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US 20120277695A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0277695A1 Cottrell et al. (43) Pub. Date: Nov. 1, 2012

(54) TRANSDERMAL DELIVERY PATCH (30) Foreign Application Priority Data (76) Inventors: Jeremy Cottrell, Caulfield South Mar. 30, 2010 (US) ...... 603.190O2 (AU); Giacinto Gaetano, South Melbourne (AU); Mahmoud Publication Classification El-Tamimy, Meadow Heights (51) Int. Cl. (AU); Nicholas Kennedy, Boronia A6M 35/00 (2006.01) (AU); Paul David Gavin, B29C 39/38 (2006.01) Chadstone (AU) A6II 47/32 (2006.01) (21) Appl. No.: 131501,499 (52) U.S. Cl...... 604/304: 514/772.4; 264/330 (22) PCT Filed: May 18, 2010 (57) ABSTRACT (86). PCT No.: PCT/AU1O/OO58O A composition Suitable for use in a transdermal delivery patch S371 (c)(1), for administration of an , the composition comprising a (2), (4) Date: Apr. 12, 2012 phosphate compound of tocopherol and a polymer carrier. Backing material Matrix film Packaging liner is is:

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TRANSIDERMAL DELIVERY PATCH MW 360,000 Da), polysiloxanes and polymethyl methacry late (e.g. Eudragit E100). The composition, or matrix layer, TECHNICAL FIELD may comprise a polymer carrier in an amount of from about 0001. The present invention relates to a transdermal deliv 20% w/w up to about 90% w/w, from about 30% w/w up to ery patch for administration of therapeutic compounds. More about 80% w/w, from about 55% w/w up to about 65% w/w, specifically, the present invention relates to a transdermal of the total weight of the composition, or matrix layer. delivery patch for administration of . 0014. The polymer carrier may also comprise inert carrier components selected from the group consisting of anti-tack BACKGROUND ing agents, tackifiers, and plasticizers. 0002. In this specification where a document, act or item 0015 Inert carrier components may be present in the com of knowledge is referred to or discussed, this reference or position, or matrix layer, in an amount of from 0.001% w/w discussion is not an admission that the document, actor item up to about 50% w/w, up to about 40% w/w, from up to about of knowledge or any combination thereof was at the priority 30% w/w, of the total weight of the composition, or matrix date, publicly available, known to the public, part of common layer. general knowledge; or known to be relevant to an attempt to 0016. A third aspect provides a transdermal delivery patch solve any problem with which this specification is concerned. for administration of an opioid comprising (i) a backing layer, 0003 Drug delivery is the method or process of adminis tering a pharmaceutical compound to achieve a therapeutic and (ii) a matrix layer, which comprises a phosphate com effect in humans and animals. pound oftocopherol and a polymer carrier (as defined above), 0004 Drug delivery technologies have been developed to and an opioid. improve bioavailability, safety, duration, onset or release, of 0017. A fourth aspect provides use of a matrix patch for the pharmaceutical compound. transdermal delivery of an opioid, the matrix patch compris 0005. When developing drug delivery technologies, prob ing (i) a backing layer and (ii) a matrix layer, which comprises lems likely: to be encountered include compatibility of the a phosphate compound of tocopherol and a polymer carrier drug delivery system and the pharmaceutical compound, (as defined above), and an opioid. maintaining an adequate and effective duration, potential for 0018. The opioid may be selected from the group consist side effects, and meeting patient convenience and compli ing of , or ; , ance. As a consequence, many drug delivery technologies fall , , , , short of desired improvements and requirements. diacetylmorphine (), , dipropanoylmor 0006. Accordingly, there is still a need for alternate drug phine, or ; , pethi delivery systems that effectively deliver drugs. dine, , or ; endor phins, , , or . SUMMARY 0019. The opioid may also be selected from the group 0007. It has surprisingly been found that opioids can be consisting of agonists including morphine, effectively administered using a transdermal delivery patch. depomorphine, , heroin, hydromorphone, oxymor 0008 According to a first aspect, there is provided a com phone, , methadone, levomethadyl, meperidine, position suitable for use in a transdermal delivery patch for fentanyl, Sufentanyl, , codeine, hydrocodone, oxy administration of an opioid, the composition comprising a codone, and mixtures thereof opioid receptor antagonists phosphate compound of tocopherol and a polymer carrier. including and ; opioid receptor mixed 0009. In one embodiment, the transdermal delivery patch agonist-antagonists including , , is a matrix patch. , , and mixtures thereof, and, ethylke 0010. A second aspect provides use of a phosphate com tocyclazocine. pound oftocopherol and a polymer carrier as a matrix layer in 0020. The opioid may also be selected from the group a transdermal delivery patch for administration of an opioid. consisting of codeine, morphine, thebaine and ; 0011. The phosphate compound of tocopherol may be diacetylmorphine (heroin), , hydrocodone, selected from the group consisting of mono-(tocopheryl) hydromorphone, nicomorphine, desmorphine, ethylmor phosphate, mono-(tocopheryl)phosphate monosodium salt, phine, , oxycodone and oxymorphone; mono-(tocopheryl)phosphate disodium salt, mono-(toco fentanyl, alphamethylfentanyl, alfentanil, , pheryl)phosphate monopotassium salt, mono-(tocopheryl) , carfentanyl and ; (mep phosphate dipotassium salt, di-(tocopheryl)phosphate, di eridine), , MPPP, , and (tocopheryl)phosphate monosodium salt, di-(tocopheryl) PEPAP; propoxyphene, dextropropoxyphene, dextromora phosphate monopotassium salt, or a mixture thereof. These mide, , , methadone, , phosphate compounds may be derived from the alpha, beta, levomethadyl acetate (LAAM), , and gamma or delta form oftocopherol, or a combination thereof. , , pentazocine and ; 0012. The composition, or matrix layer, may comprise a buprenorphine, and etorphine; butorpha phosphate compound of tocopherol in an amount within the nol, nalbuphine, levorphanol and ; lefe range of about 0.01% w/w to about 10% w/w, about 0.1% w/w tamine, , , tramadol and ; to about 5% w/w, about 0.5% w/w to about 2% w/w or to , naloxone and naltrexone; and pharmaceutically about 3% w/w, of the total concentration of the matrix layer. acceptable salts, prodrugs, or derivatised compounds thereof. In one embodiment, the phosphate compound oftocopherol is 0021. In a preferred embodiment, the opioid is oxycodone present in an amount of about 1% w/w to about 1.5% w/w of or dihydrohydroxycodeinone (oxycodone base). the total concentration of the matrix layer. 