Aqueous Clear Solutions of Fluocinolone Acetonide for Treatment - DocsLib

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(11) EP 2 366 408 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 47/10 (2006.01) A61K 47/12 (2006.01) 18.07.2012 Bulletin 2012/29 A61K 47/14 (2006.01) A61K 47/32 (2006.01) A61K 47/38 (2006.01) A61K 9/00 (2006.01) (2006.01) (21) Application number: 10155005.1 A61K 31/58

(22) Date of filing: 01.03.2010

(54) Aqueous clear solutions of fluocinolone acetonide for treatment of otic inflammation Wässrige klare Lösungen aus Fluocinolon-Acetonid zur Behandlung von Ohrentzündungen Solutions claires aqueuses d’acétonide de fluocinolone pour le traitement de l’inflammation otique

(84) Designated Contracting States: • Izquierdo Torres, Francisca AT BE BG CH CY CZ DE DK EE ES FI FR GB GR E-08950 HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL Esplugues de LLobregat - Barcelona (ES) PT RO SE SI SK SM TR (74) Representative: ABG Patentes, S.L. (43) Date of publication of application: Avenida de Burgos, 16D 21.09.2011 Bulletin 2011/38 Edificio Euromor 28036 Madrid (ES) (73) Proprietor: Laboratorios SALVAT, S.A. 08950 Esplugues de Llobregat, Barcelona (ES) (56) References cited: EP-A1- 0 995 435 DE-A1- 2 515 594 (72) Inventors: GB-A- 1 013 180 GB-A- 1 133 800 • Ruiz i Pol, Jaume GB-A- 1 411 432 US-A1- 2009 325 938 E-08950, US-A1- 2010 036 000 Esplugues de LLobregat-Barcelona (ES)

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 366 408 B1

Printed by Jouve, 75001 PARIS (FR) EP 2 366 408 B1

Description

[0001] The present invention relates to compositions of Fluocinolone Acetonide as anti-inflammatory active pharmaceutical ingredient, for use in the treatment of otic inflammation, optionally accompanied by bacterial infection. 5 BACKGROUND ART

[0002] Fluocinolone Acetonide is an anti-inflammatory corticosteroid successfully used for topical treatment of otic inflammation. It is known in combination with an antibacterial and an antiseptic for treatment of external or middle ear 10 infections (cf. e.g. US 20090111780 A1). [0003] Fluocinolone Acetonide (a 6,9-difluoro- 16,17-acetonide corticosteroid) is classified as high to medium potency anti-inflammatory agent depending on the concentration and the vehicle used. The 9-F group increases glucocorticoid activity and prevents metabolic oxidation of the 11- OH group (cf. e.g. T.L. Lemke and D.A. Williams, "Foye’s Principles of Medicinal Chemistry", Wolters Kluwer 2007, 6th ed., p. 902). 15 [0004] Fluocinolone Acetonide is virtually insoluble in water. It is actually more insoluble than other corticosteroids (e.g. Dexamethasone or Hydrocortisone) that are also used for similar purposes. The acetonide (ketal) moiety at the 16,17-position of fluocinolone provides potency as topical anti-inflammatory agent as it enhances lipophilicity (ibid, p. 895), but consequently reduces solubility. In fact, otic drops containing Fluocinolone Acetonide are organic solutions (e.g. otic oil drops commercialized by Hill Dermaceuticals) or aqueous- organic suspensions (e.g. the aqueous suspension 20 preparations described in EP 1312356 A1). Otic drops containing Fluocinolone Acetonide and Ciprofloxacin are on the market in the form of aqueous- organic composition containing preservatives and less than 75% of water (e.g. otic drops commercialized by Salvat in Spain for treatment of external otitis). [0005] Examples of disorders that entail otic inflammation are eczematoid external otitis, keloids, granular myringitis, bullous myringitis or sudden deafness. 25 [0006] Examples of disorders that entail otic inflammation accompanied by bacterial infection are diffuse external otitis (swimmers’s ear), localized external otitis (forunculosis), traumatic tympanic membrane perforations, herpes zoster oticus (Ramsay Hunt syndrome), otitis media with effusión (OME, also called serous or secretory otitis media (SOM) or glue ear), otorrhea through tympanostomy tubes, acute otitis media with tympanostomy tubes (AOMT), acute otitis media (AOM) or chronic suppurative otitis media (CSOM). 30 [0007] In some cases, the presence in otic drops of solvents different from water and/or preservatives entails some adverse effects, such as allergic responses or irritation (cf. e.g. J. Coloe and M.J. Zirwas, "Allergens in corticosteroid vehicles", Dermatitis 2008, vol. 19(1), pp. 38-42). Also, some concerns about the suitability of using preservatives such as parabens for topical application have been raised due to their potential toxicity (cf. e.g. P.D. Darbre and P.W. Harvey, "Paraben esters: review of recent studies of endocrine toxicity, absorption, esterase and human exposure, and discussion 35 of potential human health risks", J Appl Toxicol. 2008, vol. 28(5), pp. 561-578). Thus, it is highly desirable to provide improved pharmaceutical compositions with vehicles of higher water content for treatment of otic inflammation, especially in cases where it is accompanied by bacterial infection. [0008] US 2010/036000 A1 discloses the treatment of several otic diseases with antimicrobials and possibly additional therapeutic agents in sterile preparations to be administered locally GB 1 411 432 A discloses preparations comprising 40 urea and surfactants (where the surfactants also act as viscosifiers), as a vehicle for e.g. fluocinolone acetonide (FA) in dermatologic compositions.

