Bi-Layer Tablet Containing 0346) Maintenance Dose and Loading Dose: 0342. The first layer is made from the granules prepared in Step 1a, and the second layer is made from granules prepared Ingredients % Wiw in Step 1b. A double rotary press was set-up to produce a Opadry 75 OO Oxycodone 2S.OO bi-layer tablet (The Karnavati UNIK I FC double rotary and (particle size double layer tablet press was used). Granules from Step 1 a <400 microns) were charged into a first feed hopper and granules from Step Water qs 1b were charged into a second feed hopper and the bi-layer tablet was produced from the double rotary press. Step 3. Preparation of Coating Suspension of the Ingredients Formula for the Pod-Like Envelope for a Pod-Like Envelope was Applied on the Bi-Layer Tablet: 0343 (I) Water was added into a stainless steel vessel 0347 followed by sodium lauryl sulfate and stearic acid, step-by step, while stirring vigorously with a high shear mixer until Ingredients % Wiw all ingredients are dissolved. (II) Eudragit E was added, step by-step, while stirring vigorously with a high shear mixer Eudragit E 59.29 Sodium Laurylsulfate 5.93 until all ingredients were dissolved. (III) Talc and simethi Stearic acid 8.89 cone was added while stirring using a high shear mixer until Talc 20.75 finely dispersed in the solution. Simethicone 17.09 Step 4. Application of Coating Suspension from Step 3 to Water qs Form a Pod-Like Envelope Surrounding the Bi-Layer Tablet from Step 2: 0344 Tablets from step 2 were charged into a rotating Processing Techniques drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 3 was applied to the tablets obtained from Step 2, using a Step 1. Preparation of Granules for the Maintenance Dose: peristaltic pump and spray gun. The Suspension was dried as a film onto the tablets, using heated air drawn through the 0348 All the ingredients with the exception of the mag tablet bed from an inlet fan. A sufficient amount of the sus nesium Stearate from the maintenance dose formula were US 2015/025.0733 A1 Sep. 10, 2015 charged into a high shear granulator and dry mixed for less Example 8 than 10 minutes. The dry mixed granules were discharged into a Paterson Kelly V-Blender. The magnesium stearate was Zolpidem Sustained Action (SA) 15 mg Tablets then added to the V-Blender. The granules were blended for less than 10 minutes. (15 mg Tablets Contain 15 mg Maintenance Dose and 5 mg Loading Dose) Step 2. Preparation of Tablets Containing Maintenance Dose: Formula for Maintenance Dose 0349. A rotary press was set-up to produce tablets (The Hata rotary tablet press was used). Granules from Step 1 were 0355 discharged into the feed hopper and compressed to form tablets. Ingredients % Wiw Zolpidem (particle size S.OO Step 3. Preparation of Coating Suspension of the Ingredients <500 microns) for the Loading Dose was Applied on the Tablet: Polyethylene Oxide 76.OO (particle size <600 microns) 0350 (I) Water was added into a stainless steel vessel. (II) Lactose 6.OO Opadry was added while stirring with a propeller mixer until Crospovidone 2.OO Microcrystalline cellulose S.OO all ingredients were finely dispersed in a suspension. (III) Eudragit RL S.OO Oxycodone was added to the Opadry water mixture while Sucrose Octaacetate OSO stirring using a propeller mixer. Magnesium Stearate OSO Step 4. Application of coating Suspension from Step 3 to form part of the loading dose surrounding the tablet from Step 2: 0351 Tablets from step 2 were charged into a rotating Formula for Loading Dose drum of a side vented automated Tablet coater (Rama Cota 0356 Tablet Film Coater was used). The suspension from Step 3 was applied to the tablets obtained from Step 2, using a peristaltic pump and spray gun. The Suspension was dried as Ingredients % Wiw a film onto the tablets, using heated air drawn through the Opadry 75.00 tablet bed from an inlet fan. The suspension was applied to Crospovidone S.OO form a coat Surrounding the tablet. Zolpidem 2O.OO (particle size <500 microns) Step 5. Preparation of a Coating Suspension of the Water qs Ingredients for a Pod-Like Envelope: 0352 (I) Water was added into a stainless steel vessel Formula for the Pod-Like Envelope followed by sodium lauryl sulfate and stearic acid, step-by step, while stirring vigorously with a high shear mixer until 0357 all ingredients are dissolved. (II) Eudragit E was added, step by-step, while stirring vigorously with a high shear mixer Ingredients % Wiw until all ingredients were dissolved. (III) Talc and simethi Eudragit E 57.29 cone was added while stirring using a high shear mixer until Sodium Laurylsulfate 5.93 finely dispersed in the solution. Stearic acid 8.89 Crospovidone 2.00 Step 6. Application of a Coating Suspension from Step 5 to Talc 20.75 Form a Pod-Like Envelope Surrounding the Coated Tablet Simethicone 17.09 from Step 4: Water qs 0353 Tablets from Step 4 were charged into the rotating drum of a side vented automated Tablet coater (Rama Cota Processing Techniques Tablet Film Coater was used). The suspension from Step 5 was applied to the tablets obtained from Step 4, using a Step 1. Preparation of Granules for the Maintenance Dose: peristaltic pump and spray gun. The Suspension was dried as a film onto the tablets, using heated air drawn through the 0358 All the ingredients with the exception of the mag tablet bed from an inlet fan. A sufficient amount of the sus nesium Stearate from the maintenance dose formula were pension is applied to form about 40 mg/cm to about 80 charged into a high shear granulator and dry mixed for less than 10 minutes. The dry mixed granules were discharged mg/cm of the coat surrounding the coated tablet. into a Paterson Kelly V-Blender. The magnesium stearate was 0354 Representative results are shown in FIGS. 5a, 7, 8, then added to the V-Blender. The granules were blended for 10, 11 and 12. less than 10 minutes. US 2015/025.0733 A1 Sep. 10, 2015 39
Step 2. Preparation of Tablets Containing Maintenance Dose: -continued 0359 A rotary press was set-up to produce tablets (The Hats rotary tablet press was used). Ingredients % Wiw 0360 Granules from Step 1 were discharged into the feed Polyethylene Oxide 76.50 hopper and compressed to form tablets. (particle size <400 microns) Lactose 6.OO Step 3. Preparation of Coating Suspension of the Ingredients Crospovidone 2.OO for the Loading Dose was Applied on the Tablet: Microcrystalline cellulose S.OO Eudragit RL S.OO 0361 (I) Water was added into a stainless steel vessel. (II) Magnesium Stearate OSO Opadry was added while stirring with a propeller mixer until all ingredients are finely dispersed in a Suspension. (III) Zolpidem was added to the Opadry water mixture while stir ring using a propeller mixer. Formula for Loading Dose Step 4. Application of a Coating Suspension from Step 3 to 0366 Form Part of the Loading Dose Surrounding the Tablet from Step 2: 0362 Tablets from step 2 were charged into a rotating Ingredients % Wiw drum of a side vented automated Tablet coater (Rama Cota Opadry 75.00 Tablet Film Coater was used). The suspension from Step 3 Oxycodone 2S.OO was applied to the tablets obtained from Step 2, using a (particle size peristaltic pump and spray gun. The Suspension was dried as <400 microns) a film onto the tablets, using heated air drawn through the Water qs tablet bed from an inlet fan. The suspension is applied to form a coat Surrounding the tablet. Step 5. Preparation of a Coating Suspension of the Ingredi Formula for the Pod-Like Envelope ents for a Pod-Like Envelope was Applied to the Coated Tablet from Step 4: 0367 0363 (I) Water was added into a stainless steel vessel followed by sodium lauryl sulfate and stearic acid, step-by step while stirring vigorously with a high shear mixer until all Ingredients % Wiw ingredients were dissolved. (II) Eudragit E was added, step Eudragit E SO.29 Polacrilin Potassium 9.00 by-step, while stirring vigorously with a high shear mixer Sodium Laurylsulfate 5.93 until all ingredients were dissolved. (III) Talc and simethi Stearic acid 8.89 cone was added while stirring using a high shear mixer until Talc 20.75 finely dispersed in the solution. Simethicone 17.09 Step 6. Application of Coating Suspension from Step 5 to Water qs Form a Pod-Like Envelope Surrounding the Coated Tablet from Step 4: 0364 Tablets from step 4 were charged into the rotating Processing Techniques drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 5 Step 1. Preparation of Granules for the Maintenance Dose: was applied to the tablets obtained from Step 4, using a 0368 All the ingredients with the exception of the mag peristaltic pump and spray gun. The Suspension was dried as nesium Stearate from the maintenance dose formula were a film onto the tablets, using heated air drawn through the charged into a high shear granulator and dry mixed for less tablet bed from an inlet fan. A sufficient amount of the sus than 10 minutes. The dry mixed granules were discharged pension was applied to form about 20 mg/cm to about 35 into a Paterson Kelly V-Blender. The magnesium stearate was mg/cm of the coat surrounding the coated tablet. then added to the V-Blender. The granules were blended for Example 9 less than 10 minutes. Oxycodone Sustained Action (SA) 40 mg Tablets Step 2 Preparation of Tablets Containing Maintenance Dose: 0369 A rotary press was set-up to produce tablets (The (40 mg Tablets Contain 35 mg Maintenance Dose and 5 mg Hata rotary tablet press was used). Granules from Step 1 were Loading Dose) discharged into the feed hopper and compressed to form tablets. Formula for Maintenance Dose Step 3 Preparation of Coating Suspension of the Ingredients 0365 for the Loading Dose Applied on the Tablet: 0370 (I) Water was added into a stainless steel vessel. (II) Ingredients % Wiw Opadry was added while stirring with a propeller mixer until Oxycodone (particle size S.OO all ingredients are finely dispersed in a suspension. (III) Oxy <400 microns) codone was added to the Opadry water mixture while stirring using a propeller mixer. US 2015/025.0733 A1 Sep. 10, 2015 40
Step 4. Application of a Coating Suspension from Step 3 to Formula for Loading Dose Form Part of the Loading Dose Surrounding the Tablet from Step 2: 0375 0371 Tablets from step 2 were charged into a rotating drum of a side vented automated Tablet coater (Rama Cota Ingredients % Wiw Tablet Film Coater was used). The suspension from Step 3 Opadry 75.00 was applied to the tablets obtained from Step 2, using a Oxycodone (particle 2S.OO peristaltic pump and spray gun. The Suspension was dried as size <400 microns) a film onto the tablets, using heated air drawn through the Water qs tablet bed from an inlet fan. The suspension is applied to form a coat Surrounding the tablet. Formula for the Pod-Like Envelope Step 5. Preparation of a Coating Suspension of the Ingredients for a Pod-Like Envelope: 0376
0372 (I) Water was added into a stainless steel vessel Ingredients % Wiw followed by sodium lauryl sulfate and stearic acid, step-by step, while stirring vigorously with a high shear mixer until Polyvinyl alcohol 46.73 Polacrilin Potassium 44.80 all ingredients were dissolved (II) Eudragit E was added Polethylene glycol 4.67 step-by-step while stirring vigorously with a high shear mixer Talc 1.90 until all ingredients were dissolved. (III) Talc was added Titanium dioxide 1.90 followed by Polacrilin potassium and simethicone while stir Water qs ring using a high shear mixer until finely dispersed in the Solution. Step 6. Application of Coating Suspension from Step 5 to Processing Techniques Form a Pod-Like Envelope Surrounding the Coated Tablet from Step 4: Step 1. Preparation of Granules for the Maintenance Dose: 0373 Tablets from step 4 were charged into the rotating 0377 All the ingredients with the exception of the mag drum of a side vented automated Tablet coater (Rama Cota nesium Stearate from the maintenance dose formula were Tablet Film Coater was used). The suspension from Step 5 charged into a high shear granulator and dry mixed for less was applied to the tablets obtained from Step 4, using a peristaltic pump and spray gun. The Suspension was dried as than 10 minutes. The dry mixed granules were discharged a film onto the tablets, using heated air drawn through the into a Paterson Kelly V-Blender. The magnesium stearate was tablet bed from an inlet fan. A sufficient amount of the sus then added to the V-Blender. The granules were blended for pension is applied to form about 15 mg/cm to about 20 less than 10 minutes. mg/cm of the coat surrounding the coated tablet. Step 2. Preparation of Tablets Containing Maintenance Dose: Example 10 0378. A rotary press was set-up to produce tablets (The Hata rotary tablet press was used). Granules from Step 1 were discharged into the feed hopper and compressed to form Oxycodone Sustained Action (SA) 40 mg Tablets tablets. (40 mg Tablets Contain 35 mg Maintenance Dose and 5 mg Step 3. Preparation of Coating Suspension of the Ingredients Loading Dose) for the Loading Dose was Applied on the Tablet: Formula for Maintenance Dose 0379 (I) Water was added into a stainless steel vessel. (II) Opadry was added while stirring with a propeller mixer until 0374 all ingredients are finely dispersed in a suspension. (III) Oxy codone was added to the Opadry water mixture while stirring using a propeller mixer. Ingredients % Wiw Step 4. Application of Coating Suspension from Step 3 to Oxycodone (particle S.OO Form Part of the Loading Dose Surrounding the Tablet from size <400 microns) Step 2: Polyethylene Oxide 76.50 (particle size <400 0380 Tablets from step 2 were charged into a rotating microns) drum of a side vented automated Tablet coater (Rama Cota Lactose 6.OO Tablet Film Coater was used). The suspension from Step 3 Crospovidone 1OO Microcrystalline cellulose S.OO was applied to the tablets obtained from Step 2, using a Eudragit RL S.OO peristaltic pump and spray gun. The Suspension was dried as Magnesium Stearate O.SO a film onto the tablets, using heated air drawn through the tablet bed from an inlet fan. The suspension is applied to form a coat Surrounding the tablet. US 2015/025.0733 A1 Sep. 10, 2015
Step 5. Preparation of a Coating Suspension of the Formula for the Pod-Like Envelope Ingredients for a Pod-Like Envelope: 0385 0381 (I) Hot water was added into a stainless steel vessel followed by polyethylene glycol, step-by-step, while stirring Ingredients % Wiw vigorously with a high shear mixer until dissolved. (II) Poly vinyl alcohol was added, step-by-step, while stirring vigor Eudragit E 4.67 Polyvinyl alcohol 40.19 ously with a high shear mixer until all ingredients were dis Polacrilin Potassium 40.00 solved. (III) Polacrilin potassium was added followed by Talc Sodium lauryl Sulfate 4.67 and titanium dioxide while stirring using a high shear mixer Stearic acid 1.00 Talc 4.8O until finely dispersed in the solution. Crospovidone 4.67 Step 6. Application of Coating Suspension from Step 5 to Water qs Form a Pod-Like Envelope Surrounding the Coated Tablet from Step 4: Processing Techniques 0382 Tablets from step 4 were charged into the rotating drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 5 Step 1. Preparation of Granules for the Maintenance Dose: was applied to the tablets obtained from Step 4, using a 0386 All the ingredients with the exception of the mag peristaltic pump and spray gun. The Suspension was dried as nesium Stearate from the maintenance dose formula were a film onto the tablets, using heated air drawn through the charged into a high shear granulator and dry mixed for less tablet bed from an inlet fan. A sufficient amount of the sus than 10 minutes. The dry mixed granules were discharged pension was applied to form about 10 mg/cm to about 40 into a Paterson Kelly V-Blender. The magnesium stearate was mg/cm of the coat surrounding the coated tablet. then added to the V-Blender. The granules were blended for less than 10 minutes. Example 11 Step 2. Preparation of Tablets Containing Maintenance Dose: Oxycodone Sustained Action (SA) 40 mg Tablets (0387. A rotary press was set-up to produce tablets (The Hata rotary tablet press was used). Granules from Step 1 were discharged into the feed hopper and compressed to form (40 mg Tablets Contain 35 mg Maintenance Dose and 5 mg tablets. Loading Dose) Step 3. Preparation of Coating Suspension of the Ingredients Formula for Maintenance Dose for the Loading Dose was Applied on the Tablet: 0388 (I) Water was added into a stainless steel vessel. (II) 0383 Opadry was added while stirring with a propeller mixer until all ingredients are finely dispersed in a suspension. (III) Oxy codon was added to the Opadry water mixture while stirring Ingredients % Wiw using a propeller mixer. Oxycodone (particle S.OO Step 4. Application of Coating Suspension from Step 3 to size <400 microns) Form Part of the Loading Dose Surrounding the Tablet from Polyethylene Oxide 82.50 Step 2: (particle size <400 microns) 0389 Tablets from step 2 were charged into a rotating Crospovidone 2.OO drum of a side vented automated Tablet coater (Rama Cots Microcrystalline cellulose S.OO Tablet Film Coater was used). The suspension from Step 3 Eudragit RL S.OO was applied to the tablets obtained from Step 2, using a Magnesium Stearate OSO peristaltic pump and spray gun. The Suspension was dried as a film onto the tablets, using heated air drawn through the tablet bed from an inlet fan. The suspension is applied to form a coat Surrounding the tablet. Formula for Loading Dose Step 5. Preparation of Coating Suspension of the Ingredients 0384 for a Pod-Like Envelope: 0390 (I) Hot water was added into a stainless steel vessel Ingredients % Wiw followed by Sodium lauryl sulfate, Stearic acid, Eudragit E and Talc, step-by-step while stirring vigorously with a high Opadry 75.00 Oxycodone (particle 2S.OO shear mixer until dissolved. (II) Polyvinyl alcohol was added size <400 microns) step-by-step while stirring vigorously with a high shear mixer Water qS until all ingredients were dissolved. (III) Polacrilin potassium was added followed by crospovidone while stirring using a high shear mixer until finely dispersed in the solution. US 2015/025.0733 A1 Sep. 10, 2015 42
