Aqueous pharmaceutical compositions containing borate-polyol complexes

Abstract

A multi-dose ophthalmic composition comprising: first polyol, the first polyol being mannitol, wherein the first polyol is at least 0.25 but less than 1.5% w / v of the composition; second polyol, the second polyol being propylene glycol wherein the second polyol is at least 0.1 but less than 5% w / v of the composition; borate, wherein the borate is at least 0.25% w / v of the composition but less than 0.5% w / v of the composition; antimicrobial preservative wherein the preservative is at least 0.0003 but less than 0.003% w / v of the composition and wherein the preservative is a quaternary ammonium polymeric compound; travoprost; and water; in which the pH of the composition is from 6.4 to 7.2.

Description

Aqueous pharmaceutical compositions containing borate-polyol complexes. Cross-reference to related application. This application claims priority based on U.S. Provisional Patent Application No. 61 / 037, 137 filed on March 17, 2008. Technical field of the invention The present invention relates to pharmaceutical compositions containing borate-polyol complexes for improved preservation of the compositions. More specifically, the present invention relates to aqueous, multi-dose ophthalmic pharmaceutical compositions containing two or more different polyols in conjunction with a borate, a preservative, or both. Background of the invention The present invention relates to pharmaceutical compositions formulated to have sufficient antimicrobial activity to meet the preservation efficacy requirements of the United States Pharmacopeia ("USP") and analogous guidelines in other countries. The ability to achieve preservation is based on a unique combination of formulation components and, in particular, the use of two or more different polyols in combination with borate. Many pharmaceutical compositions are required to be sterile (i.e., substantially free of bacteria, fungi, and other pathogenic microorganisms). Examples of such compositions include: solutions and suspensions that are injected into the bodies of humans or other mammals; creams, lotions, solutions, or other preparations that are applied topically to wounds, abrasions, burns, rashes, surgical incisions, or other conditions where the skin is not intact; and various types of compositions that are applied directly to the eye (e.g., artificial tears, irrigation solutions, and pharmacological products) or applied to devices that will come into contact with the eye (e.g., contact lenses). The types of compositions described above can be manufactured under sterile conditions using procedures well known to those skilled in the art. However, once a product container is opened, exposing the composition to the atmosphere and other potential sources of microbial contamination (e.g., a human patient's hands), the product's sterility may be compromised. Typically, these products are used multiple times by the patient and are therefore often referred to as "multi-dose" in nature. Due to the frequent and repeated exposure of multi-dose products to the risk of microbial contamination, it is necessary to employ a means to prevent such contamination. The means employed may be: (i) a chemical agent that prevents the proliferation of microbes in a composition, referred to herein as an "antimicrobial preservative"; or (ii) a packaging system that prevents or reduces the risk of microbes reaching a pharmaceutical composition within a container. Previous multi-dose ophthalmic formulations have generally contained one or more antimicrobial preservatives to prevent the proliferation of bacteria, fungi, and other microbes. These formulations can come into contact with the cornea directly or indirectly. The cornea is particularly sensitive to exogenous chemical agents. Therefore, to minimize the potential for harmful effects on the cornea, it is preferable to use antimicrobial preservatives that are relatively non-toxic to the cornea and to use such preservatives at relatively low concentrations. Sometimes it is difficult to strike a balance between antimicrobial efficacy and the potential toxicological effects of antimicrobial preservatives. More specifically, the concentration of an antimicrobial agent required to protect ophthalmic formulations from microbial contamination can create the potential for toxicological effects on the cornea and / or other ophthalmic tissues. Using lower concentrations of antimicrobial agents generally helps reduce the potential for such toxicological effects, but these lower concentrations may still be insufficient to achieve the required level of biocidal efficacy (i.e., antimicrobial preservation). The use of an inadequate level of antimicrobial preservation can create the potential for microbial contamination. This contamination is typically undesirable for most biological systems and particularly undesirable for the human eye. Therefore, there is a need for a means to increase the activity of antimicrobial agents so that low concentrations of the agents can be used without increasing the potential for toxicological effects or subjecting patients to undesirable risks of microbial contamination and resulting ophthalmic infections. Ophthalmic compositions are generally formulated as regulated, isotonic solutions. Particularly desirable ophthalmic compositions are those containing borate or borate-polyol complexes. Examples of such compositions are described in U.S. Patents Nos. 6,503,497; 6,011,062; 6,849,253; 5,603,929; 5,653,972; 5,849,792; and 5,631,287. It is generally known that