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US 20120202780A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0202780 A1 Gavin et al. (43) Pub. Date: Aug. 9, 2012

(54) CARRIER COMPOSITION Publication Classification (76) Inventors: Paul David Gavin, Chadstone (51) Int. Cl. (AU); Mahmoud El-Tamimy, A6II 47/24 (2006.01) Meadow Heights (AU); Jeremy A6II 3/196 (2006.01) James Cottrell, Caulfield South A6IP5/00 (2006.01) (AU); Giacinto Gaetano, South A 6LX 3/573 (2006.01) Melbourne (AU); Nicholas John A6IP 23/00 (2006.01) Kennedy, Boronia (AU) A6IP 29/00 (2006.01) A6II 3/167 (2006.01) (21) Appl. No.: 13/501,494 A63L/407 (2006.01) (22) PCT Fled: Dec. 22, 2010 (52) U.S. Cl...... 514/180: 514/785: 514/788: 514/772: 514/626; 514/567; 514/413: 514/179 (86) PCT NO.: S371 (c)(1), (57) ABSTRACT (2), (4) Date: Apr. 12, 2012 A carrier composition of the present invention comprises a phosphate compound of an electron transfer agent and a rela Related U.S. Application Data tively high concentration of a polar protic solvent. A biologi (60) Provisional application No. 61/289,507, filed on Dec. cally active compound may be formulated with a carrier com 23, 2009. position of the present invention to provide a formulation. Patent Application Publication Aug. 9, 2012 Sheet 1 of 5 US 2012/0202780 A1

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FGURE 1 Patent Application Publication Aug. 9, 2012 Sheet 2 of 5 US 2012/0202780 A1

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FIGURE 2B Patent Application Publication Aug. 9, 2012 Sheet 3 of 5 US 2012/0202780 A1

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FIGURE 3 Patent Application Publication Aug. 9, 2012 Sheet 4 of 5 US 2012/0202780 A1

2O,OO 18.00 16, OO A.OO 12.OO OOO 8.00 6.OO 4.00 2.OO O.OO Woltare PM-02. Dico HS TPM-02A Diclo LS Treatment

FIGURE 4 Patent Application Publication Aug. 9, 2012 Sheet 5 of 5 US 2012/0202780 A1

Keterolac deposition in rat abdominal skir 5 11.

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FIGURE 5 US 2012/0202780 A1 Aug. 9, 2012

CARRIER COMPOSITION the electron transfer agent is a hydroxy chroman, preferably a tocol such as or . TECHNICAL FIELD 0014 Phosphate compounds of tocopherol may be 0001. The present invention relates to carrier composi selected from the group consisting of mono-(tocopheryl) tions for delivery of biologically active compounds. phosphate, mono-(tocopheryl) phosphate monosodium salt, mono-(tocopheryl) phosphate monopotassium salt, mono BACKGROUND (tocopheryl) phosphate disodium salt, mono-(tocopheryl) 0002. In this specification where a document, act or item phosphate dipotassium salt, di-(tocopheryl) phosphate, di of knowledge is referred to or discussed, this reference or (tocopheryl) phosphate monosodium salt, di-(tocopheryl) discussion is not an admission that the document, actor item phosphate monopotassium salt, or a mixture thereof. of knowledge or any combination thereof was at the priority 0015. When the carrier composition comprises a mixture date, publicly available, known to the public, part of common of a mono-(tocopheryl) phosphate to a di-(tocopheryl) phos general knowledge; or known to be relevant to an attempt to phate, the ratio is preferably at least 2:1, more preferably solve any problem with which this specification is concerned. within the range of about 4:1 to about 1:4, most preferably 0003 Drug delivery is the method or process of adminis tering a pharmaceutical compound to achieve a therapeutic within the range of about 6:4 to about 8:2. In preferred effect in humans and animals. embodiments the ratio is about 6:4 or about 8:2. 0004 Drug delivery technologies have been developed to 0016. The carrier composition comprises a phosphate improve , safety, duration, onset or release, of compound of an electron transfer agent in an amount within the pharmaceutical compound. the range of preferably about 0.01% w/w to about 20% w/w, 0005. When developing drug delivery technologies, prob more preferably about 0.01% w/w to about 10% w/w, most lems likely to be encountered include compatibility of the preferably about 0.01% w/w to about 5% w/w or about 0.01% drug delivery system and the pharmaceutical compound, wfw to about 1% w/w of the total concentration of the carrier maintaining an adequate and effective duration, potential for composition. In one embodiment the carrier composition side effects, and meeting patient convenience and compli ance. As a consequence, many drug delivery technologies fall comprises a phosphate compound of an electron transfer short of desired improvements and requirements. agent in an amount within the range of about 0.01% w/w to 0006. Accordingly, there is still a need for alternate drug about 2% w/w, preferably about 0.05% w/w, about 0.1% w/w delivery systems which effectively deliver drugs. or about 1% w/w. In a further embodiment, a range of about 5% w/w to about 10% w/w or about 10% w/w to about 15% SUMMARY w/w may be used. 0007. It has surprisingly been found that a carrier compo 0017. In a second aspect of the invention there is provided sition comprising a phosphate compound of an electron trans a formulation comprising the carrier composition and a bio fer agent and a relatively high concentration of a polar protic logically active compound. Solvent can improve the delivery of a biological active com 0018. There is also provided a process for the preparation pound. of the formulation which comprises the step of adding a 0008 According to a first aspect of the invention there is biologically active compound to the carrier composition. provided a carrier composition for delivery of a biologically 0019. In one embodiment, the biologically active com active compound comprising a phosphate compound of an pound is lipophilic having a logP value within the range of electron transfer agent and a polar protic solvent, wherein the about 1 to about 5. The biologically active compound also polar protic solvent concentration is greater than 50% w/w of preferably has a relatively low molecular mass and a rela the total concentration of the carrier composition. tively low melting point. 0009. There is also provided use of a phosphate compound of an electron transfer agent and a polar protic solvent in the 0020. A biologically active compound may be present in manufacture of the carrier composition. an amount of up to about 30% w/w of the total concentration 0010. There is further provided a process for the prepara of the carrier composition. tion of the carrier composition which comprises the step of 0021. In a third aspect of the invention there is provided combining a phosphate compound of an electron transfer use of the carrier composition to improve the delivery of a agent and a polar protic solvent until complete homogenisa biologically active compound formulated with the carrier tion is achieved. composition. 0011. The polar protic solvent concentration is within the 0022. There is also provided use of the carrier composition range of preferably about 60% w/w to about 90% w/w, more to alter A.D.M.E. properties of a biologically active com preferably about 65% w/w to about 85% w/w, most prefer pound. ably about 70% w/w to about 80% w/w. In some circum stances, a suitable range may be about 50% w/w to about 60% 0023 There is further provided use of the carrier compo w/w, about 60% w/w to about 70% w/w or about 80% w/w to sition to improve the bioavailability of a biologically active about 90% w/w. compound in a Subject. 0012. In one embodiment the polar protic solvent is an 0024. In a fourth aspect of the invention there is provided acyclic alcohol. A C-C acyclic alcohol is preferred, and a method for treating a subject for a pathological condition ethanol and propanol are most preferred. which comprises administering an effective amount of a bio 0013 The electron transfer agent may be an or logically active compound in the carrier composition. The a derivatised compound thereof. In a preferred embodiment pathological conditions include those that can be treated by US 2012/0202780 A1 Aug. 9, 2012 the biologically active compound formulated with the carrier composition.