Step 6. Application of Coating Suspension from Step 5 to Step 1 a. Preparation of Granules for the Maintenance Dose: Form a Pod-Like Envelope Surrounding the Coated Tablet 0395 All the ingredients with the exception of the mag from Step 4: nesium Stearate from the maintenance dose formula were 0391 Tablets from step 4 were charged into the rotating charged into a high shear granulator and dry mixed for less drum of a side vented automated Tablet coater (Rama Cota than 10 minutes. The dry mixed granules were discharged Tablet Film Coater was used). The suspension from Step 5 into a Paterson Kelly V-Blender. The magnesium stearate was was applied to the tablets obtained from Step 4, using a then added to the V-Blender. The granules were blended for peristaltic pump and spray gun. The Suspension was dried as less than 10 minutes. a film onto the tablets, using heated air drawn through the Step 1b. Preparation of Granules for the Loading Dose: tablet bed from an inlet fan. A sufficient amount of the sus 0396 All the ingredients with exception of the stearic acid pension was applied to form about 10 mg/cm to about 40 from the loading dose formula were charged into a high shear mg/cm of the coat surrounding the coated tablet. granulator and dry mixed for less than 10 minutes. The dry mixed granules were discharged into a Paterson Kelly Example 12 V-Blender. The stearic acid was then added to the V-Blender. The granules were blended for less than 10 minutes. Oxycodone Sustained Action (SA) 40 mg Tablets Step 2. Preparation of a Bi-Layer Tablet Containing (40 mg Tablets Contain 35 mg Maintenance Dose and 6 mg Maintenance Dose and Loading Dose: Loading Dose) 0397. The first layer is made from the granules prepared in Formula for Maintenance Dose Step 1a, and the second layer is made from granules prepared in Step 1b. A double rotary press was set-up to produce a 0392 bi-layer tablet (The Karnavati UNIK I FC double rotary and double layer tablet press was used). Granules from Step 1 a were charged into a first feed hopper and granules from Step Ingredients % Wiw 1b were charged into a second feed hopper and the bi-layer Oxycodone (particle 6.5 tablet was produced from the double rotary press. size <400 microns) Polyethylene Oxide 81.OO Step 3. Preparation of Coating Suspension of the Ingredients (particle size <400 microns) for a Pod-Like Envelope was Applied on the Bi-Layer Tablet: Crospovidone 2.OO Microcrystalline cellulose S.OO 0398 (I) Polyethylene glycol was dissolved in water. This Eudragit RL S.OO solution was added to isopropyl alcohol. (II) Eudragit E was Magnesium Stearate OSO added followed by Polyvinyl acetate, step-by-step, while stir ring vigorously with a high shear mixer until all ingredients were dissolved. (III) Talc, titanium dioxide and magnesium Stearate was added while stirring using a high shear mixer Formula for Loading Dose until finely dispersed in the solution. 0393 Step 4. Application of Coating Suspension from Step 3 to Form a Pod-Like Envelope Surrounding the Bi-Layer Tablet from Step 2: Ingredients % Wiw 0399 Tablets from step 2 were charged into a rotating Oxycodone (particle 2.50 drum of a side vented automated Tablet coater (Rama Cota size <400 microns) Tablet Film Coater was used). The suspension from Step 3 Lactose 7O.OO was applied to the tablets obtained from Step 2, using a Hydroxypropyl 4.OO peristaltic pump and spray gun. The Suspension was dried as methylcellulose Crospovidone S.OO a film onto the tablets, using heated air drawn through the Microcrystalline cellulose 17.50 tablet bed from an inlet fan. A sufficient amount of the sus Stearic acid 1.OO pension is applied to form about 10 mg/cm to about 100 mg/cm of the coat surrounding the bi-layer tablet. Example 13 Formula for the Pod-Like Envelope 0394 Oxycodone Sustained Action (SA) 40 mg Tablets 04.00 (40 mg Tablets contain 35 mg maintenance dose and 5 mg loading dose) Ingredients % Wiw Eudragit E 42.63 Formula for Maintenance Dose Polyvinyl acetate 10 Talc 22.10 04.01 Magnesium Stearate 3.23 Titanium dioxide 1894 Polyethylene glycol 6000 3.10 Ingredients % Wiw Water qS Isopropyl alcohol qS Oxycodone (particle S.OO size <400 microns) US 2015/025.0733 A1 Sep. 10, 2015
-continued Step 4. Application of Coating Suspension from Step 3 to Form Part of the Loading Dose Surrounding the Tablet from Ingredients % Wiw Step 2: Polyethylene Oxide 76.50 04.07 Tablets from step 2 were charged into a rotating (particle size <400 microns) drum of a side vented automated Tablet coater (Rama Cota Lactose 6.OO Tablet Film Coater was used). The suspension from Step 3 Crospovidone 2.OO was applied to the tablets obtained from Step 2, using a Microcrystalline cellulose S.OO Eudragit RL S.OO peristaltic pump and spray gun. The Suspension was dried as Magnesium Stearate OSO a film onto the tablets, using heated air drawn through the tablet bed from an inlet fan. The suspension is applied to form a coat Surrounding the tablet. Formula for Loading Dose Step 5. Preparation of a Coating Suspension of the 0402 Ingredients for a Pod-Like Envelope: 0408 (I) Hot water was added into a stainless steel vessel Ingredients % Wiw followed by Sodium lauryl sulfate and Stearic acid, step-by Opadry 75.00 step, while stirring vigorously with a high shear mixer until Oxycodone (particle 2S.OO size <400 microns) dissolved. (II) Eudragit E was added followed by Talc, step Water qS by-step, while stirring vigorously with a high shear mixer until all ingredients were dissolved. (III) Polyssacharide was added, followed by Simethicone while stirring using a high Formula for the Pod-Like Envelope shear mixer until finely dispersed in the solution. Step 6. Application of Coating Suspension from Step 5 to 0403 Form a Pod-Like Envelope Surrounding the Coated Tablet from Step 4: Ingredients % Wiw 04.09 Tablets from step 4 were charged into the rotating Eudragit E 36.09 drum of a side vented automated Tablet coater (Rama Cota Polysaccharide 12.00 Tablet Film Coater was used). The suspension from Step 5 Sodium Laurylsulfate 5.93 Stearic acid 8.89 was applied to the tablets obtained from Step 4, using a Talc 2O.OO peristaltic pump and spray gun. The Suspension was dried as Simethicone 17.09 a film onto the tablets, using heated air drawn through the Water qS tablet bed from an inlet fan. A sufficient amount of the sus pension was applied to form about 10 mg/1 cm to about 40 mg/cm of the coat surrounding the coated tablet. Processing Techniques Example 14 Step 1. Preparation of Granules for the Maintenance Dose: 0404 All the ingredients with the exception of the mag Oxycodone Sustained Action (SA) 40 mg Tablets nesium Stearate from the maintenance dose formula were charged into a high shear granulator and dry mixed for less than 10 minutes. The dry mixed granules were discharged (40 mg Tablets Contain 35 mg Maintenance Dose and 6 mg into a Paterson Kelly V-Blender. The magnesium stearate was Loading Dose) then added to the V-Blender. The granules were blended for less than 10 minutes. Formula for Maintenance Dose Step 2. Preparation of Tablets Containing Maintenance Dose: 0410 0405. A rotary press was set-up to produce tablets (The Hata rotary tablet press was used). Granules from Step 1 were Ingredients % Wiw discharged into the feed hopper and compressed to form tablets. Oxycodone (particle 6.5 size < 400 microns) Polyethylene Oxide 7O.OO Step 3. Preparation of a Coating Suspension of the (particle size <400 Ingredients for the Loading Dose was Applied on the Tablet: microns) Polacrilin Potassium 11.00 Crospovidone 2.OO 0406 (I) Water was added into a stainless steel vessel. (II) Microcrystalline cellulose S.OO Opadry was added while stirring with a propeller mixer until Eudragit RL S.OO all ingredients were finely dispersed in a suspension. (III) Magnesium Stearate OSO Oxycodone was added to the Opadry water mixture while stirring using a propeller mixer. US 2015/025.0733 A1 Sep. 10, 2015 44
Formula for Loading Dose Step 3. Preparation of a Coating Suspension of the Ingredients for a Pod-Like Envelope was Applied on the 0411 Bi-Layer Tablet: 0417 (I) Water was added into a stainless steel vessel Ingredients % Wiw followed by Sodium lauryl sulfate and Stearic acid, step-by Oxycodone (particle 2.50 step, while stirring vigorously with a high shear mixer until size <400 microns) Polacrilin Potassium 2.50 dissolved. (II) Eudragit E was added followed by Talc, step Lactose 67.50 by-step, while stirring vigorously with a high shear mixer Hydroxypropyl 4.OO until all ingredients were dissolved. (III) Polyssacharide was methylcellulose added followed by simethicone while stirring using a high Crospovidone S.OO Microcrystalline cellulose 17.50 shear mixer until finely dispersed in the solution. Stearic acid 1.OO Step 4. Application of a Coating Suspension from Step 3 to Form a Pod-Like Envelope Surrounding the Bi-Layer Tablet from Step 2: Formula for the Pod-Like Envelope 0418 Tablets from step 2 were charged into a rotating drum of a side vented automated Tablet coater (Rama Cota 0412 Tablet Film Coater was used). The suspension from Step 3 was applied to the tablets obtained from Step 2, using a peristaltic pump and spray gun. The Suspension was dried as Ingredients % Wiw a film onto the tablets, using heated air drawn through the Eudragit E 35.34 tablet bed from an inlet fan. A sufficient amount of the sus Polysaccharide 12.00 Sodium Laurylsulfate 5.93 pension is applied to form about 10 mg/cm to about 60 Stearic acid 8.89 mg/cm of the coat surrounding the bi-layer tablet. Talc 20.75 Simethicone 17.09 Water qS Example 16 Oxycodone Sustained Action (SA) 40 mg Tablets Processing Techniques (40 mg Tablets Contain 35 mg Maintenance Dose and 6 mg 0413 Step 1a. Preparation of Granules for the Mainte Loading Dose) nance Dose: 0414. An Oxycodone-Polacrilin complex was prepared by continuously stirring Oxycodone and Polacrilin in water for Formula for Maintenance Dose 12 hours followed by filtration and drying of the complex such that less than 10% water is present. The dried complex 0419 and all the other ingredients with the exception of the mag nesium Stearate from the maintenance dose formula were charged into a high shear granulator and dry mix for less than Ingredients % Wiw 10 minutes. The granules were discharged into a Paterson Oxycodone (particle 6.5 size <400 microns) Kelly V-Blender. The magnesium stearate was added to the Polyethylene Oxide 7O.OO V-Blender. The granules were blended for less than 10 min (particle size <400 utes. microns) Polacrilin Potassium 11.00 Step 1b. Preparation of Granules for the Loading Dose: Crospovidone 2.OO 0415 All the ingredients with the exception of the stearic Microcrystalline cellulose S.OO acid from the loading dose formula were charged into a high Eudragit RL S.OO shear granulator and dry mixed for less than 10 minutes. The Magnesium Stearate OSO dry mixed granules were discharged into a Paterson Kelly V-Blender. The stearic acid was then added to the V-Blender. The granules were blended for less than 10 minutes. Formula for Loading Dose Step 2. Preparation of a Bi-Layer Tablet Containing Maintenance Dose and Loading Dose: 0420 0416) The first layer is made from the granules prepared in Step 1a, and the second layer is made from granules prepared Ingredients % Wiw in Step 1b. A double rotary press was set-up to produce a Opadry 7O.OO Polacrilin Potassium S.OO bi-layer tablet (The Karnavati UNIK I FC double rotary and Oxycodone (particle 2S.OO double layer tablet press was used). Granules from Step 1 a size <400 microns) were charged into a first feed hopper and granules from Step Water qs 1b were charged into a second feed hopper and the bi-layer tablet was produced from the double rotary press. US 2015/025.0733 A1 Sep. 10, 2015
Formula for the Pod-Like Envelope added followed by simethicone while stirring using a high shear mixer until finely dispersed in the solution. 0421 Step 6. Application of a Coating Suspension from Step 5 to Form a Pod-Like Envelope Surrounding the Coated Tablet Ingredients % Wiw from Step 4: 0427 Tablets from step 4 were charged into the rotating Eudragit E 38.09 Polysaccharide 1O.OO drum of a side vented automated Tablet coater (Rama Cota Sodium Laurylsulfate 5.93 Tablet Film Coater was used). The suspension from Step 5 Stearic acid 8.89 was applied to the tablets obtained from Step 4, using a Talc 2O.OO peristaltic pump and spray gun. The Suspension was dried as Simethicorie 17.09 a film onto the tablets, using heated air drawn through the Water qS tablet bed from an inlet fan. A sufficient amount of the sus pension was applied to form about 15 mg/cm to about 35 mg/cm of the coat Surrounding the coated tablet. Processing Techniques Example 16 Step 1. Preparation of Granules for the Maintenance Dose: 0422. An Oxycodone-Polacrilin complex was prepared by Oxycodone Sustained Action (SA) 40 mg Tablets continuously stirring Oxycodone and Polacrilin in water for 12 to 24 hours followed by filtration and drying of the com (40 mg Tablets Contain 35 mg Maintenance Dose and 5 mg plex such that less than 10% water is present. The dried Loading Dose) complex and all the other Ingredients with the exception of the magnesium Stearate from the maintenance dose formula Formula for Maintenance Dose were charged into a high shear granulator and dry mix for less than 10 minutes. The granules were discharged into a Pater 0428 son Kelly V-Blender. The magnesium stearate was added to the V-Blender. The granules were blended for less than 10 Ingredients % Wiw minutes. Oxycodone (particle 6.5 size < 400 microns) Step 2. Preparation of Tablets Containing Maintenance Dose: Polyethylene Oxide 7O.OO (particle size <400 0423. A rotary press was set-up to produce tablets (The microns) Hats rotary tablet press was used). Granules from Step 1 were Polacrilin Potassium 11.00 discharged into the feed hopper and compressed to form Crosoovidone 2.OO tablets. Microcrystalline cellulose S.OO Eudragit RL S.OO Step 3. Preparation of a Coating Suspension of the Magnesium Stearate OSO Ingredients for the Loading Dose was Applied on the Tablet: 0424 (I) Water was added into a stainless steel vessel. (II) Formula for Loading Dose Opadry was added while stirring with a propeller mixer until all ingredients were finely dispersed in a suspension. (III) 0429 Oxycodone HC1 was added, followed by Polacrilin to the Opadry water mixture while stirring using a propeller mixer. Step 4. Application of Coating Suspension from Step 3 to Ingredients % Wiw Form Part of the Loading Dose Surrounding the Tablet from Opadry 75.00 Step 2: Oxycodone (particle 2S.OO 0425 Tablets from step 2 were charged into a rotating size <400 microns) drum of a side vented automated Tablet coater (Rama Cota Water qs Tablet Film Coater was used). The suspension from Step 3 was applied to the tablets obtained from Step 2, using a peristaltic pump and spray gun. The Suspension was dried as Formula for the Pod-Like Envelope a film onto the tablets, using heated air drawn through the tablet bed from an inlet fan. The suspension is applied to form 0430 a coat Surrounding the tablet. Step 5. Preparation of a Coating Suspension of the Ingredients % Wiw Ingredients for a Pod-Like Envelope: Eudregit E 41.27 Polysaccharide 12.00 0426 (I) Water was added into a stainless steel vessel Sodium Laurylsulfate 5.93 Stearic acid 8.89 followed by Sodium lauryl sulfate and Stearic acid, step-by Talc 20.75 step, while stirring vigorously with a high shear mixer until Simethicone 17.09 dissolved. (II) Eudragit E was added, followed by Talc, step Water qs by-step, while stirring vigorously with a high shear mixer until all ingredients were dissolved. (III) Polyssacharide was US 2015/025.0733 A1 Sep. 10, 2015 46
Processing Techniques Example 17 Step 1. Preparation of Granules for the Maintenance Dose: Morphine Sustained Action (SA) 30 mg Tablets 0431. An Oxycodone-Polacrilin complex was prepared by continuously stirring Oxycodone and Polacrilin in water for 0437 (30 mg Tablets contain 25 mg maintenance dose and 12 to 24 hours followed by filtration and drying of the com 5 mg loading dose) plex such that less than 10% water is present. The dried complex and all the other ingredients with the exception of Formula for Maintenance Dose the magnesium Stearate from the maintenance dose formula were charged into a high shear granulator and dry mix for less 0438 than 10 minutes. The granules were discharged into a Pater son Kelly V-Blender. The magnesium stearate was added to Ingredients % Wiw the V-Blender. The granules were blended for less than 10 minutes. Morphine S.OO (particle size 1000 microns Step 2. Preparation of Tablets Containing Maintenance Dose: Polyethylene Oxide 57.00 (particle size 1000 0432 A rotary press was set-up to produce tablets (The microns) Hata rotary tablet press was used). Granules from Step 1 were Crospovidone S.OO discharged into the feed hopper and compressed to form Microcrystalline cellulose S.OO tablets. Eudragit RL S.OO Triethy citrate 1O.OO Capsicum oleoresin S.OO Step 3. Preparation of a Coating Suspension of the Magnesium Stearate 1.OO Ingredients for the Loading Dose was Applied on the Tablet: 0433 (I) Water was added into a stainless steel vessel. (II) Opadry was added while stirring with a propeller mixer until Formula for Loading Dose all ingredients were finely dispersed in a suspension. (III) Oxycodone HC1 was added, followed by Polacrilin to the 0439 Opadry water mixture while stirring using a propeller mixer. Step 4. Application of a Coating Suspension from Step 3 to Form Part of the Loading Dose Surrounding the Tablet from Ingredients % Wiw Step 2: Opadry 83.OO 0434 Tablets from step 2 were charged into a rotating Capsicum oleoresin 3.35 drum of a side vented automated Tablet coater (Rama Cota Morphine 16.65 Tablet Film Coater was used). The suspension from Step 3 Water qs was applied to the tablets obtained from Step 2, using a peristaltic pump and spray gun. The Suspension was dried as a film onto the tablets, using heated air drawn through the Formula for the Pod-Like Envelope tablet bed from an inlet fan. The suspension is applied to form a coat Surrounding the tablet. 0440 Step 5. Preparation of a Coating Suspension of the Ingredients for a Pod-Like Envelope: Ingredigrents % Wiw Eudragit E (milled) 4229 0435 (I) Water was added into a stainless steel vessel Sodium Laurylsulfate 5.93 followed by Sodium lauryl sulfate and Stearic acid, step-by Stearic acid (milled) 8.89 step, while stirring vigorously with a high shear mixer until Talc 25.89 dissolved. (II) Eudragit E was added, followed by Talc, step Simethicone 17.00 by-step, while stirring vigorously with a high shear mixer Water qs until all ingredients was dissolved. (III) Polyssacharide was added followed by simethicone while stirring using a high shear mixer until finely dispersed in the solution. Processing Techniques Step 6. Application of the Coating Suspension from Step 5 to Form a Pod-Like Envelope Surrounding the Coated Tablet from Step 4: Step 1. Preparation of Granules for the Maintenance Dose by 0436 Tablets from step 4 were charged into the rotating Hot Melt Extrusion: drum of a side vented automated Tablet coater (Rama Cota 0441 All the ingredients with the exception of the mag Tablet Film Coater was used). The suspension from Step 5 was applied to the tablets obtained from Step 4, using a nesium Stearate and microcrystalline cellulose from the main peristaltic pump and spray gun. The Suspension was dried as tenance dose formula were added into a high shear granulator a film onto the tablets, using heated air drawn through the and dry mixed for less than 10 minutes. The dry mixed gran tablet bed from an inlet fan. A sufficient amount of the sus ules were discharged into a hopper of a Hot Melt Extruder and pension was applied to form about 30 mg/cm to about 60 gradually fed into the Hot Melt Extruder heated barrel, while mg/cm of the coat surrounding the coated tablet. mixing by using the rotating screw element of the extruder. US 2015/025.0733 A1 Sep. 10, 2015 47
The material was extruded through a die attached at the end of Example 18 a barrel. The extrudates were milled into granules. The milled granules were charged into a Paterson Kelly V-Blender. The Oxycodone Sustained Action (SA) 30 mg Tablets magnesium Stearate and microcrystalline cellulose were added into the V-Blender and blended for less than 10 min (25 mg Tablets Contain 25 mg Maintenance Dose and 8 mg utes. Loading Dose)