borate-polyol complexes can be used in ophthalmic compositions to increase antimicrobial activity in the presence of a preservative such as a polymeric quaternary ammonium compound; see U.S. Patents Nos. 5,505,953; 5,811,466; 6,143,799; and 6,365,636. It has also been shown that increasing the amount of polyols such as sorbitol or mannitol can significantly increase antimicrobial activity even when relatively low amounts of borate are used. However, mannitol and sorbitol can also affect the resistance to normalization of tear pH after instillation of the compositions into the eye. Generally, the borate component (e.g., boric acid) of these complexes can provide the ophthalmic composition with significant resistance to tear pH normalization. It is generally desirable for these ophthalmic compositions to exhibit at least some degree of regulation so that the composition's natural pH does not change significantly over time. However, it is also possible for the compositions to exhibit an undesirably high degree of regulation, which, upon application, can cause tearing and eye discomfort as the eye attempts to maintain its own pH. Therefore, it is desirable to minimize the composition's resistance to tear pH normalization after application. The aforementioned polyols, particularly mannitol, sorbitol, or both, can significantly increase the tear pH normalization resistance of the borate component.Therefore, in order to maintain the desired regulatory levels, it is typically desirable to maintain relatively low concentrations of these polyols in the presence of borate. However, such lower concentrations may limit or decrease the antimicrobial activity of ophthalmic compositions. U.S. Patent No. 6,743,439 describes pharmaceutical compositions of aqueous solutions preserved with a cationic preservative and comprising a cationic drug and a sulfonated styrene / maleic anhydride copolymer. The compositions are said to be particularly suitable for topical ophthalmic use. U.S. Patent Application Publication No. 2005 / 0239900 describes the use of low molecular weight amino alcohols in ophthalmic compositions. The travoprost formulation TRAVATAN-Z® was approved by the FDA in September 2006. TRAVATAN-Z® does not contain benzalkonium chloride. In view of the above, it would be particularly desirable to provide an ophthalmic composition that includes a borate-polyol complex and exhibits improved regulation, antimicrobial activity, preservative efficacy, or any combination thereof. Summary of the invention The present invention relates to a multi-dose ophthalmic pharmaceutical composition comprising travoprost. The composition includes two or more different polyols, including a first polyol and a second polyol. The first polyol is mannitol in an amount of at least 0.25% but less than 1.5% w / v of the composition, and the second polyol is propylene glycol in an amount of at least 0.1% but less than 5% w / v of the composition. The composition also includes an effective amount of borate, the effective amount being at least 0.25% w / v but less than approximately 0.5% w / v of the total composition. The composition is aqueous and preferably satisfies Ph. Eur. A or Ph. Eur. B. The composition also includes a quaternary ammonium polymeric compound as an antimicrobial preservative in an amount of at least 0.0003 but less than 0.003% w / v of the composition. Detailed description of the invention The present invention is based on providing two or more different polyols in the presence of borate to provide a pharmaceutical composition, and particularly an ophthalmic composition, that exhibits the desired buffering and antimicrobial activity. Accordingly, the ophthalmic composition includes a first polyol, a second polyol different from the first polyol, and borate. The ophthalmic composition also includes a preservative and may also include multiple other ingredients. The ophthalmic composition is a multi-dose ophthalmic composition containing travoprost as the therapeutic agent and is configured for topical application to the eye (e.g., as drops directly into the eye). Unless otherwise stated, the percentages provided for the ingredients of the ophthalmic composition of the present invention are weight / volume (w / v) percentages. As used herein, the term "borate" refers to boric acid, boric acid salts, borate derivatives, and other pharmaceutically acceptable borates, or combinations thereof. The most suitable are: boric acid, sodium borate, potassium borate, calcium borate, magnesium borate, manganese borate, and other such borate salts. Borate interacts with polyols, such as glycerol, propylene glycol, sorbitol, and mannitol, to form borate polyol complexes. The type and proportion of such complexes depend on the number of OH groups of a polyol on adjacent carbon atoms that are not in a trans configuration with respect to each other. that the weight / volume percentages of the polyol and borate ingredients include those amounts, whether as part of a complex or not. As used here, the term "polyol" includes any compound having at least one hydroxyl group on each of two adjacent carbon atoms that are not in a trans configuration with respect to each other. Polyols may be linear or cyclic, substituted or unsubstituted, or mixtures thereof, provided the resulting complex is water-soluble and pharmaceutically acceptable. Examples of such compounds include sugars, sugar alcohols, sugar acids, and uronic acids. Preferred polyols are sugars, sugar alcohols, and sugar acids, including, but not limited to, mannitol, glycerin, xylitol, sorbitol, and propylene