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(11) EP 2 735 309 A1

(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) Int Cl.: 28.05.2014 Bulletin 2014/22 A61K 31/19 (2006.01) A61K 45/06 (2006.01) A61P 19/04 (2006.01) (21) Application number: 12382463.3

(22) Date of filing: 27.11.2012

(84) Designated Contracting States: (72) Inventor: Cos Alfonso, Eduardo AL AT BE BG CH CY CZ DE DK EE ES FI FR GB 08304 Mataro (ES) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (74) Representative: Sugrañes Patentes y Marcas Designated Extension States: Calle Provenza 304 BA ME 08008 Barcelona (ES)

(71) Applicant: Cos Alfonso, Eduardo 08304 Mataro (ES)

(54) Pharmaceutical composition for the treatment of and/or calcific

(57) The present invention relates to a pharmaceu- calcificbursitis, and more particularly to a pharmaceutical tical composition for topical administration comprising composition in the form of an emulsion especially suitable acetic acid for the treatment of calcific tendinitis and/or for said use. EP 2 735 309 A1

Printed by Jouve, 75001 PARIS (FR) 1 EP 2 735 309 A1 2

Description frequent injections can harm the and might cause or trigger a serious joint infection. Puncturing-sucking the Technical Field of the Invention calcification can cause and for a week after the puncturing. Likewise, the effectiveness of ion- [0001] The present invention relates to a pharmaceu- 5 tophoresis in treating calcifications has been strongly tical composition for topical administration comprising questioned for example by M. Perron et al., Arch. Phys. acetic acid for the treatment of calcific tendinitis and/or Med. Rehabil., 78(4), 379-84 (1997), B. E. Leduc et al., , and more particularly to a pharmaceutical Arch. Phys. Med. Rehabil. 84(10), 1523-7 (2003) and C. compositionin theform ofan emulsion especiallysuitable D. Ciccone et al., , 83(1), 68-74 (2003). for said use. 10 In relation to shock wave treatment (ESWT), it is con- traindicated in the chest or lung region, in patients with Background of the Invention coagulopathies or under anti-coagulant treatments, dur- ing pregnancy, in vascular-nervous structures, in bone [0002] Calcific tendinitis/tendonitis, calcifying tendini- or target area infections, in bone or application area tu- tis or calcerous tendinitis is a common disorder charac- 15 mors and in growth plate (R. Sistermann et al., Z. Orthop terized by deposits of hydroxyapatite (a crystalline calci- lhre Grenzgeb, 136, 175-81 (1998)). Additionally, ad- um phosphate) in any tendon of the body. In most cases, verse side effects have been described with shock wave these calcific (calcium) deposits tend to accumulate treatments, including superficial hematomas, hyperven- around the , particularly in the supraspinatus tilations, rise in blood pressure and pain during the ap- tendon, proximal bicep and elbow (epicondylitis). They 20 plication thereof (M. Loew et al., J. Shoulder Elbow Sur., can also be seen less frequently, in the heel (in the Achil- 4, 101-106 (1995)). Likewise, and extirpation of les tendon), knee (in patellar tendon), wrist, fingers and the calcium deposit involves certain risks of complica- forearm. tions described for example by RJ. McKendry et al., J. [0003] Calcific tendinitis causes chronic or acute in- Rheumatol., 9, 75-80 (1982). flammatory symptoms in patients, pain aggravated by 25 [0008] Based on the foregoing, there is a need to pro- movements and local swelling which may occur together vide a new treatment for calcific tendinitis and/or calcific with mobility restrictions. It has been estimated that cal- bursitis. In particular, the present invention provides new cific tendinitis is responsible for 7% of shoulder pain syn- compositions capable of improving both the symptoms dromes (Faure G. et al., Ann. Rheum. Dis., 42, 49-53 and treating calcific tendinitis and/or calcific bursitis in a (1983)). 