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Home , Cinnamedrine, Diclofenac, Methyl salicylate

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2012/160125 Al 29 November 2012 (29.11.2012) P O P C T

(51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 9/70 (2006.01) A61K 9/00 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 47/32 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (21) International Application Number: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, PCT/EP2012/059670 HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, 24 May 2012 (24.05.2012) MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, (25) Filing Language: English SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (26) Publication Language: English TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 11167614.4 26 May 201 1 (26.05.201 1) EP kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (71) Applicant (for all designated States except US) : NO- UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, VARTIS AG [CH/CH]; Lichtstrasse 35, CH-4056 Basel TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (CH). EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (72) Inventors; and TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (75) Inventors/Applicants (for US only): MEYER, Stephan ML, MR, NE, SN, TD, TG). [CH/CH]; Consumer Health S.A., Route de l'Etraz, 1260 Prangins (CH). LANG, Aurelie [FR/CH]; Declarations under Rule 4.17 : Novartis Consumer Health S.A., Route de l'Etraz, CH-1260 — as to applicant's entitlement to apply for and be granted a Prangins (CH). patent (Rule 4.1 7(H)) (74) Agent: LIPHARDT, Bernd; Novartis Consumer Health Published: SA, OTC Patent and Trademark Group, Werk Rosental, Postfach, CH-4002 Basel (CH). — with international search report (Art. 21(3))

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o (54) Title: COMPOSITIONS FOR PERCUTANEOUS ADMINISTRATION OF PHYSIOLOGICALLY ACTIVE AGENTS (57) Abstract: Compositions intended for the percutaneous administration of physiologically active agents, e.g. or a veterinary agents, are disclosed. Said compositions are characterized forming a non-sticky, very flexible film that 'has excellent long term effic - acy. The present invention relates to compositions intended for the percutaneous administration of physiologically active agents, in particular pharmaceutically active compounds (but also e.g. agents like or veterinary drugs). Throughout this document, "percutaneous" is intended to mean any route of administering a physiologically active agent onto, into or through the ski of a subject so as to achieve one or more of a topical, local or systemic physiological effect. Local treatment of the skin is intended to also include, for example, applying such compositions to the ear, e.g. for treating otitis with e.g. antibiotics. More specifically, the invention relates to percutaneous pharmaceutical and veterinary, especially pharmaceutical, compositions with improved long term efficacy.

More speciflcally, the invention concerns compositions which when applied to the skin rapidly form a durable, flexible film comprising one or more physiologically active agents, in particular pharmaceutically active substances.

Such film forming compositions are known in the art. However, said known film forming compositions (see e.g. US 6,21 ,250) suffer from various disadvantages, e.g. when applied to the skin, they may be sticky for a while, meaning that they may adhere e.g. to clothes for some time.

The present invention overcomes said problems by providing a film forming composition, preferably in gel form, that rapidly forms a non-sticky, durable, very flexible fi m.

Thus, the present invention relates to a composition for percutaneous administration of a physiologically active agent comprising (a) ethyl acrylate/methyl methacrytate copolymer, (b) , isopropanol or a mixture thereof, (c) water, and (d) at least o e physiologically active agent.

Ethyl acrylate/methyl methacry!ate (EA M A) copolymers typically act as film forming polymer in the compositions. EA/ A copolymers (a) when combined with ethanol and/or isopropanol (b) and water (c), have been identified as beneficial film forming polymers typically providing a ge The resulting compositions of the invention can, for example, be packaged in tubes like a y conventional topical semi-solid form, or applied to the skin via special devices developed for being ab e to spray gel-like compositions, e.g. Tru-Spray®. The of the formulation can be adjusted to the optimal viscosity desired for a particular package, for example, by adapting the weight ratio of (a) (b), i.e. of ethyl acrylate/methyl methacrylate copolymer ethanol/isopropano!. By increasing the amount of ethanol/isopropanol, the viscosity of the formulation is decreased and vice versa. When using very low amounts of (a) [e.g. 2-5%, preferably 4-5%] and very high amounts of (b) [e.g. 70-90%], viscous liquids - instead of gels - may be obtained (see Examples 10- 1). Those form beneficial films on the skin as well and thus are also within the scope of the present invention. They may be applied to the skin, for example, as a spray.

All percentages given hereinbefore and hereinafter are weight-%, unless indicated otherwise.