SUMMARY OF THE INVENTION

45 [0009] The present invention provides a pharmaceutical otic sterile preservative-free composition in the form of a clear aqueous solution of Fluocinolone Acetonide that comprises more than 90% water (all percentages are w/v), and which is suitable for administration as drops from a single-dose container (obviously, although not specially preferred, administration from a multi-dose container would also be possible). [0010] Dropping an otic liquid pharmaceutical composition from single-dose containers has many advantages. For 50 example, it permits the administration of a precise dose of the composition. Another advantage is that, since a new container is open each time, the administered composition is always sterile, thus avoiding the possibility of contamination by microorganisms or by body secretions. Besides the advantage of greater hygiene, the single-dose container is also more pleasant to use and manipulate than multi-dose containers. [0011] However, to be suitable for dropping from sterile single- dose containers, an otic composition must fulfill several 55 requirements, which appeared to be difficult in the case of a highly insoluble active pharmaceutical ingredient, such as Fluocinolone Acetonide. If, as customary, sterilization is to be done by filtration through a 0.22 Pm filter, the composition must be a clear solution, i.e. substantially free from particles in suspension. Besides, it is highly desirable that the soluti on is free from preservatives, such as methylparaben and propylparaben.

2 EP 2 366 408 B1

[0012] Inventors have found that it is appropriate to use a total amount of 0.5-4.0% of one or more nonionic surfactants with a hydrophilic-lipophilic balance (HLB) value between 14 and 18 to obtain a pharmaceutical otic sterile preservative- free composition in the form of a clear aqueous solution (i.e. substantially free from particles in suspension) of 0.01-0.10% of Fluocinolone Acetonide. In this composition, a total amount of 0.5-4.0% of one or more tonicity adjusting agents is 5 appropriate for adjusting tonicity, and a total amount of 0.05-1.00% of one or more viscosity increasing agents is appropriate for adjusting viscosity. The composition can optionally comprise an amount of one or more pH adjusting agents to adjust pH between 4.0 and 5.0. These excipients, in the mentioned amounts, also provide a pharmaceutical otic sterile preservative-free composition in the form of a clear aqueous solution in the case that Fluocinolone Acetonide is accompanied by 0.1-0.8% of Ciprofloxacin or a pharmaceutically acceptable salt thereof, this composition being useful when 10 otic inflammation is accompanied by bacterial infection. [0013] The pharmaceutical composition of the present invention shows a number of advantages. It is a clear aqueous solution substantially free from solid particles in suspension that can be sterilized by filtration without loss of active ingredient, which entails good dose reproducibility. It shows also good stability. This allows having a sterile preservative- free composition that can be contained in disposable single-dose containers for topical use in drop form. Also, lack of 15 preservatives and of non-aqueous solvents avoids the possible adverse effects that might cause these compounds. [0014] Pharmaceutically acceptable examples of nonionic surfactants with a HLB value between 14 and 18 include, but are not limited to sorbitan polyoxyethylene fatty acid derivatives; polyoxyethylene hydrogenated castor oil derivatives; polyoxyethylene fatty acid derivatives, polyoxyethylene-polyoxypropylene co-polymers and block-co-polymers.. [0015] In an embodiment of the present invention the pharmaceutically acceptable examples of nonionic surfactants 20 with a HLB value between 14 and 18 are selected from the group consisting of sorbitan polyoxyethylene fatty acid derivatives such as Polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), Polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), Polysorbate 60 (polyoxyethylene (20) sorbitan monostearate) and Polysorbate 80 (polyoxyethylene (20) sorbitan monooleate); polyoxyethylene hydrogenated castor oil derivatives such as polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene glycol (60) hydrogenated castor oil and polyoxyethylene glycol (40) hydrogen- 25 ated castor oil; polyoxyethylene fatty acid derivatives such as polyoxyethylene (20) stearate, polyoxyethylene (32) distearate, polyoxyethylene (20) oleate, polyoxyethylene (32) oleate and polyoxyethylene (32) dioleate; fatty alcohol ethox- ylates such as polyoxyethylene (20) oleyl alcohol, polyoxyethylene (20) stearyl alcohol and polyoxyethylene (20) cetearyl alcohol, polyoxyethylene-polyoxypropylene co-polymers and block- co-polymers. In a preferred embodiment the nonionic surfactant is Polysorbate 80. 30 [0016] In another embodiment of the present invention the pharmaceutically acceptable tonicity adjuster agents are selected from the group consisting of dextrose, glycerin, sorbitol, mannitol, xylitol, polyethylene glycol, propylene glycol, dextran or electrolytes such as potassium chloride, sodium chloride, calcium chloride, sodium phosphate, potassium phosphate, sodium bicarbonate, calcium carbonate and sodium lactate. In a preferred embodiment the tonicity adjuster agent is glycerin. 35 [0017] In still another embodiment of the present invention the pharmaceutically acceptable viscosity increasing agents are selected from the group consisting of polyvinylpirrolidone, such as Povidone K 25, Povidone K 30 and Povidone K 90F; polyvinyl alcohol, xanthan gum, guar gum, welan gum, tragacanth gum, ceratonia gum, agar, methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, polyethylene glycol, glycerin, carrageenan , sodium alginate, potassium al- 40 ginate, propylene glycol alginate, sodium hyaluronate, carbomers and maltodextrin. In a preferred embodiment the viscosity increasing agent is a polyvinylpirrolidone selected from Povidone K 25, Povidone K 30 and Povidone K 90F. In a particularly preferred embodiment the viscosity increasing agent is Povidone K 90F. [0018] Optionally, appropriate pH adjusting agents can be added, as solids or as aqueous solutions. Pharmaceutically acceptable examples of pH adjusting agents include, but are not limited to, citric acid and salts thereof; tartaric acid and 45 salts thereof, phosphoric acid and salts thereof, carbonic acid and salts thereof, lactic acid and salts thereof, acetic acid and salts thereof, sulphuric acid and salts thereof, boric acid and salts thereof, maleic acid and salts thereof, succinic acid and salts thereof; hydrochloric acid, nitric acid, sodium hydroxide, potassium hydroxide, triethanolamine, diisopropanolamine or mixtures thereof. [0019] In another embodiment of the present invention the pharmaceutically acceptable pH adjusting agents are 50 selected from the group consisting of citric acid and salts thereof, such as sodium citrate, potassium citrate, calcium citrate and lithium citrate; tartaric acid and salts thereof, such as sodium tartrate, potassium tartrate, calcium tartrate and lithium tartrate; phosphoric acid and salts thereof, such as sodium dihydrogenphosphate and sodium monohydrogenphosphate, lithium phosphate, potassium phosphate and calcium phosphate; carbonic acid and salts thereof, such as sodium carbonate and sodium hydrogencarbonate; lactic acid and salts thereof, such as sodium lactate, potassium 55 lactate and calcium lactate; acetic acid and salts thereof, such as sodium acetate, potassium acetate and calcium acetate; sulphuric acid and salts thereof, such as sodium sulphate and potassium sulphate; boric acid and salts thereof, such as sodium borate; maleic acid and salts thereof, such as lithium maleate, sodium maleate, potassium maleate and calcium maleate; succinic acid and salts thereof, such as lithium succinate, sodium succinate, potassium succinate and calcium