0022. The opioid may be present in an amount of from 0013 The polymer carrier may comprise natural and syn about 0.1% w/w up to about 30% w/w, up to about 20% w/w, thetic polymers, co-polymers, or terpolymers. Preferred up to about 10% w/w, of the total concentration of the com polymer carriers that are Suitable for use in the composition, position, or matrix layer. In one embodiment, the composi or matrix layer, include polyvinyl pyrrolidone (e.g. PVP K90, tion, or matrix layer, will have an opioid concentration of US 2012/0277695A1 Nov. 1, 2012

about 4.5% w/w to about 5.5% w/w of the total concentration of the composition, or matrix layer. -continued 0023 Preferably the backing layer is occlusive. 0024. A fifth aspect provides a method for preparing a (I) transdermal delivery patch for administration of an opioid comprising the steps of 0025 (i) combining a polymer carrier and optional inert carrier components with a suitable solvent; 0026 (ii) combining (i) with a dispersion comprising a phosphate compound of tocopherol and an opioid; 0027 (iii) stirring (ii) until complete homogenisation is achieved; 0028 (iv) placing (iii) in a mould comprising a suitable 8-tocopherol H H CH backing layer, and 8-tocotrienol 0029 (V.) drying the compositions in the mould by heat ing them up to about 90° C. for about 0.5 to about 24 hours. Preferably, the drying is conducted at a tempera 0033. In the present invention, tocopherol in any of the ture of 75° C. four forms may be used. The alpha form of tocopherol is preferred. DETAILED DESCRIPTION 0034. The term “phosphate compound” refers to phospho rylated tocopherol, where a covalent bond is formed between 0030 The present invention relates to a composition suit an oxygenatom (typically originating from a hydroxyl group) able for use in a transdermal delivery patch for administration of the tocopherol compound and the phosphorous atom of a of an opioid, the composition comprising a phosphate com phosphate group (PO). pound oftocopherol and a polymer carrier. The composition, 0035. The phosphate compound may be a phosphate or matrix layer, may form part of a transdermal delivery mono-ester, phosphate di-ester, phosphate tri-ester, pyro patch. It has been Surprisingly found that a transdermal deliv phosphate mono-ester, pyrophosphate di-ester, or a salt or ery patch comprising this matrix layer can effectively admin derivative thereof, or a mixture thereof. The di- and tri-esters ister opioids. may comprise the same tocopherol form or different toco pherol forms. Phosphate Compound of Tocopherol 0036. The “salts' include metal salts such as alkali or alkaline earth metal salts, for example sodium, magnesium, 0031. The composition, or matrix layer, comprises a phos potassium and calcium salts. Sodium and potassium salts are phate compound of tocopherol. preferred. 0032 Vitamin E exists in eight different forms, namely 0037. The "derivatives” include phosphate compounds four tocopherols and four tocotrienols. All feature a chroman where one or more phosphate protons are replaced by a Sub ring, with a hydroxyl group that can donate a hydrogenatom stituent. Some non-limiting examples of derivatives include to reduce free radicals and a hydrophobic side chain which phosphatidyl derivatives where a phosphate proton is Substi allows for penetration into biological membranes. Such tuted with an amino-alkyl group, Sugar derivatives where a derivatives of vitamin E may be classified as “hydroxy chro phosphate proton is Substituted with a Sugar Such as glucose. mans'. Both tocopherols and tocotrienols occur in alpha, 0038. The term "amino-alkyl group' refers to a group beta, gamma and delta forms, determined by the number and comprising an amino (-NH2) group and an alkyl group. The location of methyl groups on the chroman ring. The tocot term “alkyl refers to straight chain, branched chain or cyclic rienols differ from the analogous tocopherols by the presence hydrocarbon groups having from 1 to 8 carbon atoms. of three double bonds in the hydrophobic side chain. The Examples include methyl, ethyl, propyl, isopropyl, butyl, various forms of vitamin E are shown by Formula (I): isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclohexyl, hep tyl, and octyl. Phosphatidylcholine derivatives are most pre ferred. (I) 0039. The phosphate compounds of tocopherol may be selected from the group consisting of mono-(tocopheryl) phosphate, mono-(tocopheryl)phosphate monosodium salt, mono-(tocopheryl)phosphate disodium salt, mono-(toco pheryl)phosphate monopotassium salt, mono-(tocopheryl) phosphate dipotassium salt, di-(tocopheryl)phosphate, di (tocopheryl)phosphate monosodium salt, di-(tocopheryl) phosphate monopotassium salt, or a mixture thereof. These phosphate compounds may be derived from the alpha, beta, R R2 R gamma or delta form of tocopherol, or a combination thereof. 0040. When a mixture of a mono-phosphate ester and a C-tocopherol CH CH CH di-phosphate ester, that is a mono-(tocopheryl)phosphate and C-tocotrienol B-tocopherol CH H CH di-(tocopheryl)phosphate (which may in Some instances B-tocotrienol herein be simply referred to as “TPM), the ratio is preferably Y-tocopherol H CH CH at least 2:1, more preferably within the range of about 4:1 to Y-tocotrienol about 1:4, most preferably within the range of about 6:4 to about 8:2. The ratio may be about 6:4 or about 8:2. US 2012/0277695A1 Nov. 1, 2012