Step 2. Preparation of Tablets Containing Maintenance Dose: Formula for Maintenance Dose 0442. A rotary press was set-up to produce tablets (The 0448 Hata rotary tablet press was used). 0443 Granules from Step 1 were discharged into the feed Ingredients % Wiw hopper and compressed to form tablets. Oxycodone HC (particle 5 size <500 microns) Polyethylene Oxide 66.OO Step 3. Preparation of a Coating Suspension of the (particle size <600 Ingredients for the Loading Dose was Applied on the Tablet: microns) Polacrilin Potassium 1O.OO Lactose 6.OO 0444 (I) Water was added into a stainless steel vessel. (II) Crospovidone 2.OO Opadry was added while stirring with a propeller mixer until Microcrystalline cellulose S.OO all ingredients were finely dispersed in a suspension. (III) Eudragit RL S.OO Morphine and Capsicum oleoresin was added to the Opadry Magnesium Stearate OSO water mixture while stirring using a propeller mixer. Water qs Step 4. Application of Coating Suspension from Step 3 to Form Part of the Loading Dose Surrounding the Tablet from Step 2: Formula for Loading Dose 0445 Tablets from step 2 were charged into a rotating 0449) drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 3 was applied to the tablets obtained from Step 2, using a Ingredients % Wiw Opadry 75.00 peristaltic pump and spray gun. The Suspension was dried as Crospovidone S.OO a film onto the tablets, using heated air drawn through the Oxycodene HCI 2O.OO tablet bed from an inlet fan. The suspension is applied to form (particle size <500 microns) a coat Surrounding the tablet. Water qs Step 5. Preparation of a Coating Suspension of the Ingredients for a Pod-Like Envelope: Formula for the Pod-Like Envelope 0446 (I) Water was added into a stainless steel vessel 0450 followed by Sodium lauryl sulfate and stearic acid, step-by step, while stirring vigorously with a high shear mixer until all ingredients are dissolved. (II) Eudragit E was added, step Ingredients % Wiw by-step, while stirring vigorously with a high shear mixer Eudragit E 57.29 until all ingredients were dissolved. (III) Talc was added, Sodium Laurylsulfate 5.93 followed by simethicone while stirring using a high shear Stearic Acid 8.89 mixer until finely dispersed in the solution. Crospovidone 2.00 Talc 20.75 Step 6. Application of a Coating Suspension from Step 5 to Simethicone 17.09 Form a Pod-Like Envelope Surrounding the Coated Tablet Water qs from Step 4: 0447 Tablets from step 4 were charged into the rotating drum of a side vented automated Tablet coater (Rama Cota Processing Techniques Tablet Film Coater was used). The suspension from Step 5 was applied to the tablets obtained from Step 4, using a Step 1. Preparation of Granules for the Maintenance Dose: peristaltic pump and spray gun. The Suspension was dried as a film onto the tablets, using heated air drawn through the 0451 An Oxycodone-Polacrilin complex was prepared by tablet bed from an inlet fan. A sufficient amount of the sus continuously stirring Oxycodone and Polacrilin in water for pension was applied to form about 40 mg/cm to about 50 12 to 24 hours followed by filtration and drying of the com mg/cm of the coat surrounding the two-layered tablet. plex such that less than 10% water is present. The dried US 2015/025.0733 A1 Sep. 10, 2015 48 complex and all the other ingredients with the exception of Example 19 the magnesium Stearate from the maintenance dose formula were charged into a high shear granulator and dry mix for less Oxycodone Sustained Action (SA) Tablets than 10 minutes. The granules were discharged into a Pater son Kelly V-Blender. The magnesium stearate was added to (30 mg Tablets Contain 25 mg Maintenance Dose and 6 mg the V-Blender. The granules were blended for less than 10 Loading Dose) minutes. Formula for Maintenance Dose Step 2. Preparation of Tablets Containing Maintenance Dose: 0457 0452. A rotary press was set-up to produce tablets (The Hata rotary tablet press was used). Granules from Step 1 were Ingredients % Wiw discharged into the feed hopper and compressed to form Oxycodone S.OO tablets. Polyethylene Oxide 76.OO Lactose 6.OO Crospovidone 2.OO Step 3. Preparation of Coating Suspension of the Ingredients Microcrystalline cellulose S.OO Eudragit RL S.OO for the Loading Dose was Applied on the Tablet: Sucrose Octaacetate OSO Magnesium Stearate OSO 0453 (I) Water was added into a stainless steel vessel. (II) Opadry was added while stirring with a propeller mixer until all ingredients were finely dispersed in a suspension. (III) Formula for Loading Dose Oxycodone HC1 was added to the Opadry water mixture while stirring using a propeller mixer. 0458 Step 4 Application of the Coating Suspension from Step 3 to Form Part of the Loading Dose Surrounding the Tablet from Ingredients % Wiw Step 2: Opadry 83.OO 0454 Tablets from step 2 were charged into a rotating Sucrose Octeacetate O.34 drum of a side vented automated Tablet coater (Rama Cota Oxycodone 16.65 Tablet Film Coater was used). The suspension from Step 3 Water qs was applied to the tablets obtained from Step 2, using a peristaltic pump and spray gun. The Suspension was dried as a film onto the tablets, using heated air drawn through the Formula for the Pod Like Envelope tablet bed from an inlet fan. The suspension is applied to form 0459 a coat Surrounding the tablet. Step 5. Preparation of a Coating Suspension of the Ingredients % Wiw Ingredients for a Pod-Like Envelope: Eudragit E 59.29 Sodium Laurylsulfate 5.93 Stearic acid 8.89 0455 (I) Water was added into a stainless steel vessel Talc 20.75 followed by Sodium lauryl sulfate and stearic acid step-by Simethicone 17.09 step while stirring vigorously with a high shear mixer until all Water qs ingredients were dissolved. (II) Eudragit E was added, step by-step, while stirring vigorously with a high shear mixer until all ingredients were dissolved. (III) Talc and simethi Processing Techniques cone was added while stirring using a high shear mixer until finely dispersed in the solution. Step 1. Preparation of Granules for the Maintenance Dose: 0460 All the ingredients with the exception of the mag Step 6. Application of the Coating Suspension from Step 5 to nesium Stearate from the maintenance dose formula were Form a Pod-Like Envelope Surrounding the Coated Tablet charged into a high shear granulator and dry mixed for less from Step 4: than 10 minutes. The dry mixed granules were discharged 0456 Tablets from step 4 were charged into the rotating into a Paterson Kelly V-Blender. The magnesium stearate was drum of a side vented automated Tablet coater (Rama Cota then added to the V-Blender. The granules were blended for Tablet Film Coater was used). The suspension from Step 5 less than 10 minutes. was applied to the tablets obtained from Step 4, using a peristaltic pump and spray gun. The Suspension was dried as Step 2 Preparation of Tablets Containing Maintenance Dose: a film onto the tablets, using heated air drawn through the 0461) A rotary press was set-up to produce tablets (The tablet bed from an inlet fan. A sufficient amount of the sus Hata rotary tablet press was used). Granules from Step 1 were pension was applied to form about 20 mg/cm to about 35 discharged into the feed hopper and compressed to form mg/cm of the coat surrounding the coated tablet. tablets. US 2015/025.0733 A1 Sep. 10, 2015 49
Step 3. Preparation of a Coating Suspension of the Formula for Loading Dose Ingredients for the Loading Dose was Applied on the Tablet: 0467 0462 (I) Water was added into a stainless steel vessel. (II) Opadry was added while stirring with a propeller mixer until all ingredients were finely dispersed in a suspension. (III) Ingredients % Wiw Oxycodone and Sucrose octacetate was added to the opadry Opadry 87.50 water mixture while stirring using a propeller mixer. Hydromorphone 12.SO Step 4. Application of the Coating Suspension from Step 3 to Water qs Form Part of the Loading Dose Surrounding the Tablet from Step 2: 0463 Tablets from step 2 were charged into a rotating drum of a side vented automated Tablet coater (Rama Cota Formula for the Pod Like Envelope Tablet Film Coater was used). The suspension from Step 3 was applied to the tablets obtained from Step 2, using a 0468 peristaltic pump and spray gun. The Suspension was dried as a film onto the tablets, using heated air drawn through the tablet bed from an inlet fan. The suspension is applied to form Ingredients % Wiw a coat Surrounding the tablet. Eudragit E 59.29 Sodium Laurylsulfate 5.93 Stearic acid 8.89 Step 5. Preparation of a Coating Suspension of the Talc 20.75 Ingredients for a Pod-Like Envelope: Simethicone 17.09 Water qs 0464 (I) Water was added into a stainless steel vessel followed by Sodium lauryl sulfate and stearic acid, step-by step, while stirring vigorously with a high shear mixer until all ingredients were dissolved. (II) Eudragit E was added, Processing Techniques step-by-step, while stirring vigorously with a high shear mixer until all ingredients were dissolved. (III) Talc and sim Step 1. Preparation of Granules for the Maintenance Dose: ethicone were added while stirring using a high shear mixer until finely dispersed in the solution. 0469 All the ingredients with the exception of the mag Step 6. Application of the Coating Suspension from Step 5 to nesium Stearate from the maintenance dose formula were Form a Pod-Like Envelope Surrounding the Coated Tablet charged into a high shear granulator and dry mixed for less from Step 4: than 10 minutes. The dry mixed granules were discharged 0465 Tablets from step 4 were charged into the rotating into a Paterson Kelly V-Blender. The magnesium stearate was drum of a side vented automated Tablet coater (Rama Cola then added to the V-Blender. The granules were blended for Tablet Film Coater was used). The suspension from Step 5 less than 10 minutes. was applied to the tablets obtained from Step 4, using a peristaltic pump and spray gun. The Suspension was dried as Step 2. Preparation of Tablets Containing Maintenance Dose: a film onto the tablets, using heated air drawn through the tablet bed from an inlet fan. A sufficient amount of the sus 0470 A rotary press was set-up to produce tablets (The pension was applied to form about 45 mg/cm to about 80 Hata rotary tablet press was used). Granules from Step 1 were mg/cm of the coat surrounding the coated tablet. discharged into the feed hopper and compressed to form tablets. Example 20 Step 3. Preparation of a Coating Suspension of the Hydromorphone Sustained Action (SA) Tablets Ingredients for the Loading Dose was Applied on the Tablet: (16 mg Tablets Contain 12 mg Maintenance Dose and 4 mg 0471 (I) Water was added into a stainless steel vessel. (II) Loading Dose) Opadry was added while stirring with a propeller mixer until all ingredients were finely dispersed in a suspension. (III) Formula for Maintenance Dose Hydromorphone was added to the opadry water mixture while stirring using a propeller mixer. 0466 Step 4. Application of the Coating Suspension from Step 3 to Form Part of the Loading Dose Surrounding the Tablet from Ingredients % Wiw Step 2: Hydromorphone 1.OO 0472 Tablets from step 2 were charged into a rotating Polyethylene Oxide 56.00 drum of a side vented automated Tablet coater (Rama Cota Lactose 26.OO Tablet Film Coater was used). The suspension from Step 3 Crospovidone 2.OO Microcrystalline cellulose 9.SO was applied to the tablets obtained from Step 2, using a Eudragit RL S.OO peristaltic pump and spray gun. The Suspension was dried as Magnesium Stearate OSO a film onto the tablets, using heated air drawn through the tablet bed from an inlet fan. The suspension is applied to form a coat Surrounding the tablet. US 2015/025.0733 A1 Sep. 10, 2015 50
Step 5. Preparation of a Coating Suspension of the Formula for the Pod-Like Envelope Ingredients for a Pod-Like Envelope: 0477 0473 (I) Water was added into a stainless steel vessel followed by Sodium lauryl sulfate and stearic acid, step-by step, while stirring vigorously with a high shear mixer until Ingredients % Wiw all ingredients are dissolved. (II) Eudragit E was added, step Eudragit E 74SO by-step, while stirring vigorously with a high shear mixer Citric Acid 25.50 until all ingredients are dissolved. (III) Talc and simethicone Water qs was added while stirring using a high shear mixer until finely dispersed in the solution. Step 6. Application of the Coating Suspension from Step 5 to Formula for the Overcoat Form a Pod-Like Envelope Surrounding the Coated Tablet from Step 4: 0478 0474 Tablets from step 4 were charged into the rotating drum of a side vented automated Tablet coater (Rama Cota Ingredients % Wiw Tablet Film Coater was used). The suspension from Step 5 was applied to the tablets obtained from Step 4, using a Opadry 23.35 peristaltic pump and spray gun. The Suspension was dried as Citric Acid 76.65 a film onto the tablets, using heated air drawn through the Water qs tablet bed from an inlet fan. A sufficient amount of the sus pension was applied to form about 15 mg/cm to about 55 mg/cm of the coat surrounding the coated tablet. Processing Techniques 0479. Step 1a. Preparation of Granules for the Mainte Example 21 nance Dose: 0480 All the ingredients with exception of the magnesium Hydromorphone Sustained Action (SA) 8 mg Tablets Stearate from the maintenance dose formula were charged into a high shear granulator and dry mixed for less than 10 (8 mg Tablets Contain 7 mg Maintenance Dose and 1 mg minutes. The dry mixed materials were discharged into a Roll Loading Dose) Compactor and the materials were forced between two counter rotating rolls in the Roll Compactor in order to form Formula for Maintenance Dose flakes or compacts. The compacts were granulated to reduce their size to uniform particle size distribution by passing them 0475 through a size reduction mill fitted with rotating blades and a perforated screen. The granules were discharged into a Pater son Kelly V-Blender. The magnesium stearate was added to Ingredients % Wiw the granules in the V-Blender and blend for less than 10 Hydromorphone 2.OO minutes. (particle size 600 microns) Polyethylene Oxide 40.OO Step 1b. Preparation of Granules for the Loading Dose: (particle size <600 0481 All the ingredients, with the exception of the mag microns) nesium Stearate and pregelatinized Starch, from the loading Lactose 28.00 dose formula were discharged into a high shear granulator Crospovidone S.OO Fumaric Acid S.OO and dry mixed for less than 10 minutes. The dry mixed mate Microcrystalline cellulose 9.OO rials were discharged into a Roll Compactor and the materials Eudragit RL S.OO were forced between the two counter rotating rolls in the Roll Carbomer S.OO Compactorin order to form flakes or compacts. The compacts Magnesium Stearate 1.OO were granulated to reduce their size to uniform particle size distribution by passing them through a size reduction mill fitted with rotating blades and perforated screen. The granules Formula for Loading Dose were discharged into a Paterson Kelly V-Blender. The mag nesium Stearate and pregelatinized starch were added to the 0476 granules in the V-Blender and blended for less than 10 min utes. Ingredients % Wiw Step 2. Preparation of a Bi-Layer Tablet Containing Hydromorphone 1.OO Maintenance Dose and Loading Dose: (particle size 600 microns) Lactose 6O.OO 0482. The first layer is made from the granules prepared in Fumaric Acid S.OO Step 1a, and the second layer is made from granules prepared Hydroxypropyl methyl 4.OO in Step 1b. A double rotary press was set-up to produce a cellulose Pregelatinized starch S.OO bi-layer tablet (The Karnavati UNIK I FC double rotary and Microcrystalline cellulose 2O.OO double layer tablet press was used). Granules from Step 1 a Magnesium Stearate 1.OO were charged into a first feed hopper and granules from Step 1b were charged into a second feed hopper and the bi-layer tablet was produced from the double rotary press. US 2015/025.0733 A1 Sep. 10, 2015
Step 3. Preparation of a Coating Suspension of the -continued Ingredients of the Pod-Like Envelope Applied to the Bi-Layer Tablet: Ingredients % Wiw 0483 (I) Water was added into a stainless steel vessel and Capsicum oleoresin S.OO Eudragit E was gradually added while stirring with a high Magnesium Stearate 1.00 shear mixer with controlled speed, sufficient to prevent sedi mentation and lump formation. (II) The citric acid portion was added until a clear Solution is obtained. Formula for Loading Dose Step 4. Application of Coating Suspension from Step 3 to 0488 Form a Pod-Like Envelope Surrounding the Bi-Layer Tablet from Step 2: 0484 Tablets from step 2 were charged into a rotating Ingredients % Wiw drum of a side vented automated Tablet coater (Rama Cota Opadry 73.00 Tablet Film Coater was used). The suspension from Step 3 Fumaric acid 10 was applied to the tablets obtained from Step 2, using a Capsicum oleoresin 3.35 peristaltic pump and spray gun. The Suspension was dried as Morphine 16.65 a film onto the tablets, using heated air drawn through the Water qs tablet bed from an inlet fan. A sufficient amount of the sus pension was applied to form about 10 mg/cm to about 20 mg/cm of the coat surrounding the bi-layer tablet. Formula for the Pod-Like Envelope Step 5. Preparation of Overcoating Suspension of the Ingre 0489 dients of the Overcoat Applied to the Coated Tablet from Step 4: 0485 (I) Water was added into a stainless steel vessel and Ingredients % Wiw Opadry was gradually added while stirring with a propeller Eudragit E (milled) 59.29 mixer with controlled speed, sufficient to prevent sedimenta Sodium Laurylsulfate 5.93 Stearic acid (milled) 8.89 tion and lump formation. (II) The citric acid portion was Talc 25.89 added stepwise until no lumps was seen. Water qs Step 6. Application of Coating Suspension from Step 5 to Forman Overcoat Surrounding the Coated Tablets from Step 4: Formula for the Overcoat 0486 Tablets from step 4 were charged into a rotating drum of a side vented automated Tablet coater (Rama Cota 0490 Tablet Film Coater was used). The suspension from Step 5 was applied to the tablets obtained from Step 4, using a peristaltic pump and spray gun. The Suspension was dried as Ingredients % Wiw a film onto the tablets, using heated air drawn through the Opadry 23.35 tablet bed from an inlet fan. A sufficient amount of the sus Citric Acid 76.65 pension was applied Such that the coat contained from 10 mg Isopropyl Alcohol qs to 600 mg of citric acid per coated tablet. Water qs Example 22 Processing Techniques Morphine Sustained Action (SA) 30 mg Tablets Step 1. Preparation of Granules for the Maintenance Dose: 0491 All the ingredients with the exception of the mag (30 mg Tablets Contain 25 mg Maintenance Dose and 5 mg nesium Stearate from the maintenance dose formula were Loading Dose) charged into a high shear granulator and dry mixed for less than 10 minutes. The dry mixed granules were discharged Formula for Maintenance Dose into a Paterson Kelly V-Blender. The magnesium stearate was then added to the V-Blender. The granules were blended for 0487 less than 10 minutes.