3 EP 2 366 408 B1

succinate; hydrochloric acid, nitric acid, sodium hydroxide, potassium hydroxide, triethanolamine, diisopropanolamine or mixtures thereof. [0020] In a preferred embodiment, the pharmaceutical composition comprises the following ingredients: 0.02-0.03% of Fluocinolone Acetonide, optionally accompanied by 0.2-0.4% of Ciprofloxacin or a pharmaceutically acceptable salt 5 thereof; 2-3% of Polysorbate 80; 2-3% of glycerin; 0.1-0.3% of Povidone K 90F; optionally, an amount of one or more pharmaceutically acceptable pH adjusting agent q.s. to adjust pH 4.0-5.0; and water In a preferred embodiment the composition consist exclusively of the above mentioned ingredients. [0021] In a particularly preferred embodiment, the pharmaceutical composition has the following composition: 0.025% of Fluocinolone Acetonide; 2.5% of Polysorbate 80; 2.4% of glycerin; 0.2% of Povidone K 90F; sodium lactate q.s. to 10 adjust pH 4.0-5.0 and water q.s. 100%. [0022] In a particularly preferred embodiment, the pharmaceutical composition has the following composition: 0.025% of Fluocinolone Acetonide, 0.349% of ciprofloxacin HCl; 2.5% of Polysorbate 80; 2.4% of glycerin; 0.2% of Povidone K 90F; and water q.s. 100%. [0023] In a preferred embodiment, the pharmaceutical composition is sterilized and contained in disposable single- 15 dose containers for topical use in drop form. Another aspect of the invention relates to a method for the prevention and/or treatment of an individual suffering from otic inflammation, optionally accompanied by bacterial infection, comprising the topical administration to the individual of a therapeutically effective amount of the pharmaceutical composition as described above. [0024] In particular, the otic inflammation is eczematoid external otitis, keloids, granular myringitis, bullous myringitis 20 or sudden deafness. [0025] In particular, the otic inflammation accompanied by bacterial infection is diffuse external otitis (swimmers’s ear), localized external otitis (forunculosis), traumatic tympanic membrane perforations, herpes zoster oticus (Ramsay Hunt syndrome), otitis media with effusión (OME, also called glue ear), otorrhea through tympanostomy tubes, acute otitis media with tympanostomy tubes (AOMT), acute otitis media (AOM) or chronic suppurative otitis media (CSOM). 25 [0026] Another aspect of the invention refers to a pharmaceutical composition as described above for its use as a medicament. In particular, its use is for the prevention and/or treatment of otic inflammation, optionally accompanied by bacterial infection. [0027] Another aspect of the invention is the use of the pharmaceutical composition as described above for the preparation of a medicament for the prevention and/or treatment of otic inflammation, optionally accompanied by bacterial 30 infection. [0028] Another aspect of the invention is a method for the prevention and/or treatment of an individual suffering from otic inflammation, optionally accompanied by bacterial infection, comprising the topical administration to the individual of a therapeutically effective amount of a pharmaceutical composition described above. [0029] In one embodiment the otic inflammation is eczematoid external otitis, keloids, granular myringitis, bullous 35 myringitis or sudden deafness. [0030] In another embodiment the otic inflammation accompanied by bacterial infection is diffuse external otitis, localized external otitis, traumatic tympanic membrane perforations, herpes zoster oticus, otitis media with effusión, otorrhea through tympanostomy tubes, acute otitis media with tympanostomy tubes, acute otitis media or chronic suppurative otitis media. 40 [0031] Throughout the description and claims the term "comprise" and variations of the word, such as "comprising", is not intended to exclude other technical features, additives or components. [0032] Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention.