30 definitive, less invasive and innocuous manner. [0004] These calcium deposits can also occur in the bursa. Bursa is a sac-like structure which is located be- Disclosure of the Invention tween bones, and muscles having a function facilitating the movement between said structures and to [0009] The present invention relates in a broader as- reduce any friction between bones. Calcific bursitis typ- 35 pect to a topically administered pharmaceutical compo- ically leads to chronic pain, stiffness, and sometimes lim- sition comprising acetic acid for the treatment of calcific ited range of motion of the affected joint with use or when tendinitis and/or calcific bursitis and for the inflammation examined. or pain associated with said diseases. [0005] The conventional treatments for calcific tendin- [0010] The compositions for topical administration of itis and calcific bursitis typically consist of preventing the 40 the invention have valuable therapeutic properties and condition from worsening, letting the affected part rest, are especially beneficial in the treatment of calcific tend- administrating non-steroidal anti-inflammatory drugs initis and/or calcific bursitis. (NSAIDS), physiotherapy, or injecting a steroid locally. [0011] It has surprisingly been proven that after topical [0006] Other treatments intended, not only for treating administration of the compositions of the present inven- the symptoms but also, to remove the calcium deposi- 45 tion, patients diagnose with calcific tendinitis and/or cal- tions are acetic acid iontophoresis (J. Rioja Toro et al., cific bursitis experience a quicker relief of symptoms as- Rehabilitation, 35(3), 166-170 (2001) and B. E. Leduc et sociated with these diseases and the calcium deposits al., Arch Phys Med Rehabil., 84(10),1523-7 (2003)), disappear after the treatment with said compositions. shock wave therapy (ESWT) (described for example by Therefore, the compositions for topical administration of MD. Po-Jung Pan et al., Arch. Phys. Med. Rehabil., 84, 50 theinvention provide an easyto apply and highly effective 988-994 (2003)) and puncturing-sucking the calcification alternative treatment of calcific tendinitis and/or calcific (described for example by C. Parlier-Cuau et al., Clin. bursitis. North. Am. 36, 589-96 (1998)). If the methods mentioned [0012] The present invention further provides stable above are not successful, surgical treatment would be compositions with good topical penetration and without considered by means of extirpating the calcium deposi- 55 causing any skin irritation for the local treatment of calcific tion with arthroscopy or with a surgical procedure. tendinitis and/or calcific bursitis. [0007] However, these treatments may have unde- [0013] Therefore, in a first aspect, the present inven- sired side effects or entail certain risks. For example, tion relates to a pharmaceutical composition for topical