Ingredients % Wiw Step 2. Preparation of Tablets Containing Maintenance Dose: 0492 A rotary press was set-up to produce tablets (The Morphine S.OO (particle size 1000 Hate rotary tablet press was used). Granules from Step 1 were microns) discharged into the feed hopper and compressed to form Polyethylene Oxide SO.OO tablets. (particle size 1000 microns) Step 3. Preparation of a Coating Suspension of the Crospovidone 7.OO Microcrystalline cellulose 1S.OO Ingredients for the Loading Dose was Applied to the Tablet: Eudragit RL 1O.OO 0493 (I) Water was added into a stainless steel vessel. (II) Opadry was added while stirring with a propeller mixer until US 2015/025.0733 A1 Sep. 10, 2015 52 all ingredients are finely dispersed in a suspension. (III) Mor Example 23 phine and Capsicum oleoresin was added to the Opadry water mixture while stirring using a propeller mixer. Codeine Sustained Action (SA) 30 mg Tablets Step 4. Application of the Coating Suspension from Step 3 to (30 mg Tablets Contain 25 mg Maintenance Dose and 5 mg Form Part of the Loading Dose Surrounding the Tablet from Loading Dose) Step 2: 0494 Tablets from step 2 were charged into a rotating Formula for Maintenance Dose drum of a side vented automated Tablet coater (Rama Cota 0499 Tablet Film Coater was used). The suspension from Step 3 was applied to the tablets obtained from Step 2, using a peristaltic pump and spray gun. The Suspension was dried as Ingredients % Wiw a film onto the tablets, using heated air drawn through the Codeine S.OO tablet bed from an inlet fan. The suspension is applied to form (particle size 600 microns) Polyethylene Oxide 40.OO a coat Surrounding the tablet. (particle size <600 Step 5. Preparation of a Coating Suspension of the Ingredi microns) Lactose 2S.OO ents for a Pod-Like Envelope was Applied to the Coated Crospovidone 4.OO Tablet from Step 4: Pre-gelatinized starch S.OO Microcrystalline cellulose 1S.OO 0495 (I) Water was added to a stainless steel vessel, fol Eudragit RL S.OO lowed by Sodium lauryl Sulfate and Stearic acid, step-by-step, Magnesium Stearate 1.OO while stirring vigorously with a high shear mixer until all ingredients are dissolved. (II) Eudragit E was added step-by step while stirring vigorously with a high shear mixer until all Formula for Loading Dose ingredients were dissolved. (III) Talc was added while stirring using a high shear mixer until finely dispersed in the solution. 0500 Step 6. Application of the Coating Suspension from Step 5 to Form a Pod-Like Envelope Surrounding the Coated Tablet Ingredients % Wiw from Step 4: Codeine 2.50 (particle size 600 microns) 0496 Tablets from Step 4 were charged into the rotating Lactose 37.OO drum of a side vented automated Tablet coater (Rama Cota Hydroxypropyl 2.OO Tablet Film Coater was used). The suspension from Step 5 methylcellulose Crospovidone 7.50 was applied to the tablets obtained from Step 4, using a Citric Acid 4...SO peristaltic pump and spray gun. The Suspension was dried as Microcrystalline cellulose 2OSO a film onto the tablets, using heated air drawn through the Stearic acid 1...SO tablet bed from an inlet fan. A sufficient amount of the sus pension was applied to form about 20 mg/cm to about 50 mg/cm of the coat surrounding the coated tablet. Formula for the Pod-Like Envelope Step 7. Preparation of Overcoating Suspension of the Ingre 0501) dients of the Overcoat Applied to the Coated Tablet from Step 6: 0497 (I) Water and Isopropyl alcohol was added into a Ingredients % Wiw stainless Steel vessel and citric acid was gradually added Eudragit E 52.63 Talc 22.10 while stirring with a propeller mixer with controlled speed, Magnesium Stearate 3.23 Sufficient to prevent sedimentation and lump formation. (II) Titanium dioxide 1894 The Opadry portion was added stepwise until no lumps were Polyethylene glycol 6000 3.10 See. Water qs Isopropyl alcohol qs Step 8. Application of Coating Suspension from Step 7 to Forman Overcoat Surrounding the Coated Tablets from Step 6: Formula for the Overcoat 0498 Tablets from step 6 were charged into a rotating 0502 drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 7 was applied to the tablets obtained from Step 6, using a Ingredients % Wiw peristaltic pump and spray gun. The Suspension was dried as Opadry 23.35 a film onto the tablets, using heated air drawn through the Furnaric Acid 76.65 tablet bed from an inlet fan. A sufficient amount of the sus Water qs pension was applied Such that the coat contained from 10 mg to 600 mg of citric acid per coated tablet. US 2015/025.0733 A1 Sep. 10, 2015
Processing Techniques 0510 Tablets from step 4 were charged into a rotating drum of a side vented automated Tablet coater (Rama Cota 0503 Step 1a. Preparation of Granules for the Mainte Tablet Film Coater was used). The suspension from Step 5 nance Dose: was applied to the tablets obtained from Step 4, using a 0504 All the ingredients with the exception of the mag peristaltic pump and spray gun. The Suspension was dried as nesium Stearate from the maintenance dose formula were a film onto the tablets, using heated air drawn through the charged into a high shear granulator and dry mixed for less tablet bed from an inlet fan. A sufficient amount of the sus than 10 minutes. The dry mixed granules were discharged pension was applied Such that the coat contained from 10 mg into a Paterson Kelly V-Blender. The magnesium stearate was to 600 mg of fumaric acid per coated tablet. then added to the V-Blender. The granules were blended for less than 10 minutes. Example 24 Step 1b. Preparation of Granules for the Loading Dose: 0505 All the ingredients with the exception of the stearic Oxymorphone Sustained Action (SA) Tablets acid from the loading dose formula were charged into a high shear granulator and dry mixed for less than 10 minutes. The (30 mg Tablets Contain 26 mg Maintenance Dose and 5 mg dry mixed granules were discharged into a Paterson Kelly Loading Dose) V-Blender. The stearic acid was then added to the V-Blender. The granules were blended for less than 10 minutes. Formula for Maintenance Dose 0511 Step 2 Preparation of a Bi-Layer Tablet Containing Maintenance Dose and Loading Dose: 0506. The first layer is made from the granules prepared in Ingredients % Wiw Step 1a, and the second layer is made from granules prepared Oxymorophone S.OO in Step 1b. A double rotary press was set-up to produce a Polyethylene Oxide 56.00 Lactose 2O.OO bi-layer tablet (The Karnavati UNIK I FC double rotary and Crospovidone 3.00 double layer tablet press was used). Granules from Step 1 a Microcrystalline cellulose 1O.OO were charged into a first feed hopper and granules from Step Eudragit RL S.OO 1b were charged into a second feed hopper and the bi-layer Sucrose Octaacetate OSO tablet was produced from the double rotary press. Magnesium stearate OSO Step 3. Preparation of Coating Suspension of the Ingredients for a Pod-Like Envelope was Applied on the Bi-Layer Tablet: Formula for Loading Dose 0507 (I) Isopropyl alcohol was added into a stainless steel 0512 vessel followed by Eudragit E, titanium dioxide, talc and magnesium Stearate, step-by-step, while stirring vigorously with a high shear mixer until all ingredients were finely dis Ingredients % Wiw persed in a Suspension. (II) Polyethylene glycol was dis Opadry 83.OO solved in water. (III) The polyethylene glycol water mixture Sucrose Octaacetate O.34 was added to the Eudragit E Suspension while stirring using a Oxymorphone 16.65 high shear mixer. Water qs Step 4. Application of Coating Suspension from Step 3 to Form a Pod-Like Envelope Surrounding the Bi-Layer Tablet from Step 2: Formula for the Pod Like Envelope 0508 Tablets from step 2 were charged into a rotating 0513 drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 3 was applied to the tablets obtained from Step 2, using a Ingredients % Wiw peristaltic pump and spray gun. The Suspension was dried as Eudragit E 59.29 a film onto the tablets, using heated air drawn through the Sodium Laurylsulfate 5.93 tablet bed from an inlet fan. A sufficient amount of the sus Stearic acid 8.89 pension was applied to form about 20 mg/cm to about 30 Talc 20.75 mg/cm of the coat surrounding the bi-layer tablet. Simethicone 17.09 Step 5. Preparation of Overcoating Suspension of the Ingre Water qs dients of the Overcoat Applied to the Coated Tablet from Step 4: 0509 (I) Water was added into a stainless steel vessel and Formula for the Overcoat Opadry was gradually added while stirring with a propeller 0514 mixer with controlled speed, sufficient to prevent sedimenta tion and lump formation. (II) The fumaric acid portion was added stepwise until no lumps were seen. Ingredients % Wiw Step 6. Application of Coating Suspension from Step 5 to Opadry 23.35 Forman Overcoat Surrounding the Coated Tablets from Step Fumaric Acid 38.00 4: US 2015/025.0733 A1 Sep. 10, 2015 54
-continued was applied to the tablets obtained from Step 4, using a peristaltic pump and spray gun. The Suspension was dried as Ingredients % Wiw a film onto the tablets, using heated air drawn through the tablet bed from an inlet fan. A sufficient amount of the sus Citric Acid 38.65 Isopropyl Alcohol qS pension was applied to form about 15 mg/cm to about 80 Water qS mg/cm of the coat Surrounding the coated tablet. Step 7. Preparation of Overcoating Suspension of the Ingre dients of the Overcoat Applied to the Coated Tablet from Step Processing Techniques 6: 0521 (I) Water and Isopropyl alcohol was added into a stainless steel vessel and citric acid followed by fumaric acid Step 1. Preparation of Granules for the Maintenance Dose: was gradually added while stirring with a propeller mixer 0515 All the ingredients with the exception of the mag with controlled speed, sufficient to prevent sedimentation and nesium Stearate from the maintenance dose formula were lump formation. (II) The Opadry portion was added stepwise charged into a high shear granulator and dry mixed for less until no lumps were seen. than 10 minutes. The dry mixed granules were discharged Step 8. Application of Coating Suspension from Step 7 to into a Paterson Kelly V-Blender. The magnesium stearate was Form an Overcoat Surrounding the Coated Tablets from Step then added to the V-Blender. The granules were blended for 6: less than 10 minutes. 0522 Tablets from step 6 were charged into a rotating drum of a side vented automated Tablet coater (Rama Cota Step 2. Preparation of Tablets Containing Maintenance Dose: Tablet Film Coater was used). The suspension from Step 7 was applied to the tablets obtained from Step 6, using a 0516 A rotary press was set-up to produce tablets (The peristaltic pump and spray gun. The Suspension was dried as Hata rotary tablet press was used). Granules from Step 1 were a film onto the tablets, using heated air drawn through the discharged into the feed hopper and compressed to form tablet bed from an inlet fan. A sufficient amount of the sus tablets. pension was applied Such that the coat contained from 10 mg Step 3. Preparation of Coating Suspension of the Ingredients to 600 mg of citric acid and fumaric acid per coated tablet. for the Loading Dose was Applied on the Tablet: Example 26 0517 Begin by: (I) Water was added into a stainless steel vessel. (II) Opadry was added while stirring with a propeller Oxycodone and Acetaminophen Sustained Action mixer until all ingredients are finely dispersed in a suspen (SA) 301325 mg Sion. (III) Oxymorphone and Sucrose octacetate was added to the Opadry water mixture while stirring using a propeller Tablets (301326 mg Tablets Contain 25 mg Maintenance mixer. Dose and 5 mg Loading Dose of Oxycodone and 325 mg of Step 4. Application of a Coating Suspension from Step 3 to Acetaminophen) Form Part of the Loading Dose Surrounding the Tablet from Step 2: Formula for Maintenance Dose 0518 Tablets from step 2 were charged into a rotating 0523 drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 3 was applied to the tablets obtained from Step 2, using a Ingredients % Wiw peristaltic pump and spray gun. The Suspension was dried as Oxycodone 6.25 a film onto the tablets, using heated air drawn through the (particle size <400 tablet bed from an inlet fan. The suspension was applied to microns) Polyethylene Oxide SO.OO form a coat Surrounding the tablet. (particle size <400 microns) Step 5. Preparation of a Coating Suspension of the Lactose Anhydrous DT 25.25 Ingredients for a Pod-Like Envelope: Microcrystalline cellulose 1S.OO Crospovidone S.OO 0519 (I) Water was added into a stainless steel vessel Eudragit RL 7.OO followed by sodium lauryl sulfate and stearic acid, step-by Magnesium Stearate OSO step, while stirring vigorously with a high shear mixer until all ingredients are dissolved. (II) Eudragit E was added, step by-step, while stirring vigorously with a high shear mixer Formula for Loading Dose until all ingredients were dissolved. (III) Talc and simethi cone was added while stirring using a high shear mixer until 0524 finely dispersed in the solution. Step 6. Application of the Coating Suspension from Step 5 to Ingredients % Wiw Form a Pod-Like Envelope Surrounding the Coated Tablet from Step 4: Oxycodone (particle size 1.25 <400 microns) 0520 Tablets from step 4 were charged into the rotating Acetaminophen (particle 81.25 drum of a side vented automated Tablet coater (Rama Cota size <400 microns) Tablet Film Coater was used). The suspension from Step 5 US 2015/025.0733 A1 Sep. 10, 2015
-continued Step 3. Preparation of Coating Suspension of the Ingredients for a Pod-Like Envelope was Applied on the Bi-Layer Tablet: Ingredients % Wiw 0531 (I) Water was added into a stainless steel vessel Hydroxypropyl 4.OO followed by sodium lauryl sulfate and stearic acid, step-by methylcellulose Crospovidone S.OO step, while stirring vigorously with a high shear mixer until Microcrystalline cellulose 7.50 all ingredients are dissolved. (II) Eudragit E was added, step Stearic Acid 1.00 by-step, while stirring vigorously with a high shear mixer until all ingredients were dissolved. (III) Talc and simethi cone was added while stirring using a high shear mixer until finely dispersed in the solution. Formula for the Pod-Like Envelope Step 4. Application of Coating Suspension from Step 3 to 0525 Form a Pod-Like Envelope Surrounding the Bi-Layer Tablet from Step 2: 0532 Tablets from step 2 were charged into a rotating Ingredients % Wiw drum of a side vented automated Tablet coater (Rama Cota Eudragit E 59.29 Tablet Film Coater was used). The suspension from Step 3 Sodium Laurylsulfate 5.93 was applied to the tablets obtained from Step 2, using a Stearic acid 8.89 peristaltic pump and spray gun. The Suspension was dried as Talc 20.75 a film onto the tablets, using heated air drawn through the Simethicone 17.09 tablet bed from an inlet fan. A sufficient amount of the sus Water qS pension was applied to form about 100 mg/cm of the coat surrounding the bi-layer tablet. Step 5. Preparation of Overcoating Suspension of the Ingre Formula for the Overcoat dients of the Overcoat Applied to the Coated Tablet from Step 0526 4: 0533 (I) Water was added into a stainless steel vessel and Opadry was gradually added while stirring with a propeller Ingredients % Wiw mixer with controlled speed, sufficient to prevent sedimenta Opadry 37.50 tion and lump formation. (II) The fumaric acid portion was Fumaric Acid 62.50 added stepwise until no lumps were seen. Isopropyl Alcohol qS Step 6. Application of Coating Suspension from Step 5 to Water qS Form an Overcoat Surrounding the Coated Tablets from Step 4: 0534 Tablets from step 4 were charged into a rotating Processing Techniques drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 5 0527 Step 1a. Preparation of Granules for the Mainte was applied to the tablets obtained from Step 4, using a nance Dose: peristaltic pump and spray gun. The Suspension was dried as 0528 All the ingredients with the exception of the mag a film onto the tablets, using heated air drawn through the nesium Stearate from the maintenance dose formula were tablet bed from an inlet fan. A sufficient amount of the sus charged into a high shear granulator and dry mixed for less pension was applied Such that the coat contained from 10 mg than 10 minutes. The dry mixed granules were discharged to 600 mg of fumaric acid per coated tablet. into a Paterson Kelly V-Blender. The magnesium stearate was then added to the V-Blender. The granules were blended for Example 26 less than 10 minutes. Step 1b. Preparation of Granules for the Loading Dose: Oxycodone Sustained Action (SA) 40 mg Tablets 0529 All the ingredients with the exception of the stearic 0535 (40 mg Tablets contain 30 mg maintenance dose and acid from the loading dose formula were charged into a high 10 mg loading dose) shear granulator and dry mixed for less than 10 minutes. The dry mixed granules were discharged into a Paterson Kelly Formula for Maintenance Dose V-Blender. The stearic acid was then added to the V-Blender. The granules were blended for less than 10 minutes. 0536 Step 2. Preparation of a Bi-Layer Tablet Containing Maintenance Dose and Loading Dose: Ingredients % Wiw Oxycodone (particle size 4.29 0530. The first layer is made from the granules prepared in <400 microns) Step 1a, and the second layer is made from granules prepared Polyethylene Oxide 70.71 in Step 1b. A double rotary press was set-up to produce a (particle size <400 microns) bi-layer tablet (The Karnavati UNIK I FC double rotary and Lactose S.OO double layer tablet press was used). Granules from Step 1 a Crospovidone 3.00 were charged into a first feed hopper and granules from Step Microcrystalline cellulose 11.00 1b were charged into a second feed hopper and the bi-layer Eudragit RL S.OO tablet was produced from the double rotary press. US 2015/025.0733 A1 Sep. 10, 2015 56
-continued Step 3. Preparation of coating Suspension of the ingredients for the loading dose was applied on the tablet: Ingredients % Wiw 0542 (I) Water was added into a stainless steel vessel. (II) Opadry was added while stirring with a propeller mixer until Sucrose Octaacetate OSO all ingredients were finely dispersed in a suspension. (III) Magnesium Stearate OSO Oxycodone was added to the Opadry water mixture while stirring using a propeller mixer. Step 4. Application of Coating Suspension from Step 3 to Formula for Loading Dose Form Part of the Loading Dose Surrounding the Tablet from Step 2: 0537 0543 Tablets from step 2 were charged into a rotating drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 3 Ingredients % Wiw was applied to the tablets obtained from Step 2, using a peristaltic pump and spray gun. The Suspension was dried as Opadry 84.2O Oxycodone (particle size 15.8O a film onto the tablets, using heated air drawn through the <400 microns) tablet bed from an inlet fan. The suspension was applied to Water qS form a coat Surrounding the tablet. Step 5. Preparation of a Coating Suspension of the Ingredients for a Pod-Like Envelope: Formula for the Pod-Like Envelope 0544 (I) Water was added into a stainless steel vessel followed by sodium lauryl sulfate and stearic acid, step-by 0538 step, while stirring vigorously with a high shear mixer until all ingredients are dissolved. (II) Eudragit E was added, step by-step, while stirring vigorously with a high shear mixer Ingredients % Wiw until all ingredients were dissolved. (III) Talc and simethi Eudragit E 59.29 cone was added while stirring using a high shear mixer until Sodium Laurylsulfate 5.93 finely dispersed in the solution. Stearic acid 8.89 Step 6. Application of a Coating Suspension from Step 5 to Talc 20.75 Simethicone 17.09 Form a Pod-Like Envelope Surrounding the Coated Tablet Water qS from Step 4: 0545 Tablets from Step 4 were charged into the rotating drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 5 Formula for the Overcoat was applied to the tablets obtained from Step 4, using a peristaltic pump and spray gun. The Suspension was dried as 0539 a film onto the tablets, using heated air drawn through the tablet bed from an inlet fan. A Sufficient amount of the Suspension is applied to form about Ingredients % Wiw 40 mg/cm to about 80 mg/cm of the coat surrounding the Opadry 23.35 coated tablet. Fumaric Acid 38.00 Citric Acid 38.15 Step 7. Preparation of Overcoating Suspension of the Ingre Sucrose Octaacetate OSO dients of the Overcoat Applied to the Coated Tablet from Step Isopropyl Alcohol qS 6: Water qS 0546) (I) Isopropyl alcohol was added into a stainless steel vessel. Sucroase Octaacetate was added followed by water while stirring. Gradually add citric acid followed by fumaric Processing Techniques acid while stirring with a propeller mixer under controlled speed, Sufficient to prevent sedimentation and lump forma tion. (II) The Opadry portion was added stepwise until no Step 1. Preparation of Granules for the Maintenance Dose: lumps were seen. 0540 All the ingredients with the exception of the mag Step 8. Application of Coating Suspension from Step 7 to nesium Stearate from the maintenance dose formula were Form an Overcoat Surrounding the Coated Tablets from Step charged into a high shear granulator and dry mixed for less 6: than 10 minutes. The dry mixed granules were discharged 0547 Tablets from step 6 were charged into a rotating into a Paterson Kelly V-Blender. The magnesium stearate was drum of a side vented automated Tablet coater (Rama Cota then added to the V-Blender. The granules were blended for Tablet Film Coater was used). The suspension from Step 7 less than 10 minutes. was applied to the tablets obtained from Step 6, using a peristaltic pump and spray gun. The Suspension was dried as Step 2. Preparation of Tablets Containing Maintenance Dose: a film onto the tablets, using heated air drawn through the tablet bed from an inlet fan. A sufficient amount of the sus 0541. A rotary press was set-up to produce tablets (The pension was applied Such that the coat contained from 10 mg Hata rotary tablet press was used). Granules from Step 1 were to 600 mg of citric acid and fumaric acid per coated tablet and discharged into the feed hopper and compressed to form enough Sucrose octaacetate to make the tablet objectionable tablets. tO taste US 2015/025.0733 A1 Sep. 10, 2015 57