Ethyl acrylate/methyl methacrylate (EA/MMA) copolymers (a) can be used in pure form but also e.g. in the form of a dispersion or a solution. Preferably, they are used in the form of an aqueous suspension, for example as a product of the Eudragit® NE series, e.g. Eudragit® NE 30 D or Eudragit® NE 40 D, or Eudragit N 30 D, all provided e.g. b the company Evonik Industries. For example, Eudragit® NE 40 D includes 40% of EA MMA copolymer and 60% of water. Typically, the compositions of the invention contain EA MMA copolymers (a) - calculated in pure form, i.e. by excluding e.g. any solvents that may be present - in an amount of at least 2%, preferably at least 5%, more preferably at least 10%, or in an amount of from 2 up to 30%, in particular of from 5 up to 25%.

The solvent or mix o solvents (b) used, i.e. ethanol and/or isopropanol, are volatile so that they quickly evaporate after administration and allow formation of a film on the skin. Preferred as (b) are isopropanol or a mixture of isopropanol and ethanol, and in particular isopropanol. Typically, the compositions of the invention contain the solvent or mix of solvents (b) in an amount of at least 30%, preferably at least 40%, or in an amount of from 35% up to 90%, or of from 35% up to 80%, or of from 40 up to 70%.

Typically, the compositions of the invention contain EA MA copolymers (a) - calculated in

pure form - and component (b) [= ethanol and/or isopropanol] in a weight ratio of from 1:1 up to :45, preferably 1: 1 up to 1:25, especially 1:1 up to 1:15 , and i particular of from 1:1 up to 1:10.

Water (c) typically is either incorporated by using aqueous dispersions of component (a) , e.g. Eudragit® NE 40 D, and/or is added separately to the composition. Typically, the compositions of the invention contain water (c) in an amount of at least 1%, preferably at least 5%, more preferably at least 10%, especially at least 15%, or of from 1% up to 50%, preferably of from 5% up to 40%, and i particular of from 15% up to 35%.

Physiologically active agents (d) are, in particular, pharmaceutically active compounds but also include e.g. agents helping in smoking cessation e.g. nicotine, or veterinary drugs.

Used as physiologically active agents (d) can be any pharmaceutically - or veterinarily - active substance suitable for percutaneous delivery. Even physiologically active agents that are normally delivered by the oral, parenteral or rectal route, may come into consideration.

As far as the physiologically active agents (d) are capable of forming physiologically acceptable salts, prodrugs, hydrates or solvates, the latter are included by naming (d) in free, neutral form.

Examples of physiologically active agents (a) are:

Cardioactive , for example, organic nitrates such as nitroglycerine, isosorbide dinitrate, and isosorbide mononitrates; sulfate; ; thiazides such as bendroflumethiazide, chlorothiazide, and hydrochlorothyazide; ; ; adrenergic blocking agents, such as and ; ; ; captopril; and .

Androgenic steroids, such as testosterone, methyltestosterone and fluoxymesterone.

Estrogens, such as conjugated estrogens, esterified estrogens, estropipate, 17beta , 17beta-estradiol valerate, equilin, mestranol, estrone, estriol, 17beta-ethinyl estradiol, and diethylstilboestrol. Progestational agents, such as , - norprogesterone, norethindrone, norethindrone acetate, melengestrol, chlormadinone, ethisterane, medroxyprogesterone acetate, hydroxyprogesterone caproate, ethynodiol diacetate, norethynodrel, 1/alpha hydroxyprogesterone, dydrogesterone, dimethisterone, ethinylestrenol, norgestrei, demegestone, promegestone, and megestrol acetate.

Drugs having an action on the central nervous system, for example sedatives, hypnotics, antianxiety agents, and anaesthetics, such as chloral, , naloxone, , , pentobarbital, phenobarbital, secobarbital, , , and nicotine.

Local anesthetics, e.g. , , dyclonine, , dibucaine, methocaine, , , , or .

Nutritional agents, such as vitamins, e.g. Vitamin B12, essential amino acids, and essential fats.

Anti-inflammatory agents, such as steroids, e.g. hydrocortisone, desonide, cortisone, dexamethasone, fluocinolone, triamcinolone, medrysone, prednisolone, flurandrenolide, prednisone, halcinonide, methylprednisolone, flurandrenolide, prednisone, halcinonide, methylprednisolone, fludrocortisone, corticosterone, paramethasone, betamethasone; and non-steroidal anti-inflammatory drugs, e.g. , , , , , , , , , indomethacin, , , , , , , , , meclofenamate sodium or .