glycol. As used herein, the phrase "less than" in relation to a specified concentration (e.g., 1% w / v) means that the specified component (e.g., antimicrobial preservative) is not present in the composition or is present at a concentration less than the specified limit (e.g., 1% w / v). As used herein, the phrase "an effective amount of" means that a specified component is present in the composition in a sufficient quantity to have an impact on the therapeutic capacity, regulatory capacity, preservative capacity, and / or antimicrobial capacity of the composition. The compositions of the present invention include a preservative. Potential preservatives include, without limitation, hydrogen peroxide, chlorine-containing preservatives such as benzalkonium chloride, or others. However, according to a preferred aspect, the ophthalmic composition of the present invention is substantially free of any chloride-containing preservative and, in particular, is substantially free of benzalkonium chloride. One preservative included in the ophthalmic composition is a quaternary ammonium polymer compound. As used here, the phrase "substantially free from" as referring to an ingredient of the ophthalmic composition means that it is contemplated that the ophthalmic solution may be completely devoid of that particular ingredient or include only a nominal amount of that particular ingredient. The quaternary ammonium polymer compounds useful in the compositions of the present invention are those that have an antimicrobial effect and are ophthally acceptable. Preferred compounds of this type are described in U.S. Patents Nos. 3,931,319; 4,027,020; 4,407,791; 4,525,346; 4,836,986; 5,037,647; and 5,300,287; and PCT application WO 91 / 09523 (Dziabo et al.). The most preferred ammonium polymer compound is polyquaternium-1, also known as POLYQUAD.RTM. or ONAMERM.RTM., with a number-average molecular weight between 2,000 and 30,000. Preferably, the numerical mean molecular weight is between 3,000 and 14,000. Quaternary ammonium polymer compounds are used in the compositions of the present invention in an amount that is at least 0.0003% w / v and typically greater than approximately 0.0007% w / v of the ophthalmic composition. Furthermore, quaternary ammonium polymer compounds are used in the compositions of the present invention in an amount that is less than approximately 0.003% w / v and typically less than approximately 0.0015% w / v of the ophthalmic composition. As previously suggested, the ophthalmic composition will include a combination of two or more polyols, with the first polyol being different from the second polyol. The first polyol is preferably one that significantly improves the resistance of the borate component to normalization of tear pH following instillation of the ophthalmic composition into the eye. In contrast, the second polyol is preferably one that does not improve, or only minimally improves, the resistance of the borate component of the ophthalmic composition. The first polyol is mannitol ((2R, 3R, 4R, 5R)-hexane-1,2,3,4,5,6-hexol). In a preferred embodiment, the first polyol is entirely or substantially entirely (i.e., at least 95 wt%) mannitol. Of these, it is typically preferred that the first polyol be substantially entirely mannitol. As used herein, the term "substantially entirely", when used to describe which ingredient or ingredients are part of a component of the ophthalmic composition, means that the component is contemplated to be formed entirely of one or more particular ingredients or is formed substantially entirely of those one or more particular ingredients with only a nominal amount of the component being formed of others than those one or more particular ingredients. The first polyol is at least approximately 0.25% w / v of the ophthalmic composition. The first polyol is also less than 1.5% w / v, typically less than approximately 0.5% w / v of the ophthalmic composition. The second polyol is propylene glycol (propane-1,2-diol). In a preferred embodiment, the second polyol is entirely or substantially entirely (i.e., at least 95 wt%) propylene glycol. Of these, it is typically preferred that the second polyol be substantially entirely propylene glycol. The second polyol is at least approximately 0.1% w / v, more typically at least approximately 0.2% w / v, and even more typically at least approximately 0.3% w / v of the ophthalmic composition. The first polyol is also less than approximately 5% w / v, more typically less than approximately 1.8% w / v and even more typically less than approximately 1.2% w / v of the ophthalmic composition. It is generally envisaged that various amounts of borate may be included in the ophthalmic compositions of the present invention. However, it has been found that lower concentrations of borate, when used in combination with two or more different polyols, can produce unexpectedly superior antimicrobial activity, preservative efficacy, desired regulation, or a combination thereof. For the present invention, the borate is at least approximately 0.25% w / v of the ophthalmic composition. Furthermore, the borate is less than approximately 0.5% w / v, more typically less than approximately 0.4% w / v, and possibly even less than approximately 0.35% w / v of the ophthalmic composition. This is particularly the case when the combination of polyols and borate is employed in the presence of a quaternary ammonium polymer compound (e.g., polyquaternium-1) as a preservative. The resistance of the ophthalmic composition to normalization of tear pH within the eye is typically within a