GB2223166A - Stable ophthalmic composition comprising methazolamide - Google Patents

Abstract

There is provided a stable, ophthalmic aqueous composition for topical administration, comprising (a) methazolamide and either (b) a pre-formed pharmaceutically acceptable, aqueous gel or (c) an aqueous gel-forming liquid capable of forming a pharmaceutically acceptable gel in situ when applied topically to a patient; said composition having a pH above 4.5 and below 6.8.

Description

STABLE OPHTHALMIC PREPARATIONS CONTAINING METHAZOLAMIDE This invention relates to pharmaceutical preparations for topical application in the treatment of eye conditions and which are either pre-formed gels or liquids which gel in situ when applied to the patient.

More particularly, the invention is concerned to provide such preparations which contain a dosage of methazolamide suitable for the treatment of glaucoma.

Methazolamide or N-[5-(aminosulphonyl)-3 methyl-1,3,4-thiadiazol-2(3H)-ylidene]-acetamide to give its full name, is an effective ocular hypotensive agent when it is administered systemically, and it is widely used for the treatment of glaucoma. However, the use of methazolamide is commonly associated with undesirable side effects, including metabolic acidosis, lethargy, anorexia, paresthesias, nephrolithiasis and impotence.

In view of the undesirable side effects on patients which can be produced when methazolamide is administered systemically, it has become recognized that there could be advantages in administering this drug topically.

Attempts have been made, therefore, to formulate methazolamide as an aqueous solution which can be administered through an eye dropper. However these topically applied aqueous solutions of methazolamide, using the sodium salt to achieve the required solubility, have been found to be ineffective in lowering intraocular pressure. It is difficult to achieve therapeutic levels of methazolamide when it is applied in the form of eye drops, because methazolamide is only slowly absorbed across the cornea of the eye. This may result in insufficient amounts of the drug being taken up by the patient in the relatively short time that the drops containing the active ingredient remain in contact with the cornea.

An ophthalmic gel offers the possibility of improving the contact time between the cornea and the methazolamide to ensure a sufficient dosage of the drug.

In a recently published paper reporting on a study to assess whether topical acetazolamide and methazolamide could be delivered by contact lenses, Friedman and his co-workers speculate on whether methazolamide would be effective topically applied as a gel formation (Arch.

Ophthalmol., 103 963-966, July 1985). Techniques for formulating gels for delivering ophthalmically active drugs topically are known in the art, see for example GB-A-2013084 disclosing aqueous pre-formed pharmaceutical gels for application to the conjunctival sac of the eye, and GB-A-1571832 and EP-A-0126684 disclosing drug delivery systems in the form of liquids which gel in situ when warmed by the body of the patient and useful in the treatment of a variety of ocular conditions.

However, we have found that when an aqueous solution of methazolamide is formulated into an aqueous gel at a pH in the range of 8.2-8.5, corresponding to the pH of the ophthalmic preparations used in the Friedman et al study, using gel-forming techniques known in the art, the resulting gels are insufficiently stable to be useful. Thus, in one accelerated storage experiment we determined, by HPLC, that the anticipated storage shelflife (defined as the time for the potency of the methazolamide to drop to 90% of its claimed potency) of an aqueous gel containing 1% by weight of the methazolamide (pH = 8.2-8.5) can be expected to be of the order of only 18 days at room temperature (23*C).

Despite these discouraging results, and despite the fact that it has hitherto been considered desirable to formulate at a relatively high pH in order to keep methazolamide fully in solution we have continued our investigations. Quite unexpectedly we have found that the stability of aqueous gels containing methazolamide at pH values of pH 6.8 and below is excellent and that this excellent stability is maintained provided that the pH is not below pH 4.5. Thus, based on solution studies, the predicted useful shelf-life at 25 C of aqueous gels of pH 7.0 is only about 60 weeks, whereas at pH 6.5 this has more than doubled, and over the pH range of 5.2 to 5.6 reaches about 4 years. As the pH drops to 4.5 or below, there is a sharp fall off in stability, the predicted useful shelf-life being about 100 weeks at pH 4.6 but only about 25 weeks at pH 4.0.

Thus, the present invention broadly provides a stable ophthalmic aqueous composition for topical administration, comprising (a) methazolamide and either (b) a pre-formed, pharmaceutically acceptable, aqueous gel or (c) an aqueous gel-forming liquid capable of forming a pharmaceutically acceptable gel in situ when applied topically to a patient; said composition having a pH of from 4.5 to 6.8.

Still better improvements in stability are achieved if the compositions of this invention have a pH in the range of 5.2 to 5.6, as indicated above, and preferably a pH of 5.3 to 5.5. The optimum pH appears to be 5.5, at which the predicted useful shelf-life is at least 5 years.

The preferred embodiment of the invention is a pre-formed gel. A number of high molecular weight gelforming organic polymers are known to be suitable for the preparation of pre-formed pharmaceutical gels. We prefer to use high molecular weight carboxy vinyl polymers (MW above 1,000,000) such as those sold by B.F.