0041. The matrix layer may comprise a phosphate com ibility and “tackiness' for the polymer carrier to enable the pound of tocopherol in an amount within the range of about matrix layer to adhere to the surface of skin, and thus provide 0.01% w/w to about 10% w/w, about 0.1% w/w to about 5% consistent delivery. w/w, about 0.5% w/w to about 2% w/w or to about 3% w/w, 0050 For polymers which are naturally “tacky' and may of the total concentration of the matrix layer. In one embodi need anti-tackiness to have an appropriate consistency, anti ment, the phosphate compound oftocopherol is present in an tacking agents that are solid with no stickiness property (i.e. amount of about 1% w/w to about 1.5% w/w of the total low ability to retain solvents upon drying) and that can be concentration of the matrix layer. mixed well (i.e. do not crystallise upon drying) with the polymer carrier may be suitable. The selection would be Polymer Carrier based on the polymer-type. Many surfactants are suitable for 0042. The composition, or matrix layer, also comprises a use as an anti-tacking agent with a polymer carrier. A more polymer carrier. specific example of an anti-tacking agent is succinic acid. 0043. The polymer carrier may comprise natural and syn 0051. In order to enhance the ability of the matrix layer to thetic polymers, co-polymers, or terpolymers. adhere to the Surface of skin, it may optionally contain a 0044 Natural polymers include rubbers, elastomers, tackifier (or tacking agent). Tack can be controlled by com polysaccharides Such as cellulose, natural resins such as shel bining adhesives of varying hardnesses (glass temperature or lac and amber. T). Typically, a tackifier is a polymer which is insoluble in 0045 Synthetic polymers include, for example, polyacry water and composed of a monomer which contains partly or lates, polyamides, polyesters, polycarbonates, polyimides, wholly a (meth)acrylic alkyl ester. Such types of polymers polystyrenes, acrylonitrile butadiene styrene, polyacryloni include, but are not limited to, acrylic, N-butyl-methacrylic trile, polybutadiene, poly(butylene terephthalate), poly(ether copolymer (Primal N580NF, sold by Japan Acrylic Chemical Sulphone), poly(ether)ketones, polyethylene, poly(ethylene Company, Ltd.), acrylic methyl, acrylic 2-ethylhexyl copoly glycol), poly(ethylene terphthalate), polypropylene, polytet mer (Nikasol TS-6520, sold by Nippon Carbide Industries ratfluroethylene, styrene-acrylonitrile resin, poly(trimethyl Company, Ltd), polyacrylic acid (Jurymer AC-IOLPH, sold ene terephthalate), polyurethanes, polyvinylbutyral, polyvi by Nihon Junyaku Company, Ltd), methacrylic copolymer L nylchlorides, polyvinylidenedifluoride, poly(vinyl (Plastoid L50, sold by Rohm Pharma GmbH), and ami pyrrolidone), polychloroprene, fluoroelastomers, chloro-sul noalkylmethacrylate copolymer E (Plastoid E35L, Plastoid phonated rubbers, hypromellose, polyolefine elastomer, E35M, Plastoid E35H, all sold by Rohm Pharma GmbH). polyacrylamide, chlorinated polyethylene, polyetherSul Other non-limiting examples include rosin esters, hydroge phone, nylon, liquid crystal polymers, polyethylene tereph nated rosins, dipropylene glycol dibenzoate, and/or mixed thalate (PET), polyphenylsulphone, polypthalaminepolyvi hydrocarbons, and acrylic copolymers (e.g. Flexbond 150 nyl derivatives, polyethylene glycols, ethylene vinyl adhesive by Air Products). acetate, polymethyl methacrylate, cellulose derivatives Such 0.052 Plasticizers are additives that increase the plasticity as ethyl cellulose, hydroxyl propyl methyl cellulose, Sugar or fluidity of the material to which they are added. Plasticizers derivatives (gums) including derivatives of sorbitol and man may be used in the present invention to soften the final prod nitol, and silicone oil derivatives Such as polysiloxanes. uct increasing its flexibility and making it less brittle. Suitable 0046 Preferred polymer carriers that are suitable for use plasticizers include phthalates, esters of polycarboxylic acids in the matrix layer of the present invention include polyvinyl with linear or branched aliphatic alcohols of moderate chain pyrrolidone (e.g. PVP K90, MW 360,000 Da), polysiloxanes length, acetylated monoglycerides, alkyl citrates, triethyl cit and polymethyl methacrylate (e.g. Eudragit E100). rate (TEC), acetyl triethyl citrate (ATEC), tributyl citrate 0047. The polymer carrier used in the matrix layer may (TBC), acetyl tributyl citrate (ATBC), trioctyl citrate (TOC), have sufficient tackiness to enable the matrix patch to adhere acetyl trioctyl citrate (ATOC), trihexylcitrate (THC), acetyl to skin. For instance, amine-resistant polysiloxanes and mix trihexylcitrate (ATHC), butyryl trihexylcitrate (BTHC, tri tures thereof can be used in the matrix layer. A mixture of a hexyl o-butyryl citrate), trimethyl citrate (TMC), alkyl sul polysiloxane of medium tack and a polysiloxane of high tack phonic acid phenyl ester, bis(2-ethylhexyl)phthalate (DEHP). is used would be most suitable. The polysiloxanes may be bis(n-butyl)phthalate (DnBP, DBP), diisooctyl phthalate synthesized from linear bifunctional and branched polyfunc (DIOP), bis(n-butyl)phthalate (DnBP, DBP), diisobutyl tional oligomers. It has been found that the ratio of both types phthalate (DIBP), bis(2-ethylhexyl)adipate (DEHA), dim of oligomers determines the physical properties of the poly ethyl adipate (DMAD), monomethyl adipate (MMAD), dio mers. More polyfunctional oligomers result in a more cross ctyl adipate (DOA), dibutyl sebacate (DBS), dibutyl maleate linked polymer with a higher cohesion and a reduced tack, (DBM), diisobutyl maleate (DIBM), benzoates, epoxidized less polyfunctional oligomers result in a higher tack and a vegetable oils, N-ethyl toluene sulfonamide (o?p ETSA), reduced cohesion. A high tack version should be tacky N-(2-hydroxypropyl)benzene sulfonamide (HPBSA), N-(n- enough for the matrix patch to adhere to the Surface of skin. A butyl)benzene sulfonamide (BBSA-NBBS), tricresyl phos medium tack version, on the other hand, may not be tacky at phate (TCP), tributyl phosphate (TBP), triethylene glycol all but could be useful by providing a softening effect to other dihexanoate (3G6, 3GH), tetraethylene glycol diheptanoate components included in the matrix layer. To increase the (4G7), and polyvinylpyrrolidone. Dibutyl sebacate (DBS) is adhesive power of the matrix layer, a silicone oil (e.g. dime a preferred plasticizer. thicone) could be added. 