desired range. This resistance can be quantified in terms of the amount or volume of base or acid per volume of ophthalmic composition used to change the composition's pH to a predetermined pH. The amount of base or acid required per volume of ophthalmic composition to change the composition's natural pH to tear pH (7.5) can be significant, as it may represent the resistance the composition will offer to normalizing to tear pH after instillation into the eye. In particular, for the present invention, the resistance to normalization to the pH of tears can be quantified as the volume of 1 N NaOH (1 normal NaOH) or 1 N HCl (1 normal HCl) required per volume of ophthalmic composition to change the natural pH of the composition to a pH of 7.5.For example, the addition of 10 microliters (ml) of 1 N NaOH can move the pH of one milliliter (ml) of the ophthalmic composition from its natural pH (e.g., pH less than 7.0) to a pH of 7.5. The ophthalmic composition of the present invention may not require any NaOH or HCl to achieve a pH of 7.5. Typical ophthalmic compositions of the present invention typically require at least 0.5 ml, more typically at least 1.0 ml, and still more typically at least 2.0 ml of 1 N NaOH to bring one (1) ml of the ophthalmic composition to a pH of 7.5. It is also typical that less than 20 ml, more typically less than 15 ml, still more typically less than 10 ml, and possibly even less than 6.0 ml of 1 N NaOH can bring one (1) ml of the ophthalmic composition to a pH of 7.5.Several examples are provided below in which the resistance to pH normalization of tears has been given as microliters of 1 N NaOH to bring one (1) ml of the ophthalmic composition to a pH of 7.5. The present invention relates particularly to the provision of multi-dose ophthalmic compositions having sufficient antimicrobial activity to enable the compositions to meet the preservative efficacy requirements of the USP, as well as other preservative efficacy standards for aqueous pharmaceutical compositions. The preservative efficacy standards for multi-dose ophthalmic solutions in the United States and other countries / regions are shown in the following table: Preservative Efficacy Test Criteria ("PET") (Log Reduction of Microbial Inoculum Order over Time) Bacterium Fungus USP 27 A reduction of 1 log (90%) for day 7; 3 logs (99.9%) for day 14; and no increase after day 14 The compositions must demonstrate throughout the testing period that there are no increases of 0.5 logs or more, with respect to the initial inoculum. Japan logs for day 14; and there is no increase from day 14 to day 28. There is no increase from the initial account at $14 and $28. Ph. Eur. A1 A reduction of 2 logs (99%) for 6 hours; 3 logs for 24 hours; and no recovery after 28 days. A 2 log (99%) reduction for day 7, and no further increase in ahl Ph. Eur. B A reduction of 1 log for the 24 hours; 3 logs for day 7; and no increase in ahl thereafter A 1 log (90%) reduction for day 14, and no further increase in ahl FDA / ISO 14730 A 3-log reduction from the initial stimulus to day 14; and a 3-log reduction from restimulation No increase greater than the initial value on day 14, and no increase greater than the restimulo count from day 14 to day 28. In the European Pharmacopoeia there are two standards of preservation efficacy '"A" and 'B'. The standards identified above for USP 27 are substantially identical to the requirements set forth in earlier editions of the USP, particularly USP 24, USP 25, and USP 26. The borate / polyol systems described herein can be included in various types of pharmaceutical compositions to enhance antimicrobial activity and improve preservation, such as in ophthalmic, otic, nasal, and dermatological formulations, but are particularly useful in ophthalmic compositions. Examples of such compositions include ophthalmic pharmaceuticals, such as topical compositions used in the treatment of glaucoma, infections, allergies, or inflammation. These compositions may be aqueous or non-aqueous, but are generally aqueous. The compositions of the present invention may contain various types of therapeutic agents. The invention may include therapeutic agents that are nonionic. Cationic therapeutic agents may also be used in the compositions, particularly if the agent is included in the compositions in the form of a free base or in the form of a salt with a monovalent anion, such as a hydrochloride salt. Examples of therapeutic agents that may be contained in the ophthalmic compositions of the present invention include prostaglandin analogues (e.g., latanoprost, travoprost, and unoprostone), hypotensive lipids (e.g., bimatoprost), and glucocorticoids (e.g., prednisolone, dexamethasone, and lotoporedonol). Examples that may be additional to or alternative to those mentioned above include, without limitation, timolol (e.g., timolol maleate), olopatadine (e.g., olopatadine hydrochloride), brinzolamide, dorzolomide, brimonidine, emadastine, tandospirone, roscovitin, nepafenac, bradykinin, PDE4 inhibitors, and combinations thereof. The ophthalmic compositions of the present invention include travoprost. The present invention may be directed to the provision of multi-dose ophthalmic compositions in connection with the treatment of conditions in which the cornea or adjacent ocular tissues are irritated, or conditions requiring frequent application of a composition, such as in the treatment of patients with dry eye. The compositions may also be particularly useful for treating glaucoma. The compositions of the present invention shall generally be formulated as sterile aqueous