(I) DETAILED DESCRIPTION 0025. A carrier composition of the present invention com prises a phosphate compound of an electron transfer agent and a relatively high concentration of a polar protic solvent. A biologically active compound may be formulated with a car rier composition of the present invention to provide a formu lation. 0026. In this specification, except where the context R R2 R requires otherwise, the words “comprise”, “comprises, and C-tocopherol CH CH CH “comprising mean “include”, “includes”, and “including C-tocotrienol CH CH CH respectively, i.e. when the invention is described or defined as B-tocopherol CH H CH B-tocotrienol CH H CH comprising specified features, various embodiments of the Y-tocopherol H CH CH same invention may also include additional features. Y-tocotrienol H CH CH 8-tocopherol H H CH Phosphate Compound of an Electron Transfer Agent 8-tocotrienol H H CH 0027. The term “electron transfer agent” refers to a com 0032. Retinol belongs to the family of chemical com pound that may be phosphorylated and which, in the non pounds known as . There are three generations of phosphorylated form, can accept an electron to generate a retinoids. First generation retinoids include retinol, , relatively stable molecular radical or can accept two electrons (, Retin-A), and alitretin to allow the compound to participate in a reversible redox oin. Second generation retinoids include and its system. Examples of electron transfer agents include antioxi metabolite . Third generation retinoids include taz dants and derivatives thereof. arotene, and . 0028. The term “antioxidant’ refers to a molecule capable 0033 Ubiquinol is a benzoquinol and is the reduced form of slowing or preventing the oxidation of other molecules. of ubiquinone (coenzyme Qo). Oxidation is a chemical reaction that transfers electrons from 0034 Calciferol ( D) comes in several forms. The a Substance to an oxidizing agent. Oxidation reactions can two major forms are . (e.g. ) and produce free radicals, which start chain reactions that damage vitamin D. (e.g. , ). The other forms cells. terminate these chain reactions by remov include vitamin D (molecular compound of ergocalciferol ing free radical intermediates, and inhibit other oxidation with lumisterol. 1:1), vitamin D (22-dihydroergocalciferol) reactions by being oxidized themselves. As a result, antioxi and (sitocalciferol, made from 7-dehydrosito dants are often reducing agents. sterol). 0029 Antioxidants are generally classified into two broad 0035 Any antioxidant or derivative thereof described divisions, depending on whether they are soluble in water herein would be suitable for the present invention. Preferred (hydrophilic) or in (hydrophobic). Ascorbic acid (vita antioxidants and derivatives thereof are selected from the min C) is an example of a water Soluble antioxidant. Car group consisting of , hydroxy chromans, caro otenes, tocopherol (), retinol (), tenoids, retinoids, benzoquinols and calcitriols. Hydroxy ubiquinol (the reduced form of coenzyme Q) and calciferol chromans are preferred. Tocols such as a tocopherol, in any (Vitamin D) are examples of soluble antioxidants. form, is most preferred. 0030 are carotenoids containing no oxygen. 0036. The term “phosphate compound” refers to a phos Carotenoids are based on carotenes with one or more hydro phorylated compound, where a covalent bond is formed gen atoms Substituted by a hydroxyl group and/or some pairs between an oxygen atom (typically originating from a of hydrogenatoms are substituted by oxygenatoms. The term hydroxyl group) of the compound and the phosphorous atom “hydroxy carotenoids’ refers to carotenes substituted with of a phosphate group (PO): in this context, the compound is one or more hydroxyl groups. Cryptoxanthin is an example of an electron transfer agent. a hydroxy : it is closely related to beta- 0037. The phosphate compound may be a phosphate with only the addition of a hydroxyl group. mono-ester, phosphate di-ester, phosphate tri-ester, pyro 0031. Vitamin E exists in eight different forms, namely phosphate mono-ester, pyrophosphate di-ester, or a salt or four and four . All feature a chroman derivative thereof, or a mixture thereof. The di- and tri-esters ring, with a hydroxyl group that can donate a hydrogenatom may comprise the same electron transfer agent or different to reduce free radicals and a hydrophobic side chain which electron transfer agents. allows for penetration into biological membranes. Such 0038. The “salts' include metal salts such as alkali or derivatives of Vitamin E may be classified as “hydroxy chro alkaline earth metal salts, for example sodium, magnesium, mans'. Both tocopherols and tocotrienols occur in alpha, potassium and calcium salts. Sodium and potassium salts are beta, gamma and delta forms, determined by the number and preferred. location of methyl groups on the chroman ring. The tocot 0039. The "derivatives” include phosphate compounds rienols differ from the analogous tocopherols by the presence where one or more phosphate protons are replaced by a Sub of three double bonds in the hydrophobic side chain. The stituent. Some non-limiting examples of derivatives include various forms of Vitamin E are shown by Formula (I): phosphatidyl derivatives where a phosphate proton is Substi US 2012/0202780 A1 Aug. 9, 2012 tuted with an amino-alkyl group, Sugar derivatives where a 0047. The carrier composition may comprise only one phosphate proton is Substituted with a Sugar Such as glucose. polar protic solvent; however, a combination of polar protic 0040. The term "amino-alkyl group' refers to a group solvents may also be used. For the avoidance of any doubt, it comprising an amino (-NH2) group and an alkyl group. The is to be noted that the singular forms “a”, “an and “the as term “alkyl refers to straight chain, branched chain or cyclic used herein for any feature should be read as encompassing hydrocarbon groups having from 1 to 8 carbon atoms. plural forms, unless the context clearly indicates otherwise. Examples include methyl, ethyl, propyl, isopropyl, butyl, 0048. The carrier composition has a relatively high polar isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclohexyl, hep protic solvent concentration. The polar protic solvent concen tyl, and octyl. Phosphatidylcholine derivatives are most pre tration is within the range of preferably about 60% w/w to ferred. about 90% w/w, more preferably about 65% w/w to about 0041. When the electron transfer agent is tocopherol, for 85% w/w, most preferably about 70% w/w to about 80% w/w. example, the phosphate compounds of tocopherol may be The polar protic solvent concentration may be about 70% selected from the group consisting of mono-(tocopheryl) wfw or about 80% w/w. In some circumstances a suitable phosphate, mono-(tocopheryl) phosphate monosodium salt, range of polar protic solvent concentration may be about 50% mono-(tocopheryl) phosphate monopotassium salt, mono w/w to about 60% w/w, about 60% w/w to about 70% w/w or (tocopheryl) phosphate disodium salt, mono-(tocopheryl) about 80% w/w to about 90% w/w. phosphate dipotassium salt, di-(tocopheryl) phosphate, di (tocopheryl) phosphate monosodium salt, di-(tocopheryl) Biologically Active Compound phosphate monopotassium salt, or a mixture thereof. These 0049. The term “biologically active compound” refers to phosphate compounds may be derived from the alpha, beta, any chemical Substance that has a biological effect in humans gamma or delta form oftocopherol, or a combination thereof. or animals for medical, therapeutic, cosmetic and Veterinary 0042. When the carrier composition contains a mixture of purposes, and encompasses pharmaceuticals including drugs, a mono-phosphate ester and a di-phosphate ester, for example cosmeceuticals, nutraceuticals, and nutritional agents. It will a mono-(tocopheryl) phosphate and di-(tocopheryl) phos be appreciated that some of biologically active compounds phate, the ratio is preferably at least 2:1, more preferably can be classified in more than one of these classes. within the range of about 4:1 to about 1:4, most preferably 0050 A wide range of biologically active compounds may within the range of about 6:4 to about 8:2. The ratio may be be delivered with a carrier composition of the present inven about 6:4 or about 8:2. tion. Preferably, the biologically active compound is lipo 0043. The carrier composition comprises a phosphate philic, and has a relatively low molecular mass and a rela compound of an electron transfer agent in an amount within tively low melting point. the range of preferably about 0.01% w/w to about 20% w/w, 0051. The term “lipophilicity” refers to the ability of a more preferably about 0.01% w/w to about 10% w/w, most chemical compound to dissolve in fats, oils, lipids, and non preferably about 0.01% w/w to about 5% w/w or about 0.01% polar solvents such as hexane or toluene. The lipophilicity of wfw to about 1% w/w of the total concentration of the carrier a biologically active compound may be assessed by its composition. The carrier composition may comprise a phos octanol/water partitioning coefficient (logP value), which is phate compound of an electron transfer agent in an amount believed to approximate membrane permeability. within the range of about 0.01% w/w to about 2% w/w, 0.052 Transdermally permeable biologically active com preferably about 0.05% w/w, about 0.1% w/w or about 1% pounds are likely to have a logP value between about 2.5 to w/w. In a further embodiment, a range of about 5% w/w to about 3.5. It has been found that biologically active com about 10% w/w or about 10% w/w to about 15% w/w may be pounds having a logP value within this range and biologically suitable. active compounds having a logP value outside this range (either above or below) formulated with a carrier composition Polar Protic Solvent of the present invention are more transdermally permeable, 0044 Organic solvents may be grouped as non-polar or that is, biologically active compounds having a logP value polar aprotic solvents, and polar protic solvents. within the range of about 1 to about 5. Therefore, the biologi 0045. The organic solvent of the present invention is a cally active compound may have a logP value within the polar protic solvent. A “protic solvent' is a solvent that has a range of about 1 to about 2.5, within the range of about 2.5 and hydrogen atom bound to an oxygen atom or a nitrogenatom about 3.5, and within the range of about 3.5 to about 5. as in a hydroxyl group or an amine group, respectively. More 0053. Not wishing to be bound by theory, it is believed that generally, any molecular solvent which contains a hydrogen a carrier composition of the present invention can alter one or ion capable of dissociation may be considered a protic Sol more A.D.M.E. (Absorption, Distribution, Metabolism, and vent. Conversely, an “aprotic solvent cannot donate hydro Excretion) properties of a biological active compound to gen ions. improve the delivery of the biological active compound. To be 0046. The polar protic solvent may be an acyclic alcohol, an effective biological active compound, the biological active alkyl ester, ketone or nitrile. The acyclic alcohol may be compound not only must be active against a target, but also selected from the group consisting of C-C acyclic alcohols possess the appropriate A.D.M.E. properties necessary to including polyols, polymers and derivatives (e.g. esters, alkyl make it suitable for use as a biological active compound. esters, ethers) thereof. Some examples of these include etha 0054. A “relatively low molecular mass' refers to a nol, n-propanol, isopropanol, glycols such as propylene gly molecular mass of less than about 1000 Daltons, preferably col, polyethylene glycol (e.g. PEG400), diethylene glycol less than about 500 Daltons, more preferably within the range monoethylether and ethyl acetate. The ketone may be of about 200 Daltons to about 300 Daltons. selected from the group consisting of methyl isobutyl ketone 0055. A “relatively low melting point” refers to a melting and acetone. The nitrile may be acetonitrile. point of less than about 400° C. US 2012/0202780 A1 Aug. 9, 2012

