(12) United States Patent (10) Patent No.: US 8,617,602 B2 Howard Et Al

USOO86176O2B2

(12) United States Patent (10) Patent No.: US 8,617,602 B2 HOWard et al. (45) Date of Patent: Dec. 31, 2013

(54) IMMEDIATE RELEASE COMPOSITIONS Related U.S. Application Data AND METHODS FOR DELIVERING DRUG FORMULATIONS USING WEAKACD ON (63) Continuation-in-part of application No. 12/807,434. EXCHANGE RESINS IN ABNORMALLY filed on Sep. 3, 2010, now Pat. No. 8,187,617. HIGH PHENVIRONMENTS (51) Int. Cl. (76) Inventors: William Wayne Howard, Morristown, A619/24 (2006.01) NJ (US); Russell Francis Somma, (52) U.S. Cl. Sparta, NJ (US); Sajeev Chandran, CPC ...... A61 K9/209 (2013.01) Pune, IN (US); Pravin Megharji USPC ...... 424/472: 424/400; 424/465; 424/452: Bhutada, Pune, IN (US); Ashish 424/483 Ashokkao Deshmukh, Pune, IN (US); (58) Field of Classification Search Hemant Hanumant Bhalerao, Pune, IN None (US) See application file for complete search history. (*) Notice: Subject to any disclaimer, the term of this Primary Examiner — Bethany Barham patent is extended or adjusted under 35 (74) Attorney, Agent, or Firm — Sheldon Kavesh U.S.C. 154(b) by 0 days. (57) ABSTRACT (21) Appl. No.: 13/506,512 Multi-layer solid oral dosage immediate release and extended release compositions and methods for delivering drug formu (22) Filed: Apr. 23, 2012 lations using weak acid ion exchange resins in abnormally (65) Prior Publication Data high pH environments. US 2013/0273159 A1 Oct. 17, 2013 9 Claims, 8 Drawing Sheets

Example : hydroxodone R layer . Orug-RP 38 resinate Costed Feet

------Hydrochone ER iiyet (Drug-tRP69 resinate - Anhydrus (Kls. Hyp forelosa) Pseudoepherine reit grantation sayer U.S. Patent Dec. 31, 2013 Sheet 1 of 8 US 8,617,602 B2

Figure 1

Desire ReSn (ArbaiellRP88)

U.S. Patent Dec. 31, 2013 Sheet 2 of 8 US 8,617,602 B2

Figure 2

EFFECT OF pH (ONRELEASE (CODEINE ERP88 WITHOUT RELEASE ENHANCER 100 90 ss..." 88.3" "'883 seasure. ... 871 80

l as K(67.5

lo-62.2

S O or pH1.0

-, epH4.5

500 3000 4500 (6000 MINUES U.S. Patent Dec. 31, 2013 Sheet 3 of 8 US 8,617,602 B2

Figure 3

CODENESring RP88 DISSOLUTION DATA at pH 4.5 WITH AND WITHOUT RELEASE ENHANCER

80 ... anti-Sil.2" st states 835 ...(76.9 70 uris83 se26 (57.5 e (62.2

5 O oil 98g/g (Fed3 hexahydrate

2 otNo Release Enhancer

500 3000 MINUTEs 4500 (60.00 U.S. Patent Dec. 31, 2013 Sheet 4 of 8 US 8,617,602 B2

Figure 4

hydroxodore R layer w (Orug-RP 38 resinate e cited Feet

---- hydroekrie ER is ef E.---

EEEEErr (Drug-tRP69 resinate - Anhydrus (€ls Hypforelease)

Pseudoepherine neit grantiation ayer U.S. Patent Dec. 31, 2013 Sheet 5 of 8 US 8,617,602 B2

Figure 5

Dissolution profile of hydrocodone bittartirate

* s s:

h S. 6080 2 &A es E 40 s U matrilayer Tab (Example-l) e-Bilayer Tab U.S. Patent Dec. 31, 2013 Sheet 6 of 8 US 8,617,602 B2

Figure 6

Dissolution Profile of Hydrocodonebitartirate

s g S 0.1N HC

ed 4)(O.ON HEC E amph 4.5 0.01M Acetate Buffer s l - a pH 6.8 0.01 M Phosphate Buffer U.S. Patent Dec. 31, 2013 Sheet 7 of 8 US 8,617,602 B2

Figure 7

Dissolution profile of Pseudoephedrine HC

s r

As S c e A. co).ON HC s -a-ph 4.5 0.0M Acetate Buffer E s ut -A-pH 6.8.0.0 M Phosphate Buffer U.S. Patent Dec. 31, 2013 Sheet 8 of 8 US 8,617,602 B2