45 EXAMPLES

[0033] The following examples are provided by way of illustration, and are not intended to be limiting of the present invention.

50 Example 1: Aqueous solution comprising Fluocinolone

[0034]

Ingredients Amount (w/v) 55 Fluocinolone Acetonide 0.025% Polysorbate 80 2.500%

4 EP 2 366 408 B1

(continued)

Ingredients Amount (w/v) Povidone K 90F 0.200% 5 Glycerin 2.400% Lactic acid/NaOH q.s. to adjust pH 4.0-5.0 Water q.s. to 100%

10 Example 2: Aqueous solution comprising Fluocinolone + Ciprofloxacin

[0035]

15 Ingredients Amount Fluocinolone Acetonide 0.025% Ciprofloxacin HCl 0.349% Polysorbate 80 2.500% 20 Povidone K 90F 0.200% Glycerin 2.400% Water q.s. to 100% 25

Example 3: Aqueous solution comprising Fluocinolone

[0036]

30 Ingredients Amount Fluocinolone Acetonide 0.025% PEG-60 hydrogenated castor oil 2.500%

35 Povidone K 90F 0.200% Glycerin 2.400% Lactic acid/NaOH q.s. to adjust pH 4.0-5.0 Water q.s. to 100% 40

Example 4: Aqueous solution comprising Fluocinolone + Ciprofloxacin

[0037] 45 Ingredients Amount Fluocinolone Acetonide 0.025% Ciprofloxacin HCl 0.349% 50 Polysorbate 20 2.500% Sodium carboxymethylcellulose 0.500% Glycerin 2.400%

55 Lactic acid/NaOH q.s. to adjust pH 4.0-5.0 Water q.s. to 100%

5 EP 2 366 408 B1

Example 5: Aqueous solution comprising Fluocinolone

[0038]

5 Ingredients Amount Fluocinolone Acetonide 0.025% Ceteareth-20 2.500% Povidone K 90F 0.200% 10 Glycerin 1.000% Sodium chloride 0.500% Lactic acid/NaOH q.s. to adjust pH 4.0-5.0 15 Water q.s. to 100%

Example 6: Absence of solid particles in suspension

20 [0039] Concentrations of active ingredient in two batches of a pharmaceutical composition comprising Fluocinolone Acetonide and Ciprofloxacin were measured before and after filtration to confirm the absence of active particles in suspension that could be retained in the 0.22 Pm filter leading to a loss of active ingredient.

Batch 1 25 [0040]

Active ingredient Before filtration After filtration Concentration % of theoretical Concentration % of theoretical 30 Ciprofloxacin HCl 0.342% 98.0% 0.341% 97.7% Fluocinolone Acetonide 0.025% 100.0% 0.025% 100.0%

35 Batch 2

[0041]

Active ingredient Before filtration After filtration 40 Concentration % of theoretical Concentration % of theoretical Ciprofloxacin HCl 0.342% 98.0% 0.342% 98.0% Fluocinolone Acetonide 0.025% 100.0% 0.025% 100.0%

45 Example 7: Absence of solid particles in suspension

[0042] Dynamic light scattering determinations of a pharmaceutical composition comprising Fluocinolone Acetonide and ciprofloxacin were carried out before and after filtration to confirm the absence of active particles in suspension that 50 could be retained in the 0.22 Pm filter leading to a loss of active ingredient.

Before filtration After filtration ZAve (nm) Poly. Index ZAve (nm) Poly. Index 55 11.933 0.177 11.326 0.184

6 EP 2 366 408 B1

Example 8: Absence of solid particles in suspension

[0043] Dynamic light scattering determinations of a pharmaceutical composition comprising Fluocinolone Acetonide were carried out before filtration to confirm the absence of active particles in suspension that could be retained in the 5 0.22 Pm filter leading to a loss of active ingredient.

Before filtration ZAve (nm) Poly. Index 10 9.276 0.152

Claims

15 1. A pharmaceutical otic sterile preservative-free composition in the form of a clear aqueous solution comprising the following ingredients, in w/v percentages:

(i) 0.01-0.10% of Fluocinolone Acetonide, optionally accompanied by 0.1-0.8% of Ciprofloxacin or a pharmaceutically acceptable salt thereof; 20 (ii) a total of 0.5-4.0% of one or more pharmaceutically acceptable nonionic surfactants with a hydrophilic- lipophilic balance (HLB) value between 14 and 18; (iii) a total of 0.5-4.0% of one or more pharmaceutically acceptable tonicity adjusting agents; (iv) a total of 0.05-1.00% of one or more pharmaceutically acceptable viscosity increasing agents; (v) optionally, an amount of one or more pharmaceutically acceptable pH adjusting agents in q.s. to adjust pH 25 4.0-5.0; and (vi) water

2. The pharmaceutical composition according to claim 1, wherein the one or more pharmaceutically acceptable nonionic surfactant is selected from the group consisting of Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 80, 30 polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene glycol (60) hydrogenated castor oil, polyoxyethylene glycol (40) hydrogenated castor oil, polyoxyethylene (20) stearate, polyoxyethylene (32) distearate, polyoxyethylene (20) oleate, polyoxyethylene (32) oleate, polyoxyethylene (32) dioleate, polyoxyethylene (20) oleyl alcohol, polyoxyethylene (20) stearyl alcohol, polyoxyethylene (20) cetearyl alcohol, polyoxyethylene-polyoxypropylene co-polymers, polyoxyethylene-polyoxypropylene co-polymers block-co-polymers, and mixtures thereof. 35 3. The pharmaceutical composition according to claim 2, wherein the pharmaceutically acceptable nonionic surfactant is Polysorbate 80.

