MXPA00001103A - Ophthalmic compositions containing galactomannan polymers and borate - Google Patents

Abstract

The present invention is directed to ophthalmic compositions containing a gelling amount of a combination of galactomannan polysaccharides and borates. The compositions gel or partially gel upon administration to the eye. The present inventionalso discloses methods of topical ophthalmic administration of the compositions of the eye.

Description

OPHTHALMIC COMPOSITIONS CONTAINING GALACTOMANANE AND BORATE POLYMERS BACKGROUND OF THE INVENTION The present invention relates to the use of adjuvants in topical ophthalmic compositions. In particular, the present invention relates to pharmaceutical compositions comprising galactomannan polymers in combination with borates, and methods for the controlled administration of pharmaceutically active agents to patients, wherein the compositions are administered as liquids that are thickened to form gels after instill them in the eye. The transition from liquid to gel is mainly due to the change in pH and ionic concentration. Topical ophthalmic compositions have taken the form of liquids, ointments, gels and inserts. Liquid compositions for drip instillation of pharmaceutically active agents in the eye provide for easy administration, however, they do not always provide a precise dose amount, because the liquid portions are normally expelled by blinking during administration or drained into the nasal passage. . The ointments and gels that normally remain in the eye for longer than a liquid, and therefore provide more effective administration, often interfere with the patient's vision. The eye inserts, both biodegradable and non-biodegradable, are available and allow less frequent administration of the drug. These inserts, however, require complex and detailed preparation and are often uncomfortable for the user. An additional problem with non-biodegradable inserts is that they must be removed after use. The patents of E.U.A. Nos. 4,136,173 (Pramoda, et al) and 4,136,177 (Lin, et al) describe the use of therapeutic compositions containing xanthan gum and locust bean gum which are administered in liquid and gel form after instillation. These descriptions show a fluid-to-gel transition mechanism that involves a change in pH. PH-sensitive gels such as carbomers, xanthan, gellan, and those described above, need to be formulated at or below the pKa of their acid groups (usually at a pH of about 2 to 5). However, compositions formulated at a low pH are irritating to the eye. The patent of E.U.A. do not. 4,861, 760 (Mazuel, et al.) Describes ophthalmic compositions containing gellan gum which are administered to the eye as ungelled liquids and gel after instillation due to the change in ionic strength. These systems do not involve the use of small interlacing molecules, but provide gelling characteristics due to self-entanglement during changes in the ionic condition. Gels comprising the entanglement of polysaccharides with borates are described for use, as well as fracture fluids in the U.S. Patents. numbers 5,082,579, 5,144,590 and 5,160,643. These patents describe the use of borates and polysaccharides for the excavation of industrial oil wells.