Anti-inflammatory agents that are often used, inter alia, in veterinary medicine, e.g. triamcinolone, betamethasone, dexamethasone, isoflupredone, hydrocortisone or prednisolone.

Antihistamines, such as dimetindene, , dimenhydrinate, perphenazine, triprolidine, pyrilamine, chlorcyctizine, , carbinoxamine, tripelennamine, brompheniramine, , cyclizine, meclizine, clorprenaline, , and chlorpheniramine.

Anti-emetic agents, e.g. scopolamine. Anti-hypertensive drugs, e.g. clonidine.

Respiratory agents, such as theophilline and beta2-adrenergic agonists such as albuterol, , metaproterenol, , , , quirrterenol, , solmefamol, soterenol, and tetroquinol.

Sympathomimetics, such as , , , , , , , and epinephrine. Miotics, e.g. pilocarpine. Cholinergic agonists, such as choline, , methacholine, , bethanechol, pilocarpine, muscarine, and .

Antimuscarinic or muscarinic cholinergic blocking agents such as atropine, scopolamine, homatropine, methscopolamine, homatropine methylbromide, methantheline, cyclopentolate, tropica mide, propantheline, anisotropine, dicyclomine, and eucatropine. Mydriatics, such as atropine, cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine and hydroxyamphetamine.

Psychic energizers, e.g. 3-(2-aminopropyl)indole or 3-(2-aminobutyl) indole.

Antibiotics, e.g. clindamycin, , tetracycline, penicillin, chloramphenicol, sulfacetamide, sulfamethazine, sulfadiazine, sulfamerazine, sulfamethizole or sulfisoxazole.

Antibiotics that are often used, inter alia, in veterinary medicine, e.g. benzylpenicillin, methycyllin, ampillicin, amoxicillin, streptomycin, neomycin, tetracyclines, chloramphenicol, erythromycin, griseofulvin, thiostrepton, florfenicol, enrofloxacin, bacitracin, gentamycin, polymyxin B , chloramphenicol, marbofloxacirt or framecytin.

Antiparasitizides that are often used, especially in veterinary medicine, e.g. malachite green, , chloramine T or B , emmamectin benzoate or alpha-cypermethrin.

Anthelmintics that are often used, inter alia in veterinary medicine, e.g. arecoline, ivermectin, praziquantel, mebendazole or thiabendazole. Antipsoriatic agents, e.g. calcipotriol or calcipotriot/betamethasone combinations.

Antivirals, e.g. penciclovir, acyclovir or idoxuridine.

Anti-acne agents, e.g. benzoyl peroxide.

Dermatological agents, such as vitamins A and E .

Humoral agents, such as the , natural and synthetic, for example PGE1, PGF2alpha, and PGF2aipha, and the PGE1 analog .

Antispasmodics, such as atropine, methantheline, papaverine, cinnamedrine, and methscopolamine.

Antidepressant drugs, such as , isocarboxazid, phenelzine, , , , , , , nortriptyline, protriptyline, , , and .

Drugs for the treatment of Alzheimer's disease, e.g. rivastigmine.

Drugs for the treatment of urinary incontinence, e.g. oxybutynin.

Contraceptives, e.g. a mixture of norelgestromin and ethinyl estradiol.

Anti-diabetics, such as insulin, and anticancer drugs such as tamoxifen and methotrexate.

Anorectic drugs, such as , , phenylpropanolamine, , diethylpropion, , and .

Anti-allergenics, such as antazoline, methapyrilene, chlorpheniramine, pyrilamine and pheniramine. Tranquilizers, such as reserpine, , and antianxiety benzodiazepines such as alprazolam, chiordiazepoxide, clorazeptate, halazepam, oxazepam, prazepam, clonazepam, flurazepam, triazolam, iorazepam and diazepam.

Antipsychotics, such as thiopropazate, chlorpromazine, triflupromazine, mesoridazine, piperacetazine, , acetophenazine, fluphenazine, perphenazine, , chlorprathixene, thiothixene, haloperidol, bromperidol, , a d molindone.

Decongestants, e.g. , , phenylephrine, or .

Antipyretics, e.g. acetylsalicylic acid or .

Antimigraine agents, e.g. or pizotyline.

