PRESERVATIVE SYSTEM FOR TOPICALLY ADMINISTRABLE PHARMACEUTICAL COMPOSITIONS

Abstract: Anionic surfactants are used in conjunction with an antifungal acid and a chelating agent to preserve topically administrable pharmaceutical compositions without the need for a conventional preservative such as benzalkonium chloride.

Description: PRESERVATIVE SYSTEM FOR TOPICALLY ADMINISTRABLE PHARMACEUTICAL COMPOSITIONS Background of the Invention The present invention relates generally to the preservation of pharmaceutical compositions. In particular, the present invention relates to the use of certain anionic surfactants in combination with an antifungal acid and a chelating agent as a preservative system for topically administrable pharmaceutical compositions. Multi-dose pharmaceutical products, particularly those intended for topical administration to the eyes, nose or ears, often contain or are required to contain a preservative. Such products are sterilized when manufactured, but contain preservatives to prevent or inhibit microbial growth in the event they are contaminated during use. The most common preservatives for topical, multi- dose ophthalmic products are quaternary ammonium preservatives, such as benzalkonium chloride and polyquatemium-1. Other known preservatives for topical, multi-dose ophthalmic products are chlorobutanol; chlorhexidine; parabens; and thimerosal (though thimerosal is not as common as it used to be, due to regulatory and environmental concerns related to the fact it contains mercury). In some instances, preservatives alone are insufficient to meet regulatory standards for preservative efficacy. In such cases, preservative aids or adjuncts are used. Examples of preservative enhancing additives include the chelating agent EDTA (edetate disodium) and the antifungal agent boric acid. Additional examples of preservative enhancing additives include certain sarcosinate and lactylate surfactants. U.S. Patent No. 5,520,920 (Castillo, et al.) discloses the use of certain modified sarcosinates and lactylates to enhance antimicrobial effectiveness of ophthalmic compositions, particularly in the case where cationic preservatives otherwise bind to anionic polyelectrolytes. Representative modified sarcosinates include those sold under the Hamposyl ® trade name, such as lauroyl sarcosine (Hamposyl ® L), oleoyl sarcosine (Hamposyl ® O), myristoyl sarcosine (Hamposyl ® M), cocoyl sarcosine (Hamposyl ® C), stearoyl sarcosine (Hamposyl ® S), and pelargodoyl sarcosine (Hamposyl ® P). Representative lactylates include sodium capryl lactylate (Pationic ® 122A). Anionic amino acid based surfactants other than the Hamposyl ® surfactants are known and include, for example, those surfactants sold under the Amilite ™ and Amisoft ™ trade names (Ajinomoto Co., Inc., Tokyo, Japan). According to its product brochure, one such surfactant, Amilite ™ GCK-12, is used as a detergent, a foaming agent, an emulsifier, a solubilizer and a dispersing agent. Examples of applications of Amilite ™ GCK-12 include cosmetics and toiletries (hair shampoo and body wash), face wash (facial washing foam, facial washing creme, facial washing liquid and make-up remover), facial soap, toothpaste, bath soap, contact lens cleaners and household cleaners. Amisoft ™ surfactants are described as gentle cleansers for the skin and hair. Major applications of Amisoft ™ surfactants include facial and body cleansers, hair shampoos, syndet bars, body care and dermatological products. Alternative preservative systems for topically administrable pharmaceutical compositions are desired, especially in those instances when conventional preservatives, such as benzalkonium chloride, are incompatible with other ingredients in the composition. Summary of the Invention The present invention provides a preservative system for topically administrable pharmaceutical compositions. The preservative system consists essentially of i) at least one anionic surfactant of formula I or formula II below, ii) one or more pharmaceutically acceptable antifungal acids, and iii) one or more pharmaceutically acceptable chelating agents. wherein: R = Cβ - C 24 saturated or unsaturated hydrocarbon; X = H or CH 3 ; Y = H, (CH 2 ) 4 NH 2 or (CH 2 ) 3 NHC(NH 2 )=N + H 2 ; and M + = H or a pharmaceutically acceptable