2 3 EP 2 735 309 A1 4 administration comprising acetic acid for the treatment num majorana, Salix alba, Silybum marianum, Tanace- of calcific tendinitis and/or calcific bursitis. tum parthenium, Uncaria guianensis and mixtures there- [0014] In a second aspect, the present invention also of, among others. Preferably, the compound, extract or relates to a pharmaceutical composition for topical ad- oil with or anti-inflammatory activity is arnica ministration comprising acetic acid for the treatment, pre- 5 or a combination of betamethasone and hydrocortisone. vention or prophylaxis of inflammation or pain associated [0019] Additionally, the pharmaceutical composition of with calcific tendinitis and/or calcific bursitis. the present invention can further comprise a dermato- [0015] In a particular embodiment of the invention, the logically acceptable agent, i.e., a skin compatible agent. pharmaceutical composition described herein above can This dermatologically acceptable agent can preferably further includes a percutaneous absorption promoting 10 be presented in all pharmaceutical dosage forms normal- agent, such as for example and without limitation, urea, ly used for topical application, for example and without Aloe Vera, surfactants, azone (1-dodecylazacyclohep- limitation, in the form of an aqueous, hydroalcoholic or tan-2-one), ethoxydiglycol, propylene glycol or polyeth- oily solution, an oil-in-water or water-in-oil emulsion, or ylene glycol, among others. Preferably, the percutane- multiple emulsions, an aqueous or oily gel emulsion, an ous absorption promoting agent is urea. 15 emulsion of a liquid anhydrous product, an emulsion of [0016] In a preferred embodiment of the invention, the an oil dispersion in an aqueous phase with the aid of pharmaceutical composition for topical administration spheroids (such as nanospheres, nanocapsules and lipid comprises approximately between 17% and 22% by vesicles, for example), silicone in water emulsions, mi- weight of acetic acid with respect to the total weight of croemulsions, pastes, milks, balsams, foams, lotions, hy- the composition. 20 droalcoholic solutions, hydroglycolic solutions, liniment, [0017] In another preferred embodiment, the pharma- serums, polysaccharide films, salves, fatty salves, ceutical composition for topical administration of the mousses, ointments, gels, cream gels, foam gels, emul- present invention comprises approximately between 3% sion-gels and solutions. The preparation and composi- and 5% by weight of a percutaneous absorption promot- tion of such dermatologically and/or cosmetically accept- ing agent with respect to the total weight of the compo- 25 able agents for topical use are already known in the art sition. Preferably, said percutaneous absorption promot- (see, for example, WO 98/00168 A1, pages 8-15 or pat- ing agent is urea. ent US 5.681.849). Preferably, this dermatologically ac- [0018] Likewise, the pharmaceutical composition of ceptable agent is in the form of a cream, an ointment, a the present invention can further comprise at least one salve or an emulsion. compound, extract or oil with analgesic or anti-inflamma- 30 [0020] The dermatologically acceptable agent com- tory activity, such as for example and without limitation, prised by the pharmaceutical composition of the present hydrocortisone, clobetasol, dexamethasone, pred- invention is preferably an oil-in-water-type emulsion. nisone, paracetamol, acetylsalicylic acid, amoxiprin, Preferably, said dermatologically acceptable agent in the benorilate, betamethasone, choline salicylate, diflunisal, form of an oil-in-water-type emulsion can comprises, at faislamine, methyl salicylate, magnesium salicylate, sal- 35 least and without limitation, an aqueous phase, an oily salate, diclofenac, aceclofenac, acemetacin, bromfenac, phase, emulsifiers, solvents (including water and alco- etodolac, indometacin, sulindac, tolmetin, ibuprofen, car- hol), viscosity regulating agents, surface-active agents, profen, fenbufen, fenprofen, flurbiprofen, ketoprofen, dispersants, surfactants, thickeners (for example car- ketorolac, loxoprofen, naproxen, oxaprozin, tiaprofenic bomers (polyacrylic acid derivatives)) or a structuring acid, suprofen, mefenamic acid, meclofenamate,40 agent. meclofenamic acid, nabumetone, phenylbutazone, az- [0021] Any topically acceptable oil or lipid can be used apropazone, metamizole, oxyphenbutazone, sulfinpyra- for the oily phase (see for example, the "fatty phase con- zone, piroxicam, lornoxicam, meloxicam, tenoxicam, stituents" cited in patent US 4,917,886, columns 4-5). celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, The oily phase preferably comprises oily materials such valdecoxib, nimesulide, licofelone, oxycodone, hydroco- 45 as natural or synthetic oils selected from mineral oils, done, heroin, pethidine, tramadol, buprenorphine, ben- plant oils and animal oils, fats and waxes, fatty acid es- zocaine, lidocaine, chloroprocaine, tetracaine, procaine, ters, fatty alcohols, fatty acids and mixtures thereof. The tricyclic antidepressants, amitriptyline, carbamazepine, oily phase can also comprise active fat soluble substanc- gabapentin, pregabalin, bisabolol, pantenol, biotin, dis- es for skin care. odium lauriminodipropionate tocopheryl phosphate,50 [0022] The aqueous phase can also include water mis- ciclopirox olamine, nordihydroguaiaretic acid, Arnica, cible organic solvents, stabilizing agents, or any water madecassoside, echinacin, amaranth seed oil, sandal- soluble or water dispersible compound compatible with wood oil, peach leave extract, aloe vera extract, Artem- an aqueous phase, such as gelling agents, film-forming isia vulgaris, Asarum maximum, Calendula officinalis, polymers, thickeners, surface-active agents and the mix- capsicum, Centipeda cunninghamii, Chamomilla recuti- 55 tures thereof. ta, Crinum asiaticum, Hamamelis virginiana, Harpago- [0023] In a preferred embodiment of the invention, the phytum procumbens, Hypericum perforatum, Lilium can- pharmaceutical composition for topical administration didum, Malva sylvestris, Melaleuca alternifolia, Origa- comprises acetic acid and a dermatologically acceptable