4. The pharmaceutical composition according to any of claims 1 to 3, wherein the one or more pharmaceutically 40 acceptable tonicity adjuster agent is selected from the group consisting of dextrose, glycerin, sorbitol, mannitol, xylitol, polyethylene glycol, propylene glycol, dextran, potassium chloride, sodium chloride, calcium chloride, sodium phosphate, potassium phosphate, sodium bicarbonate, calcium carbonate, sodium lactate, and mixtures thereof.

5. The pharmaceutical composition according to claim 4, wherein the pharmaceutically acceptable tonicity adjuster 45 agent is glycerin.

6. The pharmaceutical composition according to any of claims 1 to 5, wherein the one or more pharmaceutically acceptable viscosity increasing agent is selected from the group consisting of polyvinylpirrolidone, polyvinyl alcohol, xanthan gum, guar gum, welan gum, tragacanth gum, ceratonia gum, agar, methylcellulose, ethylcellulose, hydrox- 50 yethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, polyethylene glycol, glycerin, carrageenan, sodium alginate, potassium alginate, propylene glycol alginate, sodium hyaluronate, carbomers, maltodextrin, and mixtures thereof.

7. The pharmaceutical composition according to claim 6, wherein the one or more pharmaceutically acceptable viscosity 55 increasing agent is a polyvinylpirrolidone selected from the group consisting of Povidone K 25, Povidone K 30, Povidone K 90F, and mixtures thereof.

7 EP 2 366 408 B1

8. The pharmaceutical composition according to claim 7, wherein the pharmaceutically acceptable viscosity increasing agent is Povidone K 90F.

9. The pharmaceutical composition according to any of claims 1 to 8, wherein the one or more pharmaceutically 5 acceptable pH adjusting agent is selected from the group consisting of citric acid, sodium citrate, potassium citrate, calcium citrate, lithium citrate, tartaric acid, sodium tartrate, potassium tartrate, calcium tartrate, lithium tartrate, phosphoric acid, sodium dihydrogenphosphate, sodium monohydrogenphosphate, lithium phosphate, potassium phosphate, calcium phosphate, sodium carbonate, sodium hydrogencarbonate, lactic acid, sodium lactate, potassium lactate, calcium lactate, acetic acid, sodium acetate, potassium acetate, calcium acetate, sulphuric acid, sodium 10 sulphate, potassium sulphate, boric acid, sodium borate, maleic acid, lithium maleate, sodium maleate, potassium maleate, calcium maleate, succinic acid, lithium succinate, sodium succinate, potassium succinate, calcium succinate, hydrochloric acid, nitric acid, sodium hydroxide, potassium hydroxide, triethanolamine, diisopropanolamine, and mixtures thereof.

15 10. The pharmaceutical composition according to claim 1, wherein the w/v percentages are as follows:

(i) 0.02-0.03% of Fluocinolone Acetonide, optionally accompanied by 0.2-0.4% of Ciprofloxacin or a pharmaceutically acceptable salt thereof; (ii) 2-3% of Polysorbate 80; 20 (iii) 2-3% of glycerin; (iv) 0.1-0.3% of Povidone K 90F; (v) optionally, an amount of one or more pharmaceutically acceptable pH adjusting agents in q.s. to adjust pH 4.0-5.0; and (vi) water. 25 11. The pharmaceutical composition according to any of claims 1 to 10, wherein the pharmaceutical composition is sterilized and contained in disposable single-dose containers for topical use in drop form.

12. A pharmaceutical composition as defined in any of claims 1 to 11 for use as a medicament. 30 13. The pharmaceutical composition according to claim 12, for use in the prevention and/or treatment of otic inflammation, optionally accompanied by bacterial infection.

14. The pharmaceutical composition according to claim 13, wherein the otic inflammation is eczematoid external otitis, 35 keloids, granular myringitis, bullous myringitis or sudden deafness.

15. The pharmaceutical composition according to claim 13, wherein the otic inflammation accompanied by bacterial infection is diffuse external otitis, localized external otitis, traumatic tympanic membrane perforations, herpes zoster oticus, otitis media with effusión, otorrhea through tympanostomy tubes, acute otitis media with tympanostomy 40 tubes, acute otitis media or chronic suppurative otitis media.

Patentansprüche

45 1. Pharmazeutische, sterile, konservierungsmittelfreie Zusammensetzung für das Ohr in Form einer klaren, wässrigen Lösung, umfassend die folgenden Bestandteile, in G/V-Anteilen:

(i) 0,01-0,10% Fluocinolonacetonit, gegebenenfalls zusammen mit 0,1-0,8% Ciprofloxacin oder einem seiner pharmazeutisch akzeptablen Salze; 50 (ii) insgesamt 0,5-4,0% eines oder mehrerer pharmazeutisch akzeptabler, nicht-ionischer Tenside mit einem hydrophilen-lipophilen Bilanz-(HLB)-Wert zwischen 14 und 18; (iii) insgesamt 0,5-4,0% eines oder mehrerer pharmazeutisch akzeptabler, tonizitätseinstellender Mittel; (iv) insgesamt 0,05-1,00% eines oder mehrerer pharmazeutisch akzeptabler, viskositätssteigernder Mittel; (v) gegebenenfalls eine Menge eines oder mehrerer pharmazeutisch akzeptabler, pH-einstellender Mittel in 55 q.s., um pH 4,0-5,0 einzustellen; und (vi) Wasser.