0056. A wide range of biologically active compounds may pain, ophthalmological diseases, epilepsy, gynaecological be delivered with the carrier composition of the present inven disorders, CNS diseases, viral infections, bacterial infections, tion. Examples include, but are not limited to, cardiovascular parasitic infections, GI diseases, obesity, and haemological drugs, in particular antihypertensive agents (e.g. calcium diseases. channel blockers (or calcium antagonists)) and antiarrhyth 0057. A person skilled in the art of the invention would be mic agents; congestive heart-failure pharmaceuticals; inotro able to determine whether or not a particular biologically pic agents; vasodilators. ACE inhibitors; diuretics; carbonic active compound would be suitable for use with the carrier anhydrase inhibitors; cardiac glycosides; phosphodiesterase composition of the present invention. Some specific non inhibitors; a blockers; B blockers; sodium channel blockers: limiting examples of Suitable biologically active compounds potassium channel blockers; B-adrenergic agonists; platelet include: inhibitors; angiotensin II antagonists; anticoagulants; throm Anaesthetics: bolytic agents; treatments for bleeding; treatments for anaemia; thrombin inhibitors; antiparasitic agents; antibacte 0.058 including amino-ester and amino-amide anaesthet rial agents; antiinflammatory agents, in particular non-steroi ics such as benzocaine, chloroprocaine, cocaine, reserpine, dal antiinflammatory agents (NSAIDs), more particularly guanethidine, cyclomethycaine, dimethocaine/larocaine, COX-2 inhibitors; steroidal antiinflammatory agents; pro propoxycaine, procaine/novocaine, proparacaine, tetracaine/ phylactic antiinflammatory agents; antiglaucoma agents; amethocaine; articaine, bupivacaine, carticaine, cinchocaine/ mast cell Stabilisers; mydriatics; agents affecting the respira dibucaine, etidocaine, levobupivacaine, lidocaine/lignocaine, tory system; allergic pharmaceuticals; alpha-adrener mepivacaine, piperocaine, prilocaine, ropivacaine, tri gic agonists; corticosteroids; chronic obstructive pulmonary mecaine, propofol, halothane, enflurane barbiturates, benzo disease pharmaceuticals; Xanthine-oxidase inhibitors; antiar diazepines, neostigmine and ketamine thritis agents; gout treatments; autacoids and autacoid Alkylating Agents: antagonists; antimycobacterial agents; antifungal agents; antiprotozoal agents; anthelmintic agents; antiviral agents 0059 including carmustine, cyclophosphamide, ifosfa especially for respiratory, herpes, cyto-megalovirus, human mide, Streptozotocin and mechlorethamine immunodeficiency virus and hepatitis infections; treatments for leukemia and kaposi's sarcoma; pain management agents Calcium Channel Blockers: in particular anaesthetics and analgesics, opioids including 0060 including amlodipine, aranidipine, azelnidipine, opioid agonists, opioid receptor partial agonists, barnidipine, benidipine, cilnidipine, clevidipine, cronidipine, opioid antagonist or opioid receptor mixed agonist-antago darodipine, dexniguldipine, efonidipine, elnadipine, elgo nists; neuroleptics; sympathomimetic pharmaceuticals; adr dipine, felodipine, flordipine, furnidipine, iganidipine, israd energic agonists; drugs affecting neurotransmitter uptake or ipine, lacidipine, lemildipine, lercanidipine, manidipine, release; anticholinergic pharmaceuticals; antihaemorrhoid mesuldipine, nicardipine, nifedipine, niludipine, nilvadipine, treatments; agents to prevent or treat radiation orchemothera nimodipine, nisoldipine, nitrendipine, olradipine, oxodipine, peutic effects; liopgenisis drugs; fat reducing treatments; palonidipine, pranidipine, Sagandipine, Sornidipine, telu antiobesity agents such as lipase inhibitors; sympathomi dipine, tiamdipine, trombodipine, watanidipine, Verapamil, metic agents; treatments for gastric ulcers and inflammation gallopamil, benzothiazepine, diltiazem, mibefradil, bepridil, Such as proton pump inhibitors; ; VEGF fluspirilene and fendiline inhibitors; antihyperlipidemic agents, in particular statins: Antiarrhythmic and Antiangina Agents: drugs that affect the central nervous system (CNS) such as antipsychotic, antiepileptic and antiseizure drugs (anticon 0061 including amiodarone, disopyramide, flecainide Vulsants), psychoactive drugs, stimulants, antianxiety and acetate, quinidine Sulphate, nitroglycerine, ranolazine, amio hypnotic drugs, antidepressant drugs; antiparkinson's phar darone, isosorbide and alteplase maceuticals; hormones and fragments thereof Such as sex hormones; antagonists; gonadotropin Antibacterial, Antibiotic and Antiacne Agents: releasing hormones and analogues thereof. hormones 0062 including amoxicillin, amplicillin, azithromycin, and their antagonists; selective estrogen modulators; growth benethamine penicillin, bleomycin, benzoyl peroxide, cino factors; antidiabetic pharmaceuticals such as hypoglycaemic Xacin, chloramphenicol, daunorubicin, plicamycin, fluoro agents; H1, H2, H3 and H4 antihistamines; agents used to quinolones, ciprofloxacin, clarithromycin, clindamycin, treat migraine headaches; asthma pharmaceuticals; cholin clindesse, clofazimine, chlorohexidine gluconate, cloxacil ergic antagonists; glucocorticoids; androgens; antiandro lin, demeclocycline, doxycycline, erythromycin, ethiona gens: inhibitors of adrenocorticoid biosynthesis; osteoporo mide, imipenem, indomethacin, lymocycline, minocycline, sis treatments such as biphosphonates; antithyroid nalidixic acid, nitrofurantoin, penicillin, rifampicin, spiramy pharmaceuticals; Suncreens, Sun protectants and filters; cin, Sodium sulfacetamide, Sulphabenzamide, Sulphadoxine, cytokine agonists; cytokine antagonists; anticancer drugs; Sulphamerazine, Sulphacetamide, Sulphadiazine, Sulphafura antialzheimer drugs; HMGCoA reductase inhibitors: Zole, Sulphamethoxazole, Sulphapyridine, tetracycline, ceph fibrates; cholesterol absorption inhibitors: HDL cholesterol alexin, cefdinir, triclosan, ofloxacin, Vancocin, glyburide, elevating agents; triglyceride reducing agents; antiageing or , cefprozil, cefuroxime axetil, norfloxacin, iso antiwrinkle agents; antibacterial agents; antiacne agents; niazid, lupulone, D-penicillamine, levofloxacin, gatifoxacin, antioxidants; hair treatments and skin whitening agents; and trimethoprim Small molecule therapeutic agents for the treatment, or pre vention of human and animal diseases such as allergy/asthma, Anticancer: arthritis, cancer, diabetes, growth impairment, cardiovascular 0063 including doxorubicin, 6-thioguanine, paclitaxel, diseases, inflammation, immunological disorders, baldness, docetaxel, camptothecin, megestrol acetate, navelbine, cyt US 2012/0202780 A1 Aug. 9, 2012