3 5 EP 2 735 309 A1 6 agent. Preferably, said dermatologically acceptable ple in the form of an emulsion, can be applied once, twice agent is an emulsion. More preferably, the dermatologi- or three times a day. cally acceptable agent is an oil-in-water-type emulsion. [0032] Preferably, the pharmaceutical compositions [0024] The dermatologically acceptable agent in the for topical administration of the invention, for example in form of an emulsion can additionally contain excipients, 5 the form of an emulsion, can be applied on the skin for adjuvants and other dermatological additives, such as a time period between 20 days to 40 days. Preferably, preservatives/antioxidants, fat/oil substances, water, or- the pharmaceutical compositions for topical administra- ganic solvents, silicones, thickeners, softeners, emulsi- tion in the form of an emulsion of the present invention fiers, anti-foaming agents, moisturizers, fragrances, sur- are applied on the skin once a day for a minimum time face-active agents, fillers, sequestering agents, anionic, 10 period of 35 days. cationic, non-ionic or amphoteric polymers or the mix- [0033] The present invention also relates to the med- tures thereof, propellants, acidifying or basifying agents, ical and pharmaceutical uses of a topical composition dyes, colorings, pigments or nanopigments, or any other comprising acetic acid. Additionally, the present inven- ingredient normally formulated in dermatological or cos- tion also relates to the medical and pharmaceutical uses metic compositions and products. 15 of a topical composition comprising acetic acid, a percu- [0025] In a preferred embodiment, the pharmaceutical taneous absorption promoting agent and a compound, composition in the form of an emulsion for topical use of extract or oil with analgesic and/or anti-inflammatory ac- the present invention comprises between 30% and 55% tivity. Preferably, said topical composition is in the form by weight of a dermatologically acceptable agent with of an emulsion. respect to the total weight of the composition. Said emul- 20 [0034] In the context of the present invention, calcific sion is preferably in the form of an oil-in-water emulsion. bursitis and/or calcific tendinitis include, for example and [0026] In another preferred embodiment, the pharma- without limitation: calcific tendinitis/tendonitis of the ceutical composition for topical administration in the form shoulder, calcific tendinitis of the supraspinatus, calcific of an emulsion of the present invention comprises acetic subdeltoid bursitis, calcific , calcific acid, urea and arnica. Preferably, said emulsion is in the 25 , bilateral calcific bursitis in the glenoid form of an oil-in-water emulsion. insertion of the long tendon of the bicep, calcific subac- [0027] In another preferred embodiment, the pharma- romiodeltoid tendinitis, calcific subacromiodeltoid bursi- ceutical composition for topical administration in the form tis, calcific tendinitis of the , calcifying tro- of an emulsion of the present invention comprises acetic chanteritis of the hip, calcifying tendinitis of the sole of acid, urea, hydrocortisone acetate and betamethasone. 30 the foot, calcific tendinitis of the Achilles tendon and ep- Preferably, said emulsion is in the form of an oil-in-water icondilitis (). emulsion. [0035] The term "emulsion" refers to a mixture of im- [0028] Said emulsions can, for example, be obtained miscible liquids, where a liquid (the dispersed phase) is by means of a method comprising dissolving the acetic dispersed in another liquid (the continuous or dispersing acid and optionally other components, such as for exam- 35 phase). The resulting mixture has the macroscopic ap- ple, a percutaneous absorption promoting agent and a pearance of a single distinct phase created by means of compound, extract or oil with analgesic or anti-inflamma- mixing the two immiscible phases. tory activity, in water. This mixture can then be emulsified [0036] As used in this specification, the term "oil/water with the dermatologically acceptable agent into an emul- emulsion", also called a "O/W emulsion" or "oil-in-water- sion. Said dermatologically acceptable agent is prefera- 40 type emulsion", relates to emulsions in which the oily bly an oil-in-water emulsion. phase is dispersed in the aqueous phase, which is the [0029] This composition in the form of an oil-in-water continuous phase. In the present invention, the oil-in-wa- emulsion can be more or less fluid and can have the ter emulsion acts as a pharmaceutical vehicle. appearance of a white or colored cream, of an ointment, [0037] As used herein, the term "active ingredient", of a cream, of a salve, of a milk, of a lotion, of a serum, 45 "active substance", "pharmaceutically active substance", of a paste, of a foam, or of a gel. Optionally, it can be or "pharmaceutically active ingredient" refers to any com- applied on skin in the form of an aerosol or by means of ponent which potentially provides a pharmacological ac- a patch. Likewise, it can be presented in solid form, for tivity or another different effect in diagnosing, curing, al- example in the form of a bar. leviating, treating, or preventing a disease, or which af- [0030] The pharmaceutical composition provided by 50 fects the structure or function of the human body or body this invention is useful for administration or application of other animals. on the body of a mammal, preferably a human. [0031] The application frequency of the pharmaceuti- Brief Description of the Drawings cal composition can vary greatly depending on several factors, such as the severity of the disorder and/or pa- 55 [0038] thology, sex, age, weight and condition or needs of each subject. Preferably, the pharmaceutical composition for Figure 1 shows an X-ray of a patient diagnosed with topical administration of the present invention, for exam- a calcificationin the supraspinatus tendon before be-