solutions. The compositions of the present invention shall also be formulated to be compatible with the eye and / or other tissues to be treated with the compositions. Ophthalmic compositions intended for direct application to the eye shall be formulated to have a pH and tonicity compatible with the eye. It is also contemplated that the compositions may be suspensions or other types of solutions. The compositions will have a pH in the range of 6.4 to 7.2. The compositions will have an osmolality of 200 to 400 or 450 milliosmoles per kilogram (mOsm / kg), more preferably 240 to 360 mOsm / kg. The compositions of the present invention may contain various types of pharmaceutical excipients, such as surfactants, viscosity modifiers (e.g., hydroxyethylcellulose (HEC), hydroxypropyl methylcellulose (HPMC), or a combination thereof), and so forth. A surfactant is typically desirable, although not required unless otherwise specified. Preferably, when used, the surfactant for the present invention is a nonionic surfactant derived from vegetable oil. Vegetable oils, seed oils, and / or nut oils that have been hydrogenated, ethoxylated, or a combination thereof are particularly preferred.Such surfactants derived from vegetable, seed, and / or nut oils include, but are not limited to, babassu oil, almond oil, malt oil, palm kernel oil, castor oil, coconut oil, cottonseed oil, jojoba oil, linseed oil, mustard oil, olive oil, peanut oil, safflower oil, sesame oil, soybean oil, sunflower oil, and wheat germ oil, their hydrogenated or ethoxylated derivatives, or combinations thereof. Preferred oils are castor oil, babassu oil, almond oil, malt oil, and palm kernel oil, more preferably castor oil and babassu oil, such as Crovol oils obtained from Croda Oleochemicals, England. For example, the non-ionic surfactant, polyoxyl 40 hydrogenated castor oil, can be used for the solubilization or stabilization of drugs, such as travoprost. Particularly preferred surfactants include polyoxyethylene (POE) (40) hydrogenated castor oil (or PEG (40 hydrogenated castor oil) (HCO-40) , POE (60) hydrogenated castor oil (HCO-60) and POE (200) hydrogenated castor oil (HCO-200). When a quantity, concentration, or other value or parameter is given as an interval, a preferred interval, or a list of preferred upper and preferred lower values, this is to be understood as specifically describing all intervals formed from any pair of any upper interval limit or preferred value and any lower interval limit or preferred value, regardless of whether the intervals are described separately. When an interval of numerical values ​​is recited here, unless otherwise stated, the interval is intended to include the endpoints and all whole numbers and fractions. within the range. The scope of the invention is not intended to be limited to the specific values ​​cited in defining a range. Other realizations of the present invention will be evident to those experienced in the art from consideration of the present description and practice of the present invention described herein. Table A below provides a list of exemplary ingredients suitable for an exemplary preferred formulation of the ophthalmic composition of the present invention and a desired weight / volume percentage for such ingredients. TABLE A Ingredient Percentage w / v travoprost 0.004 POE 40 hydrogenated castor oil (HCO-40) 0.5 or 0.1 Boric Acid 0.3 Propylene glycol 0.75 Mannitol 0.3 Sodium Chloride 0.35 quaternary ammonium polymer compound 0.001 NaOH sufficient to achieve a pH = 6.8 Purified water QS 100 It is understood that the weight / volume percentages in Table A may vary by ±10%, ±20%, ±30%, or more, and that these variances may be used specifically to create ranges for the ingredients of the present invention. For example, a weight / volume percentage of 10% for an ingredient with a variance of ±20% means that the ingredient may have a weight / volume percentage range of 8 to 12% w / v. The following examples are presented to further illustrate selected embodiments of the present invention. The formulations shown in the examples were prepared using procedures well known to persons of ordinary experience in the field of ophthalmic pharmaceutical compositions. The efficacy of the antimicrobial preservative was determined as described in the examples below, using an organism exposure test according to the methods described in the United States Pharmacopeia 24 (USP) for Category 1A products. Samples were inoculated with known levels of one or more of the following: gram-positive vegetative bacteria (Staphylococcus aureus ATCC 6538), gram-negative vegetative bacteria (Pseudomonas aeruginosa ATCC 9027 and Escherichia coli ATCC 8739), yeast (Candida albicans ATCC 10231), and mold (Aspergillus niger ATCC 16404). Samples were drawn at specified intervals to determine whether the antimicrobial preservative system was capable of destroying or inhibiting the propagation of organisms intentionally introduced into the formulation. The rate or level of antimicrobial activity determines compliance with USP preservative efficacy standards for the cited preparation categories. Table B Standards for preservatives for Category 1A products in the United States presented as a reduction in Log of the organism's population Extraction time hours hours dlas dlas dlas For Bacteria (S. aureus) P. aeruginosa, and E. coli) Ph. Eur. A 2, 0 3, 0 NA NA NR Ph. Eur. B NA 1, 0 3, 0 NEITHER NEITHER USP NA NA 1, 0 3, 0 NEITHER For fungi (C. albicans and A. niger) Ph. Eur. A NA NA 2, 0 NA NEITHER Ph. Eur. B NA NA NA 1, 0 NEITHER USP NA NA NEITHER