arabine, fludarabine, 6-mercaptopurine, 5-fluorouracil, teni undecenoic acid; benznidazole, clioquinol, decoquinate, poside, vinblastine, Vincristine, cisplatin, colchicine, carbo diiodohydroxyquinoline, diloxanide furoate, dinitolmide, platin, procarbazine and etopside furzolidone, metronidazole, nimorazole, nitrofuraZone, ornidazole, terbinafine, clotrimazole, chloroquine, meflo Antidepressants, Antipsychotics and Antianxiety: quine, itraconazole, Pyrimethamine, praziquantel, quina 0.064 including alprazolam, amoxapine, bentazepam, crine, mebendazole and tinidazole bromazepam, cloraZipine, clobazam, clotiazepam, diazepam, lorazepam, flunitrazepam, flurazepam, lormetazepam, Antihypertensive and Cardiac Therapeutic Agents: medazepam, nitrazepam, oxazepam, temazepam, mapro 0071 including candesartan, hydralazine, clonidine, tri tiline, mianserin, nortriptyline, risperidone, Sertraline, traZ amterene, felodipine, gemfibrozil, fenofibrate, nifedical, pra odone, baloperidol, trimipramine maleate fluoxetine, Zosin, mecamylamine, doxazosin, dobutamine and cilexetil ondansetron, midazolam, chlorpromazine, haloperidol, tria Zolam, clozapine, fluopromazine, fluphenazine decanoate, Antimigraine Agents: fluianisone, perphenazine, pimozide, prochlorperazine, Sulpiride, thioridazine, paroxitine, citalopram, bupropion, 0072 including dihydroergotamine mesylate, ergotamine phenelZine, olanzapine, divalproex sodium and Venlafaxine tartrate, methysergide maleate, pizotifen maleate and Sumatriptan Succinate Opioids: Antimuscarinic Agents: 0065 including opioid receptor agonists and antagonists, compounds which exhibit mixed agonist/antagonist activity 0073 including atropine, benzhexol, biperiden, ethopro and compounds which exhibit partial agonist activity, includ pazine, hyoscyamine, mepenZolate bromide, oxybutynin, ing morphine, depomorphine, etorphine, diacetylmorphine, oxyphencylcimine and tropicamide hydromorphone, oxymorphone, levorphanol, methadone, levomethadyl, meperidine, fentanyl, Sufentanyl, alfentanil, Antineoplastic Agents (Or Immunosuppressants): codeine, hydrocodone, oxycodone, thebaine, desomorphine, 0074 including aminoglutethimide, amsacrine, azathio nicomorphine, dipropanoylmorphine, benzylmorphine, eth prine, buSulphan, chlorambucil, cyclosporin, dacarbazine, ylmorphine, pethidine, methadone, tramadol, dextropro estramustine, etoposide, lomustine, melphalan, mercaptopu poxyphene; naloxone and naltrexone; buprenorphine, nalbu rine, methotrexate, mitomycin, mitotane, mitoZantrone, pro phine, butorphanol, pentazocine and ethylketocyclazocine carbazine, tamoxifen citrate, testolactone, tacrolimus, mer Tricyclics: captopurine and Sirolimus 0066 including azothiopine, amitriptyline, famotidine, Antiparkinsonian Agents: promethazine, paroXatine, oXcarbazapine and mertazapine 0075 including bromocriptine mesylate, levodopa, tolca pone, ropinirole, bromocriptine, hypoglycaemic agents such Antidiabetics: as Sulfonylureas, biguanides, a-glucosidase inhibitors, thai 0067 including acetohexamide, chlorpropamide, glib aZolidinediones, cabergoline, carbidopa and lysuride maleate enclaraide, gliclazide, glipizide, metformin, tolaZamide, gly buride, and tolbutamide Antithyroid Agents: Antiepileptics: 0076 including carbimazole and propylthiouracil 0068 including beclamide, carbamazepine, gapapentin, tiagabine, vigabatrin, topiramate, clonazepam, ethotoin, Antiviral Drugs: methoin, methSuximide, methylphenobarbitone, oXcarba 0077 including amantadine, retinovir, cidofovir, acyclo Zepine, paramethadione, phenacemide, phenobarbitone, phe Vir, famciclovir, ribavirin, amprenavir, indinavirm, rimanta nyloin, phensuximide, primidone, Sulthiamine, phenytoin dine and efavirenz, penciclovir, ganciclovir, Vidarabine, aba Sodium, nirofurantoin monohydrate, gabapentin, lamot cavir, adefovir, apmrenavir, delavirdine, didanosine, rigine, Zonisamide, ethoSuximide and valproic acid stavudine, Zalcitabine, zidovudine, enfuvirtide and interferon Hypnotics/Sedatives and Muscle Relaxants: Cardiac Inotropic Agents: 0069 including Zolpidem tartrate, amylobarbitone, barbi 0078 including amrinone, milrinone, digitoxin, digoxin, tone, butobarbitone, pentobarbitone, brotizolam, carbromal, enoXimone, lanatoside C and medigoxin chlordiazepoxide, chlormethiazole, ethinamate, meprobam ate, methaqualome, cyclobenzaprene, cyclobenzaprine, tiza Hypo and Hyper Lipidemic Agents: nidine, baclofen, butalbital, Zopiclone, atracurium, tub ocurarine and phenobarbital 0079 including fenofibrate, clofibrate, probucol, eZetimibe and torcetrapib Antifungal, Antiprotazoal and Antiparasitic Agents: Antiinflammatory: 0070 including amphotericin, butoconazole nitrate, clot rimazole, econazole nitrate, fluconazole, flucytosine, griseof 0080 including meoxicam, , cromolyn, ulvin, itraconazole, ketoconazole, miconazole, natamycin, , hydroxychloroquine, montelukast, Zileuton, nystatin, Sulconazole nitrate, terconazole, tioconazole and Zafirlukast and US 2012/0202780 A1 Aug. 9, 2012