The ophthalmic use of current liquid gelling systems presents a series of inconveniences. For example, natural polymers such as xanthan gum have the disadvantage of variability due to variations in source controls and / or limited manufacturing during processing. These variabilities cause significant undesirable changes in the properties of the compound, such as variable gelation characteristics. Thermoregulatory systems such as polyethylene oxide / propylene oxide block copolymers ("PEO / PPO") lose water to form the gels, and as a result turbid gels are produced. Combination gelling systems of polyvinyl alcohol ("PVA") - borate need to be formulated at a low pH, and therefore, can cause eye irritation upon instillation. Other gelling systems have problems of viscosity, rehydration and turbidity point associated with the autoclave. The entanglement of polyvinyl alcohol with borates is described in the U.S. patent. Number 4255,415 (Sukhbir et al). These compositions are preformed gels, and therefore difficult to supply. WIPO Publication No. WO 94/10976 (Goldenberg et al.) Discloses a low pH PVA-borate delivery system that carries out the liquid / ge !. transition. This system has the disadvantage, however, of limited gelling effects, and only in certain concentrations of PVA depending on the molecular weight of the PVA used. In addition, because the entanglement sites are unlimited with this system, strong local gelation after the addition of the base has limited its manufacture, and therefore, polyvinylpyrrolidone has been included in these compositions to solve the problem. The novel gelling system of the present invention does not have the above limitation.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to topical ophthalmic compositions comprising polymers of galactomannan and borate compound that provide controlled administration of a drug to the eye. The invention is based on a new gelling system comprising a galactomannan polysaccharide and a borate interlayer which forms a gel by increasing the pH and the ion concentration. In this novel system, the bisdiol borates are intertwined with the cis diol groups of the sugar portions of the polysaccharide. The compositions are administered as liquids or partially gelled liquids (hereinafter "liquids") that are thickened to form gels after instillation in the eye. Alternatively, the compositions may comprise a pharmaceutically active agent, and may be administered to the eye for lubrication or to deliver tears in the treatment of, for example, dry eye. The galactomannan-borate gelling system of the present invention has several advantages over other gelling systems. An advantage is that the compositions of the present invention are clear solutions and the resulting gel is also clear crystalline. While other systems may become opaque or cloudy after instillation, the clear crystalline gel of the present invention provides greater clarity of vision to the eye under treatment. The compositions of the present invention can be formulated at a slightly acidic to neutral pH and only require a lower pH change to activate gelation (i.e., a pH unit of about 0.5 to 1.0). This feature decreases the possible eye irritation that results from acid exposure, as could occur with other pH sensitive systems that require a pH change of about 2.4 to about 4.4 pH units (ie, they are formulated with a pH of around 3-5). The galactomannan polymers are also stable to heat and do not show a cloud point even during autoclave conditions. Thus, problems of viscosity and rehydration resulting from a rise in charge, such as those that exist in the PVA and carbomer polymer systems, do not occur with the galactomannan polymer-containing compositions of the present invention. The galactomannan polysaccharides are non-ionic and, in combination with borates at an acid to neutral pH, they are also essentially non-ionic. Therefore, the polymer system is completely compatible with anionic, neutral and cationic drugs. In addition, the preservation efficiency of the preservatives is not affected by the presence of the polymers. Normally, the efficacy of benzalkonium chloride and other cationic preservatives is affected with anionic polymers such as gelano and caragenan, and therefore an excess of preservatives in those systems may be needed. The increase in the concentration of preservative can also increase the irritation and toxicity of the composition. The galactomannan-borate gelling system of the present invention has other advantages. The galactomannan polymers have a relatively low molecular weight and are therefore easy to manufacture and carry on a larger scale. Galactomannan polymers are easily found and have been used in food and personal care products so they are considered safe. In addition, the control or manipulation of the gelling characteristics of the galactomannan-borate gelling compositions of the present invention is relatively simple in comparison with the systems of the prior art. The gelling properties of other simple polymer systems, such as ionomers, for example, gelano and caragenanos, and thermogels, for example, poloxamines and poloxamers, are usually related to the molecular weight and number of groups of functional groups of the polymers. Therefore, in order to change the gelling point or degree of gelling of said prior art systems, it would be necessary to modify the base polymer, a labor-intensive activity. In contrast, by simply manipulating the borate to galactomannan ratio in the compositions of the present invention, there is a wide range of gelling characteristics to be able to adjust the compositions to the objective requirements (see Figures 1 and 2). In addition, as illustrated in Figure 3, the galactomannans of the present invention (eg, guar gum) exhibit excellent gelling consistency and reproducibility, although the type or source of galactomannan varies. The present invention still has other advantages. The galactomannan polymer and the borate crosslinker compositions of the present invention are liquid and, therefore, easy to supply. Some gelling systems such as gellan gum, as described in US Patent No. 4,861, 760 (Mazuel et al.), Are thixotropic, and require agitation to increase fluidity and ease of delivery. The compositions of the present invention contain a relatively low concentration of galactomannan (about 0.2 to 0.5%) as compared to some thermogelling systems such as PEO / PPO block copolymers, which require very high concentrations. Low concentrations of gelling polymer provide less potential for toxicity and ease of conservation from microbial contamination compared to high concentration systems. The methods of the present invention comprise topical administration of the galactomannan-borate-containing compositions of the present invention. The present invention also relates to methods of sterilizing galactomannans including autoclaving.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph illustrating the gelling characteristics of various concentrations of guar gum in the presence of borate, relative to pH. Figure 2 is a graph illustrating the gelling characteristics of various concentrations of borate in the presence of guar gum, relative to pH. Figure 3 is a graph illustrating the uniformity of the gelling characteristics of three different types / sources of guar gum.