Drugs for treating nausea and vomiting, such as chlorpromazine, perphenazine, prochlorperazine, promethazine, triethylperazine, triflupromazine, and trimeprazine.

Anti-malariais, such as the 4-aminoquinolines, alpha-aminoquinolines, chloroquine, and pyrimethamine.

Anti-ulcerative agents, such as misoprostol, , and .

Peptides and proteins, such as drugs for Parkinson's disease, spasticity, and acute muscle spasms, such as levodopa, carbidopa, , apomorphine, bromocriptine, selegiline (deprenyl), trihexyphenidyl hydrochloride, benztropine mesylate, procyciidine hydrochloride, , diazepam, dantrolene, insulin, erythropoietin and growth hormone.

Anti-estrogen or hormone agents, such as tamoxifen or human chorionic gonadotropin.

Nucleotides and nucleic acids (e.g. DNA). Antifungals, e.g. terbinafine, nafttfine, butenafine, bifonazole, , econazole, isoconazole, , miconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, tolnaftate, terconazole, amorolfine, ciclopirox or undecylenic acid.

Antifungals that are often used, inter alia, in veterinary medicine, e.g. fluconazole, ketoconazole, isoconazole, miconazole, Amphotericin B , flucytosine, terbinafine, nystatin, thiabendazol or clotrimazol.

The physiologically active agents (d) ca be present in the composition in different forms, depending on which form yields the optimum delivery characteristics. For example, they can be in its free base or acid form, or in the form of salts, , or any other pharmacologically acceptable derivatives, or e.g. as components of molecular complexes.

Preferred physiologically active agents (d) are nicotine, lidocaine, hydrocortisone, diclofenac, ibuprofen, naproxen, indomethacin, piroxicam, methyl salicylate, phenylbutazone, mefenamic acid, betamethasone, dimetindene, scopolamine, benzoyl peroxide, calcipotriol, penciclovir, acyclovir, vitamin A , vitamin E , xylometazoline, oxymetazoline, phenylephrine, ephedrine, naphazoline, terbinafine, naftifine, butenafine, bifonazole, clotrimazole, econazole, isoconazole, ketoconazole, miconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, tolnaftate, terconazole, amorolfine, ciclopirox, undecylenic acid, clonidine, testosterone, nitroglycerin, selegiline, rivastigmine and oxybutynin.

Especially preferred physiologically active agents (d) are nicotine, lidocaine, hydrocortisone, diclofenac, dimetindene, scopolamine, benzoyl peroxide, calcipotriol, penciclovir, acyclovir, xylometazoline, terbinafine, tolnaftate, clotrimazole and rivastigmine.

In a particular embodiment of the invention, the physiologically active agents (d) are selected from the group consisting of -relieving pharmaceutically active substances, antihistamines, antifungals and nicotine.

A pain-relieving pharmaceutically active substance is e.g. a non-steroidal anti-inflammatory ("NSAID"), or a , or a warming agent, e.g. or vanillyl butyl ether - and preferably a NSAID. NSAIDs are e.g. diclofenac, indomethacin, ibuprofen, piroxicam, acetylsalicylic acid (Aspirin®), naproxen, methyl salicylate, ketoprofen, , phenylbutazone, piroxicam, , , and pharmaceutically acceptable salts of any of said compounds. Preferred as NSAID is diclofenac or a pharmaceutically acceptable salt thereof. Especially preferred are diclofenac free acid, diclofenac sodium, diclofenac potassium, diclofenac diethylammonium and diclofenac epolamine, more especially diclofenac sodium and diclofenac diethylammonium, and in particular diclofenac sodium.

Local anesthetics are e.g. lidocaine, benzocatne, dibucaine or procaine.

Also combinations, e.g. of a NSAID and a warming agent, or of a NSAID and a local anesthetic, come into consideration as pain-relieving active substances.

The compositions of the invention may optionally include further excipients known in the art, for example fra rances/perf umes, antioxidants, e.g. butylhydroxytoluene, antimicrobial preservatives, e.g. benzyl , benzalkonium chloride or parabens, coloring agents or pH regulator components (sometimes required to optimize a drug's permeation).

The compositions of the invention typically form a discreet flexible transparent film. If desired, they can also be modified to form an opaque white or colored film by e.g. adding corresponding coloring agents.