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ing subjected to the treatment of the present inven- tion. Materials % weight

Figure 2 shows an X-ray of a patient diagnosed with Glacial acetic acid 21.18 % a calcification in the supraspinatus tendon after be- 5 Urea 4.28 % ing subjected to the treatment of the present inven- Arnica 18.75 % tion. W/O emulsion 52.64 % Detailed Description of the Invention Distilled water 3.15 % 10 [0039] The following examples serve to illustrate the nature of the present invention. These examples are in- [0044] The O/W emulsion is used already prepared cluded only for illustrative purposes and must not be in- and it comprises: water, isopropyl palmitate, glyceryl terpreted as limiting the invention claimed. stearate, paraffinum liquidum, glycerin, Steareth-21, mi- [0040] Two topical pharmaceutical compositions, their 15 crocrystalline wax, Steareth-2, Peg-8 distearate, dime- method of preparation and the results obtained in the thicone, benzyl alcohol, lanolyn alcohol and phenoxy eth- treatment of calcific tendinitis and/or bursitis are de- anol. scribed below. Example 3: Preparation of compositions (I) and (II). Example 1: Composition (I) in the form of a cream with 20 hydrocortisone acetate and betamethasone. [0045] Compositions (I) and (II) are prepared accord- ing to the following method. [0041] The following table shows the different compo- [0046] The amounts of urea and arnica (arnica flower nents of the composition (I) wherein the percutaneous glycolic extract) specified above for composition (I) or of absorption promoting agent is urea, the compounds, ex- 25 urea and hydrocortisone acetate/betamethasone for tracts or oils with analgesic and/or anti-inflammatory ac- composition (II)are addedto a suitable amountof distilled tivity are hydrocortisone acetate and betamethasone, water at 37°C stirring at approximately 500-1000 rpm. and the dermatologically and/or cosmetically acceptable The mixture is left to settle in a water bath at 40°C. agent is an oil-in-water (O/W) emulsion. [0047] Separately, the O/W emulsion is heated be- 30 tween 37-50°C with stirring at approximately 1100-2600 Materials % weight rpm for 5 minutes; after this time the previously prepared aqueous mixture is added at 40°C to the O/W emulsion Glacial Acetic acid 21.04 % stirring at 500-1000 rpm and maintaining the temperature Urea 4.28 % between 37-50°C. 35 [0048] Finally, acetic acid is added to the cream thus Hydrocortisone acetate 3.57 % prepared stirring at 500-1000 rpm and maintaining the Betamethasone 0.21 % temperature at 37-50°C. O/W emulsion 35.20 % Results Distilled water 35.70 % 40 [0049] The cream of composition (II) was applied lo- cally on a patient diagnosed with calcification in the su- [0042] The O/W emulsion is used already prepared praspinatus tendon of the right shoulder, as shown in the and comprises: water, isopropyl palmitate, glyceryl stea- X-ray of Figure 1. The cream was applied daily on the rate, paraffinum liquidum, glycerin, Steareth-21, microc- 45 affected area for a period comprised between 30 and 40 rystalline wax, Steareth-2, Peg-8 distearate, dime- days. Heat was locally applied by means of an electric thicone, benzyl alcohol, lanolyn alcohol and phenoxy eth- pad for 20 minutes after each application of composition anol. (II). [0050] Composition (II) showed active ingredient (ace- Example 2: Composition (II) in the form of a cream with 50 tic acid) skin penetration without skin irritation. arnica. [0051] Figure 2 shows an X-ray of the same patient after the treatment with composition (II) wherein a com- [0043] In composition (II), the percutaneous absorp- plete disappearance of the calcification and the integrity tion promoting agent is urea, the compound, extract or of the tendon can be seen. oil with analgesic and/or anti-inflammatory activity is ar- 55 nica, and the dermatologically and/or cosmetically ac- ceptable agent is an oil-in-water (O/W) emulsion.