NEITHER NEITHER NI = no increase in this or any of the following extraction times NA = time point not required for the applicable standard (e.g., USP, Ph. Eur. B) NR = no organisms were recovered As shown in Table B, the USP Antimicrobial Efficacy Test 27 requires that compositions containing Category 1A products have sufficient antibacterial activity to reduce an initial inoculum of approximately 10⁵ to 10⁶ bacteria by one log (i.e., a 90% reduction in the population of 5 microorganisms) during a seven (7) day period and by three logs (i.e., a 99.9% reduction in the population of microorganisms) during a fourteen (14) day period, and requires that there can be no increase in the population of microorganisms after the fourteen-day period ends. With respect to fungi, the USP criteria require that the compositions maintain stasis (i.e., no growth) with respect to the initial inoculum population throughout the 28-day test period.A Category 1A product is an injection, or other parenteral product, including emulsions, otic, sterile nasal products, and ophthalmic products made with aqueous bases or vehicles. The margin of error in calculating microorganism populations is generally accepted as + / - 0.5 logs. Therefore, the term "stasis," as used here in relation to the aforementioned USP criteria, means that the initial population cannot increase by more than 0.5 log orders relative to the initial population. Examples The formulations in the AU Examples are provided as an illustration of the desirability of the present invention. The examples illustrate the antimicrobial activity and / or preservative efficacy of the ophthalmic compositions of the present invention containing the combination of two different polyols, particularly in combination with borate, the polymeric quaternary ammonium compound, or both. The ingredient percentages in the AU Examples are weight / volume percentages. Examples A to D Table C provides formulations A through D and data related to those formulations. TABLE C Examples TO B C D Travoprost Ph. Eur 0.004 0.004 0.004 0.004 HCO40 TO 0.5 0.5 0.5 0.5 Sodium Chloride requirements 0.72 0.69 0.66 None Propylene glycol None None None 1, 8 Mannitol 0, 1 0.3 0.9 0.3 Boric Acid 0.3 0.3 0.3 0.3 Polyquaternium-1 0.001 0.001 0.001 0.001 Sodium hydroxide, hydrochloric acid Change pH to 6.5 Change pH to 6.5 Change pH to 6.5 Change pH to 6.5 Purified Water QS 100% QS 100% QS 100% QS 100% Resistance to normalization of tear pH (pl / ml) 3, 6 7, 2 7, 6 S. Aureus Hours 2, 0 1, 4 1, 8 2, 1 5, 1 Hours 3, 0 1, 9 2, 7 3.0 5, 1 Days 5, 1 5, 1 5, 1 5, 1 Days 5, 1 5, 1 5, 1 5, 1 Days all 5, 1 5, 1 5, 1 5, 1 Pseudomonas Hours 2.0 3, 4 3, 3 2, 8 5, 1 THE Hours 3.0 3, 6 4, 4 3, 8 5, 1 Days 5, 1 5, 1 5, 1 5, 1 Days 5, 1 5, 1 5, 1 5, 1 Days. all 5, 1 5, 1 5, 1 5, 1 E. coli Hours 2.0 2.5 4, 5 2, 4 5, 1 Hours 3.0 5, 1 5, 1 4, 9 5, 1 Days 5, 1 5, 1 5, 1 5, 1 Days 5, 1 5, 1 5, 1 5, 1 Days. all 5, 1 5, 1 5, 1 5, 1 Candida A. Days 2.0 1, 0 1, 3 1, 4 4, 9 Days NI 1.5 1, 9 1, 9 4, 9 Days. NI 1, 9 2, 3 2.5 4, 9 A. Niger Days 2.0 3.0 3.0 3, 7 3, 5 Days NI 3, 5 3, 7 3, 6 3, 7 Days. NI 3, 7 3, 9 3, 8 3, 9 Examples A through D contain 0.001% polyquaternium-1 and 0.3% boric acid. Examples A through C contain only one polyol, mannitol, at concentrations of 0.1%, 0.3%, or 0.9%. These three formulations meet only the criteria of Ph. Eur. B. All of them fail to meet the Ph. Eur. A criteria for Candida albicans. In addition, Examples A and B do not meet the Ph. Eur. A criteria for Staphylococcus aureus. Example D, which contains a combination of two polyols, 0.3% mannitol and 1.8% propylene glycol, meets the Ph. Eur. A criteria. Examples THE Tables D and E provide formulations E to L and data related to those formulations. TABLE D Examples AND F G H Travoprost 0.004 0.004 0.004 0.004 HCO40 0, 1 0, 1 0, 1 0, 1 Sodium Chloride 0.35 0.35 0.35 0.35 Propylene glycol 0.75 0.75 0.75 0.75 Examples AND F G H Mannitol 0.3 0.3 0.3 None Boric Acid 0.3 0.3 None 0.3 Polyquaternium-1 0.001 None 0.001 0.001 Sodium hydroxide, hydrochloric acid Change pH to 6.8 Change pH to 6.8 Change pH to 6.8 Change pH to 6.8 Purified Water QS 100% QS 100% QS 100% QS 100% Resistance to normalization of tear pH (pl / ml) 5, 6 0.9 1, 6 S. Aureus 6 Hours 2, 0 4, 0 0, 0 1.8 3, 6 Hours 3.0 4, 9 0, 0 2.0 5.0 Days 4, 9 0.5 5.0 5.0 Days 4, 9 2, 1 5.0 5.0 Days all 4, 9 4, 4 5.0 5.0 Pseudomonas A 6 Horas 2.0 5.0 0, 2 2, 6 4, 9 Hours 3.0 5.0 0.3 4, 5 4, 9 Days 5.0 0.6 4, 9 4, 9 Days 5.0 0.9 4, 9 4, 9 Days. all 5.0 1, 2 4, 9 4, 9 E. coli 6 Hours 2.0 5.0 0, 1 3, 3 5.0 Hours 3.0 5.0 0, 0 5.0 5.0 Days 5.0 0, 0 5.0 5.0 Days 5.0 0, 0 5.0 5.0 Days. all 5.0 0.4 5.0 5.0 Candida A. 7 Days 2.0 4, 6 0.3 2.9 4, 9 Days NI 4, 9 0.3 4, 3 4, 9 Days. NI 4, 9 0.7 4, 9 4, 9 A. Niger 7 Days 2, 0 3, 0 3, 0 0, 1 1, 1 Days NEITHER 3, 6 3, 6 0.6 1, 1 Days. NEITHER 3, 6 2, 9 0.6 1, 0 TABLE E Examples Yo J K L Travoprost 0.004 0.004 0.004 0.004 HCO40 0, 1 0, 1 0, 1 0, 1 Sodium Chloride 0.35 0.66 None None Propylene glycol None None None 0.75 Mannitol 23 0.3 4, 6 23 Boric Acid 0.3 0.3 0.3 0.3 Polyquaternium-1 0.001 0.001 0.001 0.001 Sodium hydroxide, hydrochloric acid Change pH to 6.8 Change pH to 6.8 Change pH to 6.8 Change pH to 6.8 Purified Water QS 100% QS 100% QS 100% QS 100% Resistance to normalization of tear pH pl / ml 6, 2 2.5 8, 7 S. Aureus 6 Hours 2, 0 2, 7 2, 0 4, 9 4, 9 Hours 3, 0 3, 9 2, 9 4, 9 4, 9 Days 4, 9 4, 9 4, 9 4, 9 Days 4, 9 4, 9 4, 9 4, 9 Days All 4, 9 4, 9 4, 9 4, 9 Pseudomonas A 6 Horas 2.0 3, 7 2.5 4, 8 4, 8 Hours 3.0 4, 8 4, 3 4, 8 4, 8 Days 4, 8 5.0 4, 8 4, 8 Days 4, 8 5.0 4, 8 4, 8 Days. all 4, 8 5.0 