Figure 8

Dissolution profile of Bydrocodonebitatrate in pl 2 (0.108C) US 8,617,602 B2 1. 2 IMMEDIATE RELEASE COMPOSITIONS Thus, one can attain the rapid release properties of weak AND METHODS FOR DELIVERING DRUG acid resinates while retaining the low sensitivity to pH change FORMULATIONS USING WEAKACD ON associated strong acid resins by adding a release enhancing EXCHANGE RESINS IN ABNORMALLY agent to the weak acid drug formulation. HGH PHENVIRONMENTS Immediate release is defined as at least 80% release of a pharmaceutically active agent within 45 minutes in a standard CROSS REFERENCE TO RELATED dissolution apparatus according to the USP 34NF 26 section APPLICATIONS 711. It is also desirable in many instances that a drug be released This application is a continuation-in-part of application 10 in a sustained manner over a period of about 8 hours. Both immediate release (IR) and extended release (ER) of one or Ser. No. 12/807,434 filed Sep. 3, 2010 now U.S. Pat. No. more drugs may be needed. Surprisingly, it is found that that 8,187,617 and published as US 2011/006572 on Mar. 17, by creating an oral dosage form possessing multiple distinct 2011 layers, drug release is more rapid and more complete than if 15 IR and ER components are mixed in a single layer. BACKGROUND OF THE INVENTION In a first embodiment, the invention is a multi-layer solid oral dosage form pharmaceutical composition comprising: The present invention relates to the use of weak acid ion (i) a first distinct layer comprising: exchange resins (IER) to create an immediate release (IR) (a) a first pharmaceutically active agent bound to a weak drug delivery system using release enhancers to overcome the acid ion exchange resin to form a weak acid ion-ex pH dependent release characteristics normally associated change resinate; and with weak acid resins. (b) a release-enhancing agent consisting of FeCls: Formulations containing weak acidion exchange resins are (ii.) at least a second distinct layer comprising: frequently used for immediate release of pharmaceutical (a) a drug selected from the group consisting of said first agents in a patient’s stomach. However, release from weak 25 pharmaceutically active agent and a second pharmaceu acid resins is slowed and/or reduced at higher than normal tically active agent, said drug being bound to a strong stomach pH levels. High pH levels could occur if the patient acid ion exchange resin to form a strong acid ion-ex is taking medications such as proton pump inhibitors (PPIs) change resinate; and or has a disease state that induces hypochlorhydria or achlo (b) optionally, a coating to slow and extend release of the rhydria. In either case, a weak acid formulation may not 30 drug contained therein; release the medicament at a rate or to an extent adequate to wherein said pharmaceutical composition is capable of achieve the desired therapeutic effect. immediate release of said first pharmaceutically active agent Approximately 60 million prescriptions were written for from said weak acid resinate at a pH of at least 1.5, immediate PPIs in 2006. Additionally, in the U.S., another 10 million release being defined as at least 80% release of said pharma people were reported to have self medicated with PPIs in 35 ceutically active agent within 45 minutes in a standard disso 2008. Furthermore, about one in three adults usedantacids on lution apparatus according to USP34NF 26 section 711; and a regular basis. Collectively, these statistics suggest that close wherein said release of the drug from said strong acid resinate to 100 million people in the U.S. could be taking a drug that continues over a period of at least 8 hours after ingestion. could significantly interfere with the release profile of a weak In a second embodiment, the invention is a method of acid IER formulation. The history of prior art dosage forms 40 treating a patient with a stomach pH of at least about 1.5 indicates that a serious need exists for a novel and useful solid comprising administration of a multilayer Solid oral dosage oral dosage form that provides an unexpected advancement in form, said dosage form comprising: the science of IER dosage forms. For example, prior art (i) a first distinct layer comprising: dosage forms lack the ability to provide the immediate release (a) a first pharmaceutically active agent bound to a weak properties of weak acid IER formulations when administered 45 acid ion exchange resin to form a weak acid ion-ex to a patient with stomach pH environments at about 1.5 to 2.0 change resinate; and and above. Surprisingly and unexpectedly, weak acid (b) a release-enhancing agent selected from the group con resinates can be formulated to have immediate release char sisting of an inorganic salt and an organic base; acteristics at pH levels above about 1.5 to 2.0. The present (ii.) at least a second distinct layer comprising: invention creates a release enhancing weak acid resin drug 50 (a) a drug selected from the group consisting of said first formulation by adding a release enhancing agent to the for pharmaceutically active agent and a second pharmaceu mulation to increase the rate and extent of drug release from tically active agent, said drug bound to a strong acidion the formulation such that it meets an a priori definition of exchange resin to form a strong acid ion-exchange immediate release. resinate; and 55 (b) optionally, a coating to slow and extend release of the SUMMARY OF THE INVENTION drug contained therein; wherein said pharmaceutical composition is capable of Surprisingly it has been found that by adding a release immediate release of said first pharmaceutically active agent enhancing agent with a strong affinity for the ionic resin to a from said weak acid resinate at a pH of at least 1.5, immediate weak acid resin drug formulation, much more rapid and com 60 release being defined as at least 80% release of said pharma plete release of a resinated drug can be attained in abnormal ceutically active agent within 45 minutes in a standard disso gastric fluid than otherwise would occur without the presence lution apparatus according to USP34NF 26 section 711; and of the release enhancing agent in abnormal human gastric wherein release of the drug from said strong acid resinate fluid wherein the pH is much higher than normal due to the continues over a period of at least 8 hours after ingestion. use of drugs such as PPI or the presence of disease states such 65 In a third embodiment, the invention is a method of treating as H. pylori or atrophic gastritis that can lead to hypochlo a patient having a first condition and a second condition with rhydria and achlorhydria. a pharmaceutically active agent effective for treating said US 8,617,602 B2 3 4 second condition, said method comprising the step of admin (i) a first distinct layer comprising: istering a Solid oral dosage pharmaceutical composition, said (a) a first pharmaceutically active agent bound to a weak Solid oral dosage