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Claims itriptyline, carbamazepine, gabapentin, pregabalin, bisabolol, pantenol, biotin, disodium lauriminodipro- 1. A pharmaceutical composition for topical adminis- pionate tocopheryl phosphate, ciclopirox olamine, tration comprising acetic acid for use in the treatment nordihydroguaiaretic acid, madecassoside, echina- of calcific tendinitis and/or calcific bursitis. 5 cin, amaranth seed oil, sandalwood oil, peach leaf extract, Aloe vera, Arnica,Artemisia vulgaris, 2. A pharmaceutical composition for topical adminis- Asarum maximum, Calendula officinalis, capsicum, tration comprising acetic acid for use in the treat- Centipeda cunninghamii, Chamomilla recutita, ment, prevention or prophylaxis of inflammation or Crinum asiaticum, Hamamelis virginiana, Harpago- pain associated with calcific tendinitis and/or calcific 10 phytum procumbens, Hypericum perforatum, Lilium bursitis. candidum, Malva sylvestris, Melaleuca alternifolia, Origanum majorana, Salix alba, Silybum marianum, 3. The pharmaceutical composition according to claim Tanacetum parthenium, Uncaria guianensis and 1 or 2, wherein the pharmaceutical composition fur- mixtures thereof. ther comprises a percutaneous absorption promot- 15 ing agent selected from the group consisting of urea, 8. The pharmaceutical composition according to claim Aloe Vera, surfactants, azone (1-dodecylazacy- 7, wherein the compound, extract or oil with analge- cloheptan-2-one), ethoxydiglycol, propylene glycol sic or anti-inflammatory activity is arnica. and polyethylene glycol. 20 9. The pharmaceutical composition according to claim 4. The pharmaceutical composition according to claim 7, wherein the compound, extract or oil with analge- 3, wherein the percutaneous absorption promoting sic or anti-inflammatory activity is betamethasone, agent is urea. hydrocortisone or a mixture thereof.