DETAILED DECRIPTION OF THE INVENTION The present invention relates to ophthalmic compositions comprising one or more galactomannan polysaccharides and one or more borate compounds. The present invention also relates to methods for using these compositions for the treatment of various ophthalmic disorders including dry eye, glaucoma, ocular hypertension, infection, allergy and inflammation. The types of galactomannans that can be used in the present invention are usually derived from guar gum, locust bean gum and tara gum. As used herein, the term "galactomannan" refers to polysaccharides derived from the above natural gums or similar natural or synthetic gums containing mannose or galactose moieties, or both groups, as the major structural components. Preferred galactomannans of the present invention are formed of linear chains of (1-4) -β-D-mannopyranosyl units with -D-galactopyranosyl units linked by linkages (1-6). With the preferred galactomannans, the ratio of D-galactose to D-mannose varies, but will generally be about 1: 2 to 1: 4. Galactomannans having a D-galactose: D-mannose ratio of about 1: 2 are most preferred. Additionally, other chemically modified variations of the polysaccharides are included in the definition "galactomannan". For example, it is possible to make substitutions of hydroxyethyl, hydroxypropyl and carboxymethylhydroxypropyl to the galactomannans of the present invention. Nonionic variations to galactomannans, such as those containing alkoxy and (C 1 -C 6) alkyl groups are particularly preferred when a soft gel is desired (eg, hydroxypropyl substitutions). Substitutions in the non-cis hydroxyl positions are most preferred. An example of non-ionic substitution of a galactomannan of the present invention is hydroxypropyl guar, with a molar substitution of about 0.4. It is also possible to make anionic substitutions to galactomannans. Anionic substitution is particularly preferred when strong response gels are desired. The borate compounds that can be used in the compositions of the present invention are boric acid and other pharmaceutically acceptable salts such as sodium borate (borax) and potassium borate. As used herein, the term "borate" refers to all pharmaceutically suitable forms of borate. Borates are common excipients in ophthalmic formulations due to the good regulation capacity at a physiological pH, and they are known to be safe and compatible with a wide variety of drugs and preservatives. Borates have inherent bacteriostatic and fungistatic properties, and therefore aid in the preservation of compositions. The compositions of the present invention comprise one or more galactomannans in an amount of about 0.1 to 5% w / v ("w / v") and borate in the amount of about 0.05 to 5% (w / v). Preferably, the compositions contain from 0.2 to 20% (w / v) of galactomannan and 0.1 to 2.0% (w / v) of a borate compound. Most preferably, the compositions contain from 0.3 to 0.8% (w / v) of galactomannan and 0.25 to 1.0% (w / v) of a borate compound. The particular amounts will vary, depending on the gelling properties desired. In general, the concentration of borate or galactomannan can be manipulated in order to reach the proper viscosity of the composition after activation of the gel (i.e., after administering). As shown in Figures 1 and 2, manipulation of the borate or galactomannan concentration provides stronger or weaker gelation at a given pH. If a stronger gelling composition is desired, then the concentration of borate or galactomannan should be increased. If a weaker gelling composition is desired, such as a partial gelling composition, then the concentration of borate or galactomannan should be reduced. Other factors may influence the gelling characteristics of the compositions of the present invention, such as the nature and concentration of additional ingredients in the compositions, such as salts, preservatives, chelating agents, among others. Generally, the preferred non-gelled compositions of the present invention, ie, compositions that are not activated to gel in the eye will have a viscosity of about 5 to 1000 cps. In general, the preferred gelled compositions of the present invention, i.e., compositions activated to gel in the eye, will have a viscosity of about 50 to 50,000 cps. The galactomannans of the present invention can be obtained from numerous sources. These sources include guar gum, locust bean gum and tara gum, as will be written later. Additionally, galactomannans can also be obtained by classical synthetic routes or by chemical modification of galactomannans as they occur in nature. Guar gum is the ground endosperm of Cyamopisis tetragonolobus (L) Taub. The water-soluble fraction (85%) is known as "guarano" (molecular weight of 220,000), which consists of linear chains of (1-4) -β-D mannopyranosyl units with aD-galactopyranosyl units linked by linkages (1- 6). The ratio of D-galactose to D-mannose in guarano is around 1: 2. Gum has been grown in Asia for centuries and is mainly used in food and personal care products because of its thickening property. It has five to eight times the thickening power of starch. Its derivatives, such as those containing substitutions of hydroxypropyl chloride or hydroxypropyltrimonium, have been commercially available for more than a decade. Guar gum can be obtained, for example, from Rhone-Polulenc (Cranbury, New Jersey), Hercules, Inc. (Wilmington, Delaware) and TIC Gum, Inc. (Belcamp, Maryland). Locust bean gum is the refined endosperm of the ervilla tree seed, ceratonia siliqua. The ratio of galactose to mannose for this type of gum is around 1: 4. The cultivation of the ervilla tree is an ancient practice and well known in the art. This type of gum is commercially available and can be obtained from TIC Gum, Inc. (Bekamp, Maryland) and Rhone-Polulenc (Cranbury, New Jersey). Tara gum is derived from the refined seed gum of the tara tree. The ratio of galactose to mannose is around 1: 3. Tara gum is not produced commercially in the United States, but can be obtained from several sources outside the United States. In order to limit the degree of entanglement to provide a softer gel characteristic, chemically modified galactomannans such as hydroxypropyl guar can be used. Modified galactomannans of varying degrees of substitution are commercially available from Rhone-Poulenc (Cranbury, New Jersey).