Antihistamine: Stimulants: 0081 including fexofenadine, chloral hydrate, hydrox I0088 including amphetamine, phentermine, tyramine, yZine, promethazine, cetirazine, cimetidine, clyclizine, , metaraminol, , dexamphetamine, meclizine, dimenhydrinate, loratadine, nizatadine and dexfenfluramine, fenfluramine, nicotine, caffeine and mazin promethazine dol Antiulcer: Vasocontrictors: 0082 including omeprazole, lanSoprazole, pantoprazole I0089 including desmopressin and ranitidine Vasodilitors: Diuretics: 0090 including carvedilol, teraZosin, phentolamine and 0083) including hydrochlorothiazide, amiloride, aceta Zolamide, furosemide and torsemide Antialzheimers: NSAIDS: 0091 including levetiracetam, levitiracetam and done 0084 including arylalkanoic acid sub-group of class pezil which includes , , , , , , , indometacin ACE Inhibitors: farnesil, , , , 0092 including benzapril, enalapril, ramipril, fosinopril and , 2-arylpropionic acid (profens) Sub-group of Sodium, lisinopril, minoxidil, isosorbide, rampril and class which includes , , , quinapril , , , , flunox aprofen, , , , , Beta Adrenoreceptor Antogonists: , , , , , 0093 including atenolol, timolol, pindolol, propanolol , , , tarenflurbil and tiaprofenic hydrochloride, bisoprolol, esmolol, metoprolol Succinate, acid; and N-arylanthranilic acid () Sub-group of metoprolol and metoprolol tartrate class which includes , , Angiotensin II Antagonists: including losartan and ; tromethamine, cele coxib, , , , naproxen, Sulindac, Platelet Inhibitors: , pheylbutaZone, tolmetin, indomethacin, acetomi nophen (), tramadol and propoxyphene 0094 including abciximab, clopidrogel, tirofiban and aspirin Retinoids: Alcohols and Phenols: 0085 including first generation retinoids such as retinol, retinal, tretinoin (retinoic acid, Retin-A), isotretinoin and ali 0.095 including tramadol, tramadol hydrochloride, tretinoin; second generation retinoids such as etretinate and allopurinol, calcitriol, cilostazol, Soltalol, urasodiol bromp its metabolite acitretin; third generation retinoids such as eridol, droperidol, flupenthixol decanoate, albuterol, , beXarotene and adapalene albuterol sulphate, carisoprodol, chlobetasol, ropinirol, labe talol, and methocarbamol Hormones and : Ketones and Esters: I0086 including adrenocorticotrophic hormone (ACTH), antidiruetic hormone (vasopressin), atrial-nartreuretic factor 0096 including amioderone, , spironolactone, (ANF), beclomethasone, cortisone, Scopolamine, dopamine, prednisone, triazodone, desoximetasone, methyl prednis epinephrine, catecholamines, cholecystokinin, clomiphene done, benzonatate nabumetone and buspirone citrate, danazol, , diethylstilbestrol (DES). ethinyl estradiol, fludrocortison, finasteride, follicle stimulat Antiemetics: ing hormone, gastrin, hydroxyprogesterone, leptin, luteiniz 0097 including metoclopramide ing hormone, medroxyprogesterone acetate, mestranol, quinestrol, methyltestosterone, nandrolone, norethindrone, Ocular Treatments: norethisterone, norgestrel, estradiol, conjugated oestrogens, 0.098 including dorzolamide, brimonidine, , Oxandrolone, oxytocin, prednisone, progesterone, prolactin, cyclopentolate, pilocarpine and echothiophate protogalndins, somatostatin, stanozolol, Stilbestrol, thyroX ine, phosphate, triamcinolone, mifepristone Anticoagulant and Antithrombitic Agents: acetonide, , levothyroxine, testosterone, testoster one cypionate, fluoxymesterone, flutamide, 0099 including warfarin, enoxaparin and lepirudin furoate, cyproterone, fluromethalone, goserelin, leuprolide, calcitonin, halobetasol, hydrocortisol and tibolone Treatments for Gout: 0100 including probenecid and Statins and Derivatives: 0087 including atorvastatin, fluvastatin, lovastatin, nysta COPD and Asthma Treatments: tin, rosuvastatin, pravastatin, orlistat and simvastatin 0101 including ipratropium US 2012/0202780 A1 Aug. 9, 2012

Treatments for : active compounds which are, within the scope of sound medi 0102 including raloxifene, pamidronate and risedronate. cal judgment, Suitable for use in contact with the tissues of a 0103 Particularly preferred biologically active com Subject with undue toxicity, irritation, allergic response, and pounds include lidocaine, diclofenac, ketoralac, prilocaine, the like, commensurate with a reasonable benefit/risk ratio, halobetasol, hydrocortisol and combinations thereof. and effective for their intended use, as well as the Zwitterionic 0104. It is to be understood that pharmaceutically accept forms, where possible, of the compounds of the invention. able derivatives of biologically active compounds are The term “prodrug” refers to compounds that are rapidly included within the scope of the present invention. transformed in vivo to yield the parent compound of the above 0105. The term “pharmaceutically acceptable derivatives' formula, for example by hydrolysis in blood. A thorough includes, but is not limited to, pharmaceutically acceptable discussion is provided in T. Higuchi and V. Stella, Pro-drugs salts, esters, salts of such esters, ethers, or any other derivative as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium including prodrugs and metabolites, which upon administra Series, and in Edward B. Roche, ed., Bioreversible Carriers in tion to a subject in need is capable of providing, directly or Drug Design, American Pharmaceutical Association and Per indirectly, a biologically active compound as otherwise gamon Press, 1987. described herein. 0109. A biologically active compound may be present in 0106. As used herein, the term “pharmaceutically accept an amount of up to about 30% w/w of the total concentration able salt” refers to those salts which are, within the scope of of the carrier composition. The amount of biologically active Sound medical judgment, Suitable for use in contact with the compound is preferably up to about 10% w/w, more prefer tissues of humans and lower animals without undue toxicity, ably up to about 6% w/w, most preferably within the range of irritation, allergic response and the like, and are commensu about 0.1% w/w to about 5% w/w. rate with a reasonable benefit/risk ratio. Pharmaceutically 0110. The carrier composition improves the delivery of a acceptable salts are well known in the art. For example, S. M. biological active compound by altering the A.D.M.E. prop Berge, et al. describe pharmaceutically acceptable salts in erties of the biological active compound. Not wishing to be detail in J. Pharmaceutical Sciences, 66:1-19, 1977. bound by theory, it is believed that the A.D.M.E. properties of Examples of pharmaceutically acceptable nontoxic acid addi a biological active compound are altered because the combi tion salts are salts of an amino group formed with inorganic nation of a phosphate compound of an electron transfer agent acids such as hydrochloric acid, hydrobromic acid, phospho and a relatively high concentration of a polar protic solvent ric acid, Sulfuric acid and perchloric acidor with organic acids changes the of the biologically active compound in Such as , oxalic acid, maleic acid, tartaric acid, different barriers (skin, mucous membranes, muscle, and so citric acid. Succinic acid, or malonic acid or by using other on). This solubility change affects the residence time of the methods used in the art such as ion exchange. Other pharma drug in these tissues and delays, or shortens, the time at which ceutically acceptable salts include adipate, alginate, ascor the drug will be introduced to the elimination phase. Accord bate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, ingly, a carrier composition of the present invention can pro butyrate, camphorate, camphorsulfonate, citrate, cyclopen vide the advantage of tanepropionate, digluconate, dodecylsulfate, ethane 0.111 reduced side effects (i.e. minimalising the unre Sulfonate, formate, fumarate, glucoheptonate, glycerophos quired systemic effect); phate, gluconate, hernisulfate, heptanoate, hexanoate, 0112 restricting the biologically active compound dis hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lac tribution to specific areas (e.g. drug-targeting); tate, laurate, lauryl Sulfate, malate, maleate, malonate, meth 0113 improving patient compliance (e.g. less amount anesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, used, Smaller application); oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 0114 improving aesthetic feeling (e.g. fast-drying); 3-phenylpropionate, phosphate, picrate, pivalate, propionate, and Stearate. Succinate, Sulfate, tartrate, thiocyanate, p-toluene 0115 increasing duration of action and/or shorten Sulfonate, undecanoate, Valerate salts, and the like. Represen On Set. tative alkali or alkaline earth metal salts include Sodium, 0116. A carrier composition of the present invention may lithium, potassium, calcium, magnesium, and the like. Fur also improve the bioavailability of a biologically active com ther pharmaceutically acceptable salts include, when appro pound in a subject. priate, nontoxic ammonium, quaternary ammonium, and 0117 The present invention can also be used in a method amine cations formed using counterions such as halide, for treating a subject for a pathological condition which com hydroxide, carboxylate, Sulfate, phosphate, nitrate, lower prises administering an effective amount of a biologically alkyl Sulfonate, and aryl Sulfonate. active compound in a carrier composition of the present 0107 The term “pharmaceutically acceptable ester” refers invention. The pathological conditions include those that can to esters which are hydrolysed in vivo and include those that be treated by the biologically active compound formulated break down readily in the human body to leave the parent with the carrier composition. compound or a salt thereof. Suitable ester groups include, for 0118. The term “subject' as used herein refers to any example, those derived from pharmaceutically acceptable ali animal having symptoms associated with or caused by a phatic carboxylic acids, particularly alkanoic, alkenoic, pathological condition, which requires treatment with a bio cycloalkanoic and alkanedioic acids, in which each alkyl or logically active compound. The animal may be a mammal, alkenyl moiety advantageously has not more than 6 carbon preferably a human, or may be a non-human primate or non atoms. Examples of particular esters include formates, primates Such as used in animal model testing. While it is acetates, propionates, butyrates, acrylates and ethylsucci particularly contemplated that a formulation of the invention nates. is suitable for use in medical treatment of humans, it is also 0108. The term “pharmaceutically acceptable prodrugs' applicable to veterinary treatment, including treatment of as used herein refers to those prodrugs of the biologically companion animals such as dogs and cats, and domestic US 2012/0202780 A1 Aug. 9, 2012