5. The pharmaceutical composition according to any 25 10. The pharmaceutical composition according to any one of claims 1 to 4, wherein the percentage of acetic one of claims 1 to 9, wherein the pharmaceutical acid is between 17% and 22% by weight with respect composition further comprises a dermatologically to the total weight of the composition. acceptable agent selected from the group consisting of an aqueous solution, a hydroalcoholic solution, an 6. The pharmaceutical composition according to any 30 oily solution, an oil-in-water emulsion, a water-in-oil one of claims 3 to 5, wherein the percentage of per- emulsion, a multiple emulsion, an aqueous gel emul- cutaneous absorption promoting agent is between sion, an oily gel emulsion, an emulsion of a liquid 3% and 5% by weight with respect to the total weight anhydrous product, an emulsion of an oil dispersion of the composition. in an aqueous phase with the aid of spheroids, a 35 silicone in water emulsion, microemulsions, pastes, 7. The pharmaceutical composition according to any milks, balsams, foams, lotions, hydroalcoholic solu- one of claims 1 to 6, wherein the pharmaceutical tions, hydroglycolic solutions, liniment, serums, composition further comprises at least one com- polysaccharide films, salves, fatty salves, mousses, pound, extract or oil with analgesic or anti-inflamma- ointments, gels, cream gels, foam gels, an emulsion- tory activity selected from the group consisting of 40 gels and solutions. hydrocortisone, clobetasol, dexamethasone, pred- nisone, paracetamol, acetylsalicylic acid, amoxiprin, 11. The pharmaceutical composition according to claim benorilate, betamethasone, choline salicylate, diflu- 10, wherein the dermatologically acceptable agent nisal, faislamine, methyl salicylate, magnesium sal- is an oil-in-water emulsion. icylate, salsalate, diclofenac, aceclofenac, acemet- 45 acin, bromfenac, etodolac, indometacin, sulindac, 12. The pharmaceutical composition according to claim tolmetin, ibuprofen, carprofen, fenbufen, fenprofen, 10 or 11, wherein the percentage of dermatologically flurbiprofen, ketoprofen, ketorolac, loxoprofen, acceptable agent is between 30% and 55% by naproxen, oxaprozin, tiaprofenic acid, suprofen, weight with respect to the total weight of the compo- mefenamic acid, meclofenamate, meclofenamic ac- 50 sition. id, nabumetone, phenylbutazone, azapropazone, metamizole, oxyphenbutazone, sulfinpyrazone, 13. An emulsion comprising the pharmaceutical compo- piroxicam, lornoxicam, meloxicam, tenoxicam, sition defined in any one of claims 1 to 12. celecoxib, etoricoxib, lumiracoxib, parecoxib, ro- fecoxib, valdecoxib, nimesulide, licofelone, oxyco- 55 14. A cream comprising the pharmaceutical composition done, hydrocodone, heroin, pethidine, tramadol, bu- defined in any one of claims 1 to 12. prenorphine, benzocaine, lidocaine, chloroprocaine, tetracaine, procaine, tricyclic antidepressants, am-

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• WO 9800168 A1 [0019] • US 4917886 A [0021] • US 5681849 A [0019]

Non-patent literature cited in the description

• FAURE G. et al. Ann. Rheum. Dis., 1983, vol. 42, • B. E. LEDUC et al. Arch. Phys. Med. Rehabil., 2003, 49-53 [0003] vol. 84 (10), 1523-7 [0007] • J. RIOJA TORO et al. Rehabilitation, 2001, vol. 35 • C. D. CICCONE et al. Physical Therapy, 2003, vol. (3), 166-170 [0006] 83 (1), 68-74 [0007] • B. E. LEDUC et al. Arch Phys Med Rehabil., 2003, • R. SISTERMANN et al. Z. Orthop lhre Grenzgeb, vol. 84 (10), 1523-7 [0006] 1998, vol. 136, 175-81 [0007] • PO-JUNG PAN et al. Arch. Phys. Med. Rehabil., • M. LOEW et al. J. Shoulder Elbow Sur., 1995, vol. 4, 2003, vol. 84, 988-994 [0006] 101-106 [0007] • C. PARLIER-CUAU et al. Clin. North. Am., 1998, vol. • RJ. MCKENDRY et al. J. Rheumatol., 1982, vol. 9, 36, 589-96 [0006] 75-80 [0007] • M. PERRON et al. Arch. Phys. Med. Rehabil., 1997, vol. 78 (4), 379-84 [0007]

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