Particularly preferred is hydroxypropyl guar with low molar substitution (eg, less than about 0.6). It is possible to add other ingredients to the compositions of the present invention. Such ingredients generally include tonicity adjusting agents, chelating agents, pharmaceutically active agents, solubilizers, preservatives, pH adjusting agents and vehicles. Other polymeric or monomeric agents such as polyethylene glycol and glycerol can also be added for special processing. The tonicity agents useful in the compositions of the present invention can include salts such as sodium chloride, potassium chloride and calcium chloride; nonionic tonicity agents may include propylene glycol and glycerol; chelating agents may include EDTA and its salts; solubilizing agents may include Cremophor EL® and tween 80; other vehicles may include amberlite ® IRP-69; pH adjusting agents may include hydrochloric acid, Tris, triethanolamine and sodium hydroxide; and suitable preservatives may include benzalkonium chloride, polyquaternium-1 and polyhexamethylene biguanide. The above list of examples is given for purposes of illustration and is not intended to be exhaustive. Examples of other agents useful for the above purposes are well known in the ophthalmic formulation and are comprised within the present invention. The gelling system combination of the present invention with prior art gelling system is also understood in the present invention. Such systems may include the inclusion of ionomers, such as xanthan, gellan, caragenan and carbomers, and thermogels, such as ethylhydroxyethylcellulose. In general, the compositions of the present invention will be used to administer various pharmaceutically active compounds to the eye. Such pharmaceuticals include, but are not limited to antihypertensive, anti-glaucoma, neuroprotective, antiallergic, muco-secretagogue, angiostatic, antimicrobial, pain relievers and anti-inflammatory agents. Examples of pharmaceutically active agents that can be included in the compositions of the present invention, and administered through the methods of the present invention include, but are not limited to: glaucoma agents, such as betaxolol, timolol, pilocarpine, anhydrase inhibitors carbonic and prostaglandins; dopamine antagonists; post-surgical antihypertensive agents, such as para-amino clonidine (apraclonidine); anti-infectious, such as ciprofloxacin and tobramycin; nonsteroidal and spheroidal anti-inflammatories, such as naproxen, diclofenac, suprofen, ketorolac, tetrahydrocortisol and dexamethasone; proteins; growth factors, such as epidermal growth factor; and anti-allergic. Optionally, the compositions of the present invention can be formulated without a pharmaceutically active compound. Said compositions can be used to lubricate the eye or provide artificial tears solutions to treat, for example, dryness in the eye. In general, artificial tears solutions contain tonicity, polymeric and preservative agents, as described above. The amount of galactomannan and borate contained in artificial tears solutions will vary, as described above, but will generally be around 0.1 to 3.0% (w / v) and 0.1 to 2.0% (w / v), respectively. In general, the compositions of the present invention are formulated in two parts. The galactomannan polymer is hydrated and sterilized (part I). Any pharmaceutical agent and / or other ingredients that will be included in the composition are dissolved in water and filtered under sterile conditions (part II). Parts I and II are combined and the pH of the resulting mixture is adjusted to a target level, generally 6.0 to 7.0. If the pharmaceutical agent that will be included has low solubility in water, will usually be added at the end. In some cases, it would be preferable to sterilize the pharmaceutical agent separately, and then aseptically add the agent and other ingredients together. The sterilization of the galactomannan polysaccharide can be achieved by autoclaving. Because the polymers suffer from depolymerization under the extreme autoclave conditions, the non-aqueous autoclave is generally preferred. This can be achieved by dispersing the polymer in a suitable organic liquid such as low molecular weight polyethylene glycol. The resulting suspension can be autoclaved to sterilize the polymer. The sterilized polymer is hydrated aseptically, before mixing it with other ingredients.