4, 8 4, 8 E. coli 6 Hours 2.0 4, 1 3, 1 4, 2 4, 8 Hours 3.0 4, 8 4, 9 4, 8 4, 8 Days 4, 8 4, 9 4, 8 4, 8 Days 4, 8 4, 9 4, 8 4, 8 Days. all 4, 8 4, 9 4, 8 4, 8 Candida A. 7 Days 2.0 3, 3 1, 0 4, 2 5.0 Days NI 3, 5 1, 3 5.0 5.0 Days. NI 4, 6 3.0 5.0 5.0 A. Niger 7 Days 2.0 1.8 3, 6 0, 1 2, 0 Days NEITHER 2, 7 3, 7 0.9 2, 6 Days. NEITHER 2, 9 3, 6 0.9 3, 0 Example E is a representative example of this invention. It contains lower concentrations of boric acid (0.3%) and mannitol (0.3%). It has a preferred concentration of propylene glycol (0.75%). This formulation is also isotonic and pH stable. Eur A. Example F has the same composition as Example E except that it does not contain Polyquaternium-1 and is substantially free of any conventional preservatives; rather, the antimicrobial activity is provided by a system consisting of, or essentially consisting of, borate and a combination of polyols. It fails to preserve USP, Ph. Eur. B, and Ph. Eur. A; however, it has good activity against A. niger. Therefore, Polyquaternium-1 is typically desirable for the present invention. Example G has the same composition as Example E, except that it does not contain boric acid. It meets the preservation criteria of the USP, but does not meet the preservation criteria of Ph. Eur. B and Ph. Eur. A. This removal of boric acid significantly affects the antimicrobial activity against A. niger. It also reduces the activity against S. aureus. Therefore, boric acid is desirable for the ophthalmic composition of the present invention. Example H has the same composition as Example E except that it does not contain mannitol. It meets the preservation criteria of USP and Ph. Eur. B but does not meet the preservation criteria of Ph. Eur. A. The removal of mannitol significantly impairs antimicrobial activity against A. niger. Mannitol itself is believed to have no activity against A. niger, as shown in Example G. However, at a lower concentration, its complex with boric acid has very significant activity against A. niger. Therefore, it is desirable that the ophthalmic composition of the present invention have at least a low concentration of mannitol. Examples I, J, and K do not contain propylene glycol. In Example I, the propylene glycol was replaced with additional mannitol. Increasing the mannitol-to-boric acid ratio significantly increases complexation and ionization of boric acid. However, it is believed that the activity of the boric acid-polyol complex against A. niger increases with a lower level of boric acid ionization / complexation and that the activity begins to decrease as boric acid complexation / ionization increases further. As a result, the microbial activity of Example J against A. niger is higher than that of Example H, but lower than that of Example E. The composition of Example I does not meet the criteria of Ph. Eur. A PET. Furthermore, this increased ionization of boric acid increases resistance to tear pH normalization and is therefore undesirable beyond a certain point.Therefore, for the present invention, it is generally preferred to keep the mannitol concentration below approximately 1.5%. Higher concentrations of mannitol are typically undesirable. In example J, propylene glycol has been replaced with an additional amount of sodium chloride. For this example, the removal of propylene glycol affects Candida albicans and Staphylococcus aureus. However, the activity of A. niger is not significantly affected. The formulation meets the criteria of USP and Ph. Eur. B but fails the criteria of Ph. Eur. A. In example K, both propylene glycol and sodium chloride are replaced by mannitol. Therefore, the formulation has a high concentration of mannitol (4.6%). Such a high concentration of mannitol in 0.3% boric acid provides significantly increased polyquaternium-1 activity against Candida albicans and Staphylococcus aureus; however, it has relatively poor activity against A. niger. Therefore, a high concentration of mannitol alone is not typically sufficient to provide preservation of Ph. Eur. A or even Ph. Eur. B. In Example L, sodium chloride is replaced with additional mannitol. Therefore, the mannitol concentration is 2.3%. The formulation also contains 0.75% propylene glycol. It complies with the preservation requirements of Ph. Eur. A. However, its activity against A. niger is slightly lower than that of Examples E with 0.3% boric acid. Therefore, it is believed that activity against A. niger decreases beyond a certain mannitol concentration as higher amounts of boric acid form a complex. Therefore, it is typically preferred to keep the mannitol concentration below 1.5% w / v. With reference to example D above, there is additional propylene glycol instead of sodium chloride. This formulation passes Ph. Eur A. and has good activity against A. niger. Therefore, unlike mannitol, a higher concentration of propylene glycol is not typically thought to reduce microbial activity because it does not form complexes with boric acid in the same way. MP Examples Table F provides the formulations M to P and the data related to those formulations. TABLE F Examples M N EITHER P Travoprost 0.002 0.002 0.004 0.002 HCO40 0, 1 0, 1 0, 1 0, 1 Sodium Chloride 0.66 0.60 0.46 0.35 Propylene glycol None 0.25 0.5 0.75 Mannitol 0.3 0.3 0.3 0.3 Boric Acid 0.3 0.3 0.3 0.3 Polyquaternium-1 0.001 0.001 0.001 0.001 Sodium Hydroxide, hydrochloric acid Change pH to 6.8 Change pH to 6.8 Change pH to 6.8 Change pH to 6.8 Purified Water QS 100% QS 100% QS 100% QS 100% Tear resistance |jl / ml pH normalization 7, 4 6, 8 S. Aureus Hours 2, 0 2, 0 1, 8 3, 0 3, 2 3, 0 3, 0 3, 0 4, 2 4, 9 Hours Days 4, 9 4, 9 4, 9 4, 9 4, 9 4, 9 4, 9 4, 9 Days all 4, 9 4, 9 4, 9 4, 9 Days Pseudomonas A Hours 2.0 5.0 4, 8 3, 5 5.0 3.0 5.0 5.0 4, 8 5.0 Hours Days 5.0 5.0 4, 8 5.0 Days 5.0 5.0 4, 8 5.0 all 5.0 5.0 4, 8 5.0 Days. E. coli Hours 2.0 2, 3 2, 8 4, 4 4, 5 hours 3.0 4, 6 4, 9 4, 8 4, 9 Days 4, 9 4, 9 4, 8 4, 9 Days 4, 9 4, 9 4, 8 4, 9 Days. all 4, 9 4, 9 4, 8 4, 9 Candida A. Days 2.0 1, 3 2, 4 5.0 5.0 Days NI 1.5 2, 3 5.0 5.0 Days NI 2, 6 2, 4 5.0 5.0 A. Niger Days 2.0 3, 1 3, 7 3, 0 3, 7 Days NEITHER 3, 7 3, 7 3, 1 3, 7 Days. NEITHER 3, 1 3, 7 3, 1 3, 6 Examples M through P illustrate the effect of propylene glycol concentration. The results show that 0.25% propylene glycol significantly improves preservation against Candida albicans. 