In a special embodiment of the invention, the compositions for percutaneous administration of the invention, as defined hereinbefore or hereinafter, in addition comprise of from 0.5 up to 8% (w w) - preferably of from 1 up to 6% (w/w), in particular of from .5 up to 4% (w w) - of a compound selected from the group consisting of oleic alcohol, oleic acid, linoleic alcohol, , myristyl alcohol, dimethyl sulofoxide, , , preferably levomenthol, and any mixtures thereof. Especially preferred is a mixture of levomenthol and oleyl alcohol.

In another embodiment of the invention, the compositions for percutaneous administration of the invention, as defined hereinbefore or hereinafter, are devoid of ethyl acetate. n a further embodiment of the invention, the compositions for percutaneous administration of the invention, as defined hereinbefore or hereinafter, are devoid of esters of C1-C10 alcohols with C1-C10 carboxylic acids.

n a stili further embodiment of the invention, the compositions for percutaneous administration of the invention, as defined hereinbefore or hereinafter, are devoid of both ethyl acetate and salicylic acid.

In another embodiment of the invention, the compositions for percutaneous administration of the invention, as defined hereinbefore or hereinafter, are devoid of both esters of C1-C10 alcohols with C1-C10 carboxylic acids and salicylic acid

In another embodiment of the invention, the compositions for percutaneous administration of the invention, as defined hereinbefore or hereinafter, are devoid of all of ethyl acetate, salicylic acid and cellulose nitrate.

In another embodiment of the invention, the compositions for percutaneous administration of the invention, as defined hereinbefore or hereinafter, are devoid of a keratolyticaily active agent, in particular devoid of a keratolyticaily active agent being defined as an agent which is suitable to effect the dissolution and detachment of korneocytes from the stratum corneum, and which keratolyticaily active agent is selected, for example, from the group consisting of agonists, such as adapalene and , particularly tretinoin, isotretinoin, motretinide, tazarotene and/or retinol; urea; organic acids, particularly hydroxy carboxylic acids, especially glycolic acid, , lactic acid and/or salicylic acid; and mixtures thereof.

Preferred embodiments of the invention are characterized by replacing in a l definitions and embodiments of the invention hereinbefore and hereinafter (including the claims) "[composition ...] comprising" with ""[composition ..] consisting essentially of.

Even more preferred embodiments of the invention are characterized by replacing in all definitions and embodiments of the invention hereinbefore and hereinafter (including the claims) "[composition ,..] comprising" with ""[composition ...] consisting of. The compositions for percutaneous administration of the invention can be manufactured in a manner k own per se, for example by conventional mixing and homogenizetion methods, and as described in the Examples section below.

The compositions for percutaneous administration of the invention show inter alia excellent long term efficacy, mechanical robustness and waterproofness as well as a high skin permeation of the drug, as far as desired, over a long period of time. Said beneficial properties can be demonstrated e.g. by the following tests:

1) The mechanical properties of the films are tested by, in particular, measuring the tensile strength, the Young's modulus and the elongation of the film. Moreover, the films are tested e.g. i a shear test, a stress relaxation or an elastic deformation test.

(2) Film robustness is determined e.g. by oscillating a piece of gauze over glass slides on which 100 g of a test composition have been evenly spread and allowed to dry at 50°C for 10 min.

3) Specific properties related to the application of the compositions of the i ventio that are tested are their spreadability, their resistance to water and their skin adhesion.

(4) Waterproofness is determined e.g. by evenly spreading a test composition on glass slides, allowing to dry it and weighing the glass slide with the dried film. The glass slides are immersed i a beaker of deionized water at 20°C for 20 min. Then they are removed, dried in an oven at 50°C and weighed again. Waterproofness is calculated from the weights of the glass slides before and after water treatment.

5) I vitro skin retention of drug component: The skin levels of the drug are determined after application of the test composition on the skin surface after 24h and within the epidermis after 24h. In vitro diffusion cells using excised human epidermis are used. The test composition is applied to epidermal membrane and the amount of drug penetrating subsequently measured (HPLC and UV detection).

Another embodiment of the invention concerns the compositions for percutaneous administration of the invention, comprising at least one pain-relieving pharmaceutically active substance - preferably a non-steroidal anii-inflammatory drug, in particular diclofenac - for use in the treatment of pain.