The following example illustrates a novel method of sterilization of a galactomannan polysaccharide of the present invention: EXAMPLE 1 Firstly, a mixing container (20 L stainless steel pressure can), a 0.2 micron sterilizing filter, a receiving container (20 L bottle), a 4.5 micron polishing filter, a filter filter, and an autoclave are sterilized by autoclaving. 0.2 micron sterilization, a ventilation filter, and filler equipment. In a beaker equipped with a stirrer, add the heavy amount of polyethylene glycol 400 (200g). While mixing, slowly disperse the heavy amount of guar / hydroxypropyl ("HP") gum (100 g). Mix until the mixture is completely homogenous. In a 500 ml Schott bottle, equipped with a magnetic stir bar, weigh exactly 120.0 g of the guarHP / PEG-400 rubber dispersion. Prepare to sterilize by autoclave. In a second identical Schott bottle of 500 ml we weigh exactly 120.0 g of the same dispersion. Prepare to use as a model during the autoclave cycle. In both bottles add 1.3 ml of purified water (equivalent quantity, in volume, of the microorganism suspension used to inoculate the bottles during the validation study). Mix both bottles for 10 minutes using a magnetic stir plate. Autoclave the guarHP / PEG-400 rubber dispersion using the validated temperature-time cycle of 80 minutes at 125 ° C. The other series of ingredients that will be included in the final formulation can be prepared separately by various methods known in the art. The resulting mixture can be added by sterile filtration to the mixing vessel, together with the HP / PEG-400 guar gum preparation. Aseptically transfer the GuarHP / PEG-400 gum dispersion into the pre-sterilized mixing vessel. Rinse the contents of the bottle with sterilized purified water. Bring the content of the mixing vessel to exactly 95% of the theoretical loading weight (19.0 liter or 19.06 Kg) using sterilized purified water at room temperature. Allow the GuarHP / PEG gum suspension to hydrate while mixing, at moderate speed, in the mixing vessel for a minimum of 2 hours. Transfer the content of the mixing vessel through a 4.5 micron pre-sterilized polishing filter into the pre-sterilized receiver vessel equipped with a stir bar. There will be some loss of content due to the product that remains in the filter housing and in the filter cartridge. (If a pressure can is used as the mixing vessel, the recommended pressure for clarification filtration is approximately 2.10 kg / cm2). Verify and adjust the pH, if necessary, to 6.9-7.1 (objective 7.0) using 1 N NaOH or 1 N HCl. Approximately 3-4 ml of 1 N NaOH per 1 liter of final charge weight is needed to reach the desired pH. As a sufficient quantity for the final load weight, sterilized purified water is used. Mix at low speed for a minimum of 30 minutes. The following examples further illustrate the preferred ophthalmic compositions of the present invention: EXAMPLE 2 The following is an example of a topical ophthalmic composition containing timolol. * 0.68% Timolol Maleate is equivalent to 0.5% Timolol. The above formulation is prepared by making a mixture of part I and part II. Guar gum is first dispersed in PEG-400 and autoclaved as part I. The other ingredients are dissolved in approximately 90% of the volume of water and filtered by sterilization in a recipient vessel as part II. Part I is added to part II aseptically. The pH can be adjusted aseptically and the load is carried to the final weight (volume). The combined solution passes through a 1.0 μm polishing filter, aseptically, to remove the particulate material.

EXAMPLE 3 The following is another example of a topical ophthalmic composition containing timolol. * 0.34% Timolol Maleate is equivalent to 0.25% Timolol. The above composition can be prepared in a similar manner as the composition of example 2.

EXAMPLE 4 The following is an example of a solution of artificial tears.

The above composition can be prepared in a similar manner as the composition of Example 2. In its broader aspects the invention is not limited to the specific details shown and described herein. Such details may be departed from within the scope of the appended claims without departing from the principles of the invention and without sacrificing its advantages.

Claims (22)

NOVELTY OF THE INVENTION CLAIMS

1. A topical ophthalmic composition comprising one or more galactomannans and one or more borate compounds, wherein the galactomannan and the borate compound are comprised in the composition in effective concentrations to create a gel or partial gel when the composition is administered to a eye.