0.5% propylene glycol further improves preservation against Staphylococcus aureus and Candida albicans. Therefore, propylene glycol concentrations of 0.3% and higher are typically required to produce the desired results, and concentrations of 0.5% and higher are typically preferred. Example Q Table G provides the formulation Q and the data related to that formulation. TABLE G Examples Q Travoprost 0.004 HCO40 0, 1 Sodium Chloride 0.35 Propylene glycol 0.75 Mannitol 0.3 Boric Acid 0.3 Polyquaternium-1 0.001 Sodium Hydroxide, hydrochloric acid change pH to 7.4 Purified Water QS 100% S. Aureus Hours 2.0 4, 9 Hours 3.0 4, 9 Days 4, 9 Days 4, 9 Days all 4, 9 Pseudomonas A Hours 2.0 5.0 Hours 3.0 5.0 Days 5.0 Days 5.0 Days. All 5.0 E. coli Hours 2.0 5.0 Hours 3.0 5.0 Days 5.0 Days 5.0 Days. all 5.0 Candida A. Days 2.0 4, 9 Days NI 4, 9 Days. NI 4, 9 A. Niger Days 2.0 2, 8 Days NI 3, 4 Days NI 2, 8 As mentioned above, Example E in Table D is a representative example of this invention. It contains lower concentrations of boric acid (0.3%) and mannitol (0.3%). It has the preferred concentration of propylene glycol (0.75%). Example Q has the same composition, except that it has a pH of 7.4 instead of 5.6.8. Formulation Q also complies with the preservation requirements of Ph. Eur. A. UK examples Table H provides the RU formulations and data related to those formulations. TABLE H Examples R S T OR Travoprost Requirements for the Ph. Eur. A. 0.004 0.004 0.004 0.004 Timolol maleate 0.5 0.5 0.68 0.68 HCO40 0, 1 0, 1 0, 1 0, 1 Sodium Chloride 0.25 0.25 0.25 0.25 Propylene glycol 0.75 0.75 0.75 0.75 Manitol 0, 3 0, 3 0, 3 0, 3 Boric Acid 0, 3 0, 3 0, 3 0, 3 Polyquaternium-1 0.001 0.001 0.001 0.001 Sodium hydroxide, hydrochloric acid Adjust pH to 6.2 Adjust pH to 6.5 Adjust pH to 6.8 Adjust pH to 7.4 Purified Water QS 100% QS 100% QS 100% QS 100% Resistance to normalization of tear pH (pl / ml) 7, 2 S. Aureus Hours 2, 0 1.5 2, 0 2, 8 3, 7 Hours 3, 0 2, 4 3.0 4, 2 5.0 Days 5.0 5.0 5.0 5.0 Days 5.0 5.0 5.0 5.0 Days all 4, 9 4, 9 5.0 5.0 Pseudomonas A Hours 2.0 3, 9 4, 9 5.0 5.0 Hours 3.0 4, 9 4, 9 5.0 5.0 Days 4, 9 4, 9 5.0 5.0 Days 4, 9 4, 9 5.0 5.0 Days. all 4, 9 4, 9 5.0 5.0 E. coli Hours 2.0 3, 3 3, 2 3, 9 4, 4 Examples R S T U Hours 3.0 4.0 4, 9 5.0 5.0 Days 4, 9 4, 9 5.0 5.0 Days 4, 9 4, 9 5.0 5.0 Days. all 4, 9 4, 9 5.0 5.0 Candida A. Days 2.0 4, 8 4, 8 3, 8 4, 4 Days NI 4, 8 4, 8 5.0 5.0 Days NI 4, 8 4, 8 5.0 5.0 A. Niger Days 2.0 3, 6 2.9 2, 1 1, 1 Days NI 3, 1 3, 1 2.0 1, 7 Days NI 3.0 3.0 2, 8 2.0 Example T is similar to Example E except that it contains timolol maleate and a lower concentration of sodium chloride. The addition of timolol maleate, which has multivalent maleate ions, has a slightly adverse effect on the preservative's performance. However, it meets the activity criteria of Ph. Eur. A. Formulations R and U, at extreme pH values ​​of 6.2 and 7.4, meet the criteria of Ph. Eur. B, but fail the criteria of Ph. Eur. A for Staphylococcus aureus and Aspergillus niger, respectively.

Claims

1. A multiple-dose ophthalmic composition comprising: a first polyol, the first polyol being mannitol, wherein the first polyol is at least 0.25 but less than 1.5% w / v of the composition; a second polyol, the second polyol being propylene glycol, wherein the second polyol is at least 0.1 but less than 5% w / v of the composition; a borate, wherein the borate is at least 0.25% w / v of the composition but less than 0.5% w / v of the composition; an antimicrobial preservative, wherein the preservative is at least 0.0003 but less than 0.003% w / v of the composition and wherein the preservative is a quaternary ammonium polymeric compound; travoprost; and water; wherein the pH of the composition is from 6.4 to 7.

2.

2. A composition according to claim 1, wherein the composition satisfies Ph. Eur. A, Ph. Eur. B or both.

3. A composition as in claim 1 or 2, wherein the preservative includes polyquaternium-1. 4.A composition as in any of claims 1-3, wherein the composition is substantially free from any chlorine-containing agent.

5. A composition as in any of claims 1-4, wherein the composition is substantially free from any benzalkonium chloride.

6. A composition according to any of claims 1-5, further comprising a surfactant.

7. A composition as in claim 6, wherein the surfactant is HCO-40.

8. A composition as in claim 6, wherein the HCO-40 is at least 0.03% but less than 0.5% w / v of the composition.

9. A composition as in any of claims 1-8, wherein the resistance provided by the composition to the normalization of tear pH after instillation into the eye is less than 15 ml of 1M NaOH / mL of composition, preferably less than 10 ml of 1M NaOH / mL of composition. 10.A composition as in any of claims 1-9, wherein the second polyol is at least 0.5 but less than 5% w / v of the composition.