0053 Inert carrier components may be present in the 0048. The matrix layer may comprise a polymer carrier in matrix layer in an amount of from 0.001% w/w up to about an amount of from about 20% w/w up to about 90% w/w, from 50% w/w, up to about 40% w/w, up to about 30% w/w, of the about 30% w/w up to about 80% w/w, from about 55% w/w total weight of the matrix layer. In one embodiment, the up to about 65% w/w, of the total weight of the matrix layer. matrix layer comprises an anti-tacking agent (such as Suc 0049. The polymer carrier may also comprise inert carrier cinic acid) and a plasticizer (such as dibutyl sebacate) in a components, such as for example, anti-tacking agents, tacki total amount of about 35% w/w of the total weight of the fiers, and plasticizers to achieve appropriate softness, flex matrix layer. US 2012/0277695A1 Nov. 1, 2012

0054 The amount of polymer carrier and optional inert 0064. An opioid receptor mixed agonist-antagonist has carrier components present in the matrix layer will depend on mixed opioid agonist/antagonist activities, or one that exhib the specific opioid to be administered. Generally, however, its only partial agonist activity. Compounds which exhibit the matrix layer may comprise these components in an mixed agonist/antagonist activity include, but are not limited amount of from about 50% w/w up to about 99% w/w, from to, buprenorphine, nalbuphine, butorphanol, pentazocine, about 80% w/w up to about 98% w/w, from about 90% w/w and mixtures of such compounds. Compounds which exhibit up to about 98% w/w, of the total weight of the matrix layer. partial agonist activity include, but are not limited to ethylke In one embodiment, the matrix layer comprises these com tocyclazocine. ponents in the amount of about 95% w/w of the total weight 0065. The present invention is not limited to the delivery of the matrix layer. of a single opioid: embodiments of the invention may include 0055. It should be noted that, in some instances herein, the mixtures of opioids. For the avoidance of any doubt, it is to be term “polymer carrier could be used collectively to refer to noted that the singular forms “a”, “an and “the should be the polymer carrier and the inert carrier components. read as encompassing plural forms, unless the context clearly indicates otherwise. Additional Optional Components 0066. The present invention is also not limited to the spe cific opioid compounds mentioned herein: pharmaceutically 0056. The matrix layer may optionally further comprise acceptable salts, prodrugs, and other derivatised compounds one or more excipients (in addition to the inert carrier com are envisioned as well. ponents discussed above). 0067. The present invention is further not limited solely to 0057. A person skilled in the art of the invention would the administration of opioids: other therapeutic compounds appreciate what are Suitable excipients for inclusion in the may be incorporated into the matrix layer in addition to the matrix layer of the invention. Some examples include, but are opioid. Such as for example, Steroidal and non-steroidal anti not limited to, Solvents, thickeners or gelling agents, preser inflammatory agents, local anaesthetics and/or antibiotics. Vatives, Surfactants, stabilizers, plasticizers, adhesives or 0068 Examples of “opioids' include, but are not limited glues, buffers, emollients, colours, fragrances, and appear to: alkaloids including Phenanthrenes naturally ance modifiers. It will be appreciated that any excipients occurring in opium Such as codeine, morphine, thebaine and which have been approved for use in pharmaceutical products oripavine (the active metabolite of thebaine); Synthetic by the regulatory bodies may be employed in the matrix derivatives such as diacetylmorphine (heroin), dihydroco layers (or compositions) of the present invention. The amount deine, hydrocodone, hydromorphone, nicomorphine, des of a particular excipient or excipients to be used in a matrix morphine, ethylmorphine, dipropanoylmorphine, oxycodone layer of the present invention would also be appreciated by a and oxymorphone: Synthetic opioids including Anilidopip person skilled in the art. eridines such as fentanyl, alphamethylfentanyl, alfentanil, sufentanil, remifentanil, carfentanyl and ohmefentanyl, Phe Opioids nylpiperidines Such as pethidine (meperidine), ketobemi done, MPPP, allylprodine, prodine and PEPAP, Diphenylpro 0058. It has been surprisingly found that the transdermal pylamine derivatives Such aS propoxyphene, delivery patch of the present invention can effectively admin dextropropoxyphene, , bezitramide, piritra ister opioids. mide, methadone, dipipanone, levomethadyl acetate 0059 An opioid is a chemical that works by binding to (LAAM), difenoxin, diphenoxylate and loperamide, Benzo opioids receptors, which are found principally in the central morphan derivatives such as dezocine, pentazocine and nervous system and the gastrointestinal tract. The receptors in phenazocine, Oripavine derivatives such as buprenorphine, these two organ systems mediate both the beneficial effects dihydroetorphine and etorphine, Morphinan derivatives such and the side effects of opioids. as butorphanol, nalbuphine, levorphanol and levomethor 0060. There are a number of broad classes of opioids: phan, and others such as , meptazinol, tilidine, natural which are alkaloids contained in the resin of tramadol and tapentadol; Opioid receptor antagonists includ the opium poppy Such as morphine, codeine and thebaine; ing nalmefene, naloxone and naltrexone; and pharmaceuti semi-synthetic opioids created from natural opiates such as cally-acceptable salts, prodrugs, or