2. A composition according to claim 1, further characterized in that the concentration of galactomannan is around 0.1 to 5% (w / v) and the concentration of the borate compound is around 0.05 to 5.0% (p / v).

3. A composition according to claim 1, further characterized in that the galactomannan is selected from the group consisting of guar gum, locust bean gum, tara gum and chemically modified derivatives thereof.

4. A composition according to claim 1, further characterized in that the borate compound is selected from the group consisting of boric acid, sodium borate, potassium borate and combinations thereof.

5. - A composition according to claim 1, further characterized in that the galactomannan is hydroxypropyl guar and the borate compound is boric acid.

6. A composition according to claim 1, further characterized in that the galactomannan is guar gum and the borate compound is boric acid.

7. A composition according to claim 5, further characterized in that the composition comprises hydroxypropyl guar in a concentration of 0.2 to 2.0% (w / v) and boric acid in a concentration of 0.1 to 2.0% (w / v) .

8. A composition according to claim 6, further characterized in that the composition comprises guar gum in a concentration of 0.2 to 2.0 (w / v) and boric acid in a concentration of 0.1 to 2.0 (w / v).

9. A composition according to claim 1, further characterized in that it comprises one or more pharmaceutically active agents.

10. A composition according to claim 9, further characterized in that the concentration of galactomannan is about 0.1 to 5% (w / v) and the concentration of the borate compound is about 0.05 to 5.0% (p / v).

11. A composition according to claim 9, further characterized in that the pharmaceutically active agent or agents is selected from the group consisting of: anti-hypertensive, anti-glaucoma, neuro-protective, anti-allergic, muco-secretagogue, angiostatic, antimicrobial, pain relievers and anti-inflammatory.

12. A composition according to claim 9, further characterized in that the pharmaceutically active agent is selected from the group consisting of: betaxolol, timolol, pilocarpine, carbonic anhydrase inhibitors, prostaglandins; post-surgical antihypertensive agents, apraclonidine; ciprofloxacin, tobramycin; naproxen, diclofenac, suprofen, cetoralac, tetrahydrocortisol, dexamethasone; proteins and growth factors.

13. A method for delivering a pharmaceutical agent to the eye comprising topical administration of a composition comprising one or more pharmaceutically active agents, one or more galactomannans and one or more borate compounds, wherein the galactomannan and the borate compound they are comprised in the composition in effective concentrations to create a gel or partial gel when the composition is administered to the eye.

14. A method according to claim 13, further characterized in that the composition comprises galactomannan in a concentration of about 0.1 to 5% (w / v) and the borate compound in a concentration of about 0.05 to 5% ( p / v).

15. A method according to claim 13, further characterized in that the galactomannan is selected from the group consisting of guar gum, locust bean gum, tara gum and chemically modified derivatives thereof.

16. A method according to claim 13, further characterized in that the borate compound is selected from the group consisting of boric acid, sodium borate, potassium borate and combinations thereof.

17. A method according to claim 13, further characterized in that the galactomannan is hydroxypropyl guar and the borate compound is boric acid.

18. A method according to claim 13, further characterized in that the galactomannan is guar gum and the borate compound is boric acid.

19. A method according to claim 17, further characterized in that the composition comprises hydroxypropyl guar in a concentration of 0.2 to 2.0% (w / v) and boric acid in a concentration of 0.1 to 2.0% (w / v) .

20. A method according to claim 18, further characterized in that the composition comprises guar gum in a concentration of 0.2 to 2.0% (w / v) and boric acid in a concentration of 0.1 to 2.0% (w / v).

21. A composition according to claim 13, further characterized in that the pharmaceutically active agent or agents is selected from the group consisting of: anti-hypertensive, anti-glaucoma, neuro-protective, anti-allergic, muco-secretagogue, angiostatic, antimicrobial, pain relievers and anti-inflammatory.

22. A composition according to claim 13, further characterized in that the pharmaceutically active agent is selected from the group consisting of: betaxolol, timolol, pilocarpine, carbonic anhydrase inhibitors, prostaglandins; post-surgical antihypertensive agents, apraclonidine; ciprofloxacin, tobramycin; naproxen, diclofenac, suprofen, cetoralac, tetrahydrocortisol, dexamethasone; proteins and growth factors.