pharmaceutical composition comprising: acid ion exchange resin to form a weak acid ion-ex (i) a first distinct layer comprising: change resinate; and (a) a first pharmaceutically active agent bound to a weak (b) a release-enhancing agent selected from the group con acid ion exchange resin to form a weak acid ion-ex sisting of an inorganic salt and an organic base; change resinate; and (ii.) at least a second distinct layer comprising: (b) a release-enhancing agent selected from the group con (a) pharmaceutically active agent selected from the group sisting of an inorganic salt and an organic base; consisting of said first pharmaceutically active agent and (ii.) at least a second distinct layer comprising: 10 a second pharmaceutically active agent, said pharma (a) pharmaceutically active agent selected from the group ceutically active agent bound to a strong acid ion consisting of said first pharmaceutically active agent and exchange resin to form a strong acid ion-exchange a second pharmaceutically active agent, said pharma resinate; and, ceutically active agent bound to a strong acid ion (b) optionally, a coating to slow and extend release of the 15 drug contained therein; exchange resin to form a strong acid ion-exchange wherein said pharmaceutical composition is capable of resinate; and immediate release of said first pharmaceutically active agent (b) optionally, a coating to slow and extend release of the from said weak acid resinate at a pH of at least 1.5, immediate drug contained therein; release being defined as at least 80% release of said pharma wherein said pharmaceutical composition is capable of ceutically active agent within 45 minutes in a standard disso immediate release of said first pharmaceutically active agent lution apparatus according to USP34NF 26 section 711; and, from said weal acid resinate at a pH of at least 1.5, immediate wherein release of the drug from said strong acid resinate release being defined as at least 80% release of said pharma continues over a period of at least 8 hours after ingestion. ceutically active agent within 45 minutes in a standard disso lution apparatus according to USP 34NF 26 section 711; 25 BRIEF DESCRIPTION OF THE DRAWINGS wherein release of the drug from said strong acid resinate continues over a period of at least 8 hours after ingestion; and FIG. 1 is a flow chart that illustrates a process for creating wherein said first condition is selected from the group con a drug/resin complex, the drug resination process. sisting of Helicobacter pylori infection, atrophic gastritis, FIG. 2 shows the effect of pH on the release of codeine hypochlorhydria and achlorhydria in the stomach; and 30 from a weak acid resinate in the absence of a release enhancer. wherein said second condition is a condition other than said FIG. 3 shows dissolution of codeine weak acid resinate first condition. with and without a release enhancer. FIG. 4 is an illustration of a tablet of the invention consist In a fourth embodiment, the invention is a method of treat ing of three distinct layers. ing a patient wherein the patient has within the past 24 hours 35 FIG. 5 shows the dissolution of hydrocodone bitartrate been administered a compound selected from the group con from a three layer tablet of the invention as illustrated in FIG. sisting of a proton pump inhibitor, an H2 receptor antagonist, 4 wherein a weak acid resinate and a strong acid resinate are and an antacid, said method comprising the step of adminis in separate and distinct layers compared to a two layer tablet tering a solid oral dosage pharmaceutical composition, said in which the weak acid and the strong acid resinates are mixed Solid oral dosage pharmaceutical composition comprising: 40 together in the same layer. (i) a first distinct layer comprising: FIG. 6 shows the dissolution of hydrocodone bitartrate (a) a first pharmaceutically active agent bound to a weak from a three layer tablet of the invention as a function of pH acid ion exchange resin to form a weak acid ion-ex and time. change resinate; and FIG.7 shows the dissolution of pseudoephedrine HCl from (b) a release-enhancing agent selected from the group con 45 a three layer tablet of the invention as a function of pH and sisting of an inorganic salt and an organic base; time. (ii.) at least a second distinct layer comprising: FIG. 8 shows the contributions of the immediate release (a) pharmaceutically active agent selected from the group and extended release components to the dissolution of hydro consisting of said first pharmaceutically active agent and codone bitartrate from a three layer tablet of the invention a second pharmaceutically active agent, said pharma 50 ceutically active agent bound to a strong acid ion DETAILED DESCRIPTION OF THE INVENTION exchange resin to form a strong acid ion-exchange resinate; and In a first embodiment, the invention is a multi-layer solid (b) optionally, a coating to slow and extend release of the oral dosage form pharmaceutical composition comprising: drug contained therein; 55 (i) a first distinct layer comprising: wherein said pharmaceutical composition is capable of (a) a first pharmaceutically active agent bound to a weak immediate release of said first pharmaceutically active agent acid ion exchange resin to form a weak acid ion-ex from said weak acid resinate at a pH of at least 1.5, immediate change resinate, and release being defined as at least 80% release of said pharma (b) a release-enhancing agent consisting of FeCls: ceutically active agent within 45 minutes in a standard disso 60 (ii.) at least a second distinct layer comprising: lution apparatus according to USP34NF 26 section 711; and, (a) a drug selected from the group consisting of said first wherein release of the drug from said strong acid resinate pharmaceutically active agent and a second pharmaceu continues over a period of at least 8 hours after ingestion. tically active agent, said drug being bound to a strong In a fifth embodiment, the invention is a method of deliv acid ion exchange resin to form a strong acid ion-ex ering a pharmaceutically active agent to a patient, said 65 change resinate, and method comprising orally administering a Solid oral dosage (b) a coating to slow and extend release of the drug con composition comprising: tained therein; US 8,617,602 B2 5 6 wherein said pharmaceutical composition is capable of the drug to resin weight ratio in a resinate is from about 1:0.75 immediate release of said first pharmaceutically active agent to about 1:5. Most preferably, the drug to resin weight ratio in from said weak acid resinate at a pH of at least 1.5, immediate a resinate is from about 1:1 to about 1:3. release being defined as at least 80% release of said pharma The weight ratio of drug in the IR layer to the drug in the ER ceutically active agent within 45 minutes in a standard disso 5 layer can also be varied to adjust a release profile. The weight lution apparatus according to USP 34NF 