Example 27 -continued
Oxycodone and Acetaminophen Sustained Action Ingredients % Wiw (SA) 301325 mg Isopropyl Alcohol qs Tablets (301325 mg Tablets Contain 25 mg Maintenance Water qs Dose and 5 mg Loading Dose of Oxycodone and 325 mg of Acetaminophen) Processing Techniques Formula for Maintenance Dose 0552 Step 1a. Preparation of Granules for the Mainte 0548 nance Dose: 0553 All the ingredients with the exception of the mag nesium Stearate from the maintenance dose formula were Ingredients % Wiw charged into a high shear granulator and dry mixed for less Oxycodone 6.25 than 10 minutes. The dry mixed granules were discharged (particle size <400 into a Paterson Kelly V-Blender. The magnesium stearate was microns) Polyethylene Oxide SO.OO then added to the V-Blender. The granules were blended for (particle size <400 less than 10 minutes. microns) Step 1b. Preparation of Granules for the Loading Dose: Lactose Anhydrous DT 2S.OO Sucrose octaacetate O.25 0554 All the ingredients with the exception of the stearic Microcrystalline cellulose 1S.OO acid from the loading dose formula were charged into a high Crospovidone S.OO shear granulator and dry mixed for less than 10 minutes. The Eudragit RL 7.OO dry mixed granules were discharged into a Paterson Kelly Magnesium Stearate OSO V-Blender. The stearic acid was then added to the V-Blender. The granules were blended for less than 10 minutes. Formula for Loading Dose Step 2. Preparation of a Bi-Layer Tablet Containing 0549 Maintenance Dose and Loading Dose: 0555. The first layer is made from the granules prepared in Step 1a, and the second layer is made from granules prepared Ingredients % Wiw in Step 1b. A double rotary press was set-up to produce a Oxycodone (particle size 1.25 bi-layer tablet (The Karnavati UNIK I FC double rotary and <400 microns) Acetaminophen (particle 81.OO double layer tablet press was used). Granules from Step 1 a size <400 microns) were charged into a first feed hopper and granules from Step Sucrose Octaacetate O.25 1b were charged into a second feed hopper and the bi-layer Hydroxypropyl 4.OO tablet was produced from the double rotary press. methylcellulose Crospovidone S.OO Microcrystalline cellulose 7.50 Step 3. Preparation of Coating Suspension of the Ingredients Stearic Acid 1.OO for a Pod-Like Envelope was Applied on the Bi-Layer Tablet: 0556 (I) Water was added into a stainless steel vessel followed by sodium lauryl sulfate and stearic acid, step-by Formula for the Pod-Like Envelope step, while stirring vigorously with a high shear mixer until 0550 all ingredients are dissolved. (II) Eudragit E was added, step by-step, while stirring vigorously with a high shear mixer until all ingredients were dissolved. (III) Talc and simethi Ingredients % Wiw cone was added while stirring using a high shear mixer until finely dispersed in the solution. Eudragit E 59.29 Sodium Laurylsulfate 5.93 Step 4. Application of Coating Suspension from Step 3 to Stearic acid 8.89 Form a Pod-Like Envelope Surrounding the Bi-Layer Tablet Talc 20.75 from Step 2: Simethicone 17.09 Water qS 0557. Tablets from step 2 were charged into a rotating drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 3 was applied to the tablets obtained from Step 2, using a Formula for the Overcoat peristaltic pump and spray gun. The Suspension was dried as 0551 a film onto the tablets, using heated air drawn through the tablet bed from an inlet fan. A sufficient amount of the sus pension was applied to form from about 10 mg/cm to about Ingredients % Wiw 100 mg/cm of the coat surrounding the bi-layer tablet. Opadry 37.50 Step 5. Preparation of Overcoating Suspension of the Ingre Furnaric Acid 62.50 dients of the Overcoat Applied to the Coated Tablet from Step 4: US 2015/025.0733 A1 Sep. 10, 2015
0558 (I) Water was added into a stainless steel vessel and -continued Opadry was gradually added while stirring with a propeller mixer with controlled speed, sufficient to prevent sedimenta Ingredients % Wiw tion and lump formation. (II) The fumaric acid portion was Talc 20.75 added stepwise until no lumps were seen. Simethicone 17.09 Step 6. Application of Coating Suspension from Step 5 to Water qs Forman Overcoat Surrounding the Coated Tablets from Step 4: 0559 Tablets from step 4 were charged into a rotating Formula for the Overcoat drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 5 0563 was applied to the tablets obtained from Step 4, using a peristaltic pump and spray gun. The Suspension was dried as a film onto the tablets, using heated air drawn through the Ingredients % Wiw tablet bed from an inlet fan. A sufficient amount of the sus Opadry 23.35 pension was applied Such that the coat contained from 10 mg Fumaric Acid 38.00 to 600 mg of fumaric acid per coated tablet. Citric Acid 38.15 Sucrose Octaacetate OSO Isopropyl Alcohol qs Example 28 Water qs Oxycodone Sustained Action (SA) 40 mg Tablets (40 mg Tablets Contain 30 mg Maintenance Dose and 10 mg Processing Techniques Loading Dose) Step 1. Preparation of Granules for the Maintenance Dose: Formula for Maintenance Dose 0564 All the ingredients with the exception of the mag 0560 nesium Stearate from the maintenance dose formula were charged into a high shear granulator and dry mixed for less than 10 minutes. The dry mixed granules were discharged Ingredients % Wiw into a Paterson Kelly V-Blender. The magnesium stearate was Oxycodone (particle size 4.29 then added to the V-Blender. The granules were blended for <400 microns) less than 10 minutes. Polyethylene Oxide 70.71 (particle size <400 Step 2. Preparation of Tablets Containing Maintenance Dose: microns) Lactose S.OO 0565 A rotary press was set-up to produce tablets (The Crospovidone 3.00 Microcrystalline cellulose 11.00 Hata rotary tablet press was used). Granules from Step 1 were Eudragit RL S.OO discharged into the feed hopper and compressed to form Sucrose Octaacetate O.2O tablets. Magnesium Stearate OSO Step 3. Preparation of Coating Suspension of the Ingredients for the Loading Dose was Applied on the Tablet: Formula for Loading Dose 0566 (I) Water was added into a stainless steel vessel. (II) Opadry followed by sucrose octaacetate was added while 0561 stirring with a propeller mixer until all ingredients were finely dispersed in a Suspension. (III) Oxycodone was added to the Ingredients % Wiw Opadry/octaacetate water mixture while stirring using a pro peller mixer. Opadry 84.2O Oxycodone (particle size 15.8O Step 4. Application of Coating Suspension from Step 3 to <400 microns) Form Part of the Loading Dose Surrounding the Tablet from Sucrose octaacetate O.2O Step 2: Water qS 0567 Tablets from step 2 were charged into a rotating drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 3 Formula for the Pod-Like Envelope was applied to the tablets obtained from Step 2, using a peristaltic pump and spray gun. The Suspension was dried as 0562 a film onto the tablets, using heated air drawn through the tablet bed from an inlet fan. The suspension was applied to form a coat Surrounding the tablet. Ingredients % Wiw Eudragit E 59.00 Step 5. Preparation of a Coating Suspension of the Sucrose Octaacetate O.29 Ingredients for a Pod-Like Envelope: Sodium Laurylsulfate 5.93 Stearic acid 8.89 0568 (I) Water was added into a stainless steel vessel followed by sodium lauryl sulfate and stearic acid, step-by US 2015/025.0733 A1 Sep. 10, 2015 59 step, while stirring vigorously with a high shear mixer until -continued all ingredients are dissolved. (II) Eudragit E was added, step by-step, while stirring vigorously with a high shear mixer Ingredients % Wiw until all ingredients were dissolved. (III) Talc and simethi Eudragit RL S.OO cone was added while stirring using a high shear mixer until Sucrose Octaacetate O.OO finely dispersed in the solution. Magnesium Stearate O.SO Step 6. Application of a Coating Suspension from Step 5 to Form a Pod-Like Envelope Surrounding the Coated Tablet from Step 4: 0569 Tablets from Step 4 were charged into the rotating Formula for Loading Dose drum of a side vented automated Tablet coater (Rama Cota 0574) Tablet Film Coater was used). The suspension from Step 5 was applied to the tablets obtained from Step 4, using a peristaltic pump and spray gun. The Suspension was dried as Ingredients % Wiw a film onto the tablets, using heated air drawn through the tablet bed from an inlet fan. Opadry 84.2O Oxycodone (particle size 15.8O 0570 A sufficient amount of the suspension is applied to <400 microns) form about 20 mg/cm to about 60 mg/cm of the coat sur Water qs rounding the coated tablet. Step 7. Preparation of Overcoating Suspension of the Ingre dients of the Overcoat Applied to the Coated Tablet from Step 6: Formula for the Pod-Like Envelope 0571 (I) Isopropyl alcohol was added into a stainless steel (0575 vessel. Sucroase Octaacetate was added followed by water while stirring. Gradually add citric acid followed by fumaric acid while stirring with a propeller mixer under controlled Ingredients % Wiw speed, Sufficient to prevent sedimentation and lump forma Eudragit E 59.29 tion. (II) The Opadry portion was added stepwise until no Sodium Laurylsulfate 5.93 lumps were seen. Stearic acid 8.89 Step 8. Application of Coating Suspension from Step 7 to Talc 20.75 Forman Overcoat Surrounding the Coated Tablets from Step Simethicone 17.09 6: Water qs 0572 Tablets from step 6 were charged into a rotating drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 7 Formula for the Overcoat was applied to the tablets obtained from Step 6, using a peristaltic pump and spray gun. The Suspension was dried as 0576 a film onto the tablets, using heated air drawn through the tablet bed from an inlet fan. A sufficient amount of the sus pension was applied Such that the coat contained from 10 mg Ingredients % Wiw to 600 mg of citric acid and fumaric acid per coated tablet and Opadry 23.35 enough Sucrose octaacetate to make the tablet objectionable Fumaric Acid 38.00 tO taste Citric Acid 38.6S Isopropyl Alcohol qs Example 29 Water qs Oxycodone Sustained Action (SA) 40 mg Tablets Processing Techniques (40 mg Tablets Contain 30 mg Maintenance Dose and 10 mg Loading Dose) Step 1. Preparation of Granules for the Maintenance Dose: Formula for Maintenance Dose 0577 All the ingredients with the exception of the mag nesium Stearate from the maintenance dose formula were 0573 charged into a high shear granulator and dry mixed for less than 10 minutes. The dry mixed granules were discharged into a Paterson Kelly V-Blender. The magnesium stearate was Ingredients % Wiw then added to the V-Blender. The granules were blended for Oxycodone (particle size 4.29 less than 10 minutes. <400 microns) Polyethylene Oxide 50.71 (particle size <400 Step 2. Preparation of Tablets Containing Maintenance Dose: microns) Lactose 2O.OO 0578. A rotary press was set-up to produce tablets (The Crospovidone 6.OO Hata rotary tablet press was used). Granules from Step 1 were Microcrystalline cellulose 13.50 discharged into the feed hopper and compressed to form tablets. US 2015/025.0733 A1 Sep. 10, 2015 60
Step 3. Preparation of Coating Suspension of the Ingredients to 600 mg of citric acid and fumaric acid per coated tablet and for the Loading Dose was Applied on the Tablet: enough Sucrose octaacetate to make the tablet objectionable tO taste 0579 (I) Water was added into a stainless steel vessel. (II) Opadry was added while stirring with a propeller mixer until Example 30 all ingredients were finely dispersed in a suspension. (III) Oxycodone was added to the Opadry water mixture while stirring using a propeller mixer. Zolpidem Sustained Action (SA) 15 mg Tablets Step 4. Application of Coating Suspension from Step 3 to (15 mg Tablets Contain 16 mg Maintenance Dose and 5 mg Form Part of the Loading Dose Surrounding the Tablet from Loading Dose) Step 2: 0580 Tablets from step 2 were charged into a rotating Formula for Maintenance Dose drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 3 0586 was applied to the tablets obtained from Step 2, using a peristaltic pump and spray gun. The Suspension was dried as a film onto the tablets, using heated air drawn through the Ingredients % Wiw tablet bed from an inlet fan. The suspension was applied to Zolpidem (particle size S.OO <500 microns) form a coat Surrounding the tablet. Polyethylene Oxide 76.OO (particle size <600 Step 5. Preparation of a Coating Suspension of the microns) Ingredients for a Pod-Like Envelope: Lactose 6.OO Crospovidone 2.OO Microcrystalline cellulose S.OO 0581 (I) Water was added into a stainless steel vessel Eudragit RL S.OO followed by sodium lauryl sulfate and stearic acid, step-by Sucrose Octaacetate OSO step, while stirring vigorously with a high shear mixer until Magnesium Stearate OSO all ingredients are dissolved. (II) Eudragit E was added, step by-step, while stirring vigorously with a high shear mixer until all ingredients were dissolved. (III) Talc and simethi cone was added while stirring using a high shear mixer until Formula for Loading Dose finely dispersed in the solution. 0587 Step 6. AApplication of a Coating Suspension from Step 5 to Form a Pod-Like Envelope Surrounding the Coated Tablet from Step 4: Ingredients % Wiw 0582 Tablets from Step 4 were charged into the rotating Opadry 75.00 drum of a side vented automated Tablet coater (Rama Cota Crospovidone S.OO Tablet Film Coater was used). The suspension from Step 5 Zolpidem (particle size 2O.OO was applied to the tablets obtained from Step 4, using a <500 microns) peristaltic pump and spray gun. The Suspension was dried as Water qs a film onto the tablets, using heated air drawn through the tablet bed from an inlet fan. 0583. A sufficient amount of the suspension is applied to Formula for the Pod-Like Envelope form about 8 mg/cm to about 60 mg/cm of the coat sur rounding the coated tablet. 0588 Step 7. Preparation of Overcoating Suspension of the Ingre dients of the Overcoat Applied to the Coated Tablet from Step Ingredients % Wiw 6 Eudragit E 57.29 0584 (I) Isopropyl alcohol followed by water was added Sodium Laurylsulfate 5.93 into a stainless steel vessel. Gradually add citric acid followed Stearic acid 8.89 by fumaric acid while stirring with a propeller mixer under Crospovidone 2.00 Talc 20.75 controlled speed, Sufficient to prevent sedimentation and Simethicone 17.09 lump formation. (II) The Opadry portion was added stepwise Water qs until no lumps were seen. Step 8, Application of Coating Suspension from Step 7 to Forman Overcoat Surrounding the Coated Tablets from Step 6: Formula for the Overcoat 0585 Tablets from step 6 were charged into a rotating 0589 drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 7 was applied to the tablets obtained from Step 6, using a Ingredients % Wiw peristaltic pump and spray gun. The Suspension was dried as Opadry 23.35 a film onto the tablets, using heated air drawn through the Fumaric Acid 38.00 tablet bed from an inlet fan. A sufficient amount of the sus Citric Acid 38.6S pension was applied Such that the coat contained from 10 mg US 2015/025.0733 A1 Sep. 10, 2015 61
-continued pension was applied to form about 10 mg/cm to about 35 mg/cm of the coat Surrounding the coated tablet. Ingredients % Wiw Step 7. Preparation of Overcoating Suspension of the Ingre Isopropyl Alcohol qS dients of the Overcoat Applied to the Coated Tablet from Step Water qS 6: 0596 (I) Isopropyl alcohol followed by water was added into a stainless steel vessel. Gradually add citric acid followed Processing Techniques by fumaric acid while stirring with a propeller mixer under controlled speed, Sufficient to prevent sedimentation and Step 1. Preparation of Granules for the Maintenance Dose: lump formation. (II) The Opadry portion was added stepwise 0590 All the ingredients with the exception of the mag until no lumps were seen. nesium Stearate from the maintenance dose formula were Step 8. Application of Coating Suspension from Step 7 to charged into a high shear granulator and dry mixed for less Form an Overcoat Surrounding the Coated Tablets from Step than 10 minutes. The dry mixed granules were discharged 6: into a Paterson Kelly V-Blender. The magnesium stearate was 0597 Tablets from step 6 were charged into a rotating then added to the V-Blender. The granules were blended for drum of a side vented automated Tablet coater (Rama Cota less than 10 minutes. Tablet Film Coater was used). The suspension from Step 7 was applied to the tablets obtained from Step 6, using a Step 2. Preparation of Tablets Containing Maintenance Dose: peristaltic pump and spray gun. The Suspension was dried as 0591. A rotary press was set-up to produce tablets (The a film onto the tablets, using heated air drawn through the Hate rotary tablet press was used). Granules from Step 1 were tablet bed from an inlet fan. A sufficient amount of the sus discharged into the feed hopper and compressed to form pension was applied Such that the coat contained from 10 mg tablets. to 600 mg of citric acid and fumaric acid per coated tablet and enough Sucrose octaacetate to make the tablet objectionable Step 3. Preparation of Coating Suspension of the Ingredients tO taste for the Loading Dose was Applied on the Tablet: 0592 (I) Water was added into a stainless steel vessel. (II) Example 31 Opadry was added while stirring with a propeller mixer until all ingredients are finely dispersed in a Suspension. (III) Oxycodone Sustained Action (SA) 40 mg Tablets Zolpidem was added to the Opadry water mixture while stir ring using a propeller mixer. (40 mg Tablets Contain 35 mg Maintenance Dose and 5 mg Step 4. Application of a Coating Suspension from Step 3 to Loading Dose) Form Part of the Loading Dose Surrounding the Tablet from Step 2: 0593 Tablets from step 2 were charged into a rotating Formula for Maintenance Dose drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 3 0598 was applied to the tablets obtained from Step 2, using a peristaltic pump and spray gun. The Suspension was dried as a film onto the tablets, using heated air drawn through the Ingredients % Wiw tablet bed from an inlet fan. The suspension is applied to form Oxycodone (particle size S.OO <400 microns) a coat Surrounding the tablet. Polyethylene Oxide 46.50 Step 5. Preparation of a Coating Suspension of the Ingredi (particle size <400 ents for a Pod-Like Envelope was Applied to the Coated microns) Tablet from Step 4: Sucrose octaacetate OSO Lactose 26.OO 0594 (I) Water was added into a stainless steel vessel Crospovidone S.OO followed by sodium lauryl sulfate and stearic acid, step-by Microcrystalline cellulose 12.00 step while stirring vigorously with a high shear mixer until all Eudragit RL S.OO ingredients were dissolved. (II) Eudragit E was added, step Magnesium Stearate OSO by-step, while stirring vigorously with a high shear mixer until all ingredients were dissolved. (III) Talc and simethi cone was added while stirring using a high shear mixer until finely dispersed in the solution. Formula for Loading Dose Step 6. Application of Coating Suspension from Step 5 to Form a Pod-Like Envelope Surrounding the Coated Tablet 0599 from Step 4: 0595 Tablets from step 4 were charged into the rotating Ingredients % Wiw drum of a side vented automated Tablet coater (Rama Cola Opadry 75.00 Tablet Film Coater was used). The suspension from Step 5 Oxycodone (particle size 2S.OO was applied to the tablets obtained from Step 4, using a <400 microns) peristaltic pump and spray gun. The Suspension was dried as Water qs a film onto the tablets, using heated air drawn through the tablet bed from an inlet fan. A sufficient amount of the sus US 2015/025.0733 A1 Sep. 10, 2015 62