2. Pharmazeutische Zusammensetzung nach Anspruch 1, wobei das eine oder die mehreren pharmazeutisch akzep-

8 EP 2 366 408 B1

table (n) nicht-ionische(n) Tensid(e) ausgewählt ist/sind aus der Gruppe bestehend aus Polysorbat 20, Polysorbat 40, Polysorbat 60, Polysorbat 80, Polyoxyethylene-(60)-hydriertes Rizinusöl, Polyoxyethylenglykol-(60)-hydriertes Rizinusöl, Polyoxyethylenglykol-(40)-hydriertes Rizinusöl, Polyoxyethylen-(20)-stearat, Polyoxyethylen-(32)-di- stearat, Polyoxyethylen-(20)-oleat, Polyoxyethylen-(32)-oleat, Polyoxyethylen-(32)-dioleat, Polyoxyethy- 5 len-(20)-oleylalkohol, Polyoxyethylen-(20)-stearylalkohol, Polyoxyethylen-(20)-cetearylalkohol, Polyoxyethylen-polyoxypropylen-Copolymere, Polyoxyethylen-polyoxypropylen-Copolymere-Blockcopolymere, und Mischungen davon.

3. Pharmazeutische Zusammensetzung nach Anspruch 2, wobei das pharmazeutisch akzeptable, nicht- ionische Ten- 10 sid Polysorbat 80 ist.

4. Pharmazeutische Zusammensetzung nach einem der Ansprüche 1 bis 3, wobei das eine oder die mehreren pharmazeutisch akzeptable (n), tonizitätseinstellende (n) Mittel ausgewählt ist/sind aus der Gruppe bestehend aus Dex- trose, Glycerin, Sorbitol, Mannitol, Xylitol, Polyethylenglykol, Propylenglykol, Dextran, Kaliumchlorid, Natriumchlorid, 15 Calciumchlorid, Natriumphosphat, Kaliumphosphat, Natriumbicarbonat, Calciumcarbonat, Natriumlactat und Mi- schungen davon.

5. Pharmazeutische Zusammensetzung nach Anspruch 4, wobei das pharmazeutisch akzeptable, tonizitätseinstel- lende Mittel Glycerin ist. 20 6. Pharmazeutische Zusammensetzung nach einem der Ansprüche 1 bis 5, wobei das eine oder die mehreren pharmazeutisch akzeptable (n), viskositätssteigernde(n) Mittel ausgewählt ist/sind aus der Gruppe bestehend aus Po- lyvinylpyrrolidon, Polyvinylalkohol, Xanthan, Guargummi, Welangummi, Traganthgummi, Karobengummi, Agar, Me- thylcellulose, Ethylcellulose, Hydroxyethylcellulose, Hydroxyethylmethylcellulose, Hydroxypropylcellulose, Natrium- 25 carboxymethylcellulose, Calciumcarboxymethylcellulose, Polyethylenglykol, Glycerin, Carrageen, Natriumalginat, Kaliumalginat, Propylenglykolalginat, Natriumhyaluronat, Carbomere, Maltodextrin und Mischungen davon.

7. Pharmazeutische Zusammensetzung nach Anspruch 6, wobei das eine oder die mehreren pharmazeutisch akzeptable (n), viskositätssteigernde(n) Mittel ein Polyvinylpyrrolidon ausgewählt aus der Gruppe bestehend aus Povidon 30 K 25, Povidon K 30, Povidon K 90F und Mischungen davon ist.

8. Pharmazeutische Zusammensetzung nach Anspruch 7, wobei das pharmazeutisch akzeptable, viskositätssteigern- de Mittel Povidon K 90F ist.

35 9. Pharmazeutische Zusammensetzung nach einem der Ansprüche 1 bis 8, wobei das eine oder die mehreren pharmazeutisch akzeptable (n), pH-einstellende(n) Mittel ausgewählt ist/sind aus der Gruppe bestehend aus Zitronen- säure, Natriumcitrat, Kaliumcitrat, Calciumcitrat, Lithiumcitrat, Weinsäure, Natriumtartrat, Kaliumtartrat, Calciumtart- rat, Lithiumtartrat, Phosphorsäure, Natriumdihydrogenphosphat, Natriummonohydrogenphosphat, Lithiumphos- phat, Kaliumphosphat, Calciumphosphat, Natriumcarbonat, Natriumhydrogencarbonat, Milchsäure, Natriumlactat, 40 Kaliumlactat, Calciumlactat, Essigsäure, Natriumacetat, Kaliumacetat, Calciumacetat, Schwefelsäure, Natriumsul- fat, Kaliumsulfat, Borsäure, Natriumborat, Maleinsäure, Lithiummaleat, Natriummaleat, Kaliummaleat, Calciumma- leat, Bernsteinsäure, Lithiumsuccinat, Natriumsuccinat, Kaliumsuccinat, Calciumsuccinat, Salzsäure, Salpetersäu- re, Natriumhydroxid, Kaliumhydroxid, Triethanolamin, Diisopropanolamin und Mischungen davon.