animals such as horses, ponies, donkeys, mules, llama, association the biologically active compound with the carrier, alpaca, pigs, cattle and sheep, or Zoo animals such as pri and then, if necessary, shaping the formulation into the mates, felids, canids, bovids, and ungulates. desired product. 0119 Generally, the terms “treating”, “treatment' and the like are used herein to mean affecting a subject, tissue or cell Preparation of a Carrier Composition to obtain a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely I0126. A carrier composition of the present invention may or partially preventing one or more pathological conditions, be prepared by a variety of techniques. and/or may be therapeutic in terms of a partial or complete I0127. One method of preparing the carrier composition cure of one or more pathological conditions. involves combining the components of the carrier composi tion, in Suitable quantities, with stirring, until complete Routes of Administration homogenisation is achieved. I0128. In a preferred method, a phosphate compound of an 0120 Routes of administration can broadly be divided electron transfer agent is combined with a polar protic Sol into a three categories by effect, namely, “topical” where the vent, and warmed at 40° C. until a solution is formed. An desired effect is local, so the substance is applied directly aqueous phase, usually of lower volume, is heated to 40°C. where its action is desired, “enteral' where the desired effect and then added drop wise to the solution to form the carrier is systemic (non-local) so the Substance is given via the diges composition. Alternately in some circumstances the phos tive tract, and “parenteral' where the desired effect is sys phate compound of the electron transfer agent combined with temic, so the Substance is given by routes other than the the polar protic solvent may be added dropwise to the aqueous digestive tract. phase. The final pH of the carrier composition may be 0121 The U.S. Food and Drug Administration recognise adjusted to improve stability, for example by the addition of 111 distinct routes of administration. The following is a non Sodium hydroxide. The carrier composition is usually a clear limiting list of examples of routes of administration. to translucent solution. 0122 Examples of topical routes of administration having I0129. Depending on the solubility and stability of the bio a local effect include epicutaneous (onto the skin) and intra logically active compound, it may be dissolved in either the vitreal (onto the eye). aqueous or solvent phase. 0123 Examples of enteral routes of administration having 0.130. The carrier composition may optionally further a systemic (non-local) effect include any form of administra comprise one or more excipients. A person skilled in the art of tion that involves any part of the , Such as the invention would appreciate suitable excipients which oral (into the mouth), intranasal (into the nose), rectal (into could be included with a carrier composition or a formulation the rectum), and vaginal (into the vagina). of the present invention. The choice of other excipients will 0.124 Examples of parenteral routes of administration by depend on the characteristics of the biologically active com injection, infusion or diffusion having a systemic effect pound and the form of administration used. Examples of other include intravenous (into a vein), intraarterial (into an artery), excipients include additional solvents such as water, thicken intramuscular (into a muscle), intracardiac (into the heart), ers or gelling agents, Surfactants, buffers, emollients, Sweet Subcutaneous (under the skin), percutaneous (via needle eners, disintegrators, flavours, colours, fragrances, electro puncture into the skin), intradermal (into the skin itself), lytes, appearance modifiers, film foaming polymers, intrathecal (into the spinal canal), intraperitoneal (infusion or propellants and the like. Suitable sweeteners include sucrose, injection into the peritoneum), intravesical infusion (infusion lactose, glucose, aspartame or saccharin. Suitable disintegra into the urinary bladder), epidural (injection or infusion into tors include corn starch, methylcellulose, polyvinylpyrroli the epidural space), transdermal or transcutaneous (diffusion done, Xanthan gum, bentonite, alginic acid or agar. Suitable through the intact skin), transmucosal (diffusion through a gelling agents include hydroxy propyl cellulose (HPC) and mucous membrane), insufflation (diffusion through the carbopol. Suitable flavours include peppermint oil, oil of nose), inhalational (diffusion through the mouth), Sublingual wintergreen, cherry, orange or raspberry flavouring. Suitable (under the tongue), and buccal (absorbed through cheek near propellants include butane, carbon dioxide, ethane, hydro gumline). chloroflurocarbons, isobutane, nitrogen, nitrous oxide, pro 0.125 Formulations according to the present invention can pane, dimethyl ether, isopentanol, pentane and mixtures be in any suitable administration form (see, for example, thereof such as Propellant A-46 (20% propane and 80% Pharmaceutics and Pharmacy Practice, J. B. Lippincott Com isobutane). The relatively high concentration of organic Sol pany, Philadelphia, Pa., Banker and Chalmers, eds., pages vent may avoid the need for a further preservative to be added: 238-250 (1982)). Examples of suitable administration forms includes, but are not limited to, Solutions, liquids, Suspen however if considered necessary, suitable preservatives that sions, gels, poultices, reservoir patches, and creams. The may be added include sodium benzoate, methylparaben, pro formulations may also be prepared and stored in one form and pylparaben, and Sodium bisulphite. delivered in another, for example the formulation may be I0131 The amount of excipient or excipients, if present, is stored in liquid form and delivered in the form of a foam. The preferably up to about 10% w/w, more preferably up to about formulations and can be prepared by any methods well known 5% w/w, most preferably up to about 3% w/w, and even more in the art of pharmacy Such as described in Remington J. P. preferably either 0.01-3% w/w or 0.1-1% w/w of the total The Science and Practice of Pharmacy, ed. A. R. Gennaro, concentration of the carrier composition. 20" edition, Lippincott, Williams and Wilkins Baltimore, 0.132. The carrier composition and formulation according Md. (2000). Such methods include the step of bringing into to the present invention have been found to be physically US 2012/0202780 A1 Aug. 9, 2012

stable, have no particle size larger than 300nm. There is also polar protic solvent concentration (Formulation 2B). Details no spontaneous sol-gel transformation. of the each formulation are as follows: FIGURES 0133. The examples will be described with reference to the accompanying figures in which: Formulation 2A 0134 FIG. 1 shows the transdermal delivery of formula Components Amounts tions comprising oxycodone in Franz cells in vitro: A mixture of mono- (tocopheryl) phosphate and 1% Wiw 0135 FIGS. 2A and 2B show the relative behaviour of di-(tocopheryl) phosphate in a ratio of 6:4 formulations comprising oxycodone in a dose response; Isopropanol 70% wiw 0.136 FIG.3 shows comparative skin deposition results of Oxycodone 5% Wiw Molecular mass: 315.40 g/mol formulations comprising lidocaine; Melting point: 218-220° C. 0.137 FIG. 4 shows comparative skin deposition results of Hydroxypropyl cellulose (HPC) H 1% Wiw formulations comprising diclofenac; and QS dHO 0138 FIG. 5 shows comparative skin deposition results of formulations comprising ketorolac. EXAMPLES 0139 Various embodiments/aspects of the present inven Formulation 2B tion will now be described with reference to the following non-limiting examples. Components Amounts A mixture of mono- (tocopheryl) phosphate and 2% Wiw di-(tocopheryl) phosphate in a ratio of 7:3 Example 1 Isopropanol 10% ww. Ethanol 10% ww. 0140 Carrier compositions were prepared according to Oxycodone 1.5% ww the preferred method described above. Carbopol NF10 0.25% wiw 01.41 Each of the five carrier compositions comprised 1% QS dHO W/w of a mixture of mono-(tocopheryl) phosphate and di (tocopheryl) phosphate in a ratio of 8:2 and water, and the following polar protic solvent concentrations: 0144. Formulation 2A had a pH of 6. Formulation 2B had a pH of 6.4. Method % polar protic solvent 0145 Formulation 2A was prepared according to the pre (i) 50% Wiv ethanol ferred method described above. Formulation 2B was simi (ii) 60% w/v ethanol larly prepared. (iii) 70% Wiv ethanol (iv) 80% w/v ethanol 0146 Full thickness rat abdominal skin was used in 12ml (v) 90% Wiv ethanol vertical Franz diffusion cells (PermeCear, Pa.). Rats were killed by asphyxiation using CO gas and the abdominal area carefully shaved and excised. All underlying fat and connec Method for Thermal Cycling tive tissue was removed. Skin was frozen flat between sheets of aluminium foil and stored at -20°C. until the morning of 0142. The carrier compositions were refrigerated at about experimentation. 5° C. for approximately 12 hours, and then subjected to a 0147 PBS was used in the Franz cells as the receptor temperature of about 30° C. for approximately 12 hours for 3 solution (12 ml) and the Franz cells had a surface area of 1.77 cycles. Between each change oftemperature the carrier com cm. During experiments, the cells were maintained at 32°C. positions were left at room temperature for 3 hours and Finite dosing (40 ul) was used to approximate the conditions observed for any turbidity and precipitation. to be used in vivo. Receiver solutions were sampled regularly over 4 hours to determine the percutaneous oxycodone absorption and analysed using HPLC. The results are pre Clarity of sented in FIG. 1. The results are the averages of n=8-10 solution Precipitate diffusion cells conducted across two separate days. Bars rep resent SEM. (i) slightly turbid Ole (ii) clear Ole (iii) clear Ole Results (iv) clear Ole (v) clear Ole 0.148. It was found that Formulation 2A, which has a polar protic solvent concentration of 70% w/w, could maintain a concentration of oxycodone of 5% w/w. Formulation 2B, Example 2 which has a polar protic solvent concentration of 20% w/w on the other hand, could only maintain a maximum concentra 0143. This example compares percutaneous oxycodone tion of oxycodone of 1.5% w/w. delivery in vitro using a formulation of the present invention 0149. Although both formulations were able to transder (Formulation 2A) and a formulation which comprises a low mally deliver oxycodone, the results show that, after 4 hours, US 2012/0202780 A1 Aug. 9, 2012