26 section 711; and ratio of IR drug to ER drug is preferably from about 10:90 to wherein release of the drug from said strong acid resinate about 90:10. More preferably, the weight ratio of IR drug to ER drug is from about 20:80 to about 80:20; yet more pref continues over a period of at least 8 hours after ingestion. erably from about 30:70 to about 70:30; and most preferably The pharmaceutical compositions of the invention are from about 40:60 to about 60:40. characterized by faster, and/or more complete, drug release 10 By “release-enhancing agent' is meant an agent that, when compared to a weak acid resin formulation without the added to a drug resin formulation, increases the rate and/or release enhancing agent in pH environments at or above about the extent of drug release than would otherwise occur without 1.5 to 2.0. When administered to a patient, the release-en the release-enhancing agent in the same formulation. hancing agent results in immediate release of the pharmaceu By “pharmaceutically active agent' is meant agents other tically active agent(s) from the weak acid ion exchange resin 15 than food articles that are intended to diagnose, cure, miti in pH environments at or above about 1.5 to 2.0. gate, treat or prevent disease in man or other animals or that The pharmaceutical composition can be formulated, for are intended to affect the structure or any function of the body example, as a multi-particle containing capsule or multiple of man or other animals that are physiologically acceptable. layer compressed tablet. The immediate release component The agent could be a combination of drug therapies as well as comprises a first distinct layer of the tablet or distinct particle a single agent. in the capsule. By "physiologically acceptable' is meant those Substances The drug release kinetics of weak acid resins can be that are adequately tolerated without causing unacceptable affected by higher pH levels in the gastric fluid such that the negative side effects. rate and/or extent of drug release can be greatly reduced. By “ion exchange resin' is meant an insoluble solid matrix that carries exchangeable ions with either a positive or nega Adding a release enhancing agent to a weak acid formulation 25 tive charge. The trapping of ions takes place only with simul is useful for assuring that the resinated drug is released from taneous releasing of other ions. Ions are exchanged in Sto an IER formulation when stomach acid is reduced or elimi ichiometrically equivalent amounts of other ions with the nated (hypochlorhydria and achlorhydria) by disease states same electrical charge when the ion exchange material is in Such as Helicobacter (H.) pylori infection or atrophic gastri contact with an electrolyte solution. tis. 30 By “resinate' is meant the complex formed when a drug By adding a release enhancing agent with a strong affinity exchanges an ion with a resin particle in the Stoichiometric for the ionic resin to the weak acid resin drug formulation can process described above and a drug/resin compound is facilitate release of the resinated drug in abnormal human formed. gastric fluid where the pH is much higher than normal due to By “weak acidion exchange resin' is meant in a weak acid resin the ionizable group introduced to the polymer is a car the use of drugs such as proton pump inhibitors or the pres 35 boxylic acid (COOH) as opposed to the sulfonic acid group ence of disease states such as H. pylori infection or atrophic (SOH) used in strong acid resins. These resins behave simi gastritis. larly to weak organic acids so are weakly dissociated i.e. have Weak acid ion exchange resins useful in the invention fewer ions available for exchange. include, for example, the potassium salt of carboxylated poly By “immediate release” (IR) is meant that the pharmaco methacrylic resins such as Amberlite IRP88 (CAS Registry 40 logically active agent is released from the IR portion of the Number 39394-76-5) manufactured by Dow Chemical, and formulation such that 80%, 85%, 90%, or even 95% of the DOWEX MAC-3, manufactured by Dow Chemical but other pharmaceutically active agent in the IR portion is released weak acid ion exchange resins may be used. within 45 minutes when dissolution is measured according to The release-enhancing agent can be, for example, a highly the USP 34 NF 26 Section 711. soluble inorganic salt (e.g., FeCls. FeCl2, Fe(SO4), CaCl, 45 By “extended release' is meant that the pharmaceutically NaCl, MgCl) or an organic base (e.g., thymine, guanine, or active agent is released from the formulation at a controlled cytosine). rate Such that the formulation allows for a reduction in dosing The pharmaceutical composition includes at least a second frequency as compared to that presented by a conventional distinct layer. This second layer comprises a pharmaceutical dosage form, e.g. an immediate release dosage form. active agent bound to strong acidion exchange resin forming 50 Release-Enhancing Agents a resinate and optionally coated with an extended release The drug-containing weak acid ion exchange resins of the coating. The strong acid ion exchange resin in the second invention are formulated with release-enhancing agents. layer can be bound to the same or different pharmaceutically These release-enhancing agents result in immediate release active agent as the weak acid ion exchange resin. of the drug from the weak acid ion exchange resins in pH environments at or above 2.0. Examples of suitable release Strong acid ion exchange agents useful in the invention 55 enhancing agents are: include Sulfonated polystyrenic resins such as Amberlite Inorganic Agents: IRP69, and DoweX 88, but other strong acid ion exchange FeCls, Fe(SO) resins may be used. CaCl The coating can be any of a number of materials conven MgCl, tionally used such for extending drug release Such as ethyl 60 FeCl cellulose, the EudragitTM polymers (manufactured by Organic Agents: Degussa Rohm Pharma Polymers of Germany), AquacoatTM Thymine (by FMC Biopolymer) and SureleaseTM (by Colocon Inc.) Guanine The weight ratio of drug to ion-exchange resin in either a Cytosine weak acid or strong acid resinate can be varied to adjust a 65 Pharmaceutically Active Agents release profile. Preferably, the drug to resin weight ratio in a The invention features methods and compositions for resinate is from about 1:0.5 to about 1:10. More preferably, immediate release of pharmaceutically active agents using a US 8,617,602 B2 7 8 weak acid ion exchange resin. Examples of such pharmaceu P: Anti-diarrheals, e.g., bismuth Subsalicylate and lopera tically active agents suitable for the compounds and methods mide. of the inventions are: R: CNS stimulants, e.g., caffeine, cocaine, and amphet A: Anti-tussives, e.g., benzonatate, caramiphen edisylate, amines. chlophedianol, codeine, dextromethorphan hydrobromide, S: Attention Deficit and Hyperactivity Disorder drugs, e.g., hydrocodone, levopropoxyphene, morphine codeine, ethyl