45 10. Pharmazeutische Zusammensetzung nach Anspruch 1, wobei die G/V-Anteile die folgenden sind:

(i) 0,02-0,03% Fluocinolonacetonid, gegebenenfalls zusammen mit 0,2-0,4% Ciprofloxacin oder eines seiner pharmazeutisch akzeptablen Salze; (ii) 2-3% Polysorbat 80; 50 (iii)2-3% Glycerin; (iv) 0,1-0,3% Povidon K 90F; (v) gegebenenfalls eine Menge eines oder mehrerer pharmazeutisch akzeptabler, pH-einstellender Mittel in q.s., um den pH 4,0-5,0 einzustellen; sowie (vi) Wasser. 55 11. Pharmazeutische Zusammensetzung nach einem der Ansprüche 1 bis 10, wobei die pharmazeutische Zusammen- setzung sterilisiert wird und in Einweg-Einzeldosis-Behältern zur topischen Anwendung in Form von Tropfen ent- halten ist.

9 EP 2 366 408 B1

12. Pharmazeutische Zusammensetzung, wie in einem der Ansprüche 1 bis 11 definiert, zur Anwendung als ein Medi- kament.

13. Pharmazeutische Zusammensetzung nach Anspruch 12, zur Anwendung bei der Prävention und/ oder Behandlung 5 einer Ohrenentzündung, gegebenenfalls begleitet von einer bakteriellen Infektion.

14. Pharmazeutische Zusammensetzung nach Anspruch 13, wobei die Ohrenentzündung eine ekzematöse Otitis externa, Keloide, granuläre Myringitis, bullöse Myringitis oder ein Hörsturz ist.

10 15. Pharmazeutische Zusammensetzung nach Anspruch 13, wobei die Ohrenentzündung, begleitet von einer bakteriellen Infektion Otitis externa diffusa, lokalisierte Otitis externa, traumatische Trommelfellperforationen, Herpes Zoster oticus, Otitis media mit Effusion, Otorrhoe durch Paukenröhrchen, akute Otitis media mit Paukenröhrchen, akute Otitis media oder chronische, eitrige Otitis media ist.

15 Revendications

1. Composition pharmaceutique auriculaire stérile sans conservateurs sous la forme d’une solution aqueuse claire comprenant les ingrédients suivants, en pourcentages en p/v: 20 (i) de 0,01 à 0,10 % de fluocinolone acétonide, facultativement accompagné de 0,1 à 0,8 % de ciprofloxacine ou d’un sel pharmaceutiquement acceptable de celle-ci ; (ii) un total de 0,5 à 4,0 % d’un ou plusieurs tensioactifs non ioniques pharmaceutiquement acceptables avec une valeur d’équilibre hydrophile-lipophile (HLB) entre 14 et 18 ; 25 (iii) un total de 0,5 à 4,0 % d’un ou plusieurs agents ajustant la tonicité pharmaceutiquement acceptables ; (iv)un total de 0,05 à 1,00 % d’un ou plusieurs agents augmentant la viscosité pharmaceutiquement acceptables ; (v) facultativement, une quantité d’un ou plusieurs agents ajustant le pH pharmaceutiquement acceptables en quantité suffisante pour ajuster le pH à 4,0 à 5,0 ; et (vi) de l’eau. 30 2. Composition pharmaceutique selon la revendication 1, dans laquelle le ou les tensioactifs non ioniques pharmaceutiquement acceptables sont sélectionnés dans le groupe constitué par le Polysorbate 20, le Polysorbate 40, le Polysorbate 60, le Polysorbate 80, l’huile de ricin hydrogénée au polyoxyéthylène (60), l’huile de ricin hydrogénée au polyoxyéthylène glycol (60), l’huile de ricin hydrogénée au polyoxyéthylène glycol (40), le stéarate de polyoxyé- 35 thylène (20), le distéarate de polyoxyéthylène (32), l’oléate de polyoxyéthylène (20), l’oléate de polyoxyéthylène (32), le dioléate de polyoxyéthylène (32), l’alcool oléylique de polyoxyéthylène (20), l’alcool stéarylique de polyoxyé- thylène (20), l’alcool cétéarylique de polyoxyéthylène (20), les copolymères de polyoxyéthylène- polyoxypropylène, les copolymères à blocs de copolymères de polyoxyéthylène-polyoxypropylène, et des mélanges de ceux-ci.

40 3. Composition pharmaceutique selon la revendication 2, dans laquelle le tensioactif non ionique pharmaceutiquement acceptable est le Polysorbate 80.

4. Composition pharmaceutique selon l’une quelconque des revendications 1 à 3, dans laquelle le ou les agents ajustant la tonicité pharmaceutiquement acceptables sont sélectionnés dans le groupe constitué par le dextrose, 45 la glycérine, le sorbitol, le mannitol, le xylitol, le polyéthylène glycol, le propylène glycol, le dextran, le chlorure de potassium, le chlorure de sodium, le chlorure de calcium, le phosphate de sodium, le phosphate de potassium, le bicarbonate de sodium, le carbonate de calcium, le lactate de sodium, et des mélanges de ceux-ci.

5. Composition pharmaceutique selon la revendication 4, dans laquelle l’agent ajustant la tonicité pharmaceutiquement 50 acceptable est la glycérine.