derivatised compounds hydromorphone, hydrocodone, oxycodone, oxymorphone, thereof. desomorphine, diacetylmorphine (heroin), nicomorphine, 0069. In a preferred embodiment, the opioid is oxycodone dipropanoylmorphine, benzylmorphine and ethylmorphine; or dihydrohydroxycodeinone (oxycodone base). fully synthetic opioids such as fentanyl, pethidine, metha 0070 The opioid may be presentinatherapeutically effec done, tramadol and dextropropoxyphene; and, endogenous tive amount, that is, an amount necessary to achieve a desired opioid peptides, produced naturally in the body, such as therapeutic effect. Typically, the opioid will be present in an endorphins, enkephalins, dynorphins, and endomorphins. amount of from about 0.1% w/w up to about 30% w/w, up to 0061 Opioids produce an effect, generally about 20% w/w, up to about 10% w/w, of the total concentra through their interaction with opioid receptors. Opioid anal tion of the matrix layer. In one embodiment, the matrix layer gesics may be opioid receptor agonists, opioid receptor par will have an opioid concentration of about 4.5% w/w to about tial agonists, or opioid receptor mixed ago 5.5% w/w of the total concentration of the matrix layer. nist-antagonists. 0062 Opioid receptoragonists include, but are not limited Preparation of the Matrix Patch to, morphine, depomorphine, etorphine, heroin, hydromor 0071. The matrix patch of the present invention may be phone, oxymorphone, levorphanol, methadone, prepared by a variety of techniques. levomethadyl, meperidine, fentanyl, Sufentanyl, alfentanil, 0072. One technique involves combining the polymer car codeine, hydrocodone, oxycodone, and mixtures of the fore rier and any inert carrier components such as an anti-tacking going. agent and/or plasticizer with a suitable solvent. This is com 0063 Opioid receptorantagonists include, but are not lim bined with a dispersion comprising the opioid and the phos ited to, naloxone and naltrexone. phate compound of tocopherol, and is stirred until complete US 2012/0277695A1 Nov. 1, 2012 homogenisation is achieved. The composition may then be nylon, silicone elastomers, rubber-based polyisobutylene, placed in a suitable mould and dried. In a preferred method, styrene, styrene-butadiene, and styrene-isoprene copoly the composition may be dried by heating up to about 90° C. mers, polyethylene, and polypropylene. preferably for 0.5 to 24 hours. However, formulating and/or drying may be conducted at a temperature within the range of I0083. The release liner may be of any thickness, however about 30° C. to about 90° C. It has been found that formulat in the art, release liners typically have a thickness of about ing and/or drying at a temperature of about 75° C. results in 0.01 mm to about 2 mm. better delivery of the opioid. I0084. The matrix patch may also comprise an adhesive 0073. The ratio of components in of this composition, layer. The adhesive layer may be an additional layer to the polymer carrier to opioid to phosphate compound of toco matrix layer, or may be included on the outer margin of the pherol, is preferably at least 10:5:1, 14:5:1 or 14:10:2. The backing layer where the backing layer extends beyond the opioid:TP ratios may be between about 5:5 to about 5:0.5, edges of the matrix layer. Polymeric adhesives useful for with the most preferred value of about 5:1. The polymer transdermal patches include polyacrylate polymers, rubber carrier: opioid and TP is about 1:1 to about 3:1, with pre based adhesives and polysiloxane adhesives. These types of ferred values of about 7:6 to about 7:3. materials, as well as others, are described by Van Norstrand 0074 The composition comprising the phosphate com (The Handbook of Pressure Sensitive Adhesive Technology pound oftocopherol and the polymercarrier is suitable for use Second Edition 1989), which is hereby incorporated by ref in a transdermal delivery patch for administration of an erence. Examples of commercially available adhesives opioid. This composition essentially forms the matrix layer in a transdermal delivery patch. The matrix layer may be a solid include, but are not limited to, polyacrylate adhesives sold or semi-solid layer. under the trademarks DUROTAK (registered trademark) by 0075. The transdermal delivery patch usually would also National Starch and Chemical Corporation, Bridgewater, comprise a backing layer. The backing layer acts as a Support N.J., as well as GELVA-MULTIPOLYMER SOLUTION or substrate for the matrix layer. When preparing a matrix (registered trademark) by Cytek Surface Specialties, Smyrna, patch using a mould, the backing layer would be placed in the Ga. mould before addition of the matrix layer composition. 0076 Accordingly, the matrix layer essentially has two Advantages Surfaces: a first Surface and a second Surface opposite the first surface, where the first surface is in contact with the backing I0085. It has surprisingly been found that opioids can be layer and the second Surface being adapted to be in diffusional effectively administered using a transdermal delivery patch contact with the skin of a subject. The subject may be a human comprising a matrix layer which comprises a phosphate com or animal. pound oftocopherol and a polymer carrier. 0077. The present invention therefore also provides use of I0086 Transdermal delivery options for include, for a matrix patch for transdermal delivery of an opioid, the example, topical creams and gels, and skin patches. matrix patch comprising (i) a backing layer, and (ii) a matrix I0087 Creams and gels may present difficulties with com layer which comprises a phosphate compound oftocopherol, pliance and dosage control, and may be considered messy or a polymer carrier, and an opioid. unpleasant by patients. 