salt. wherein: R 1 = Cβ - C 24 saturated or unsaturated hydrocarbon; and M + is as defined above. According to the present invention, topically administrable pharmaceutical compositions are preserved without the need for a conventional preservative ingredient. Thus, the compositions of the present invention do not contain any preservatives selected from the group consisting of quaternary ammonium preservatives, such as benzalkonium chloride, benzalkonium bromide, and po.yquaternium-1 ; chlorhexidine; chlorobutanol; cetylpyridinium chloride; parabens; and thimerosal. The present invention also relates to a method of preserving a topically administrable pharmaceutical composition, wherein the method comprises adding the preservative system described above to such composition. Among other factors, the present invention is based on the finding that topically administrable pharmaceutical compositions can be preserved using a preservative system consisting of one or more anionic surfactants of formula I or II, one or more pharmaceutically acceptable antifungal acids and one or more pharmaceutically acceptable chelating agents, without the need for a conventional preservative ingredient. Detailed Description of the Invention Unless indicated otherwise, all amounts of composition ingredients expressed in percentage terms are expressed as weight/weight. The anionic surfactants of the present invention can be made by known methods and, in some cases, are commercially available. For example, Amilite ™ GCK-12 is commercially available from Ajinomoto Co., Inc. (Tokyo, Japan). Amilite ™ GCK-12 is described by formula I above when R is selected to be cocoyl (derived from coconut oil); X is H; Y is H; and M + is K + (i.e., potassium cocoyl glycinate). Lauroyl sarcosine is available from W.R. Grace (Lexington, MA) as Hamposyl ® L. Lauroyl sarcosine is described by formula I above when R is selected to be lauroyl; X is CH 3 ; Y is H; and M + is H + . Pationic ® 122A is available from RITA, Corp. (Woodstock, IL). Pationic ® 122A is described by formula II above when R 1 is selected to be a Cg saturated hydrocarbon and M + is Na + . Preferred anionic fatty acid/amino acid surfactants of formula I include those where R is a C-ι 2 - C-ι 8 saturated or unsaturated hydrocarbon and M + is selected from the group consisting of H + ; Na + ; K + ; and triethanolamine. s Preferred anionic surfactants of formula II include those where R 1 is a Cι 2 - C-i δ saturated or unsaturated hydrocarbon and M + is selected from the group consisting of H + ; Na + ; K + ; and triethanolamine. In general, the amount of anionic amino acid/fatty acid surfactant of 0 formula I in the compositions of the present invention is from about 0.001 to about 1 %, preferably from about 0.01 to about 0.2%. The amount of anionic surfactant of formula II in the compositions of the present invention is from about 0.05 to about 1.5%, preferably about 0.1 to about 1%, and most preferably about 0J to about 0.5%. For topical ophthalmic preparations, the concentration s of anionic surfactant (formula I or II) should not be so high that it causes severe discomfort. The preservative systems of the present invention also contain one or more pharmaceutically acceptable antifungal acids selected from the group 0 consisting of boric acid; benzoic acid; salicylic acid; sorbic acid; lactic acid; acetic acid; and pharmaceutically acceptable salts thereof. Boric acid is the most preferred antifungal acid. In general, the amount of antifungal acid present in the compositions of the present invention is from about 0.01 to about 1 %, preferably about 0J to about 0.6%, and most preferably from about 0.3 to about 5 0.4%. The antifungal acid component can be added to pharmaceutical compositions in the form of a pharmaceutically acceptable salt. In addition to the anionic surfactant(s) and antifungal acid(s), the preservative system contains one or more pharmaceutically acceptable o chelating agents. Such chelating agents are selected from the group consisting of ethylene diamine tetraacetic acid (EDTA); ethylene glycol-bis-(b- aminoethylethe -N.N.N'.N'-tetraacetic acid (EGTA); 1 ,2-bis(2- aminophenoxyJethane-N.N.N'.N'-tetraacetic acid (BAPTA); ethylene-N,N'-diglycine (EDDA); 2,2'-(ethylendiimino)-dibutyric acid (EDBA); and pharmaceutically acceptable salts thereof. The most preferred ctielating agent is EDTA. The chelating agents can be added to pharmaceutical compositions in the form of a pharmaceutically acceptable salt. For example, EDTA may be added in the form of edetate disodium. In general, the amount of chelating agent present in the compositions of the present invention is from about 0.001 to about 1 %, preferably about 0.01 to about 0.2%, and most preferably about 0.01 to about 0.1 %. The preservative system of the present invention can be used in all types of topically administrable pharmaceutical compositions (e.g., solutions, suspensions, emulsions, gels), but is preferably used for topically administrable ophthalmic, otic, nasal or dermal compositions. Most preferred are topically administrable ophthalmic or otic compositions. The topically administrable pharmaceutical compositions of the present invention optionally comprise, in addition to the preservative system described above, conventional ingredients, provided that the compositions do not contain a conventional preservative. For example, the compositions of the present invention may contain one or more active ingredients (though, in some instances, such as in the case of dry eye products, no drug will be present). Other optional ingredients include, but are not limited to, pharmaceutically acceptable buffers, tonicity agents, drug carriers, sustained-release agents, viscosity modifying agents, comfort-enhancing agents, solubilizing aids, pH adjusting agents, antioxidants and other stabilizing agents. The active ingredient or ingredients that can be included in the compositions of the present invention include all ophthalmic, dermatological, otic or nasal agents that can be topically applied. For example, such ophthalmic agents include (but are not limited to): anti-glaucoma agents, such as beta- blockers (e.g., betaxolol and timolol), muscarinics (e.g., pilocarpine), prostaglandins, carbonic anhydrase inhibitors (e.g., acetazolamide, methazolamide and ethoxzolamide), dopaminergic agonists and antagonists, and alpha adrenergic receptor agonists, such as para-amino clonidine (also known as apraclonidine) and brimonidine; anti-infectives, such as ciprofloxacin; non-steroidal and steroidal anti-inflammatories, such as suprofen, ketorolac, dexamethasone, rimexolone and tetrahydrocortisol; proteins; growth factors, such as EGF; and anti-allergic agents, such as cromolyn sodium, emedastine and olopatadine. Compositions of the present invention may also include combinations of active ingredients. Sustained release agents include anionic polyelectrolytes, such as high molecular weight (e.g., 50,000 - 6,000,000), anionic mucomimetic polymers (e.g., carboxyvinyl polymers, such as Carbopol ® , and xanthan gum), polystyrene sulfonic acid polymers, cationic exchange resins (e.g., Amberlite ® or Dowex ® ), and the like. The following examples are presented to illustrate further various aspects of the present invention, but are not intended to limit the scope of the invention in any respect. EXAMPLE 1 Ingredient Concentration (%) Betaxolol HCI 0.28 Amberlite IRP-69 0.25 Carbopol 974P 0.45 Potassium Cocoyl Glycinate * 0.03 Boric Acid 0.4 Mannitol 4.15 Edetate Disodium 0.01 Tromethamine q.s. to pH 6.5 Purified Water q.s. to 100 * Amilite GCK-12 Preparation: 0.28g betaxolol hydrochloride and 0.250 grams of amberlite IRP 69 were stirred in -25 mL of water for - 15 minutes. To this suspension were added 22.5g 2% stock slurry of Carbomer 974P, 0.40g boric acid, 4.15g mannitol, and 0.01g disodium EDTA. The pH of the mixture was adjusted to - 6.0 by the addition of 11 mL of 10% tromethamine solution followed by 30 minutes of stirring. 