6. Composition pharmaceutique selon l’une quelconque des revendications 1 à 5, dans laquelle le ou les agents augmentant la viscosité pharmaceutiquement acceptables sont sélectionnés dans le groupe constitué par la polyvinylpyrrolidone, l’alcool polyvinylique, la gomme de xanthane, la gomme de guar, la gomme welan, la gomme 55 adragante, la gomme de caroube, la gélose, la méthylcellulose, l’éthylcellulose, l’hydroxyéthylcellulose, l’hydroxyé- thylméthylcellulose, l’hydroxypropylcellulose, la carboxyméthylcellulose de sodium, la carboxyméthylcellulose de calcium, le polyéthylène glycol, la glycérine, la carraghénine, l’alginate de sodium, l’alginate de potassium, l’alginate de propylène glycol, l’hyaluronate de sodium, les carbomères, la maltodextrine, et des mélanges de ceux-ci.

10 EP 2 366 408 B1

7. Composition pharmaceutique selon la revendication 6, dans laquelle le ou les agents augmentant la viscosité pharmaceutiquement acceptables sont une polyvinylpyrrolidone sélectionnée dans le groupe constitué par la Po- vidone K 25, la Povidone K 30, la Povidone K 90F, et des mélanges de celles-ci.

5 8. Composition pharmaceutique selon la revendication 7, dans laquelle l’agent augmentant la viscosité pharmaceutiquement acceptable est la Povidone K 90F.

9. Composition pharmaceutique selon l’une quelconque des revendications 1 à 8, dans laquelle le ou les agents ajustant le pH pharmaceutiquement acceptables sont sélectionnés dans le groupe constitué par l’acide citrique, le 10 citrate de sodium, le citrate de potassium, le citrate de calcium, le citrate de lithium, l’acide tartrique, le tartrate de sodium, le tartrate de potassium, le tartrate de calcium, le tartrate de lithium, l’acide phosphorique, le dihydrogéno- phosphate de sodium, le monohydrogénophosphate de sodium, le phosphate de lithium, le phosphate de potassium, le phosphate de calcium, le carbonate de sodium, l’hydrogénocarbonate de sodium, l’acide lactique, le lactate de sodium, le lactate de potassium, le lactate de calcium, l’acide acétique, l’acétate de sodium, l’acétate de potassium, 15 l’acétate de calcium, l’acide sulfurique, le sulfate de sodium, le sulfate de potassium, l’acide borique, le borate de sodium, l’acide maléique, le maléate de lithium, le maléate de sodium, le maléate de potassium, le maléate de calcium, l’acide succinique, le succinate de lithium, le succinate de sodium, le succinate de potassium, le succinate de calcium, l’acide chlorhydrique, l’acide nitrique, l’hydroxyde de sodium, l’hydroxyde de potassium, la triéthanola- mine, la diisopropylamine, et des mélanges de ceux-ci. 20 10. Composition pharmaceutique selon la revendication 1, dans laquelle les pourcentages en p/v sont les suivants :

(i) de 0,02 à 0,03 % de fluocinolone acétonide, facultativement accompagné de 0,2 à 0,4 % de ciprofloxacine ou d’un sel pharmaceutiquement acceptable de celle-ci ; 25 (ii) de 2 à 3 % de Polysorbate 80 ; (iii) de 2 à 3 % de glycérine ; (iv) de 0,1 à 0,3 % de Povidone K 90F ; (v) facultativement, une quantité d’un ou plusieurs agents ajustant le pH pharmaceutiquement acceptables en quantité suffisante pour ajuster le pH à 4,0 à 5,0 ; et 30 (vi) de l’eau.

11. Composition pharmaceutique selon l’une quelconque des revendications 1 à 10, dans laquelle la composition pharmaceutique est stérilisée et contenue dans des récipients à doses uniques jetables destinés à une utilisation topique sous forme de gouttes. 35 12. Composition pharmaceutique telle qu’elle est définie dans l’une quelconque des revendications 1 à 11 destinée à être utilisée en tant que médicament.

13. Composition pharmaceutique selon la revendication 12 destinée à être utilisée dans la prévention et/ou le traitement 40 d’une inflammation auriculaire, facultativement accompagnée d’une infection bactérienne.

14. Composition pharmaceutique selon la revendication 13, dans laquelle l’inflammation auriculaire est une otite externe eczématoïde, une chéloïde, une myringite granuleuse, une myringite bulleuse ou une surdité soudaine.

45 15. Composition pharmaceutique selon la revendication 13, dans laquelle l’inflammation auriculaire accompagnée d’une infection bactérienne est une otite externe diffuse, une otite externe localisée, des perforations de la membrane tympanique traumatiques, un zona auriculaire, une otite moyenne avec épanchement, une otorrhée par tubes de tympanostomie, une otite moyenne aiguë avec des tubes de tympanostomie, une otite moyenne aiguë ou une otite moyenne suppurante chronique. 50

55

11 EP 2 366 408 B1

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

• US 20090111780 A1 [0002] • US 2010036000 A1 [0008] • EP 1312356 A1 [0004] • GB 1411432 A [0008]

Non-patent literature cited in the description

• T.L. LEMKE ; D.A. WILLIAMS. Foye’s Principles of • P.D. DARBRE ; P.W. HARVEY. Paraben esters: re- Medicinal Chemistry. Wolters Kluwer, 2007, 902 view of recent studies of endocrine toxicity, absorp- [0003] tion, esterase and human exposure, and discussion • J. COLOE ; M.J. ZIRWAS. Allergens in corticoster- of potential human health risks. J Appl Toxicol., 2008, oid vehicles. Dermatitis, 2008, vol. 19 (1), 38-42 vol. 28 (5), 561-578 [0007] [0007]

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