0078 Preferably, the backing layer is occlusive or imper I0088. There are different forms of skin patches, including meable to protect the matrix layer from the outer environ ment. However, a non-occlusive backing layer could also be “reservoir patches and “matrix' patches. Patches may also used, so long as the packaging of the matrix patch is fully be single- or multi-layered. A “reservoir patch essentially occlusive to prevent degradation of the matrix layer. An has a liquid or gel compartment containing the drug Solution occlusive backing layer is preferred. or Suspension separated by a membrane and a layer of adhe 007.9 The backing layer may be of anythickness, however sive. In a "matrix' patch, the drug dispersion is present in a in the art, backing layers typically have a thickness of about semi-solid or Solid layer, which may or may not also comprise 0.0005 inches to about 0.01 inches. the adhesive material. 0080. The present invention therefore provides a transder I0089 Reservoir patches overcome some of the dosage mal delivery patch for administration of an opioid comprising difficulties with topical creams and gels, however the delivery (i) a backing layer, and (ii) the matrix layer which comprises may be uneven or inconsistent, and there is some risk of a phosphate compound of tocopherol, a polymer carrier, and perforation of the reservoir. An additional issue relates to an opioid. delivery of prescribed drugs which may be addictive and 0081. The matrix patch may further comprise a liner Subject to abuse. Gels, creams and reservoir patches provide which is a removable protective or impermeable layer, usu limited barriers to extraction of the drug substance, whereas ally but not necessarily rendered “non-stick” so as not to stick incorporation of the drug Substance within a matrix layer to the matrix layer. The liner, which may also be referred to as represents a significant, if not almost impossible barrier to the release liner, protects the matrix patch during storage. extraction of the drug Substance. During use, the release liner is to be removed. 0090 Delivery of an active orally or by injection typically 0082. The liner may be made from the same material as the backing layer, however it may also be a metal foil, Mylar results in a delivery profile which is non-linear. Transdermal (registered trademark), polyethylene terephthalate, sili delivery provides a non-invasive way of potentially achieving conized polyester, fumed silica in silicone rubber, polytre Sustained steady state delivery. trafluoroethylene, cellophane, siliconized paper, aluminized 0091. Without wishing to be bound by theory, the presence paper, polyvinyl chloride film, composite foils or films con of a phosphate compound oftocopherol may reduce any skin taining polyester Such as polyester terephthalate, polyester or irritation caused by the opioid and enhance the skin perme aluminized polyester, polytetrafluoroethylene, polyether ation of the opioid. It has also been found that the components block amide copolymers, polyethylene methyl methacrylate of the matrix layer do not formulate well together without the block copolymers, polyurethanes, polyvinylidene chloride, presence of a phosphate compound of tocopherol. US 2012/0277695A1 Nov. 1, 2012

FIGURES 0103) In both methods, the matrix layer would be rela tively thin; however, the thickness of the matrix layer can be 0092. The examples will be described with reference to varied depending on the desired properties of the matrix the accompanying figures in which: patch. 0093 FIG. 1 is a schematic diagram of a matrix patch of one embodiment of the present invention: Example 2 0094 FIG. 2 is a graph comparing the delivery of oxyc odone using a matrix patches of the present invention pre Alterbate Method for Manufacture of Matrix Patch pared with different drying regimes; 0104 Matrix patches were constructed by dissolving 20% w/w solid mixture of Eudragit E 100 granules, dibutyl seba 0095 FIG. 3 is a graph comparing the delivery of oxyc cate, succinic acid (the components other than TPM and odone using matrix patches of the present invention prepared oxycodone in the matrix layer may collectively be referred to with and without a glue layer; as the “polymer carrier'); a mixture of mono-(tocopheryl) 0096 FIG. 4 is a graph comparing the delivery of oxyc phosphate and di-(tocopheryl)phosphate in a ratio of 6:4 odone using matrix patches of the present invention prepared (TPM); and oxycodone base in 60:6.6:33.4w/w acetone/iso with and without an occlusive backing layer; propyl alcohol/ethyl alcohol. The mixture was then trans 0097 FIG. 5 is a graph showing the results of pharmaco ferred into 6cm circular aluminium cast-lined on the under kinetic testing conducted after application of matrix patches side with polyester backing (1.66 mill, 3M ScotchpakTM, 3M, of the present invention; and MN) and the solvent evaporated in an oven at either 45° C. 0098 FIG. 6 is a graph showing the results of pharmaco overnight or 75° C. for 1.5 hours. Where glue was used, the dynamic testing conducted after application of matrix patches glue was Duro-Takadhesive and in this example Succinic acid of the present invention. was omitted from the formulation. TABLE 1 EXAMPLES Composition, excipient ratios and manufacture 0099 Various embodiments/aspects of the present inven conditions of matrix patches tion will now be described with reference to the following Oxy- Vol. non-limiting examples. Patch Ratio codone stock Dry temp. Succinic No. (PC:O:TPM)* (mg) (ml) time acid Glue Example 1 1 10:5:1 10 2 45° C. Yes No overnight 2 14:5:1 10 2 45° C. Yes No Manufacture of Matrix Patch overnight 3 14:5:1 5 1 45° C., Yes No 01.00 overnight 4 14:5:1 5 1 75° C.1.5 h Yes No S 14:10:2 5 0.5 75 C.1.5 h. No Yes