methylphenidate, dextroamphetamine Sulfate, amphetamine, morphine, dihydrocodeine, benzylmorphine, laudanum, and atomoxetine hydrochloride. dihydroisocodeine, nicocodeine, nicodicodeine, hydroc The invention also includes methods and compositions for odone, hydromorphone, acetyldihydrocodeine, thebacon, delivering combinations of pharmaceutically active com 10 pounds. Examples of Such combinations are: diamorphine (heroin), acetylmorphone, noscapine, and phol A: an anti-tussive and an antihistamine codine. B: an anti-tussive and a decongestant B: Narcotic analgesics, e.g., codeine, oxycodone, hydroc C: an anti-tussive and an analgesic odone, diamorphine, pethidine, morphine, oxymorphone, D: an anti-tussive and an NSAID nalorphine, naloxone, naltrexone, opium, hydromorphone, 15 E: an anti-tussive and an antihistamine and a decongestant nicomorphine, dihydrocodeine, and papavereturn. F: an anti-tussive and an antihistamine and an analgesic C: Decongestants, e.g., pseudoephedrine hydrochloride, G: an anti-tussive and an antihistamine and an NSAID phenylephrine bitartrate, phenylephrine hydrochloride and H: an anti-tussive and an antihistamine and a decongestant pseudoephedrine Sulfate. and an analgesic D: Non-steroidal anti-inflammatory drugs, e.g., aspirin, I: a muscle relaxant and an analgesic magnesium salicylate, diclofenac, etodolac, indometacin, J: a muscle relaxant and an NSAID nabumetone, Sulindac, tolmetin, ibuprofen, ketoprofen, K: a muscle relaxant and an analgesic and an NSAID mefenamic acid, meclofenamic acid, phenylbutaZone, piroxi L: a PPI and an NSAID cam, meloxicam, celecoxib, parecoxib, rofecoxib, Valde M: an H2 antagonist and an NSAID coxib, and naproxen Sodium. 25 N: a PPI and an analgesic E: Anti-emetic drugs, e.g., dolasetron, granisetron, O: an H2 antagonist and an analgesic ondansetron, tropisetron, palonosetron, mirtazapine, meto Dosage Forms clopramide, cyclizine, diphenhydramine, dimenhydrinate, Suitable dosage forms include a multi-particle containing meclizine, promethazine, and hydroxyzine. capsule or multiple layer compressed tablet. The immediate F: Anti-histamines, e.g., diphenhydramine, loratadine, 30 release component comprises a first distinct layer of the tablet desloratadine, meclizine, fexofenadine, pheniramine, cetiriz or distinct particle in the capsule. ine, promethazine, brompheniramine, clemastine fumarate In a second embodiment, the invention is a method of and chlorpheniramine. treating a patient with a stomach pH of at least about 1.5 G: Proton pump inhibitors (PPI), e.g., omeprazole, esome comprising administration of a multilayer Solid oral dosage prazole, pantoprazole, lanSoprazole, and rabeprazole. 35 form, said dosage form comprising: H: H2 Antagonists, e.g., cimetidine, ranitidine, and famo (i) a first distinct layer comprising: tidine. (a) a first pharmaceutically active agent bound to a weak I: Anti-depressants, e.g., citalopram, escitalopram, fluox acid ion exchange resin to form a weak acid ion-ex etine, fluvoxamine, paroxetine, Sertraline, desvenlafaxine, change resinate; and dulloxetine, milnacipran, Venlafaxine, atomoxetine, mazin 40 (b) a release-enhancing agent selected from the group con dol, reboxetine, Viloxazine, amitriptyline, clomipramine, sisting of an inorganic salt and an organic base; doxepin, imipramine, trimipramine, desipramine, nortrip (ii.) at least a second distinct layer comprising: tyline, protriptyline, moclobemide, phenelzine, and sel (a) a drug selected from the group consisting of said first egiline. pharmaceutically active agent and a second pharmaceu J: Tranquilizers, e.g., amobarbital, pentobarbital, secobar 45 tically active agent, said drug bound to a strong acidion bital, phenobarbital, clonazepam, diazepam, estazolam, exchange resin to form a strong acid ion-exchange flunitrazepam, lorazepam, midazolam, nitrazepam, resinate; and oxazepam, triazolam, temazepam, chlordiazepoxide, and (b) optionally, a coating to slow and extend release of the alprazolam. drug contained therein; K: Anti-convulsants, e.g., felbamate, carbamazepine, 50 wherein said pharmaceutical composition is capable of oXcarbazepine, vigabatrin, progabide, tiagabine, topiramate, immediate release of said first pharmaceutically active agent gabapentin, pregabalin, ethotoin, and phenytoin. from said weak acid resinate at a pH of at least 1.5, immediate L: Hypnotics, e.g., Zolpidem, Zaleplon, Zopiclone, and release being defined as at least 80% release of said pharma eSZopiclone. ceutically active agent within 45 minutes in a standard disso M: Muscle relaxants, e.g., methocarbamol, carisoprodol, 55 lution apparatus according to USP34NF 26 section 711; and chlorZoxazone, cyclobenzaprine, gabapentin, metaxalone, wherein release of the drug from said strong acid resinate and orphenadrine. continues over a period of at least 8 hours after ingestion. N: Anti-psychotics, e.g., haloperidol, droperidol, chlorpro In a third embodiment, the invention is a method of treating mazine, fluiphenazine, perphenazine, prochlorperazine, thior a patient having a first condition and a second condition with idazine, trifluoperazine, mesoridazine, promazine, triflupro 60 a pharmaceutically active agent effective for treating said mazine, levomepromazine, methotrimeprazine, pimozide, second condition, said method comprising the step of admin chlorprothixene, flupenthixol, thiothixene, Zuclopenthixol, istering a solid oral dosage pharmaceutical composition, said clozapine, olanzapine, risperidone, quetiapine, Ziprasidone, Solid oral dosage pharmaceutical composition comprising: amisulpride, asenapine, and paliperidone. (i) a first distinct layer comprising: O: Anti-microbials, e.g., EDTA, Zinc compounds, tri 65 (a) a first pharmaceutically active agent bound to a weak closan, domiphen, cetyl pyridium chloride, domiphen bro acid ion exchange resin to form a weak acid ion-ex mide, fluorides, alexidine, and octenidine. change resinate; and US 8,617,602 B2 10 (b) a release-enhancing agent selected from the group con a second pharmaceutically active agent, said pharma sisting of an inorganic salt and an organic base; ceutically active agent bound to a strong acid ion (ii.) at least a second distinct layer comprising: exchange resin to form a strong acid ion-exchange (a) pharmaceutically active agent selected from the group resinate; and, consisting of said first pharmaceutically active agent and 5 (b) optionally, a coating to slow and extend release of the a second pharmaceutically active agent, said pharma drug contained therein; ceutically active agent bound to a strong acid ion wherein said pharmaceutical composition is capable of exchange resin to form a strong acid ion-exchange immediate release of said first pharmaceutically active agent resinate; and from said weak acid resinate at a pH of at least 1.5, immediate (b) optionally, a coating to slow and extend release of the 10 release being defined as at least 80% release of said pharma drug contained