approximately 130 ug of oxycodone was delivered by For 0156 Full thickness rat abdominal skin was used in 12ml mulation 2A compared to approximately 18 Jug delivered by vertical Franz diffusion cells (PermeCear, Pa.). Rats were Formulation 2B. killed by asphyxiation using CO gas and the abdominal area 0150. The drying time for Formulation 2A led to a rapid carefully shaved and excised. All underlying fat and connec rate of delivery (i.e. flux), in addition to the increased total tive tissue was removed. Skin was frozen flat between sheets amount. The linear flux (J) of percutaneous oxycodone of aluminium foil and stored at -20°C. until the morning of absorption for Formulation 2A was 40 ugh/cm, whereas experimentation. Formulation 2B had flux of 5.54 ugh/cm. (O157 PBS was used in the Franz cells as the receptor 0151. While both the increased flux and amount of oxyc solution (12 ml) and the Franz cells had a surface area of 1.77 odone delivered may be partially attributed to the increased cm. During experiments, the cells were maintained at 32°C. oxycodone concentration (and Subsequent dose), the results Finite dosing (20-60 ul) was used to approximate the condi show that Formulation 2A also had higher bioavailability. The tions to be used in vivo. Receiver solutions were sampled percentage of oxycodone delivered from the total applied regularly over 4 hours to determine the percutaneous oxyc dose was approximately 8% with Formulation 2A compared odone absorption and analysed using HPLC. The results are to only approximately 3% with Formulation 2B. presented in FIGS. 2A and 2B. Conclusion Results 0152 The formulation of the present invention (Formula 0158 Formulation 3A had increased transdermal flux tion 2A) was capable of an increased oxycodone concentra compared to Formulation 3B. The use of a high polar protic tion relative to Formulation 2B. Formulation 2A also showed solvent concentration (Formulation 3A) allowed equivalent better percutaneous oxycodone absorption, both with respect amounts of the preferred form of oxycodone (base; 5% w/w) to the rate and total oxycodone delivered, and superior bio to be formulated. availability. 0159. With equivalent doses between 10-20 ul/cm, For mulation 3A delivered twice as much oxycodone as Formu Example 3 lation 3B, with both formulations exhibiting a good dose 0153. This example is a dose response study that compares response. At a dose of 30 ul/cm, no further increase in trans the performance of a formulation of the present invention dermal delivery is seen with Formulation 3B. The dose (Formulation 3A) and an aqueous formulation (Formulation response continues for Formulation 3A even at the highest 3B) to determine their relative behaviour in a dose response. dose of 30 ul/cm. Details of the each formulation are as follows: Conclusion 0160 This dose response study particularly shows that a formulation of the present invention (Formulation3A) allows Formulation 3A for wider dynamic range in dose responses. Components Amounts A mixture of mono- (tocopheryl) phosphate and 1% Wiw Example 4 di-(tocopheryl) phosphate in a ratio of 6:4 Isopropanol 70% wiw 0.161 This example compares the stability, skin deposi Oxycodone 5% Wiw tion and other properties of a formulation of the present Molecular mass: 315.40 g/mol invention (Formulation 4A) and a formulation which com Melting point: 218-220° C. HPCH 1% Wiw prises a low polar protic solvent concentration (Formulation QS dHO 4B). Details of the each formulation are as follows:

Formulation 4A

Formulation 3B Components Amounts Components Amounts A mixture of mono- (tocopheryl) phosphate and di- 1% Wiw (tocopheryl) phosphate in a ratio of 8:2 A mixture of mono- (tocopheryl) phosphate 10.8% wiw Ethanol 80% Wiw monosodium salt and di- (tocopheryl) phosphate Lidocaine base 5% Wiw in a ratio of 2:1 Molecular mass: 234.34 Oxycodone HCl 0.7% ww Melting point: 68 C. Molecular mass: 351.83 g/mol Hydroxypropyl cellulose(GPHX grade, where G is the 3% Wiw Pemulen 0.7% ww Molecular mass grade, PHX means pharmaceutical grade.) QS dHO QS dHO

0154 Formulation 3A had a pH of 6. Formulation 3B had a pH of 8. Formulation 4B Method Components Amounts 0155 Formulation 3A was prepared according to the pre A mixture of mono- (tocopheryl) phosphate and di- 1% Wiw ferred method described above. Formulation 3B was simi (tocopheryl) phosphate in a ratio of 2:1 larly prepared. US 2012/0202780 A1 Aug. 9, 2012 11

-continued -continued

Formulation 4B Formulation 5B Components Amounts Components Amounts Ethanol 30% wiw Hydroxypropyl cellulose (GPHX grade, where G is the 0.6% ww Lidocaine base 1% Wiw Molecular mass grade, PHX means pharmaceutical grade.) Molecular mass: 234.34 QS dHO Melting point: 68 C. Carbopol (CP934) 1% Wiw QS dHO Method 0.167 Diclofenac Formulation 5A was prepared according Method to the preferred method described above. Formulation 5B was similarly prepared. 0162 Formulation 4A was prepared according to the pre ferred method described above. Formulation 4B was simi Results larly prepared. 0.168. The results of a visual stability test showed that, after 3 days of storage, there were no physical changes noted Results with Formulation 5A whereas a precipitate had formed with Formulation 5B. 0163 The results of a visual stability test showed that, (0169. After 4 hours of administration, Formulation 5A had after 3 days of storage, there were no physical changes noted a significant skin deposition (Lig) compared to Formulation with Formulation 4A whereas a precipitate had formed with 5B, as shown in FIG. 4. In FIG.4, Formulations 5A and 5B are Formulation 4B. also compared to the commercially available product com 0164. After 4 hours of administration, Formulation 4A had prising diclofenac Voltaren R. a significant skin deposition (Lig) compared to Formulation 4B, as shown in FIG. 3. Conclusion (0170 The results showed that a formulation of the present Conclusion invention (Formulation 5A) was stable and had improved 0.165. The results showed that a formulation of the present delivery compared to Formulation 5B. invention (Formulation 4A) was stable and had improved Example 6 delivery compared to Formulation 4B. 0171 This example compares the stability, skin perme Example 5 ation and other properties of a formulation of the present invention (Formulation 6A) and a formulation which com 0166 This example compares the stability, skin deposi prises a low polar protic solvent concentration (Formulation tion and other properties of a formulation of the present 6B). Details of the each formulation are as follows: invention (Formulation 5A) and a formulation which com prises a low polar protic solvent concentration (Formulation 5B). Details of the each formulation are as follows: Formulation 6A Components Amounts

