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Aqueous Clear Solutions of Fluocinolone Acetonide for Treatment

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Aqueous Clear Solutions of Fluocinolone Acetonide for Treatment (19) & (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 pharma- ceutical 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, admin- istration 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 appro- priate 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 accom- panied 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
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