0J5g Amilite GCK-12 (30% potassium cocoyl glycinate) was then added. Finally, pH is readjusted to 6.5 with 10% tromethamine and the formulation was brought to 100g by the addition of purified water. EXAMPLE 2 Ingredient Concentration (%) Levobetaxolol HCI* 0.56 Polystyrene Sulfonic Acid (130 kD) 1.5 N-Lauroyl Sarcosinate* * 0.03 Boric Acid 0.35 Mannitol 3.07 Edetate Disodium 0.01 Tromethamine q.s. to pH 6.5 Purified Water q.s. to 100 (S)-Betaxolol Hamposyl-L EXAMPLE 3 Ingredient Concentration (%) Levobetaxolol HCI 0.56 Polystyrene Sulfonic Acid 1.5 Boric Acid 0.35 Mannitol 3.07 Potassium Cocoyl Glycinate* 0.03 Edetate Disodium 0.01 Tromethamine q.s. to pH 6.5 Purified Water q.s. to 100 'Amilite GCK-12 EXAMPLE 4 Ingredient Concentration (%) Betaxolol HCI 0.28 Sodium Lauroyl Sarcosinate* 0.03 Carbopol 974P 0.45 Amberlite IRP-69 0.25 Boric Acid 0.4 Mannitol 4.15 Edetate Disodium 0.01 Tromethamine q.s. to pH 6.5 Purified Water q.s. to 100 Ηamposyl-L EXAMPLE 5 Ingredient Concentration (%) Potassium Cocoyl Glycinate* 0.03 Boric Acid 0.4 Mannitol 4.9 Tromethamine 0.726 Edetate Disodium 0.01 Purified Water q.s. to 100 'Amilite GCK-12 EXAMPLE 6 Ingredient Concentration (%) Sodium Lauroyl Sarcosinate * 0.03 Boric Acid 0.4 Mannitol 4.9 Tromethamine 0.726 Edetate Disodium 0.01 Purified Water q.s. to 100 * Hamposyl-L EXAMPLE 7 Ingredient Concentration (%) Potassium Cocoyl Glycinate* 0.03 Mannitol 5 Purified Water q.s. to 100 'Amilite GCK-12 EXAMPLE 8 Ingredient Concentration (%) Sodium Lauroyl Sarcosinate* 0.03 Mannitol 5 Purified Water q.s. to 100 *Hamposyl-L EXAMPLE 9 Ingredient Concentration (%) Levobetaxolol HCI 0.56 Brinzolamide 1 Polystyrene Sulfonic Acid (500 kD) 1 Carbopol 974P 0.35 Mannitol 3.1 Boric Acid 0.3 Edetate Disodium 0.1 Sodium Lauroyl Sarcosinate* 0.04 Tyloxapol 0.025 Tromethamine adjust pH = 6.5 Hydrochloric Acid adjust pH = 6.5 Purified Water q.s. to 100 Ηamposyl-L EXAMPLE 10 Ingredient Concentration (%) Levobetaxolol HCI 0.56 Brinzolamide 1 Amberlite IRP-69 0.75 Carbopol 974P 0.3 Mannitol 4.0 Boric Acid 0.4 Edetate Disodium 0.01 Sodium Lauroyl Sarcosinate * 0.03 Tyloxapol 0.025 Tromethamine adjust pH = 6.5 Hydrochloric Acid adjust pH = 6.5 Purified Water q.s. to 100 *Hamposyl-L EXAMPLE 11 Ingredient Concentration (%) Betaxolol HCI 0.28 Carbopol 974P 0.45 Potassium Cocoyl Glycinate* 0.03 Amberlite IRP-69 0.25 Mannitol 4.15 Edetate Disodium 0.01 Tromethamine q.s. to pH 6.5 Purified Water q.s. to 100 'Amilite GCK-12 EXAMPLE 12 ingredient Concentration (%) Levobetaxolol* HCI 0.28 Carbopol 974P 0.2 Amberlite IRP 69 0.65 Glycerine 2 Edetate Disodium 0.01 Boric Acid 0.3 Tromethamine/N-Lauroylsarcosine** 0.04 Tromethamine q.s. to pH 6.5 Hydrochloric Acid q.s. to pH 6.5 Purified Water q.s. to 100 * (S)-Betaxolol ** Hamposyl-L (free acid) COMPARATIVE EXAMPLE 1 Ingredient Concentration (%) Betaxolol HCI 0.28 Amberlite IRP-69 0.25 Carbopol 974P 0.45 Boric Acid 0.4 Mannitol 4.5 Edetate Disodium 0.01 Benzalkonium Chloride 0.01 NaOH and/or HCI q.s. to pH 6.5 Purified Water q.s. to 100 COMPARATIVE EXAMPLE 2 Ingredient -Concentration (%) Benzalkonium Chloride 0.01 Mannitol 5 Purified Water q.s. to 100 COMPARATIVE EXAMPLE 3 Ingredient Concentration (%) Benzalkonium Chloride 0.01 Boric Acid 0.4 Mannitol 4.9 Tromethamine 0.726 Edetate Disodium 0.01 Purified Water q.s. to 100 EXAMPLE 13 Antimicrobial preservative effectiveness was determined using an organism challenge test according to the methods described in the United States Pharmacopeia (USP) and European Pharmacopoeia (Ph.Eur.). Samples were inoculated with known levels of one or more of the following: gram-positive (Staphylococcus aureus ATCC 6538) and gram-negative (Pseudomonas aeruginosa ATCC 9027 and Escherichia coli ATCC 8739) vegetative bacteria, yeast (Candida albicans ATCC 10231 ) and mold (Aspergillus niger ATCC 16404). The samples were then pulled at specified intervals to determine if the antimicrobial preservative system was capable of killing or inhibiting the propagation of organisms purposely introduced into the formulation. The rate or level of antimicrobial activity determines compliance with the USP and/or Ph.Eur. preservative efficacy standards for ophthalmic preparations. The compendial preservative standards for ophthalmic preparations are presented below: For Bacteria: For Fungi: NR = No organisms recovered Nl = No increase at this or any following time pulls = No requirement at this time pull The results of the microorganism challenge tests are shown in Tables 1 and 2 below. TABLE 1 'Projected results based on S. aureus, P. aeruginosa and A. niger data TABLE 2 The invention in its broader aspects is not limited to the specific details shown and described above. Departures may be made from such details within the scope of the accompanying claims without departing from the principles of the invention and without sacrificing its advantages.