therein; ceutically active agent within 45 minutes in a standard disso wherein said pharmaceutical composition is capable of lution apparatus according to USP34NF 26 section 711; and, immediate release of said first pharmaceutically active agent wherein release of the drug from said strong acid resinate from said weal acid resinate at a pH of at least 1.5, immediate continues over a period of at least 8 hours after ingestion. release being defined as at least 80% release of said pharma 15 ceutically active agent within 45 minutes in a standard disso EXAMPLES lution apparatus according to USP 34NF 26 section 711; wherein release of the drug from said strong acid resinate Each of the compositions of the examples below are useful continues over a period of at least 8 hours after ingestion; and for oral administration for conditions such as normal stomach wherein said first condition is selected from the group con pH of about 1.5 to 2.0 or higher, Helicobacter pylori infec sisting of Helicobacter pylori infection, atrophic gastritis, tion, atrophic gastritis, hypochlorhydria and achlorhydria. hypochlorhydria and achlorhydria in the stomach; and The compositions of the examples are also useful for patients wherein said second condition is a condition other than said who have been administered a proton pump inhibitor, or a H2 first condition. receptor antagonist or an antacid within the preceding 24 In a fourth embodiment, the invention is a method of treat 25 hours. ing a patient wherein the patient has within the past 24 hours been administered a compound selected from the group con Example 1 sisting of a proton pump inhibitor, an H2 receptor antagonist, and an antacid, said method comprising the step of adminis Example of a Process for Creating a Drug/Resin tering a solid oral dosage pharmaceutical composition, said 30 Complex Solid oral dosage pharmaceutical composition comprising: (i) a first distinct layer comprising: 500 mg of Amberlite IRP88TM, the potassium salt of car (a) a first pharmaceutically active agent bound to a weak boxylated polymethacrylic ion-exchange resin from Rohm acid ion exchange resin to form a weak acid ion-ex and Haas (currently DOW), were added to deionized water change resinate; and 35 (2.5 L) which had been heated to 85°C. The resin and water (b) a release-enhancing agent selected from the group con were mixed using a magnetic stirring bar until a uniform sisting of an inorganic salt and an organic base; suspension was obtained. 150 mg of hydrocodone bitaritrate (ii.) at least a second distinct layer comprising: was made into a solution in deionized water and then added to (a) pharmaceutically active agent selected from the group the resin slurry and mixed in the primary vessel with contin consisting of said first pharmaceutically active agent and 40 ued mixing for 4.0 hours at 85°C. to create the hydrocodone a second pharmaceutically active agent, said pharma resinate. The slurry was vacuum filtered to separate the ceutically active agent bound to a strong acid ion resinate from the water. The resin particles were washed three exchange resin to form a strong acid ion-exchange times by re-suspending the particles in 5 liters of deionized resinate; and water maintained at 85°C. The resulting washed particles (b) optionally, a coating to slow and extend release of the 45 were filtered and allowed to cool for 12 hours. This process drug contained therein; was repeated in order to generate adequate amounts of the wherein said pharmaceutical composition is capable of hydrocodone resinate to prepare the number of capsules immediate release of said first pharmaceutically active agent required for dissolution testing. Care was taken during the from said weak acid resinate at a pH of at least 1.5, immediate cooling process to avoid cake formation by periodically mix release being defined as at least 80% release of said pharma 50 ing the resinate bed with a glass stirring rod. The resinate was ceutically active agent within 45 minutes in a standard disso then dried using a lab scale fluid bed dryer set at 55°C. inlet lution apparatus according to USP34NF 26 section 711; and, temperature. Drying was continued until a residual moisture wherein release of the drug from said strong acid resinate content of 2.0% was obtained. Drug loading was tested and continues overa period of at least 8 hours after ingestion. showed approximately 40% drug load or approximately 40 In a fifth embodiment, the invention is a method of delivery 55 mg of hydrocodone per 100 mg of resinate. a pharmaceutically active agent to a patient, said method FIG. 1 is an illustration of the process for creating the comprising orally administering a solid oral dosage compo resinate. A similar procedure is followed for forming a drug sition comprising: resinate of a strong acid ion-exchange resin Such as a Sul (i) a first distinct layer comprising: fonate polistirex resin such as IRP69. (a) a first pharmaceutically active agent bound to a weak 60 acid ion exchange resin to form a weak acid ion-ex Example 2 change resinate; and (b) a release-enhancing agent selected from the group con The Effect of a Release Enhancer on a Weak Acid sisting of an inorganic salt and an organic base; Resinate (ii.) at least a second distinct layer comprising: 65 (a) pharmaceutically active agent selected from the group A resinate was prepared by reacting codeine with a weak consisting of said first pharmaceutically active agent and acid ion exchange resin. The weak acid ion exchange resin US 8,617,602 B2 11 12 consisted of the potassium salt of a cross-linked polymer of resin weight ratio of 1:2. This resinate was blended with methacrylic acid and divinylbenzene commercially available anhydrous CaCl to produce a mixture containing 0.208 as AMBERLITE IRP 88TM. The resinate was divided into grams of CaCl per gram of resinate. three parts and tested as follows: Pseudoephedrine HCL was mixed with 48 percent by 24 mg of this resinate containing 15 mg codeine were weight of hydrogenated vegetable oil. Subjected to testing in a standard dissolution apparatus The weak acid hydrocodone resinate, the strong acid according to USP 34 NF26 section 711. In one test, the pH hydrocodone resinate and the pseudoephedrine HCL were was adjusted to 1.0 by 0.1 NHC1. In a second test, the pH was charged to separate hoppers on a tablet production machine. adjusted to 4.5 by means of buffers. The release of codeine Compressed tablets were produced having the distinct layers from the resinate was measured at 15 minute intervals by high 10 as shown in the table below and illustrated schematically in pressure liquid chromatography (HPLC). FIG. 4. The tablets were capsule shaped standard convex The resultant codeine release is tabulated below and is having dimension of 19x7.6 mm. plotted in FIG. 2. It will be seen that the higher pH inhibited release of codeine from the resinate. 