Formulation 5A A mixture of mono- (tocopheryl) phosphate and di- 1% Wiw (tocopheryl) phosphate in a ratio of 6:4 Components Amounts Isopropanol 70% wiw Ketorolac tromethamine 2% Wiw A mixture of mono- (tocopheryl) phosphate and di- 1% ww Hydroxypropyl cellulose (GPHX grade, where G is the 3% Wiw (tocopheryl) phosphate in a ratio of 6:4 Molecular mass grade, PHX means pharmaceutical grade) Isopropanol 70% wiw QS dHO Diclofenac diethylamine 2% Wiw Hydroxypropyl cellulose (GPHX grade, where G is the 3% Wiw Molecular mass grade, PHX means pharmaceutical grade.) QS dHO

Formulation 6B Components Amounts

Formulation 5B A mixture of mono- (tocopheryl) phosphate and di- 1% Wiw (tocopheryl) phosphate in a ratio of 6:4 Components Amounts Isopropanol 10% Wiw Ketorolac tromethamine 2% Wiw A mixture of mono- (tocopheryl) phosphate and di- 1% Wiw Hydroxypropyl cellulose (GPHX grade, where G is the 0.6% ww (tocopheryl) phosphate in a ratio of 6:4 Molecular mass grade, PHX means pharmaceutical grade) Isopropanol 10% Wiw QS dHO Diclofenac diethylamine 1% Wiw US 2012/0202780 A1 Aug. 9, 2012

Method 0180. After 4 hours of administration, Formulation 7A had a significant skin deposition (Lig) compared to Formulation 0172 Formulation 6A was prepared according to the pre 7B. ferred method described above. Formulation 6B was simi larly prepared. Conclusion 0173 A skin permeation test similar to that conducted for Example 2 was also conducted with the formulations. 0181. The results showed that a formulation of the present invention (Formulation 7A) was stable and had improved Results delivery compared to Formulation 7B. 0.174. The results of a visual stability test showed that, 0182. It will be understood to persons skilled in the art of after 3 days of storage, there were no physical changes noted the invention that many modifications may be made without with Formulation 6A whereas a precipitate had formed with departing from the spirit and scope of the invention. Formulation 6B. 1. A carrier composition for delivery of a biologically 0175. After 4 hours of administration, Formulation 6A had active compound comprising a phosphate compound of an a significant skin deposition (Lig) compared to Formulation electron transfer agent and a polar protic solvent selected 6B, as shown in FIG. 5. from the group consisting of acyclic alcohols, alkyl esters, ketones and nitriles, wherein the polar protic solvent concen Conclusion tration is within the range of about 60% w/w to about 90% 0176 The results showed that a formulation of the present w/w of the total concentration of the carrier composition. invention (Formulation 6A) was stable and had improved 2. The carrier composition of claim 1, wherein the polar delivery compared to Formulation 6B. protic solvent concentration is within the range of about 65% w/w to about 85% w/w, about 70% w/w to about 80% w/w, or Example 7 about 50% w/w to about 60% w/w, or about 60% w/w to about 70% w/w, or about 80% w/w to about 90% w/w. 0177. This example compares the stability and other prop 3. The carrier composition of claim 1, wherein the polar erties of a formulation of the present invention (Formulation protic solvent is an acyclic alcohol. 7A) and a formulation which comprises a low polar protic 4. The carrier composition of claim 1, wherein the acyclic solvent concentration (Formulation 7B). Details of the each alcohol is selected from the group consisting of C-Cacyclic formulation are as follows: alcohols, polyols of C-C acyclic alcohols, polymers of C-Cacyclic alcohols, and ester, alkyl ester and ether deriva tives thereof. Formulation 7A 5. The carrier composition of claim 4, wherein the acyclic alcohol is ethanol, n-propanol, isopropanol, ethylene glycol, Components Amounts propylene glycol, polyethylene glycol, diethylene glycol A mixture of mono- (tocopheryl) phosphate and di- 1% Wiw monoethylether or ethyl acetate. (tocopheryl) phosphate in a ratio of 6:4 6. The carrier composition of claim 1, wherein the polar Isopropanol 70% wiw protic solvent is a ketone. Felodipine 1% Wiw 7. The carrier composition of claim 6, wherein the ketone is QS dHO methyl isobutyl ketone or acetone. 8. The carrier composition of claim 1, wherein the polar protic solvent is a nitrile. 9. The carrier composition of claim 8, wherein the nitrile is Formulation 7B acetonitrile. 10. The carrier composition of claim 1, wherein the elec Components Amounts tron transfer agent is a hydroxy chroman. A mixture of mono- (tocopheryl) phosphate and di- 1% ww 11. The carrier composition of claim 10, wherein the (tocopheryl) phosphate in a ratio of 2:1 hydroxy chroman is a tocopherol or a tocotrienol. Isopropanol 10% ww. 12. The carrier composition of claim 11, wherein the phos Felodipine 1% ww phate compound of tocopherol is selected from the group Hydroxypropyl cellulose (GPHX grade, where G is the 3% Wiw Molecular mass grade, PHX means pharmaceutical grade.) consisting of mono-(tocopheryl) phosphate, mono-(toco QS dHO pheryl) phosphate monosodium salt, mono-(tocopheryl) phosphate monopotassium salt, mono-(tocopheryl) phos phate disodium salt, mono-(tocopheryl) phosphate dipotas sium salt, di-(tocopheryl) phosphate, di-(tocopheryl) phos Method phate monosodium salt, di-(tocopheryl) phosphate 0.178 Formulation 7A was prepared according to the pre monopotassium salt, or a mixture thereof. ferred method described above. Formulation 7B was simi 13. The carrier composition of claim 12, wherein the phos larly prepared. phate compound of tocopherol is a mixture of a mono-(toco pheryl) phosphate to a di-(tocopheryl) phosphate. Results 14. The carrier composition of claim 13, wherein the mix 0179 The results of a visual stability test showed that, ture of a mono-(tocopheryl) phosphate to a di-(tocopheryl) after 3 days of storage, there were no physical changes noted phosphate is in a ratio of at least 2:1, or within the range of with Formulation 7A whereas a precipitate had formed with about 4:1 to about 1:4, or within the range of about 6:4 to Formulation 7B. about 8:2. US 2012/0202780 A1 Aug. 9, 2012

15. The carrier composition of claim 1, wherein the phos 21. The formulation of claim 18, wherein the biologically phate compound of an electron transfer agent is present in an active compound is present in an amount of up to about 30% amount within the range of about 0.01% w/w to about 20% w/w of the total concentration of the carrier composition. w/w, or about 0.01% w/w to about 10% w/w, or about 0.01% w/w to about 5% w/w, or about 0.01% w/w to about 2% w/w, 22. The formulation of claim 21, wherein the biologically or about 5% w/w to about 10% w/w, or about 10% w/w to active compound is selected from the group consisting of about 15% w/w, or about 0.05% w/w, or about 0.1% w/w or lidocaine, diclofenac, ketorolac, prilocaine, halobetasol, about 1% w/w of the total concentration of the carrier com hydrocortisor, and combinations thereof. position. 23. The formulation of claim 22, wherein the biologically 16. Use of a phosphate compound of an electron transfer active compound is present in an amount of up to 5% w/w of agent and a polar protic solvent selected from the group the total concentration of the carrier composition. consisting of acyclic alcohols, alkyl esters, ketones and nitriles in the manufacture of the carrier composition, 24. A process for the preparation of a formulation of claim wherein the polar protic solvent concentration is within the 18 comprising the step of adding a biologically active com range of about 60% w/w to about 90% w/w of the total pound to a carrier composition of claim 1. concentration of the carrier composition. 25. Use of a carrier composition of claim 1 to improve the 17. A process for the preparation of a carrier composition delivery of a biologically active compound formulated with of claim 1 comprising the step of combining the phosphate the carrier composition, or to alter A.D.M.E. properties of a compound of the electron transfer agent and the polar protic biologically active compound, or to improve the bioavailabil Solvent until complete homogenisation is achieved. ity of a biologically active compound in a subject. 18. A formulation comprising a carrier composition of 26. A method for treating a Subject for a pathological claim 1 and a biologically active compound. condition which comprises administering an effective 19. The formulation of claim 18, wherein the biologically amount of a biologically active compound that will treat the active compound is lipophilic having a logP value within the pathological condition to a subject in need thereof, wherein range of about 1 to about 5. the biologically active compound is formulated in a carrier 20. The formulation of claim 18, wherein the biologically composition of claim 1. active compound has a relatively low molecular mass and/or a relatively low melting point. c c c c c