Formula for the Pod-Like Envelope Step 5. Preparation of a Coating Suspension of the Ingredients for a Pod-Like Envelope: 0600 0606 (I) Water was added into a stainless steel vessel followed by sodium lauryl sulfate and stearic acid, step-by Ingredients % Wiw step, while stirring vigorously with a high shear mixer until all ingredients were dissolved (II) Eudragit E was added Eudragit E SO.29 Polacrilin Potassium 9.OO step-by-step while stirring vigorously with a high shear mixer Sodium Laurylsulfate 5.93 until all ingredients were dissolved. (III) Talc was added Stearic acid 8.89 followed by Polacrilin potassium and simethicone while stir Talc 20.75 ring using a high shear mixer until finely dispersed in the Simethicone 17.09 Solution. Water qS Step 6. Application of Coating Suspension from Step 5 to Form a Pod-Like Envelope Surrounding the Coated Tablet from Step 4: Formula for the Overcoat 0607 Tablets from step 4 were charged into the rotating drum of a side vented automated Tablet coater (Rama Cota 0601 Tablet Film Coater was used). The suspension from Step 5 was applied to the tablets obtained from Step 4, using a peristaltic pump and spray gun. The Suspension was dried as Ingredients % Wiw a film onto the tablets, using heated air drawn through the Opadry 23.35 tablet bed from an inlet fan. A sufficient amount of the sus Fumaric Acid 76.60 pension is applied to form about 15 mg/cm to about 20 Water qs mg/cm of the coat surrounding the coated tablet. Step 7. Preparation of Overcoating Suspension of the Ingre dients of the Overcoat Applied to the Coated Tablet from Step Processing Techniques 6: 0608 (I) Isopropyl alcohol followed by water was added into a stainless steel vessel. Gradually add fumaric acid while Step 1. Preparation of Granules for the Maintenance Dose: stirring with a propeller mixer under controlled speed, suffi cient to prevent sedimentation and lump formation. (II) Add 0602 All the ingredients with the exception of the mag Opadry portion stepwise until no lumps are seen. nesium Stearate from the maintenance dose formula were Step 8. Application of Coating Suspension from Step 7 to charged into a high shear granulator and dry mixed for less Form an Overcoat Surrounding the Coated Tablets from Step than 10 minutes. The dry mixed granules were discharged 6: into a Paterson Kelly V-Blender. The magnesium stearate was 0609 Tablets from step 6 were charged into a rotating then added to the V-Blender. The granules were blended for drum of a side vented automated Tablet coater (Rama Cota less than 10 minutes. Tablet Film Coater was used). The suspension from Step 7 was applied to the tablets obtained from Step 6, using a Step 2. Preparation of Tablets Containing Maintenance Dose: peristaltic pump and spray gun. The Suspension was dried as 0603 A rotary press was set-up to produce tablets (The a film onto the tablets, using heated air drawn through the Hata rotary tablet press was used). Granules from Step 1 were tablet bed from an inlet fan. A sufficient amount of the sus discharged into the feed hopper and compressed to form pension was applied Such that the coat contained from 10 mg tablets. to 600 mg of fumaric acid per coated tablet. Example 32 Step 3. Preparation of Coating Suspension of the Ingredients for the Loading Dose Applied on the Tablet: Pregabalin Sustained Action (SA) 333 mg Tablets 0604 (I) Water was added into a stainless steel vessel. (II) (333 mg Tablets Contain 111 mg Maintenance Dose and 222 Opadry was added while stirring with a propeller mixer until mg Loading Dose of Pregabalin) all ingredients are finely dispersed in a suspension. (III) Oxy codone was added to the Opadry water mixture while stirring Formula for Maintenance Dose using a propeller mixer. Step 4. Application of a Coating Suspension from Step 3 to 0610 Form Part of the Loading Dose Surrounding the Tablet from Step 2: Ingredients % Wiw 0605 Tablets from step 2 were charged into a rotating Pregabalin 37.OO drum of a side vented automated Tablet coater (Rama Cota (particle size <400 Tablet Film Coater was used). The suspension from Step 3 microns) was applied to the tablets obtained from Step 2, using a Polyethylene Oxide 2S.OO (particle size <400 peristaltic pump and spray gun. The Suspension was dried as microns) a film onto the tablets, using heated air drawn through the Lactose Anhydrous DT 16.40 tablet bed from an inlet fan. The suspension is applied to form Microorystalline cellulose 12.00 a coat Surrounding the tablet. US 2015/025.0733 A1 Sep. 10, 2015 63
-continued V-Blender. The stearic acid was then added to the V-Blender. The granules were blended for less than 10 minutes. Ingredients % Wiw Crospovidone 2.00 Step 2. Preparation of a Bi-Layer Tablet Containing Eudragit RL 7.00 Magnesium Stearate O60 Maintenance Dose and Loading Dose: 0.617 The first layer is made from the granules prepared in Step 1a, and the second layer is made from granules prepared Formula for Loading Dose in Step 1b. A double rotary press was set-up to produce a 0611 bi-layer tablet (The Karnavati UNIK I FC double rotary and double layer tablet press was used). Granules from Step 1 a were charged into a first feed hopper and granules from Step Ingredients % Wiw 1b were charged into a second feed hopper and the bi-layer Pregabalin (particle size 37.OO tablet was produced from the double rotary press. <400 microns) Lactose 22:41 Hydroxypropyl S.OO Step 3. Preparation of Coating Suspension of the Ingredients methylcellulose for a Pod-Like Envelope was Applied on the Bi-Layer Tablet: Crospovidone S.OO Microcrystalline cellulose 12.00 0618 (I) Water was added into a stainless steel vessel Magnesium Stearate O.S followed by sodium lauryl sulfate and stearic acid, step-by step, while stirring vigorously with a high shear mixer until all ingredients are dissolved. (II) Eudragit E was added, step Formula for the Pod-Like Envelope by-step, while stirring vigorously with a high shear mixer 0612 until all ingredients were dissolved. (III) Talc and simethi cone was added while stirring using a high shear mixer until finely dispersed in the solution. Ingredients % Wiw Step 4. Application of Coating Suspension from Step 3 to Eudragit E 59.29 Form a Pod-Like Envelope Surrounding the Bi-Layer Tablet Sodium Laurylsulfate 5.93 from Step 2: Stearic acid 8.89 Talc 20.75 0619. Tablets from step 2 were charged into a rotating Simethicone 17.09 Water qS drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 3 was applied to the tablets obtained from Step 2, using a peristaltic pump and spray gun. The Suspension was dried as Formula for the Overcoat a film onto the tablets, using heated air drawn through the 0613 tablet bed from an inlet fan. A sufficient amount of the sus pension was applied to form from about 10 mg/cm to about 100 mg/cm of the coat surrounding the bi-layer tablet. Ingredients % Wiw Step 5. Preparation of Overcoating Suspension of the Ingre Opadry 37.50 dients of the Overcoat Applied to the Coated Tablet from Step Fumaric Acid 62.50 Isopropyl Alcohol qS 4: Water qS 0620 (I) Water was added into a stainless steel vessel and Opadry was gradually added while stirring with a propeller mixer with controlled speed, sufficient to prevent sedimenta Processing Techniques tion and lump formation. (II) The fumaric acid portion was 0614 Step 1a. Preparation of Granules for the Mainte added stepwise until no lumps were seen. nance Dose: Step 6. Application of Coating Suspension from Step 5 to 0615. All the ingredients with the exception of the mag Form an Overcoat Surrounding the Coated Tablets from Step nesium Stearate from the maintenance dose formula were 4: charged into a high shear granulator and dry mixed for less than 10 minutes. The dry mixed granules were discharged 0621 Tablets from step 4 were charged into a rotating into a Paterson Kelly V-Blender. The magnesium stearate was drum of a side vented automated Tablet coater (Rama Cota then added to the V-Blender. The granules were blended for Tablet Film Coater was used). The suspension from Step 5 less than 10 minutes. was applied to the tablets obtained from Step 4, using a Step 1b. Preparation of Granules for the Loading Dose: peristaltic pump and spray gun. The Suspension was dried as 0616 All the ingredients with the exception of the stearic a film onto the tablets, using heated air drawn through the acid from the loading dose formula were charged into a high tablet bed from an inlet fan. A sufficient amount of the sus shear granulator and dry mixed for less than 10 minutes. The pension was applied Such that the coat contained from 10 mg dry mixed granules were discharged into a Paterson Kelly to 600 mg of fumaric acid per coated tablet. US 2015/025.0733 A1 Sep. 10, 2015 64
Example 33 Formula for the Overcoat 0625 Amphetamine Sustained Action (SA) 20 mg Tablets
(20 mg Tablets Contain 10 mg Maintenance Dose and 10 mg Ingredients % Wiw Loading Dose) Equivalent to a Total of 12.5 mg Opadry 23.35 Fumaric Acid 38.00 Amphetamine Base Citric Acid 38.6S Isopropyl Alcohol qs Formula for Maintenance Dose Water qs 0622 Processing Techniques
Ingredients % Wiw Step 1. Preparation of Granules for the Maintenance Dose: Dextroamphetamine 1.25 0626. All the ingredients with the exception of the mag Sulfate nesium Stearate from the maintenance dose formula were (particle size <400 charged into a high shear granulator and dry mixed for less microns) Amphetamine Sulfate 1.25 than 10 minutes. The dry mixed granules were discharged (particle size <400 into a Paterson Kelly V-Blender. The magnesium stearate was microns) then added to the V-Blender. The granules were blended for Polyethylene Oxide 50.71 less than 10 minutes. (particle size <400 microns) Step 2. Preparation of Tablets Containing Maintenance Dose: Lactose 22.79 Crospovidone S.OO 0627. A rotary press was set-up to produce tablets (The Microcrystalline cellulose 13.00 Hats rotary tablet press was used). Granules from Step 1 were Eudragit RL S.OO discharged into the feed hopper and compressed to form Sucrose Octaacetate OSO tablets. Magnesium Stearate OSO Step 3. Preparation of Coating Suspension of the Ingredients for the Loading Dose was Applied on the Tablet: Formula for Loading Dose 0628 (I) Water was added into a stainless steel vessel. (II) Opadry and Sucrose octaacetate were added while stirring 0623 with a propeller mixer until all ingredients were finely dis persed in a suspension. (III) Dextroamphetamine Saccharate and Amphetamine Aspartate Monohydrate was added to the Ingredients % Wiw Opadry water mixture while stirring using a propeller mixer. Step 4. Application of Coating Suspension from Step 3 to Opadry 49.75 Sucrose octaacetate O.25 Form Part of the Loading Dose Surrounding the Tablet from Dextroamphetamine 2S.OO Step 2: Saccharate 0629 Tablets from step 2 were charged into a rotating (particle size <400 microns) drum of a side vented automated Tablet coater (Rama Cota Amphetamine Aspartate Tablet Film Coater was used). The suspension from Step 3 Monohydrate was applied to the tablets obtained from Step 2, using a (particle size <400 peristaltic pump and spray gun. The Suspension was dried as microns) a film onto the tablets, using heated air drawn through the Water tablet bed from an inlet fan. The suspension was applied to form a coat Surrounding the tablet. Step 5. Preparation of a Coating Suspension of the Formula for the Pod-Like Envelope Ingredients for a Pod-Like Envelope: 0624 0630 (I) Water was added into a stainless steel vessel followed by sodium lauryl sulfate and stearic acid, step-by step, while stirring vigorously with a high shear mixer until Ingredients all ingredients are dissolved. (II) Eudragit E was added, step Eudragit E SO.29 by-step, while stirring vigorously with a high shear mixer Sodium Laurylsulfate 5.93 until all ingredients were dissolved. (III) Talc and simethi Stearic acid 8.89 cone was added while stirring using a high sheer mixer until Talc 20.75 Simethicone 17.09 finely dispersed in the solution. Water Step 6. Application of a Coating Suspension from Step 5 to Form a Pod-Like Envelope Surrounding the Coated Tablet from Step 4: US 2015/025.0733 A1 Sep. 10, 2015
06.31 Tablets from Step 4 were charged into the rotating Formula for Loading Dose drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 5 0636 was applied to the tablets obtained from Step 4, using a peristaltic pump and spray gun. The Suspension was dried as a film onto the tablets, using heated air drawn through the Ingredients % Wiw tablet bed from an inlet fan. Opadry SO.OO 0632 A sufficient amount of the suspension is applied to Dextroamphetamine 2S.OO Saccharate form about 8 mg/cm to about 60 mg/cm of the coat sur (particle size <400 rounding the coated tablet. microns) Stem 7. Preparation of Overcoating Suspension of the Ingre Amphetamine Aspartate 2S.OO Monohydrate dients of the Overcoat Applied to the Coated Tablet from Step (particle size <400 6: microns) 0633 (I) Isopropyl alcohol followed by water was added Water qs into a stainless steel vessel. Gradually add citric acid followed by fumaric acid while stirring with a propeller mixer under controlled speed, Sufficient to prevent sedimentation and lump formation. (II) The Opadry portion was added stepwise Formula for the Pod-Like Envelope until no lumps were seen. 0637 Step 8. Application of Coating Suspension from Step 7 to Forman Overcoat Surrounding the Coated Tablets from Step 6: Ingredients % Wiw 0634 Tablets from step 6 were charged into a rotating Eudragit E 59.29 drum of a side vented automated Tablet coater (Rama Cota Sodium Laurylsulfate 5.93 Tablet Film Coater was used). The suspension from Step 7 Stearic acid 8.89 Talc 2O2S was applied to the tablets obtained from Step 6, using a Sucrose octaacetate OSO peristaltic pump and spray gun. The Suspension was dried as Simethicone 17.09 a film onto the tablets, using heated air drawn through the Water qs tablet bed from an inlet fan. A sufficient amount of the sus pension was applied Such that the coat contained from 10 mg to 600 mg of citric acid and fumaric acid per coated tablet and enough Sucrose octaacetate to make the tablet objectionable Formula for the Overcoat tO taste 0638 Example 34 Amphetamine Sustained Action (SA) 20 mg Tablets Ingredients % Wiw Opadry 23.35 Fumaric Acid 38.00 (20 mg Tablets Contain 10 mg Maintenance Dose and 10 mg Citric Acid 38.6S Loading Dose) Equivalent to a Total of 12.5 mg Isopropyl Alcohol qs Amphetamine Base Water qs
Formula for Maintenance Dose 0635 Processing Techniques Step 1. Preparation of Granules for the Maintenance Dose: Ingredients % Wiw Dextroamphetamine 1.25 0639 All the ingredients with the exception of the mag Sulfate nesium Stearate from the maintenance dose formula were (particle size <400 charged into a high shear granulator and dry mixed for less microns) than 10 minutes. The dry mixed granules were discharged Amphetamine Sulfate 1.25 (particle size <400 into a Paterson Kelly V-Blender. The magnesium stearate was microns then added to the V-Blender. The granules were blended for Polyethylene Oxide 50.71 less than 10 minutes. (particle size <400 microns) Lactose 22.79 Step 2. Preparation of Tablets Containing Maintenance Dose: Crospovidone S.OO Microcrystalline cellulose 13.50 Eudragit RL S.OO 0640. A rotary press was set-up to produce tablets (The Magnesium Stearate OSO Hata rotary tablet press was used). Granules from Step 1 were discharged into the feed hopper and compressed to form tablets. US 2015/025.0733 A1 Sep. 10, 2015 66
Step 3. Preparation of Coating Suspension of the Ingredients to 600 mg of citric acid and fumaric acid per coated tablet and for the Loading Dose was Applied on the Tablet: enough Sucrose octaacetate to make the tablet objectionable 0641 (I) Water was added into a stainless steel vessel. (II) tO taste Opadry was added while stirring with a propeller mixer until all ingredients were finely dispersed in a suspension. (III) Example 35 Dextroamphetamine Saccharate and Amphetamine Aspartate Monohydrate was added to the Opadry water mixture while Amphetamine Sustained Action (SA) 20 mg Tablets stirring using a propeller mixer. Step 4. Application of Coating Suspension from Step 3 to (20 mg Tablets Contain 10 mg Maintenance Dose and 10 mg Form Part of the Loading Dose Surrounding the Tablet from Loading Dose) Equivalent to a Total of 12.5 mg Step 2: Amphetamine Base 0642 Tablets from step 2 were charged into a rotating drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 3 Formula for Maintenance Dose was applied to the tablets obtained from Step 2, using a peristaltic pump and spray gun. The Suspension was dried as 0648 a film onto the tablets, using heated air drawn through the tablet bed from an inlet fan. The suspension was applied to Ingredients % Wiw form a coat Surrounding the tablet. Dextroamphetamine 1.25 Sulfate Step 5. Preparation of a Coating Suspension of the (particle size <400 Ingredients for a Pod-Like Envelope: microns) Amphetamine Sulfate 1.25 0643 (I) Water was added into a stainless steel vessel (particle size <400 followed by sodium lauryl sulfate and stearic acid, step-by microns) step, while stirring vigorously with a high shear mixer until Polyethylene Oxide 50.71 (particle size <400 all ingredients are dissolved. (II) Eudragit E was added, step microns) by-step, while stirring vigorously with a high shear mixer Lactose 22.79 until all ingredients were dissolved. (III) Talc, sucrose octaac Crospovidone S.OO etate and simethicone was added while stirring using a high Miroccrystalline cellulose 13.50 shear mixer until finely dispersed in the solution. Eudragit RL S.OO Step 6. Application of a Coating Suspension from Step 5 to Magnesium Stearate OSO Form a Pod-Like Envelope Surrounding the Coated Tablet from Step 4: 0644 Tablets from Step 4 were charged into the rotating Formula for Loading Dose drum of a side vented automated Tablet coater (Rama Cots Tablet Film Coater was used). The suspension from Step 5 0649) was applied to the tablets obtained from Step 4, using a peristaltic pump and spray gun. The Suspension was dried as a film onto the tablets, using heated air drawn through the Ingredients % Wiw tablet bed from an inlet fan. Opadry SO.OO 0645. A sufficient amount of the suspension is applied to Dextroamphetamine 2S.OO form about 8 mg/cm to about 60 mg/cm of the coat sur Saccharate (particle size <400 rounding the coated tablet. microns) Step 7. Preparation of Overcoating Suspension of the Ingre Amphetamine Aspartate 2S.OO dients of the Overcoat Applied to the Coated Tablet from Step Monohydrate 6: (particle size <400 0646) (I) Isopropyl alcohol followed by water was added microns) into a stainless steel vessel. Gradually add citric acid followed Water qs by fumaric acid while stirring with a propeller mixer under controlled speed, Sufficient to prevent sedimentation and lump formation. (II) The Opadry portion was added stepwise Formula for the Pod-Like Envelope until no lumps were seen. Step 8. Application of Coating Suspension from Step 7 to 0650 Forman Overcoat Surrounding the Coated Tablets from Step 6: 0647 Tablets from step 6 were charged into a rotating Ingredients % Wiw drum of a side vented automated Tablet coater (Rama Cota Eudragit E 59.29 Tablet Film Coater was used). The suspension from Step 7 Sodium Laurylsulfate 5.93 was applied to the tablets obtained from Step 6, using a Stearic acid 8.89 Talc 20.75 peristaltic pump and spray gun. The Suspension was dried as Simethicone 17.09 a film onto the tablets, using heated air drawn through the Water qs tablet bed from an inlet fan. A sufficient amount of the sus pension was applied Such that the coat contained from 10 mg US 2015/025.0733 A1 Sep. 10, 2015 67
Formula for the Overcoat Step 6. Application of a Coating Suspension from Step 5 to Form a Pod-Like Envelope Surrounding the Coated Tablet 0651) from Step 4: 0657 Tablets from Step 4 were charged into the rotating Ingredients % Wiw drum of a side vented automated Tablet coater (Rama Cota Opadry 23.35 Tablet Film Coater was used). The suspension from Step 5 Fumaric Acid 38.00 was applied to the tablets obtained from Step 4, using a Citric Acid 38.65 peristaltic pump and spray gun. The Suspension was dried as Isopropyl Alcohol qS Water qS a film onto the tablets, using heated air drawn through the tablet bed from an inlet fan. 0658. A sufficient amount of the suspension is applied to Processing Techniques form about 8 mg/cm to about 60 mg/cm of the coat sur rounding the coated tablet. Step 1. Preparation of Granules for the Maintenance Dose: Step 7. Preparation of Overcoating Suspension of the Ingre dients of the Overcoat Applied to the Coated Tablet from Step 0652 All the ingredients with the exception of the mag 6: nesium Stearate from the maintenance dose formula were charged into a high shear granulator and dry mixed for less 0659 (I) Isopropyl alcohol followed by water was added than 10 minutes. The dry mixed granules were discharged into a stainless steel vessel. Gradually add citric acid followed into a Paterson Kelly V-Blender. The magnesium stearate was by fumaric acid while stirring with a propeller mixer under then added to the V-Blender. The granules were blended for controlled speed, Sufficient to prevent sedimentation and less than 10 minutes. lump formation. (II) The Opadry portion was added stepwise until no lumps were seen. Step 2. Preparation of Tablets Containing Maintenance Dose: Step 8. Application of Coating Suspension from Step 7 to 0653. A rotary press was set-up to produce tablets (The Form an Overcoat Surrounding the Coated Tablets from Step Hats rotary tablet press was used). Granules from Step 1 were 6: discharged into the feed hopper and compressed to form 0660 Tablets from step 6 were charged into a rotating tablets. drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 7 Step 3. Preparation of Coating Suspension of the Ingredients was applied to the tablets obtained from Step 6, using a for the Loading Dose was Applied on the Tablet: peristaltic pump and spray gun. The Suspension was dried as 0654 (I) Water was added into a stainless steel vessel. (II) a film onto the tablets, using heated air drawn through the Opadry was added while stirring with a propeller mixer until tablet bed from an inlet fan. A sufficient amount of the sus all ingredients were finely dispersed in a suspension. (III) pension was applied Such that the coat contained from 10 mg Dextroamphetamine Saccharate and Amphetamine Aspartate to 600 mg of citric acid and fumaric acid per coated tablet. Monohydrate was added to the Opadry water mixture while stirring using a propeller mixer. Example 36 Step 4. Application of Coating Suspension from Step 3 to Form Part of the Loading Dose Surrounding the Tablet from Oxycodone Sustained Action (SA) 40 mg Tablets Step 2: 0655 Tablets from step 2 were charged into a rotating (40 mg Tablets Contain 36 mg Maintenance Dose and 6 mg drum of a side vented automated Tablet coater (Rama Cota Loading Dose) Tablet Film Coater was used). The suspension from Step 3 was applied to the tablets obtained from Step 2, using a peristaltic pump and spray gun. The Suspension was dried as Formula for Maintenance Dose a film onto the tablets, using heated air drawn through the tablet bed from an inlet fan. The suspension was applied to 0661 form a coat Surrounding the tablet. Step 5. Preparation of a Coating Suspension of the Ingredients % Wiw Ingredients for a Pod-Like Envelope: Oxycodone (particle size S.OO <400 microns) Polyethylene Oxide 76.50 0656 (I) Water was added into a stainless steel vessel (particle size <400 followed by sodium lauryl sulfate and stearic acid, step-by microns) step, while stirring vigorously with a high shear mixer until Lactose 6.OO all ingredients are dissolved. (II) Eudragit E was added, step Crospovidone 2.OO Microcrystalline cellulose S.OO by-step, while stirring vigorously with a high shear mixer Eudragit RL S.OO until all ingredients were dissolved. (III) Talc and simethi Magnesium Stearate OSO cone was added while stirring using a high shear mixer until finely dispersed in the solution. US 2015/025.0733 A1 Sep. 10, 2015 68