15 To a third 24 mg portion of the above described resinate Ion containing 15 mg codeine was added 23.4 mg of HCBT, Exchange FeCl6H2O, CaCl2, Pseudoephedrine FeCl6HO (0.975 g/g resinate). The combined resinate and Layer ng Resin, mg ng ng HCL, mg ferric chloride was subjected to testing in the same dissolution 1 (IR) 2 4 5.85 apparatus under the same conditions at a pH of 4.5 as above. 2 (ER) 8 16 5 The resultant codeine release is tabulated below and is plotted 3 120 in FIG. 3. It will be seen from the tabulated data and/or from FIG. 3 that the Fe3+ acted as a release enhancing agent and caused a Comparative Example 1 drug release in excess of 80% at 45 minutes where otherwise 25 drug release was 62.2% without the release enhancer when a Weak Acid Resinate and Strong Acid Resinate in weak acid resinate was tested at pH 4.5. Same Layer TABLE 1. The weak acid hydrocodone resinate and the strong acid 30 Dissolution Data for a Codeine Weak Acid Resinate at pH 1.0 hydrocodone resinate described in Example 3 were blended Codeine Release From Codeine/IRP88 Resinate at 1.0 pH together. The blended resinates and the pseudoephedrine HCL were charged to separate hoppers on a tablet production Dissolution time, min Percent Release machine. Compressed tablets were produced having the dis 15 86.1 tinct layers as shown in the table below. 30 88.3 35 45 88.3 60 87.1 Ion HCBT, Exchange FeCl6H2O, CaCl2, Pseudoephedrine Layer ng Resin, mg ng ng HCL, mg TABLE 2 40 1 10 2O 15 Dissolution Data for a Codeine Weak Acid Resinate at pH 4.5 2 120 With And Without a Release Enhancer, FeCl36H2O Codeine Release From Codeine/IRP88 Resinate at 4.5 pH Percent Release 45 Example 4 Dissolution time, min Resinate Only Resinate + FeCl6H2O Dissolution of Example 3 and Comparative Example 15 41.9 68.3 1 30 S3.6 76.9 45 62.2 81.2 50 Dissolution profiles of hydrocodone from the tablets of 60 67.5 83.5 Example 3 and Comparative Example 1 were conducted in a standard dissolution apparatus according to USP31 NF 26 Section 711 at 50 RPM,900 ml and paddle method in 0.1 N Example 3 HCL. 55 The data are shown in FIG. 5. It will be seen that the Example of a Tablet of the Invention Consisting of dissolution of hydrocodone from the tri-layer tablet of the Three Distinct Layers invention (Example 3) with separate weak acid and strong acid resinate layers was more rapid and more complete than A resinate of hydrocodone bitartrate (HCBT) and the weak from the bilayer tablet (Comparative Example 1) in which the acid ion-exchange resin IRP88 was prepared by a process as 60 weak acid and strong acid resinates were mixed. in Example 1. The weak acid resinate had a drug to resin weight ratio of 1:2. This resinate was blended with FeC13.6 Example 5 HO to produce a mixture containing 0.975 gram FeC13.6 H2O per gram of resinate. Dissolution profiles of the tablets of Example 3 were con A resinate of HCBT and the strong acidion-exchange resin 65 ducted in a standard dissolution apparatus according to IRP69 (sulfonated polyacrylic resin) was prepared by a pro USP31 NF 26 Section 711 at 50 RPM, 900 ml and paddle cess as in Example 1. The strong acid resinate had a drug to method. The studies were carried out in either 0.1 NHCL US 8,617,602 B2 13 14 (pH1.2), 0.01 NHCl (pH 2.0), 0.01 Macetate buffer (pH4.5) 2. The multi-layer solid oral pharmaceutical composition and 0.01 Mphosphate buffer (pH 6.8). The dissolution profile of claim 1 having at least three distinct layers, each said layer of the hydrocodone as a function of pH is shown in FIG. 6. comprising pharmaceutically active agents in a form selected The dissolution profile of the pseudoephedrine HCl as a func from the group consisting of ion-exchange resinates and tion of pH is shown in FIG. 7. unbound pharmaceutically active agents. It will be seen that the dissolution profiles of the hydroc 3. The multi-layer solid oral pharmaceutical composition odone in the distinct layer structure of the composition of the of claim 1 where said first layer comprises a member of the invention were both rapid over the first 45 minutes and sus group consisting of hydrocodone bitartrate polacrilex weak tained for a period at least eight hours, even at pH greater than acid resinate, codeine polacrilex weak acid resinate and dex 1.5. 10 tromethorphan polacrilex weak acid resinate; and said second FIG. 8 shows the contributions of the immediate release layer comprises a member of the group consisting of hydro and extended release components to the dissolution of the codone polistirex strong acid resinate, codeine polistirex hydrocodone from the tablets of Example 3 of the invention. strong acid resinate and dextromethorphan polistirex strong In FIG. 8, the line 10 is the dissolution of the full composition acid resinate. of Example 3. The line 20 is the Example 3 structure with an 15 inert filler instead of hydrocodone polacrilex in the “imme 4. The multi-layer solid oral pharmaceutical composition diate release layer. The line 30 is the contribution from the IR of claim 2, wherein, at least one of said layers comprises an layer alone in Example 3. unbound pharmaceutically active agent. The line 40 is the Example 3 structure with an inert filler 5. The multi-layer solid oral pharmaceutical composition instead of hydrocodone polistirex in the “extended release' of claim 4 wherein said first layer comprises a member of the layer. The line 50 is the contribution from the ER layer alone group consisting of hydrocodone bitartrate polacrilex weak in Example 3. acid resinate, codeine polacrilex weak acid resinate and dex It will be seen that that 20% of the total hydrocodone, tromethorphan polacrilex weak acid resinate; and said second essentially 100% of the hydrocodone in the immediate layer comprises a member of the group consisting of hydro release, layer was released within the first 45 minutes. 25 codone polistirex strong acid resinate, codeine polistirex strong acid resinate and dextromethorphan polistirex strong Other Embodiments acid resinate; and wherein a third layer consists of an unbound pharmaceuti All publications, patent applications, and patents men cally active agent. tioned in this specification are herein incorporated by refer 30 CCC. 6. A method of treating a patient with a stomach pH of at Various modifications and variations of the described least about 1.5 comprising administration of a multilayer method and system of the invention will be apparent to those Solid oral dosage form said dosage form comprising: skilled in the art without departing from the scope and spirit of (i) a first distinct layer comprising: the invention. Although the invention has been described in 35 (a) a first pharmaceutically active agent bound to a weak connection with specific desired embodiments, it should be acid ion exchange resin to form a weak acid ion understood that the invention as claimed should not be unduly exchange resinate; and limited to such specific embodiments. Indeed, various modi (b) a release-enhancing agent selected from the group fications of the described