Still another embodiment of the invention concerns the compositions for percutaneous administration of the invention comprising at least one pain-relieving pharmaceutically active substance - preferably a non-steroidal anti-inflammatory drug, in particular diclofenac - for use in the treatment of pain in limbs or joints (articulations) as well as back pain of a patient via forming a durable film at the site of pain thus enabling said pain-relieving pharmaceutically active substance - preferably a non-steroidal anti-inflammatory drug, in particular diclofenac - to penetrate through the skin over a lo g period of time. A "long period of time" typically means of from 8 hours up to 7 days, preferably of from 8 hours up to 4 days and in particular of from 8 hours up to 48 hours.

Especially, said compositions for percutaneous administration comprising at least one NSAID are suitable to treat ankle pain - e.g. ankle sprain - , wrist pain, k ee pain - e.g. knee sprain or knee -, elbow pain - e.g. tennis elbow or elbow osteoarthritis - , shoulder pain, finger pain - e.g. finger sprain or finger osteoarthritis such as thumb osteoarthritis, or back pain.

Another embodiment of the invention concerns the use of (a) ethyl acrylate/methyl methacrylate copolymer, (b) ethanol, isopropanol or a mixture thereof, (c) water, and (d) at least one non-steroidal anti-inflammatory drug - in particular diclofenac - for the manufacture of a composition for use in the treatment of pain.

The beneficial properties of said compositions for percutaneous administration comprising at least one NSAID are demonstrated e.g. by the following tests:

(1) in vitro cumulative permeation on human skin at 24h (measured in g diclofenac/cm 2

[area of composition applied]): The compositions of Examples 1-1 1 show a high in vitro cumulative permeation on human skin at 24h.

(2) Pain relief: The compositions of Examples 1-1 show high pain relief when applied to patients suffering from ankle sprain or back pain, respectively. The following examples are intended to illustrate the invention.

Example : Transparent, homogeneous gel comprising 4.0% (w/w) of Diclofenac sodium Example 2: Transparent, homogeneous gel comprising 4.0% (w/w) of Diclofenac sodium Example 3 : Transparent, homogeneous gei comprising 4.0% (w/w) of Diclofenac sodium

(EA/MMA copolymer = ethyl acrylate/methyl methacrylate copolymer)

Example 4: Slightly opalescent gel comprising 4.6% (w/w) of Diclofenac sodium Example 5: Transparent, homogeneous gel comprising 4.0% (w/w) of Diclofenac sodium Example 6 ; Clear gel comprising 4.0% (w w) of Diclofenac sodium

Example 4 am e s Example

%(w/w) %(w w) % (w w)

Diclofenac sodium 4.6 4.0 4.0 Diclofenac diethylammonium - - -

Eudragit® NE40D 17.2, 30.0, 40.0,

consisting o ; consisting of : consisting o : consisting o :

- EA A copolymer 8.9 12.0 6.0

- water 10.3 18.0 24.0

Isopropanol 68.6 33.0 56.0

Et a o , absolute - 33.0 -

Levomenthol - - -

Oleyl alcohol - - -

Water, purified 9.6 - -

Total 100.0 100.0 100..0

Example 7: Glear gel comprising 5.1% (w/w) of Diclofenac diethylammonium Example 8: Ge comprising 4.0% (w/w) of Diclofenac sodium Example 9; Viscous gel comprising 4,0% (w/w) of Diclofenac sodium

Example 7 Example 8 m .

%(w/w) %(w w) % (w w)

Diclofenac sodium - 4.0 4.0

Diclofenac diethylammonium 5.1 - -

Eudragit® NE40D, 27.5, 40,0, 50.0,

consisting of ; consisting of : consisting of : consisting of ;

- EA MMA copolymer 11.0 18.0 20.0

- water 16.5 24.0 30.0

isopropanol 67.4 53.5 43.5

Levomenthol - 0.5 0.5

Oleyl alcohol - 2.0 2.0

Water, purified - - - Total 100.0 100.0 100.0

Example 0 : Viscous liquid comprising 4.6% (w w) of Diclofenac sodium Example 1: Viscous liquid comprising 4,8% (w/w) of Diclofenac sodium

The formulations of the Examples 1-1 are manufactured as follows: Dissolve diclofenac salt, levomenthol and oleyi alcohol n a mix of Eudragit NE40D and additional water (if present), The add tsopropanol and/or ethanol under strong mixing (with gel formation, except Examples 10-1 1). Glaims

1 A composition for percutaneous administration of a physiologically active agent comprising (a) ethyl acrylate/methyl methacrylate copolymer, (b) ethanol, isopropanol o a mixture thereof, (c) water, and ( ) at least one physiologically active agent

2 . A composiiion according to claim , wherein (b) is isopropanol.