Formula for Loading Dose Step 4. Application of Coating Suspension from Step 3 to Form Part of the Loading Dose Surrounding the Tablet from 0662 Step 2: 0668 Tablets from step 2 were charged into a rotating Ingredients % Wiw drum of a side vented automated Tablet coater (Rama Cota Opadry 75.00 Tablet Film Coater was used). The suspension from Step 3 Oxycodone (particle size 2S.OO was applied to the tablets obtained from Step 2, using a <400 microns) peristaltic pump and spray gun. The Suspension was dried as Water qS a film onto the tablets, using heated air drawn through the tablet bed from an inlet fan. The suspension is applied to form a coat Surrounding the tablet. Formula for the Pod-Like Envelope 0663 Step 5. Preparation of a Coating Suspension of the Ingredients for a Pod-Like Envelope: Ingredients % Wiw 0669 (I) Hot water was added into a stainless steel vessel Eudragit E 36.09 followed by Sodium lauryl sulfate and Stearic acid, step-by Polysaccharide 12.00 step, while stirring vigorously with a high shear mixer until Sodium Laurylsulfate 5.93 Stearic acid 8.89 dissolved. (II) Eudragit E was added followed by Talc, step Talc 2O.OO by-step, while stirring vigorously with a high shear mixer Simethicone 17.09 until all ingredients were dissolved. (III) Polyssacharide was Water qS added, followed by Simethicone while stirring using a high shear mixer until finely dispersed in the solution. Step 6. Application of Coating Suspension from Step 5 to Formula for the Overcoat Form a Pod-Like Envelope Surrounding the Coated Tablet 0664 from Step 4: 0670 Tablets from step 4 were charged into the rotating Ingredients % Wiw drum of a side vented automated Tablet coater (Rama Cota Opadry 23.35 Tablet Film Coater was used). The suspension from Step 5 Fumaric Acid 38.00 was applied to the tablets obtained from Step 4, using a Citric Acid 38.65 peristaltic pump and spray gun. The Suspension was dried as Isopropyl Alcohol qS Water qS a film onto the tablets, using heated air drawn through the tablet bed from an inlet fan. A sufficient amount of the sus pension was applied to form about 10 mg/cm to about 40 Processing Techniques mg/cm of the coat surrounding the coated tablet. Step 7. Preparation of Overcoating Suspension of the Ingre Step 1. Preparation of Granules for the Maintenance Dose: dients of the Overcoat Applied to the Coated Tablet from Step 0665 All the ingredients with the exception of the mag 6: nesium Stearate from the maintenance dose formula were charged into a high shear granulator and dry mixed for less 0671 (I) Isopropyl alcohol followed by water was added than 10 minutes. The dry mixed granules were discharged into a stainless steel vessel. Gradually add citric acid followed into a Paterson Kelly V-Blender. The magnesium stearate was by fumaric acid while stirring with a propeller mixer under then added to the V-Blender. The granules were blended for controlled speed, Sufficient to prevent sedimentation and less than 10 minutes. lump formation. (II) The Opadry portion was added stepwise until no lumps were seen. Step 2. Preparation of Tablets Containing Maintenance Dose: Step 8. Application of Coating Suspension from Step 7 to 0666. A rotary press was set-up to produce tablets (The Form an Overcoat Surrounding the Coated Tablets from Step Hata rotary tablet press was used). Granules from Step 1 were 6: discharged into the feed hopper and compressed to form tablets. 0672 Tablets from step 6 were charged into a rotating drum of a side vented automated Tablet coater (Rama Cota Step 3. Preparation of a Coating Suspension of the Tablet Film Coater was used). The suspension from Step 7 Ingredients for the Loading Dose was Applied on the Tablet: was applied to the tablets obtained from Step 6, using a 0667 (I) Water was added into a stainless steel vessel. (II) peristaltic pump and spray gun. The Suspension was dried as Opadry was added while stirring with a propeller mixer until a film onto the tablets, using heated air drawn through the all ingredients were finely dispersed in a suspension. (III) tablet bed from an inlet fan. A sufficient amount of the sus Oxycodone was added to the Opadry water mixture while pension was applied Such that the coat contained from 10 mg stirring using a propeller mixer. to 600 mg of citric acid and fumaric acid per coated tablet. US 2015/025.0733 A1 Sep. 10, 2015 69
Example 37 Processing Techniques Morphine Sustained Action (SA) 30 mg Tablets Step 1. Preparation of Granules for the Maintenance Dose by Hot Melt Extrusion: (30 mg Tablets Contain 25 mg Maintenance Dose and Mg 0677 All the ingredients with the exception of the mag Loading Dose) nesium Stearate and microcrystalline cellulose from the main tenance dose formula were added into a high shear granulator Formula for Maintenance Dose and dry mixed for less than 10 minutes. The dry mixed gran ules were discharged into a hopper of a Hot Melt Extruder and 0673 gradually fed into the Hot Melt Extruder heated barrel, while mixing by using the rotating screw element of the extruder. The material was extruded through a die attached at the end of Ingredients % Wiw a barrel. The extrudates were milled into granules. The milled Morphine S.OO granules were charged into a Paterson Kelly V-Blender. The (particle size 1000 magnesium Stearate and microcrystalline cellulose were microns) added into the V-Blender and blended for less than 10 min Polyethylene Oxide 57.00 utes. (particle size 1000 microns) Crospovidone S.OO Step 2 Preparation of Tablets Containing Maintenance Dose: Microcrystalline cellulose S.OO Eudragit RL S.OO 0678. A rotary press was set-up to produce tablets (The Triethy citrate 1O.OO Hata rotary tablet press was used). Granules from Step 1 were Capsicum oleoresin S.OO discharged into the feed hopper and compressed to form Magnesium Stearate 1.OO tablets. Step 3. Preparation of a Coating Suspension of the Formula for Loading Dose Ingredients for the Loading Dose was Applied on the Tablet: 0679 (I) Water was added into a stainless steel vessel. (II) 0674) Opadry was added while stirring with a propeller mixer until all ingredients were finely dispersed in a suspension. (III) Morphine and Capsicum oleoresin was added to the Opadry Ingredients % Wiw water mixture while stirring using a propeller mixer. Opadry 83.OO Step 4. Application of Coating Suspension from Step 3 to Capsicum oleoresin 3.35 Form Part of the Loading Dose Surrounding the Tablet from Morphine 16.65 Step 2: Water 0680 Tablets from step 2 were charged into a rotating drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 3 Formula for the Pod-Like Envelope was applied to the tablets obtained from Step 2, using a peristaltic pump and spray gun. The Suspension was dried as 0675 a film onto the tablets, using heated air drawn through the tablet bed from an inlet fan. The suspension is applied to form a coat Surrounding the tablet. Ingredients Step 5. Preparation of a Coating Suspension of the Eudragit E (milled) 4229 Sodium Laurylsulfate 5.93 Ingredients for a Pod-Like Envelope: Stearic acid (milled) 8.89 Talc 25.89 0681 (I) Water was added into a stainless steel vessel Simethicone 17.00 followed by Sodium lauryl sulfate and stearic acid, step-by Water step, while stirring vigorously with a high shear mixer until all ingredients are dissolved. (II) Eudragit E was added, step by-step, while stirring vigorously with a high shear mixer until all ingredients were dissolved. (III) Talc was added, Formula for the Overcoat followed by Slmethicone while stirring using a high shear mixer until finely dispersed in the solution. 0676 Step 6. Application of a Coating Suspension from Step 5 to Form a Pod-Like Envelope Surrounding the Coated Tablet from Step 4: Ingredients 0682 Tablets from step 4 were charged into the rotating Opadry 23.35 drum of a side vented automated Tablet coater (Rama Cota Fumaric Acid 38.00 Tablet Film Coater was used). The suspension from Step 5 Citric Acid 38.65 Isopropyl Alcohol qS was applied to the tablets obtained from Step 4, using a Water qS peristaltic pump and spray gun. The Suspension was dried as a film onto the tablets, using heated air drawn through the tablet bed from an inlet fan. A sufficient amount of the sus US 2015/025.0733 A1 Sep. 10, 2015 70 pension was applied to form about 40 mg/cm to about 50 Formula for the Pod-Like Envelope mg/cm of the coat surrounding the two-layered tablet. 0687 Step 7. Preparation of Overcoating Suspension of the Ingre dients of the Overcoat Applied to the Coated Tablet from Step 6: Ingredients % Wiw 0683 (I) Isopropyl alcohol followed by water was added Eudragit E 57.29 into a stainless steel vessel. Gradually add citric acid followed Sodium Laurylsulfate 5.93 by fumaric acid while stirring with a propeller mixer under Stearic Acid 8.89 Crospovidone 2.00 controlled speed, Sufficient to prevent sedimentation and Talc 20.75 lump formation. (II) The Opadry portion was added stepwise Simethicone 17.09 until no lumps were seen. Water qs Step 8. Application of Coating Suspension from Step 7 to Forman Overcoat Surrounding the Coated Tablets from Step 6: Formula for the Overcoat 0684 Tablets from step 6 were charged into a rotating 0688 drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 7 was applied to the tablets obtained from Step 6, using a Ingredients % Wiw peristaltic pump and spray gun. The Suspension was dried as Opadry 23.35 a film onto the tablets, using heated air drawn through the Fumaric Acid 38.00 tablet bed from an inlet fan. A sufficient amount of the sus Citric Acid 38.6S pension was applied Such that the coat contained from 10 mg Isopropyl Alcohol qs to 600 mg of citric acid and fumaric acid per coated tablet. Water qs Example 38 Processing Techniques Oxycodone Sustained Action (SA) 30 mg Tablets Step 1. Preparation of Granules for the Maintenance Dose: (25 mg Tablets Contain 25 mg Maintenance Dose and 6 mg 0689. An Oxycodone-Polacrilin complex was prepared by Loading Dose) continuously stirring Oxycodone and Polacrilin in water for 12 to 24 hours followed by filtration and drying of the com Formula for Maintenance Dose plex such that less than 10% water is present. The dried complex and all the other ingredients with the exception of 0685 the magnesium Stearate from the maintenance dose formula were charged into a high shear granulator and dry mix for less than 10 minutes. The granules were discharged into a Pater Ingredients % Wiw son Kelly V-Blender. The magnesium stearate was added to the V-Blender. The granules were blended for less than 10 Oxycodone HCl (particle 5 minutes. size <500 microns) Polyethylene Oxide 66.OO (particle size <600 Step 2. Preparation of Tablets Containing Maintenance Dose: microns) Polacrilin Potassium 1O.OO 0690. A rotary press was set-up to produce tablets (The Lactose 6.OO Crospovidone 2.OO Hata rotary tablet press was used). Granules from Step 1 were Microcrystalline cellulose S.OO discharged into the feed hopper and compressed to form Eudragit RL S.OO tablets. Magnesium Stearate OSO Water qS Step 3. Preparation of Coating Suspension of the Ingredients for the Loading Dose was Applied on the Tablet: 0691 (I) Water was added into a stainless steel vessel. (II) Formula for Loading Dose Opadry was added while stirring with a propeller mixer until all ingredients were finely dispersed in a suspension. (III) 0686) Oxycodone HC1 was added to the Opadry water mixture while stirring using a propeller mixer. Step 4 Application of the Coating Suspension from Step 3 to Ingredients % Wiw Form Part of the Loading Dose Surrounding the Tablet from Opacity 75.00 Step 2: Crospovidone S.OO Oxycodone HCl (particle 2O.OO 0692 Tablets from step 2 were charged into a rotating size <500 microns) drum of a side vented automated Tablet coater (Rama Cota Water qS Tablet Film Coater was used). The suspension from Step 3 was applied to the tablets obtained from Step 2, using a peristaltic pump and spray gun. The Suspension was dried as US 2015/025.0733 A1 Sep. 10, 2015
a film onto the tablets, using heated air drawn through the -continued tablet bed from an inlet fan. The suspension is applied to form a coat Surrounding the tablet. Ingredients % Wiw Step 5. Preparation of a coating Suspension of the ingredients Microcrystalline cellulose S.OO for a Pod-like envelope: Eudragit RL S.OO 0693 (I) Water was added into a stainless steel vessel Sucrose Octaacetate O.SO followed by Sodium lauryl sulfate and stearic acid step-by Magnesium Stearate O.SO step while stirring vigorously with a high shear mixer until all ingredients were dissolved. (II) Eudragit E was added, step by-step, while stirring vigorously with a high shear mixer Formula for Loading Dose until all ingredients were dissolved. (III) Talc and simethi cone was added while stirring using a high shear mixer until 0698 finely dispersed in the solution. Step 6. Application of the Coating Suspension from Step 5 to Form a Pod-Like Envelope Surrounding the Coated Tablet Ingredients % Wiw from Step 4: Opadry 83.OO 0694 Tablets from step 4 were charged into the rotating Sucrose Octaacetate O.34 drum of a side vented automated Tablet coater (Rama Cota Oxycodone 16.65 Tablet Film Coater was used). The suspension from Step 5 Water qs was applied to the tablets obtained from Step 4, using a peristaltic pump and spray gun. The Suspension was dried as a film onto the tablets, using heated air drawn through the Formula for the Pod Like Envelope tablet bed from an inlet fan. A sufficient amount of the sus pension was applied to form about 20 mg/cm to about 35 0699 mg/cm of the coat Surrounding the coated tablet. Step 7. Preparation of Overcoating Suspension of the Ingre Ingredients % Wiw dients of the Overcoat Applied to the Coated Tablet from Step 6: Eudragit E 59.29 Sodium Laurylsulfate 5.93 0695 (I) Isopropyl alcohol followed by water was added Stearic acid 8.89 into a stainless steel vessel. Gradually add citric acid followed Talc 20.75 by fumaric acid while stirring with a propeller mixer under Simethicone 17.09 controlled speed, Sufficient to prevent sedimentation and Water qs lump formation. (II) The Opadry portion was added stepwise until no lumps were seen. Step 8. Application of Coating Suspension from Step 7 to Formula for the Overcoat Forman Overcoat Surrounding the Coated Tablets from Step 6: 0700 0696 Tablets from step 6 were charged into a rotating drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 7 Ingredients % Wiw was applied to the tablets obtained from Step 6, using a Opadry 23.35 peristaltic pump and spray gun. The Suspension was dried as Fumaric Acid 38.00 Citric Acid 38.6S a film onto the tablets, using heated air drawn through the Isopropyl Alcohol qs tablet bed from an inlet fan. A sufficient amount of the sus Water qs pension was applied Such that the coat contained from 10 mg to 600 mg of citric acid and fumaric acid per coated tablet. Example 39 Processing Techniques Oxycodone Sustained Action (SA) Tablets Step 1. Preparation of Granules for the Maintenance Dose: (30 mg Tablets Contain 28 mg Maintenance Dose and 6 mg 0701 All the ingredients with the exception of the mag Loading Dose) nesium Stearate from the maintenance dose formula were charged into a high shear granulator and dry mixed for less Formula for Maintenance Dose than 10 minutes. The dry mixed granules were discharged into a Paterson Kelly V-Blender. The magnesium stearate was 0697 then added to the V-Blender. The granules were blended for less than 10 minutes. Ingredients % Wiw Step 2. Preparation of Tablets Containing Maintenance Dose: Oxycodone S.OO Polyethylene Oxide 76.OO 0702. A rotary press was set-up to produce tablets (The Lactose 6.OO Hata rotary tablet press was used). Granules from Step 1 were Crospovidone 2.OO discharged into the feed hopper and compressed to form tablets. US 2015/025.0733 A1 Sep. 10, 2015 72
Step 3. Preparation of a Coating Suspension of the Example 40 Ingredients for the Loading Dose was Applied on the Tablet: Hydromorphone Sustained Action (SA) Tablets 0703 (I) Water was added into a stainless steel vessel. (II) Opadry was added while stirring with a propeller mixer until (16 mg Tablets Contain 12 mg Maintenance Dose and 4 mg all ingredients were finely dispersed in a suspension. (III) Loading Dose) Oxycodone and Sucrose octacetate was added to the opadry water mixture while stirring using a propeller mixer. Formula for Maintenance Dose Step 4. Application of the Coating Suspension from Step 3 to Form Part of the Loading Dose Surrounding the Tablet from 0709) Step 2: 0704 Tablets from step 2 were charged into a rotating Ingredients % Wiw drum of a side vented automated Tablet coater (Rama Cota Hydromorphone 1.OO Tablet Film Coater was used). The suspension from Step 3 Polyethylene Oxide 6.OO was applied to the tablets obtained from Step 2, using a Lactose 26.OO peristaltic pump and spray gun. The Suspension was dried as Crospovidone 2.OO a film onto the tablets, using heated air drawn through the Microcrystalline cellulose 9.SO tablet bed from an inlet fan. The suspension is applied to form Eudragit RL S.OO a coat Surrounding the tablet. Magnesium Stearate OSO Step 5. Preparation of a Coating Suspension of the Ingredients for a Pod-Like Envelope: Formula for Loading Dose 0705 (I) Water was added into a stainless steel vessel 0710 followed by Sodium lauryl sulfate and stearic acid, step-by step, while stirring vigorously with a high shear mixer until all ingredients were dissolved. (II) Eudragit E was added, Ingredients % Wiw step-by-step, while stirring vigorously with a high shear Opadry 87.50 mixer until all ingredients were dissolved. (III) Talc and sim Hydromorphone 12.SO ethicone were added while stirring using a high shear mixer Water CS until finely dispersed in the solution. Step 6. Application of the Coating Suspension from Step 5 to Form a Pod-Like Envelope Surrounding the Coated Tablet Formula for the Pod Like Envelope from Step 4: 07.11 0706 Tablets from step 4 were charged into the rotating drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 5 Ingredients % Wiw was applied to the tablets obtained from Step 4, using a Eudragit E 59.29 peristaltic pump and spray gun. The Suspension was dried as Sodium Laurylsulfate 5.93 a film onto the tablets, using heated air drawn through the Stearic acid 8.89 tablet bed from an inlet fan. A sufficient amount of the sus Talc 20.75 pension was applied to form about 45 mgicm to about 80 Simethicone 17.09 mg/cm of the coat surrounding the coated tablet. Water qs Step 7. Preparation of Overcoating Suspension of the Ingre dients of the Overcoat Applied to the Coated Tablet from Step 6: Formula for the Overcoat 0707 (I) Isopropyl alcohol followed by water was added 0712 into a stainless steel vessel. Gradually add citric acid followed by fumaric acid while stirring with a propeller mixer under controlled speed, Sufficient to prevent sedimentation and Ingredients % Wiw lump formation. (II) The Opadry portion was added stepwise Opadry 23.35 until no lumps were seen. Fumaric Acid 38.00 Step 8. Application of Coating Suspension from Step 7 to Citric Acid 38.6S Isopropyl Alcohol qs Forman Overcoat Surrounding the Coated Tablets from Step Water qs 6: 0708 Tablets from step 6 were charged into a rotating drum of a side vented automated Tablet coater (Rama Cota Tablet Film Coater was used). The suspension from Step 7 Processing Techniques was applied to the tablets obtained from Step 6, using a peristaltic pump and spray gun. The Suspension was dried as Step 1. Preparation of Granules for the Maintenance Dose by a film onto the tablets, using heated air drawn through the Hot Melt Extrusion: tablet bed from an inlet fan. A sufficient amount of the sus 0713 All the ingredients with the exception of the mag pension was applied Such that the coat contained from 10 mg nesium Stearate and microcrystalline cellulose from the main to 600 mg of citric acid and fumaric acid per coated tablet. tenance dose formula were added into a high shear granulator US 2015/025.0733 A1 Sep. 10, 2015