modes for carrying out the invention consisting of an inorganic salt and an organic base; that are obvious to those skilled in the fields of medicine, 40 (ii.) at least a second distinct layer comprising: immunology, pharmacology, endocrinology, or related fields (a) a drug selected from the group consisting of said first are intended to be within the scope of the invention. pharmaceutically active agent and a second pharma ceutically active agent, said drug being bound to a What is claimed is: strong acid ion exchange resin to form a strong acid 1. A multi-layer Solid oral pharmaceutical composition 45 ion-exchange resinate; and, comprising: (b) optionally, a coating to slow and extend release of the (i) a first distinct layer comprising: drug contained therein; (a) a first pharmaceutically active agent bound to a weak wherein said pharmaceutical composition is capable of acid ion exchange resin to form a weak acid ion immediate release of said first pharmaceutically active agent exchange resinate; and 50 from said weak acid resinate at a pH of at least 1.5, immediate (b) a release-enhancing agent consisting of FeCl; release being defined as at least 80% release of said pharma (ii.) at least a second distinct layer comprising: ceutically active agent within 45 minutes in a standard disso (a) a drug selected from the group consisting of said first lution apparatus according to USP34NF 26 section 711; and, pharmaceutically active agent and a second pharma wherein release of the drug from said strong acid resinate ceutically active agent, said drug being bound to a 55 continues over a period of at least 8 hours after ingestion. strong acid ion exchange resin to form a strong acid 7. A method of treating a patient having a first condition ion-exchange resinate; and and a second condition with a pharmaceutically active agent (b) optionally, a coating to slow and extend release of the effective for treating said second condition, said method.com drug contained therein; prising the step of administering a solid oral dosage pharma wherein said pharmaceutical composition is capable of 60 ceutical composition, said Solid oral dosage pharmaceutical immediate release of said first pharmaceutically active agent composition comprising: from said weak acid resinate at a pH of at least 1.5, immediate (i) a first distinct layer comprising: release being defined as at least 80% release of said pharma (a) a first pharmaceutically active agent bound to a weak ceutically active agent within 45 minutes in a standard disso acid ion exchange resin to form a weak acid ion lution apparatus according to USP34NF 26 section 711; and, 65 exchange resinate; and, wherein release of the drug from said strong acid resinate (b) a release-enhancing agent selected from the group continues over a period of at least 8 hours after ingestion. consisting of an inorganic salt and an organic base; US 8,617,602 B2 15 16 (ii.) at least a second distinct layer comprising: said pharmaceutically active agent bound to a strong (a) pharmaceutically active agent selected from the acid ion exchange resin to form a strong acid ion group consisting of said first pharmaceutically active exchange resinate, and agent and a second pharmaceutically active agent, (b) optionally, a coating to slow and extend release of the 5 drug contained therein; said pharmaceutically active agent bound to a strong wherein said pharmaceutical composition is capable of acid ion exchange resin to form a strong acid ion immediate release of said first pharmaceutically active agent exchange resinate; and, from said weak acid resinate at a pH of at least 1.5, immediate (b) optionally, a coating to slow and extend release of the release being defined as at least 80% release of said pharma drug contained therein; ceutically active agent within 45 minutes in a standard disso wherein said pharmaceutical composition is capable of 10 lution apparatus according to USP34NF 26 section 711; and, immediate release of said first pharmaceutically active agent wherein release of the drug from said strong acid resinate from said weak acid resinate at a pH of at least 1.5, immediate continues over a period of at least 8 hours after ingestion. release being defined as at least 80% release of said pharma 9. A method of delivering a pharmaceutically active agent ceutically active agent within 45 minutes in a standard disso to a patient, said method comprising orally administering a lution apparatus according to USP34NF 26 section 711; and, 15 Solid oral dosage composition comprising: wherein release of the drug from said strong acid resinate (i) a first distinct layer comprising: continues over a period of at least 8 hours after ingestion; and (a) a first pharmaceutically active agent bound to a weak wherein said first condition is selected from the group con acid ion exchange resin to form a weak acid ion sisting of Helicobacter pylori infection, atrophic gastritis, exchange resinate; and hypochlorhydria and achlorhydria in the stomach; and (b) a release-enhancing agent selected from the group wherein said second condition is a condition other than said consisting of an inorganic salt and an organic base: first condition. (ii.) at least a second distinct layer comprising: 8. A method of treating a patient wherein the patient has (a) pharmaceutically active agent selected from the within the past 24 hours been administered a compound group consisting of said first pharmaceutically active Selected from the group consisting of a proton pump inhibitor, 25 agent and a second pharmaceutically active agent, an H2 receptor antagonist, and an antacid, said method com said pharmaceutically active agent bound to a strong prising the step of administering a solid oral dosage pharma acid ion exchange resin to form a strong acid ion ceutical composition, said solid oral dosage pharmaceutical exchange resinate; and, composition comprising: (b) optionally, a coating to slow and extend release of the (i) a first distinct layer comprising: 30 drug contained therein; (a) a first pharmaceutically active agent bound to a weak wherein said pharmaceutical composition is capable of acid ion exchange resin to form a weak acid ion immediate release of said first pharmaceutically active agent exchange resinate; and; from said weak acid resinate at a pH of at least 1.5, immediate (b) a release-enhancing agent selected from the group release being defined as at least 80% release of said pharma consisting of an inorganic salt and an organic base: 35 ceutically active agent within 45 minutes in a standard disso (ii.) at least a second distinct layer comprising: lution apparatus according to USP34NF 26 section 711; and, (a) pharmaceutically active agent selected from the wherein release of the drug from said strong acid resinate group consisting of said first pharmaceutically active continues over a period of at least 8 hours after ingestion. agent and a second pharmaceutically active agent, ck ck ck ck ck