Claims: We claim: 1. A preserved topically administrable " pharmaceutical composition comprising a preservative system wherein the preservative system consists essentially of i) at least one anionic surfactant selected from the group consisting of: wherein: R = Cs - C 24 saturated or unsaturated hydrocarbon; X = H or CH 3 ; Y = H, (CH 2 ) 4 NH 2 or (CH 2 ) 3 NHC(NH 2 )=N + H 2 ; and M + = H or a pharmaceutically acceptable salt; and wherein: R 1 = Cs - C 2 saturated or unsaturated hydrocarbon; and M + is as defined above; ii) one or more pharmaceutically acceptable antifungal acids selected from the group consisting of boric acid; benzoic acid; salicylic acid; sorbic acid; lactic acid; acetic acid; and pharmaceutically acceptable salts thereof; and iii) one or more pharmaceutically acceptable chelating agents selected from the group consisting of ethylene diamine tetraacetic acid; ethylene glycol-bis-(b- aminoethylether)-N,N,N',N'-tetraacetic acid; 1 ,2-bis(2-aminophenoxy)ethane- N,N,N',N'-tetraacetic acid; ethylene-N,N'-diglycine; 2,2'-(ethylendiimino)-dibutyric acid; and pharmaceutically acceptable salts thereof. 2. The preserved topically administrable pharmaceutical composition of Claim 1 wherein the anionic surfactant (i) is wherein: R = Cs - C 2 saturated or unsaturated hydrocarbon; X = H or CH 3 ; Y = H, (CH 2 ) 4 NH 2 or (CH 2 ) 3 NHC(NH 2 )=N + H 2 ; and M + = H or a pharmaceutically acceptable salt. 3. The preserved topically administrable pharmaceutical composition of Claim 2 wherein R is a Cι 2 - ds saturated or unsaturated hydrocarbon and M + is selected from the group consisting of H + ; Na + ; K + ; and triethanolamine. 4. The preserved topically administrable pharmaceutical composition of Claim 1 wherein the anionic surfactant (i) is wherein: R 1 = C 8 - C 24 saturated or unsaturated hydrocarbon; and M + is as defined above. 5. The preserved topically administrable pharmaceutical composition of Claim 4 wherein R 1 is a C-ι 2 - Cis saturated or unsaturated hydrocarbon and M + is selected from the group consisting of H + ; Na + ; K + ; and triethanolamine. 6. The preserved topically administrable pharmaceutical composition of Claim 2 wherein the amount of anionic surfactant is from about 0.001 to about 1 %. 7. The preserved topically administrable pharmaceutical composition of Claim 6 wherein the amount of anionic surfactant is from about 0.01 to about 0.2%. 8. The preserved topically administrable pharmaceutical composition of Claim 4 wherein the amount of anionic surfactant is from about 0.05 to about 1.5%. 9. The preserved topically administrable pharmaceutical composition of Claim 8 wherein the amount of anionic surfactant is from about 0J to about 1%. 10. The preserved topically administrable pharmaceutical composition of Claim 9 wherein the amount of anionic surfactant is from about 0J to about 0.5%. 11. The preserved topically administrable pharmaceutical composition of Claim 1 wherein the antifungal acid is boric acid or a pharmaceutically acceptable salt thereof. 12. The preserved topically administrable pharmaceutical composition of Claim 1 wherein the amount of antifungal acid is from about 0.01 to about 1 %. 13. The preserved topically administrable pharmaceutical composition of Claim 12 wherein the amount of antifungal acid is from about 0.1 to about 0.6%. 14. The preserved topically administrable pharmaceutical composition of Claim 13 wherein the amount of antifungal acid is from 0.3 to about 0.4%. 15. The preserved topically administrable pharmaceutical composition of Claim 1 wherein the chelating agent is EDTA or a pharmaceutically acceptable salt thereof. 16. The preserved topically administrable pharmaceutical composition of Claim 1 wherein the amount of chelating agent is from about 0.001 to about 1%. 17. The preserved topically administrable pharmaceutical composition of Claim 16 wherein the amount of chelating agent is from about 0.01 to about 0.2%. 18. The preserved topically administrable pharmaceutical composition of Claim 17 wherein the amount of chelating agent is from about 0.01 to about 0.1 %. 19. The preserved topically administrable pharmaceutical composition of Claim 1 wherein the composition is selected from the group consisting of ophthalmic and otic compositions.

Inventors: CASTILLO ERNESTO J, GERSON STEVEN HOWARD, HAN WESLEY WEHSIN, CASTILLO, ERNESTO, J., GERSON, STEVEN, HOWARD, HAN, WESLEY, WEHSIN
Applicants: ALCON LAB INC, ALCON LABORATORIES, INC.
Application year: 1999
Main classification: A61K47
IPC codes: A61K9, A61K47