and dry mixed for less than 10 minutes. The dry mixed gran by fumaric acid while stirring with a propeller mixer under ules were discharged into a hopper of a Hot Melt Extruder and controlled speed, Sufficient to prevent sedimentation and gradually fed into the Hot Melt Extruder heated barrel, while lump formation. (II) The Opadry portion was added stepwise mixing by using the rotating screw element of the extruder. until no lumps were seen. The material was extruded through a die attached at the end of Step 8. Application of Coating Suspension from Step 7 to a barrel. The extrudates were milled into granules. The milled Form an Overcoat Surrounding the Coated Tablets from Step granules were charged into a Paterson Kelly V-Blender. The 6: magnesium Stearate and microcrystalline cellulose were 0720 Tablets from step 6 were charged into a rotating added into the V-Blender and blended for less than 10 min drum of a side vented automated Tablet coater (Rama Cota utes. Tablet Film Coater was used). The suspension from Step 7 was applied to the tablets obtained from Step 6, using a Step 2. Preparation of Tablets Containing Maintenance Dose: peristaltic pump and spray gun. The Suspension was dried as 0714. A rotary press was set-up to produce tablets (The a film onto the tablets, using heated air drawn through the Hata rotary tablet press was used). Granules from Step 1 were tablet bed from an inlet fan. A sufficient amount of the sus discharged into the feed hopper and compressed to form pension was applied Such that the coat contained from 10 mg tablets. to 600 mg of citric acid and fumaric acid per coated tablet. Step 3. Preparation of a Coating Suspension of the Example 41 Ingredients for the Loading Dose was Applied on the Tablet: Morphine Sustained Action (SA) 30 mg Tablets 0715 (I) Water was added into a stainless steel vessel. (II) Opadry was added while stirring with a propeller mixer until (30 mg Tablets Contain 25 mg Maintenance Dose and 5 mg all ingredients were finely dispersed in a suspension. (III) Loading Dose) Hydromorphone was added to the opadry water mixture while stirring using a propeller mixer. Formula for Maintenance Dose Step 4. Application of the Coating Suspension from Step 3 to Form Part of the Loading Dose Surrounding the Tablet from 0721 Step 2: 0716 Tablets from step 2 were charged into a rotating Ingredients % Wiw drum of a side vented automated Tablet coater (Rama Cota Morphine S.OO Tablet Film Coater was used). The suspension from Step 3 (particle size 1000 was applied to the tablets obtained from Step 2, using a microns) peristaltic pump and spray gun. The Suspension was dried as Polyethylene Oxide 57.00 a film onto the tablets, using heated air drawn through the (particle size 1000 microns) tablet bed from an inlet fan. The suspension is applied to form Crospovidone S.OO a coat Surrounding the tablet. Microcrystalline cellulose S.OO Eudragit RL S.OO Step 5. Preparation of a Coating Suspension of the Triethy citrate 1O.OO Ingredients for a Pod-Like Envelope: Capsicum oleoresin S.OO Magnesium Stearate 1.OO 0717 (I) Water was added into a stainless steel vessel followed by Sodium lauryl sulfate and stearic acid, step-by step, while stirring vigorously with a high shear mixer until Formula for Loading Dose all ingredients are dissolved. (II) Eudragit E was added, step by-step, while stirring vigorously with a high shear mixer 0722 until all ingredients are dissolved. (III) Talc and simethicone was added while stirring using a high sheer mixer until finely dispersed in the solution. Ingredients % Wiw Step 6. Application of the Coating Suspension from Step 5 to Soluplus S400 Form a Pod-Like Envelope Surrounding the Coated Tablet Cremaphor RH 40 6.OO from Step 4: Capsicum oleoresin 3.35 Morphine 16.65 0718 Tablets from step 4 were charged into the rotating Microcrystalline cellulose 9.OO drum of a side vented automated Tablet coater (Rama Cota Magnesium Stearate 1.OO Tablet Film Coater was used). The suspension from Step 5 was applied to the tablets obtained from Step 4, using a peristaltic pump and spray gun. The Suspension was dried as a film onto the tablets, using heated air drawn through the Formula for the Pod-Like Envelope tablet bed from an inlet fan. A sufficient amount of the sus 0723 pension was applied to form about 10 mg/cm to about 55 mg/cm of the coat surrounding the coated tablet. Step 7. Preparation of Overcoating Suspension of the Ingre Ingredients % Wiw dients of the Overcoat Applied to the Coated Tablet from Step Eudragit E (milled) 4229 6: Sodium Laurylsulfate 5.93 0719 (I) Isopropyl alcohol followed by water was added Stearic acid (milled) 8.89 into a stainless steel vessel. Gradually add citric acid followed US 2015/025.0733 A1 Sep. 10, 2015 74
-continued bi-layer tablet (The Karnavati UNIK I FC double rotary and double layer tablet press was used). Granules from Step 1 a Ingredients % Wiw were charged into a first feed hopper and granules from Step Talc 25.89 1b were charged into a second feed hopper and the bi-layer Simethicone 17.00 tablet was produced from the double rotary press. Water Qs Step 3. Preparation of a Coating Suspension of the Ingredients for a Pod-Like Envelope to be Applied to the Formula for the Overcoat Bi-Layer Tablet: 0729) (I) Water was added into a stainless steel vessel 0724 followed by Sodium lauryl sulfate and stearic acid, step-by step, while stirring vigorously with a high shear mixer until Ingredients % Wiw all ingredients are dissolved. (II) Eudragit E was added, step by-step, while stirring vigorously with a high shear mixer Opadry 23.35 Fumaric Acid 38.00 until all ingredients were dissolved. (III) Talc was added, Citric Acid 38.65 followed by simethicone while stirring using a high shear Isopropyl Alcohol Qs mixer until finely dispersed in the solution. Water Qs Step 4. Application of a Coating Suspension from Step 3 to Form a Pod-Like Envelope Surrounding the Bi-Layer Tablet from Step 2: Processing Techniques 0730 Tablets from step 2 were charged into the rotating drum of a side vented automated Tablet coater (Rama Cota 0725 Step 1a. Preparation of Granules for the Mainte Tablet Film Coater was used). The suspension from Step 3 nance Dose by Hot Melt Extrusion: was applied to the tablets obtained from Step 2, using a 0726 All the ingredients with the exception of the mag peristaltic pump and spray gun. The Suspension was dried as nesium Stearate and microcrystalline cellulose from the main a film onto the tablets, using heated air drawn through the tenance dose formula were added into a high shear granulator tablet bed from an inlet fan. A sufficient amount of the sus and dry mixed for less than 10 minutes. The dry mixed gran pension was applied to form about 10 mg/cm to about 50 ules were discharged into a hopper of a Hot Melt Extruder and mg/cm of the coat surrounding the bi-layer tablet. gradually fed into the Hot Melt Extruder heated barrel, while Step 5. Preparation of Overcoating Suspension of the Ingre mixing by using the rotating screw element of the extruder. dients of the Overcoat Applied to the Coated Tablet from Step The material was extruded through a die attached at the end of 4: a barrel. The extrudates were milled into granules. The milled granules were charged into a Paterson Kelly V-Blender. The 0731 (I) Isopropyl alcohol followed by water was added magnesium Stearate and microcrystalline cellulose were into a stainless steel vessel. Gradually add citric acid followed added into the V-Blender and blended for less than 10 min by fumaric acid while stirring with a propeller mixer under utes. controlled speed, Sufficient to prevent sedimentation and Step 1b. Preparation of the Granules for Loading Dose by Hot lump formation. (II) The Opadry portion was added stepwise Melt Extrusion: until no lumps were seen. 0727 All the ingredients with the exception of the mag Step 6. Application of Coating Suspension from Step 5 to nesium Stearate and microcrystalline cellulose from the main Form an Overcoat Surrounding the Coated Tablets from Step tenance dose formula were added into a high shear granulator 4: and dry mixed for less than 10 minutes. The dry mixed gran 0732 Tablets from step 4 were charged into a rotating ules were discharged into a hopper of a Hot Melt Extruder and drum of a side vented automated Tablet coater (Rama Cota gradually fed into the Hot Melt Extruder heated barrel, while Tablet Film Coater was used). The suspension from Step 5 mixing by using the rotating screw element of the extruder. was applied to the tablets obtained from Step 4, using a The material was extruded through a die attached at the end of peristaltic pump and spray gun. The Suspension was dried as a barrel. The extrudates were milled into granules. The milled a film onto the tablets, using heated air drawn through the granules were charged into a Paterson Kelly V-Blender. The tablet bed from an inlet fan. A sufficient amount of the sus magnesium Stearate and microcrystalline cellulose were pension was applied Such that the coat contained from 10 mg added into the V-Blender and blended for less than 10 min to 600 mg of citric acid and fumaric acid per coated tablet. utes. The barrel section temperatures of the hot melt extruder are typically optimized so that the viscosity of the melt is low Example 42 enough to allow conveying down the barrel and proper mix ing, while keeping temperatures low enough to avoid thermal Results of Vaporization Studies degradation of the materials; typically about 100 to about 2009 C. Experimental Conditions Step 2. Preparation of a Bi-Layer Tablet Containing 0733 Some tablets, as noted in the Examples above, were Maintenance Dose and Loading Dose: milled and placed in a flat bottom flask. The flask was con nected to a condenser via a 3-way connector. The condenser 0728. The first layer is made from the granules prepared in was sealed at the top with a cotton plug and connected to a Step 1a, and the second layer is made from granules prepared vacuum pump to help pull the vapor produced by heating the in Step 1b. A double rotary press was set-up to produce a bottom of the flask using a hot plate at 540° C. US 2015/025.0733 A1 Sep. 10, 2015
Extraction of Oxycodone HCl (Active) after Subjecting 5. The formulation according to claim 1, wherein the for Milled Oxycodone HCl Extended Release Tablets Described mulation further comprises at least one secondary active Sub Above in the Examples to 6540 OC of Heat Usina a Hot Plate stance, wherein said at least one primary active Substance in the loading dose is released at a higher rate in comparison to another dose having said at least one secondary active Sub Amount Amount stance, wherein said at least one primary active Substance and extracted extracted said at least one secondary active Substance are the same or Description of Source of vapor extract Sample 1 Sample 2 different. Theoretical Amount of Active in milled 38.18 38.16 6. The formulation according to claim 1 further comprising tablet before heating (mg) Amount of Active extracted after heating 0.57 O.S2 a core, wherein said at least one primary active Substance is for 2 minutes in Cotton plug (mg) incorporated into the core, external to the core, or a combi Amount of Active extracted after heating O.30 O.29 nation thereof. for 2 minutes in Condenser (mg) 1.33 1.58 7. The formulation according to claim 1, wherein the for Amount of Active extracted after heating for 2 minutes in 3-Way Connector (mg) mulation further comprises a maintenance dose having at Total Amount of Active recovered after 2.20 2.39 least one secondary active Substance, wherein said at least one heatin for 2 minutes (mg) secondary active Substance is the same or different than said Recovery (%) 5.8 6.3 at least one primary active Substance. Mean Recover (%)* 6.O 8. The formulation according to claim 7, wherein the main *Material not completely burnt tenance dose comprises said at least one secondary active Substance in a controlled release matrix. 9. The formulation according to claim 8, wherein the for Amount Amount Amount mulation comprises at least one layer of said at least one extracted extracted extracted loading dose and at least one layer of said at least one main Description of Source of vapor extract Sample 1 Sample 2 Sample 3 tenance dose. Theoretical Amount of Active in milled 38.16 38.16 38.16 10. The formulation according to claim 9, wherein said at tablet before heating (mg) least one layer of said at least one loading dose covers at least Amount of Active extracted after heating O4O O.32 O.S4 a portion of said at least one layer of said at least one main for 6 minutes in Cotton plug (mg) tenance dose or vice versa, forming a layered formulation. Amount of Active extracted after heating 1.84 1.57 2.33 for 5 minutes in Condenser (mg) 11. The formulation according to claim 10, wherein said at Amount of Active extracted after heating 3.00 3.38 2.60 least one coat Surrounds said layered formulation. for 6 minutes in 3-Way Connector (mg) 12. The formulation according to claim 8 further comprises Total Amount of Active recovered after 5.23 5.27 5.46 heating for 5 minutes a core having said at least one maintenance dose and at least Recovery (%) 13.7 13.8 14.3 one coat comprising said at least one loading dose. Mean Recovery 96** 13.9 13. The formulation according to claim 12 further com prises at least one coat comprising at least one maintenance **Material completely burnt dose, which said at least one maintenance dose in the core is We claim: the same or different than said maintenance dose in said at 1. A formulation comprising: least one coat. at least one primary active Substance, wherein onset of 14. The formulation according to claim 13, wherein the action of said at least one primary active Substance is core further comprises said at least one loading dose and/or potentiated by the presence of a loading dose comprising said at least one coat of said loading dose further comprises said at least one primary active substance; and said at least one maintenance dose, which said at least one at least one coat comprising Eudragit E (dimethylamino loading dose in the core is the same or different than said ethyl methacrylate copolymer), loading dose in said at least one coat. wherein the formulation is free of any active substance 15. The formulation according to claim 12, wherein said at external to said at least one coat. least one coat comprising said at least one loading dose sig 2. The formulation according to claim 1, wherein the nificantly covers said core. release of said at least one primary active Substance shows a 16. The formulation according to claim 8 further comprises Point Of Divergence (POD), in a dissolution profile, with the a core, wherein said at least one loading dose and said at least loading dose representing a point in a timeline where the one maintenance dose are external to the core. history of the dissolution or release rate changes from an 17. The formulation according to claim 1, wherein said at onset of action to another set of points in the timeline repre least one coat comprising the Eudragit Efurther comprises at sented by a controlled release. least one active Substance, wherein said at least one active 3. The formulation according to claim 1, wherein prior to Substance and said at least one primary active Substance are the POD, there is no significant controlled release. the same or different. 4. The formulation according to claim 1, wherein the for 18. The formulation according to claim 1, wherein said at mulation further comprises at least one secondary active Sub least one coat controls the release of said at least one primary stance, wherein the formulation has a quick onset of action of active Substance. said at least one primary active Substance followed by a 19. The formulation according to claim 18, wherein release controlled release of at least one secondary active Substance, of any active substance in the formulation is activated by a pH or vice versa, wherein said at least one primary active Sub dependent mechanism, ion-exchange dependent mechanism, stance and said at least one secondary active Substance are the bacterial flora/enzymes dependent mechanism, or a combi same or different. nation thereof. US 2015/025.0733 A1 Sep. 10, 2015 76
20. The formulation according to claim 19, wherein the pH 36. The formulation according to claim 35, wherein the for the pH dependent mechanism is at most about 5. hydrophobic polymers are selected from Eudragit RL, 21. The formulation according to claim 19, wherein the Eudragit NE, Eudragit RS and/or Eudragit NM. ion-exchange mechanism is controlled by at least one ion 37. The formulation according to claim 36, wherein the at exchange resin. least one excipient comprises polyethylene oxide and 22. The formulation according to claim 21, wherein said at Eudragit RL. least one ion-exchange resin is selected from 38. The formulation according to claim 7 further comprises Cholestyramine, Colestipol, Sodium polystyrene Sulfonate, at least one Swellable material in Such an amount that disso Polacrilex resin, and/or Polacrilin potassium. lution of the pulverized/milled formulation in alcoholic and/ or non-alcoholic beverages causes the formulation to agglom 23. The formulation according to claim 19, wherein the erate, the amount of swellable material ranges from about 15 bacterial flora/enzymes dependent mechanism is controlled wt % to about 90 wt % of the maintenance dose and/or loading by at least one polymer reactive to intestinal bacterial flora/ dose. enzymes. 39. The formulation according to claim 1, wherein the 24. The formulation according to claim 23, wherein said at formulation is objectionable to chewing. Sucking, licking least polymer is selected from polysaccharides such as guar and/or holding in the mouth. gum, inulin, chondrotin Sulphate, alginates, and/or dextran. 40. The formulation according to claim 38 further com 25. The formulation according to claim 1, wherein the prises a bittering agent and/or irritant. Eudragit E comprises Eudragit E 100TM. 41. The formulation according to claim 1, wherein the 26. The formulation according to claim 1, wherein up to formulation is an oral formulation. about 55% of the total dose is released as a loading dose to 42. The formulation according to claim 1, wherein the manage pain. formulation is a solid unit form. 27. The formulation according to claim 26, wherein the 43. The formulation according to claim 1, wherein the loading dose is released within about 60 minutes of ingestion. Surface area covered by the Eudragit E in said at least one coat 28. The formulation according to claim 1, wherein the is greater than 5 mg/cm. formulation is configured such that when the formulation is 44. The formulation according to claim 42, wherein the administered in a physically compromised form to a subject, Surface area covered by the Eudragit E in the coat is greater the rate of release of said at least one primary active Substance than 10 mg/cm. in the loading dose is substantially the same or lower than the 45. The formulation according to claim 42, wherein the rate of release of said at least one primary active Substance in Surface area covered by the Eudragit E in the coat is greater the loading dose when the formulation is administered in an than 20 mg/cm. intact form. 46. The formulation according to claim 42, wherein the 29. The formulation according to claim 1, wherein when surface area covered by the Eudragit E in the coat is from the formulation is pulverized/milled and added to an alco about 5 mg/cm to about 100 mg/cm. holic and/or non-alcoholic beverage, the rate of release of said 47. The formulation according to claim 42, wherein the at least one primary active substance in the loading dose is surface area covered by the Eudragit E in the coat is from substantially the same or lower than the rate of release of said about 10 mg/cm to about 100 mg/cm. at least one primary active Substance in the loading dose when 48. The formulation according to claim 42, wherein the the formulation is administered in an intact form. surface area covered by the Eudragit E in the coat is from 30. The formulation according to claim 29, wherein the about 20 mg/cm to about 100 mg/cm. beverage is an alcoholic beverage. 49. The formulation according to claim 1, wherein the 31. The formulation according to claim 1, wherein the formulation is capable of withstanding about a 350 N force. formulation comprises at least one excipient, wherein disso 50. The formulation according to claim 1, wherein the lution of the pulverized/milled formulation in alcoholic and/ formulation is effective in preventing significant dose dump or non-alcoholic beverages causes the formulation to agglom ing in any beverage. erate. 51. The formulation according to claim 1 further comprises at least one acid to facilitate release of any active Substance in 32. The formulation according to claim 31, wherein the at the formulation. least one excipient comprises at least one Swellable material 52. The formulation according to claim 7 further comprises in such an amount that dissolution of the pulverized/milled at least one organic acid to facilitate release of any active formulation in alcoholic and/or non-alcoholic beverages Substance in the formulation, wherein at least one of said at causes the formulation to agglomerate. least one loading dose, said at least one maintenance dose, or 33. The formulation according to claim 32, wherein said at said at least one coat comprises said at least one organic acid. least one swellable material is at least one pH independent 53. The formulation according to claim 52, wherein at least polymer. one of said at least one loading dose and said at least one coat 34. The formulation according to claim 32, wherein said at comprises said at least one organic acid and the wt % ratio of least one swellable material is selected from carbomers, poly the organic acid to said at least one primary active Substance ethylene oxides or hydrophilic polymers that are lightly is from about 1:100 to about 100:1. cross-linked. Such cross-links being formed by covalent or 54. The formulation according to claim 52, wherein said at ionic bonds, which interact with water and aqueous biological least one loading dose comprises from about 1 wt % to about fluids and Swell or expand to some equilibrium state. 15 wt % by weight of said at least one organic acid based on 35. The formulation according to claim 34, wherein said at the weight of the loading dose. least one swellable material comprises hydrophobic poly 55. The formulation according to claim 52, wherein said at CS. least one maintenance dose comprises from about 1 wt % to US 2015/025.0733 A1 Sep. 10, 2015 77 about 10 wt % by weight of said at least one organic acid based on the weight of the maintenance dose. 56. The formulation according to claim 52, wherein said at least one coat comprises from about 5 wt % to about 100 wt % by weight of said at least one organic acid based on the weight of said at least one coat. 57. The formulation according to claim 53 further com prises an overcoat, wherein the overcoat comprises said at least one organic acid and at least one polymer. 58. The formulation according to claim 57, wherein the amount of said at least one organic acid is from about 5 wt % to less than about 100 wt % of the overcoat. 59. The formulation according to claim 51, wherein said organic acid is selected from lactic acid, phosphoric acid, citric acid, malic acid, fumaric acid, Stearic acid, tartaric acid, benzoic acid, or combinations thereof. 60. The formulation according to claim 1, wherein said at least one primary active Substance is an addictive Substance. 61. The formulation according to claim 60, wherein the addictive Substance is an opiod agonist and/or a narcotic analgesic.