3. A composition according to claim 1 or claim 2, wherein the at least one physiologically active agent (d) is selected from the group consisting of pain-relieving pharmaceutically active substances, antihistamines, antifungals and nicotine.

4 . A composition according to claim 3, wherein the at least one physiologically active agent (d) is diclofenac or pharmaceutically acceptable salt thereof.

5 . A composition according to any one of claims 1-4, which contains EA MMA copolymers (a) - calculated in pure form - in an amount of from 2% up to 30% (w w).

6 . A composition according to any one of claims 1-5, which contains component (b) [= ethanol and/or isopropanol] in an amount of from 35% up to 90% (w w).

7 . A composition according to any one of claims 1-6, which contains water (c) in an amount of from 5% up to 40% (w w).

8. A composition according to any one of claims 1-7, which contains EA/MMA copolymers (a) - calculated in pure form - and component (b) [= ethanol and/or isopropanol] in a weight

ratio of from 1: 1 up to :45. 9 . A composition according to a y one of claims 1-8, which in addition comprises of from 0.5 up to 8 % (w/w) of a compound selected from the group consisting of oleic alcohol, oleic acid, linoleic alcohol, linoleic acid, myristyl alcohol, dimethyl sulofoxide, thymol, menthol, and any mixtures thereof,

10. A composition according to any one of claims 3-9, comprising at least o e pain-relieving pharmaceutically active substance - preferably a non-steroidal anti-inflammatory drug, in particular diclofenac - for use i the treatment of pain.

1 . A composition according to any one of claims 3-9, comprising at least one pain-relieving pharmaceutically active substance - preferably a non-steroidal anti-inflammatory drug, i particular diclofenac - for use in the treatment of pain in limbs or joints (articulations) as well as back pain of a patient via forming a durable film at the site of pain thus enabling said pain-relieving pharmaceutically active substance - preferably a non-steroidal anti¬ inflammatory drug, in particular diclofenac - to penetrate through the skin over a period of from 8 hours up to 7 days.

12. Use of (a) ethyl acrylate/methyl methacrylate copolymer, (b) ethanol, isopropanol or a mixture thereof, (c) water, and

(d) at least one non-steroidal anti-inflammatory drug - in particular diclofenac -

for the manufacture of a composition for use in the treatment of pain. A . CLASSIFICATION O F SUBJECT MATTER INV. A61K9/70 A61K47/32 A61K9/00 ADD.

According to International Patent Classification (IPC) o r t o both national classification and IPC

B . FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) A61K

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)

EPO-Internal , BIOSIS, EMBASE, WPI Data

C . DOCUMENTS CONSIDERED TO B E RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

WO 01/87276 Al (SAMYANG CORP [KR] ; KIM HO 1-12 CHIN [KR] ; Y00N HYE JEONG [KR] ) 22 November 2001 (2001-11-22) page 1, l i ne 4 - l i ne 10 page 4 , l i ne 1 - l i ne 25 page 6, l i ne 16 - l i ne 24 page 13 , l i ne 17 - page 14, l i ne 9 exampl es

US 6 211 250 Bl (T0MLINS0N ROD [AU] ET AL) 1-12 3 Apri l 2001 (2001-04-03) ci ted i n the appl i cati on exampl es 7, 11 -/-

X| Further documents are listed in the continuation of Box C . See patent family annex.

* Special categories of cited documents : "T" later document published after the international filing date o r priority date and not in conflict with the application but cited to understand "A" document defining the general state of the art which is not considered the principle o r theory underlying the invention to be of particular relevance "E" earlier application o r patent but published o n o r after the international "X" document of particular relevance; the claimed invention cannot be filing date considered novel o r cannot b e considered to involve a n inventive "L" documentwhich may throw doubts o n priority claim(s) orwhich is step when the document is taken alone cited to establish the publication date of another citation o r other "Y" document of particular relevance; the claimed invention cannot be special reason (as specified) considered to involve a n inventive step when the document is "O" document referring to a n oral disclosure, use, exhibition o r other combined with one o r more other such documents, such combination means being obvious to a person skilled in the art "P" document published prior to the international filing date but later than the priority date claimed "&" document member of the same patent family