Final matrix layer composition *Refers to ratio of polymer carrier:oxycodone:TPM Percentage by Components weight, after drying Example 3 A mixture of mono- (tocopheryl) phosphate 1.1% ww and di- (tocopheryl) phosphate in a ratio of 6:4 Comparative Testing for Drying Temperatures Oxycodone 5.5% ww 0105. Oxycodone matrix patches were made according to Eudragit E100 (polymethyl methacrylate) 60.6% Wiw Example 1 (small scale) above, testing the variable of the two Dibutyl sebacate 27.3% wiw different heating regimes. The matrix patches were adhered to Succinic acid 5.5% ww full thickness human skin applied to a Franz cell with PBS as the receiver solution. Time points were taken at 18, 22, 24, 42, 44, 68 and 75 hours and the receiver solution was tested by Small Scale Laboratory Manufacturing HPLC to determine the concentration of oxycodone which had passed through the skin. 0101 The components were dissolved in a solvent solu tion (acetone:isopropanol:ethyl alcohol 60:6.6:33.5 by TABLE 2 weight). The resulting Solution was then poured into indi vidual casts (containing Suitable backing layers) at room tem Parameters in the patches tested perature and the solvent was allowed to evaporate at 75° C. for Vol. Dry 1.5 hours. Ratio Oxycodone stock temp. Succinic Patch (PC:O:TPM)* (mg) (ml) time acid Glue Large Scale Manufacturing A. 14:5:1 10 2 45° C. Yes No Ower 0102 All matrix layer components could be combined at a night Suitable temperature to produce a homogeneous molten mass. B 14:5:1 10 2 750 C. Yes No The molten mass can then be cast on a cold Surface (for 1.5h example, a rotating mill with a Suitable backing layer, or sheet, thereon) and allowed to solidify. Individual matrix *Refers to ratio of polymer carrier:oxycodone:TPM patches of varying sizes may then be cut. US 2012/0277695A1 Nov. 1, 2012

0106. The results outline in FIG. 2 show that the matrix 0114. The day after the matrix patches were adhered to the patch manufactured using the higher (accelerated) drying shaved section, blood samples removed from the tail tip fol temperature has increased transdermal delivery properties lowing ~1 mm tip amputation at specified times. The PK compared with the matrix patch manufactured with drying at parameters quantified were: a lower temperature. 0115 C.: the maximal observed plasma oxycodone concentration. Example 4 0116 AUC. The area under the curve between 0 and 4 hours (the duration of the experiment was 4 hours) and is a Comparative Testing to Determine Effect of an External Glue measure of the total amount of drug delivered. Layer 0117. The results in FIG. 5 and Table 5 demonstrate that 0107 Matrix patches were manufactured and the receiver the matrix patches of the present invention in various formu Solution tested as in Example 3, with testing time points of lations are able to effectively deliver the oxycodone to the rats 0.5, 1, 3, 4 and 20 hours. as demonstrated by the pharmacokinetic data. TABLE 3 TABLE 5 Parameters in the patches tested Estimated pharmacokinetic parameters Vol. Dry of rats administered matrix patches Patch Ratio Oxycodone stock temp. Succinic No. (PC:O:TPM)* (mg) (ml) time acid Glue Oxycodone Patch dose Cmax AUCoa C 14:5:1 10 2 750 C. Yes No No. (mg/kg) Occlusive in (ngmL) (ng mL/min) 1.5h D 14:5:1 10 2 750 C. No Yes 1 41.804 No 17 93 - 16 13681 - 2367 1.5h 2 45.O 21 Yes 9 92 27 11959 2910 4 21.701 Yes 5 14433 21637 51.89 *Refers to ratio of polymer carrier:oxycodone:TPM 5 18.1 O.3 Yes 5 74 - 29 11161 4636 0108. The results of this comparison outlined in FIG. 3 n = no. of animals clearly demonstrate that using a matrix patch which includes an adhesive layer results in reduced transdermal penetration of the oxycodone compared with the matrix patches formu Example 7 lated to be self-adhesive. Pharmacodynamic Testing Example 5 0118 Rats were prepared and dosed similar to Example 6 0109 Comparative Testing to Determine Effect of an using Patch Nos. 1, 3 and 5 from Example 2. Occlusive Backing Layer Compared with No Backing Layer 0119 The day after the matrix patches were adhered to the 0110. The matrix patches were manufactured and the shaved section, antinociception of the hind-paw was assessed receiver Solution tested as in Examples 3 and 4, at time points with a plantar analgesiometer with the IR source calibrated to 1, 2, 3, 4 and 5 hours. 190 Mu/cm. The following PD parameters were assessed: TABLE 4 0120 Maximum: The maximum time it took for the rat to remove its paw in response to the heat stimulus. The higher Parameters in the patches tested the number, the longer it took for the rat to respond and the deeper the oxycodone induced analgesia. Oxy- Vol. Patch Ratio codone stock Dry temp. Occlusive I0121 AUC: This is a measure of the total analgesia over No. (PC:O:TPM)* (mg) (ml) time backing Glue the observation period as measured by the area under the curve between 0 and 4 hour, and is useful for comparing the E 14:5:1 10 2 75° C. 1.5 h. Yes No response to different treatments. F 14:5:1 10 2 75° C. 1.5 h. No No 0.122 The baseline response time is indicated in FIG. 6 at *Refers to ratio of polymer carrier:oxycodone:TPM t=(-0.5 h) and t=0. (0123. The results outlined in Table 6 below and FIG. 6 0111. The results outlined in FIG. 4 clearly show that the demonstrate that analgesia was effectively administered to penetration of the oxycodone transdermally is far Superior the rats using a variety of compositions of the present inven when an occlusive backing layer is used with the patch com tion. pared with a patch without the adhesive backing layer. Example 6 TABLE 3 Pharmacodynamic parameters from rats Pharmacokinetic Testing administered different matrix patches 0112 This example compares plasma PK parameters Oxycodone using Patch Nos. 1, 2, 4 and 5 from Example 2. Patch dose Max AUCoa 0113 Matrix patches were cut from the polyester backing No. (mg/kg) l (sec.) (sec/h) and adhered to the shaved and washed back of a 10-12 week 1 41.O. O.8 5 20.73.5 57.6 9.1 old male Sprague-Dawley rat with a 6x7cm Tegaderm HPTM 3 21.8 O.6 5 22.333 76.8 13.1 (3M, MN) adhesive dressing either with the backing layer in 5 21.6 OS 4 20.5 - 23 64.O 6.4 place or removed (see Table 5). Tegaderm serves to hold the occlusive backing layer in place, or if the backing layer is n = no. of animals absent, holds the matrix patch itself in place. US 2012/0277695A1 Nov. 1, 2012