Date of the actual completion of the international search Date of mailing of the international search report

27 June 2012 05/07/2012

Name and mailing address of the ISA/ Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 N L - 2280 HV Rijswijk Tel. (+31-70) 340-2040, Fax: (+31-70) 340-3016 Gi ro, Annal i sa C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

EP 1 537 868 Al (POLA CHEM IND INC [ ] 1-9 POLA PHARMA INC [JP] ) 8 June 2005 (2005-06-08) paragraphs [0007] , [0008] 10-12 paragraph [0015] exampl e s 9 , Comp. 8 ; tabl e 5

US 2005/276842 Al (ZHANG J I E [US] ET AL) 1-12 15 December 2005 (2005-12-15) paragraph [0002] paragraph [0051] - paragraph [0062] exampl e s 6 , 10

ZURD0 SCHR0EDER ET AL: "Devel opment and 1-12 characteri zati on of f i l m formi ng polymeri c sol uti ons for ski n drug del i very" , EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, ELSEVI ER SCI ENCE PUBLISHERS B.V. , AMSTERDAM, NL, vol . 65 , no. 1 , 1 December 2006 (2006-12-01) , pages 111-121 , XP005788732 , ISSN : 0939-6411 paragraph [0001] paragraph [02 . 1] tabl e s 1 , 3 paragraph [0005]

EP 0 319 965 Al (SHI0N0GI & CO [JP] ) 1-12 14 June 1989 (1989-06-14) page 2 , l i ne 18 - l i ne 35 tabl e s 1 , 2 Patent document Publication Patent family Publication cited in search report date member(s) date

WO 0187276 Al 22-11-2001 AT 474563 T 15-08 2010 AU 9521101 A 26-11 2001 AU 2001295211 B2 28-10 2004 B R 0110843 A 30-12 2003 CA 2409069 Al 22-11 2001 CN 1429102 A 09-07 2003 EP 1282408 Al 12-02 2003 P 4091768 B2 28- 05 2008 P 2003533471 A 11-11 2003 KR 20020002199 A 09-01 2002 MX PA02011174 A 19-08 2004 NZ 522532 A 29- 04 2005 US 2003170295 Al 11-09 2003 O 0187276 Al 22-11- 2001

US 6211250 Bl 03-04-2001 AT 263577 T 15- 04 2004 AU 723143 B2 17-08 2000 CA 2271139 Al 04-06 1998 CZ 9901812 A3 13-10 1999 DE 69728556 Dl 13- 05 2004 DE 69728556 T2 24-02 2005 DK 0944398 T3 02- 08 2004 EP 0944398 Al 29- 09 1999 ES 2219758 T3 01-12 2004 HU 9903792 A2 28-03 2000 P 4358305 B2 04-11 2009 P 2001504499 A 03- 04 2001 J P 2008247912 A 16- 10 2008 NO 992290 A 14- 07 1999 PL 191824 Bl 31-07 2006 PT 944398 E 30- 07 2004 SK 64599 A3 12-06 2000 US 6211250 Bl 03- 04 2001 WO 9823291 Al 04- 06 1998 ZA 9710560 A 10-06 1998

EP 1537868 Al 08-06-2005 AT 521349 T 15-09 2011 AU 2003242238 Al 31-12 2003 CA 2489854 Al 24-12 2003 EP 1537868 Al 08-06 2005 EP 2389938 Al 30-11 2011 US 2005232879 Al 20-10 2005 US 2012015996 Al 19-01 2012 W0 03105841 Al 24-12 2003

US 2005276842 Al 15-12-2005 AU 2005251805 Al 22-12-2005 CA 2569121 Al 22-12-2005 EP 1753380 A2 21- 02-2007 J P 2008501805 A 24-01-2008 KR 20070027694 A 09-03-2007 US 2005276842 Al 15-12-2005 WO 2005120473 A2 22- 12-2005

EP 0319965 Al 14-06-1989 DE 3862017 Dl 18-04-1991 EP 0319965 Al 14-06-1989 ES 2036661 T3 01-06-1993 GR 3001862 T3 23-11-1992 J P 1149725 A 12-06-1989

page 1 of 2 Patent document Publication Patent family Publication cited in search report date member(s) date

P 8018983 B 28-02-1996 us 4935241 A 19-06-1990

page 2 of 2