0.124. In this specification, except where the context (heroin), nicomorphine, dipropanoylmorphine, benzylmor requires otherwise, the words “comprise”, “comprises, and phine or ethylmorphine; fentanyl, pethidine, methadone, tra “comprising mean “include”, “includes”, and “including madol or dextropropoxyphene; endorphins, enkephalins, respectively, i.e. when the invention is described or defined as dynorphins, or endomorphins. comprising specified features, various embodiments of the 14. The transdermal delivery patch of claim 12, wherein same invention may also include additional features. the opioid is selected from the group consisting of opioid 0.125. Although this invention has been described by receptor agonists including morphine, depomorphine, etor example and with reference to possible embodiment thereof, phine, heroin, hydromorphone, oxymorphone, levorphanol, it is to be understood that modifications or improvements may methadone, levomethadyl, meperidine, fentanyl, Sufentanyl. be made thereto without departing from the scope of the alfentanil, codeine, hydrocodone, oxycodone, and mixtures invention. thereof opioid receptor antagonists including naloxone and 1. A composition suitable for use in a transdermal delivery maltrexone; opioid receptor mixed agonist-antagonists patch for administration of an opioid, the composition com including buprenorphine, nalbuphine, butorphanol, pentaZo prising a phosphate compound of tocopherol and a polymer cine, and mixtures thereof, and, ethylketocyclazocine. carrier. 15. The transdermal delivery patch of claim 12, wherein 2. The composition of claim 1, wherein the transdermal the opioid is selected from the group consisting of codeine, delivery patch is a matrix patch. morphine, thebaine and oripavine; diacetylmorphine 3. The composition of claim 1, wherein the phosphate (heroin), dihydrocodeine, hydrocodone, hydromorphone, compound oftocopherol is selected from the group consisting nicomorphine, desmorphine, ethylmorphine, dipropanoyl of mono-(tocopheryl)phosphate, mono-(tocopheryl)phos morphine, oxycodone and oxymorphone; fentanyl, alpham phate monosodium salt, mono-(tocopheryl)phosphate diso ethylfentanyl, alfentanil, Sufentanil, remifentanil, carfentanyl dium salt, mono-(tocopheryl)phosphate monopotassium salt, and ohmefentanyl; pethidine (meperidine), ketobemidone, mono-(tocopheryl)phosphate dipotassium salt, di-(toco MPPP, allylprodine, prodine and PEPAP; propoxyphene, pheryl)phosphate, di-(tocopheryl)phosphate monosodium dextropropoxyphene, dextromoramide, bezitramide, piritra salt, di-(tocopheryl)phosphate monopotassium salt, or a mix mide, methadone, dipipanone, levomethadyl acetate ture thereof. (LAAM), difenoxin, diphenoxylate and loperamide; deZo 4. The composition of claim 3, wherein the phosphate cine, pentazocine and phenazocine; buprenorphine, dihydro compound of tocopherol is present in an amount within the etorphine and etorphine; butorphanol, nalbuphine, levorpha range of about 0.01% w/w to about 10% w/w, about 0.1% w/w nol and levomethorphan; lefetamine, meptazinol, tilidine, to about 5% w/w, or about 0.5% w/w to about 2% w/w or to tramadol and tapentadol; nalmefene, naloxone and naltrex about 3% w/w, of the total concentration of the composition. one; and pharmaceutically-acceptable salts, prodrugs, or 5. The composition of claim 4, wherein the phosphate derivatised compounds thereof. compound oftocopherol is present in an amount of about 1% 16. The transdermal delivery patch of claim 12, wherein wfw to about 1.5% w/w of the total concentration of the the opioid is oxycodone or dihydrohydroxycodeinone (oxy composition. codone base). 6. The composition of claim 1, wherein the polymer carrier 17. The transdermal delivery patch of claim 12, wherein comprises natural and synthetic polymers, co-polymers, or the opioid is present in an amount of from about 0.1% w/w up terpolymers. to about 30% w/w or up to about 20% w/w or up to about 10% 7. The composition of claim 6, wherein the polymer carrier w/w, of the total concentration of the matrix layer. comprises polyvinyl pyrrolidone, polysiloxanes or polym 18. The transdermal delivery patch of claim 12, wherein ethyl methacrylate. the opioid is present in an amount of about 4.5% w/w to about 8. The composition of claim 6, wherein the polymer carrier 5.5% w/w of the total concentration of the matrix layer. is present in an amount of from about 20% w/w up to about 19. The trandermal delivery patch of claim 12, wherein the 90% w/w, from about 30% w/w up to about 80% w/w, or from backing layer is occlusive. about 55% w/w up to about 65% w/w, of the total weight of 20. Use of a matrix patch for transdermal delivery of an the composition. opioid, the matrix patch comprising (i) a backing layer and 9. The composition of claim 6, wherein the polymer carrier (ii) a matrix layer, which comprises a composition of claim 1, also comprises an inert carrier component selected from the and an opioid. group consisting of anti-tacking agents, tackifiers, and plas 21. A method for preparing a transdermal delivery patch for ticizers. administration of an opioid comprising the steps of 10. The composition of claim 9, wherein the inert carrier (i) combining a polymer carrier and optional inert carrier components is present in an amount of from 0.001% w/w up components with a Suitable solvent; to about 50% w/w or up to about 40% w/w or up to about 30% (ii) combining (i) with a dispersion comprisingaphosphate w/w, of the total weight of the composition. compound of tocopherol and an opioid; 11. Use of a phosphate compound of tocopherol and a (iii) stirring (ii) until complete homogenisation is polymer carrier as a matrix layer in a transdermal delivery achieved; patch for administration of an opioid. (iv) placing (iii) in a mould comprising a suitable backing 12. A transdermal delivery patch for administration of an layer; and opioid comprising (i) a backing layer, and (ii) a matrix layer, (V) drying the compositions in the mould by heating them which comprises a composition of claim 1, and an opioid. up to about 90° C. for about 0.5 to about 24 hours. 13. The transdermal delivery patch of claim 12, wherein 22. The method of claim 21, wherein drying is conducted at the opioid is selected from the group consisting of morphine, a temperature of 75° C. codeine or thebaine; hydromorphone, hydrocodone, oxyc odone, oxymorphone, desomorphine, diacetylmorphine c c c c c