Goodrich Company under the trade mark "Carbopol", and more especially Carbopol 934P of a molecular weight of about 3,000,000 and Carbopol 940 of a molecular weight of about 4,000,000. However, other gel-forming polymers can be used in this invention for the preparation of pre-formed gels, for example ethylene - maleic anhydride polymers and cellulose ethers such as hydroxypropylmethyl cellulose. As is well known, aqueous solutions of these acidic types of high molecular weight polymers form hydrogels when the pH of the solution is raised.

In accordance with this invention, the pH is to be adjusted to a level to cause the aqueous polymer solution to gel but is to be kept in the range of pH 4.5 to pH 6.8 in order to secure an enhanced shelf-life. As mentioned above, we have found that maximum stability is achieved when the pH is maintained in the range 5.3 to 5.5.

Alternatively, the compositions of the present invention can be formulated as aqueous liquids which are capable of forming a pharmaceutically acceptable gel in situ when applied topically to a patient.

Preferably, in accordance with this aspect of the invention, there are used so-called "thermal gels", which are aqueous compositions which are liquids at room temperature but which are converted into gels in situ when warmed by the patient's body following topical application. Known aqueous thermal gel systems have sol-gel transition temperatures typically in the range of 250-400C and usually comprise polymers of Pluronic or Tetronic type (see, for example, UK-A-1571832 and EP-A-0126684). Such thermal gel systems are useful in the present invention, provided of course that the thermally gellable polymer chosen is one which is unaffected as to useful gelling properties at the pH values which are used herein.

At pH values below 6.8, as used herein, the methazolamide is only partially in solution, with the remainder forming a suspension in the pre-formed gel or in the thermosetting gel system. It is therefore important that the dispersed particles of the methazolamide should be sufficiently small to minimize the risk of causing irritation to the eye of the patient.

We have found that micronised methazolamide with a particle size no greater than 20 microns, and preferably no greater than about 10 microns, should desirably be used.

It is preferred to incorporate an antimicrobial agent in the ophthalmic preparation of the invention to prevent microbial or fungal growth arising from contamination during use. A preferred antimicrobial agent Chlorbutol B. P. B.P. (1,1,1-trichloro-2-methyl-2- propanol hemihydrate), although other antimicrobial agents which do not affect the stability of the composition, and which are compatible with the intended therapeutic use, can also be used.

Other conventional additives, such as ophthalmically acceptable surfactants, eg Polysorbate 80, and preservative enhancers, eg EDTA or its salts, can be included if desired.

The relative concentrations of the components of the present compositions are not especially critical.

Typically, the methazolamide will be incorporated in an amount of from 1 to 10% by weight, and preferably about 3.5%, same basis, in order to provide a useful unit dosage for the treatment of glaucoma. In the case of the preferred pre-formed gels, the concentration of the selected gel-forming polymer will be determined by the viscosity which it is desired that the gel should possess for easy application coupled with sufficient retention time in the patient. Suitably, the yield value of the gel, as determined by a Ferranti-Shirley viscometer at 25"C, ranges from 700 to 7000 dynes/cm2. With Carbopol 934P, such yield values are obtained using concentrations of sterilized gel-forming polymer of about 0.5% to 5.0% by weight, the currently preferred concentration of this polymer being approximately 2.58 by weight.When a thermal gel vehicle is employed, it is preferred that the gel-forming polymer should be present in sufficient concentration to rapidly form a fairly rigid gel upon topical application of the liquid composition to the patient. If the gelling time is too slow, then there is a risk of an unacceptable loss of acetazolamide from the treatment size.

If present, it is preferred that the antimicrobial agent should range from 0.12 to 0.70% by weight. We have found that 0.50% by weight of Chlorbutol BP is satisfactory.

It is normally required that the ophthalmic preparation of the present invention should be presented in a sterile form. In order to achieve a sterile preformed gel, we prefer to pre-sterilize the individual ingredients and prepare the gel under aseptic conditions.

We have found that post-sterilization of pre-formed gels by such conventional sterilization techniques as autoclaving and y-irradiation are unsatisfactory since irreversible breakdown of the gel structure can occur.

A preferred technique for manufacturing a preformed ophthalmic gel of the invention is as follows: Carbopol 934P is sterilized after hydration in a portion of the total water. Chlorbutol BP is dissolved in the remaining water and added to the Carbopol after sterilization by sterile filtration.

Sterile micronised methazolamide powder (particle size of 10 microns or less) is then thoroughly dispersed in the Carbopol. The gel is thickened to its final viscosity by slowly stirring in the sterile solution of sodium hydroxide, to give a final pH of 5.2 to 5.6, preferably 5.3 to 5.5. The gel can then be filled into suitable containers for administration, for example sterilized epoxy resin-lined aluminium ophthalmic tubes with latex sals. All of these manufacturing steps are conducted under strictly aseptic conditions in order to ensure a sterile final product.

Ophthalmic preparations in accordance with the preferred embodiments of this invention are effective in the treatment by topical application of glaucoma.

Typically, the preparation is administered into the interior cul de sac of the eye, which in the case of preformed gels can easily be accomplished by distending the lower lid from the eye and applying a short ribbon of gel within the sac from a dispensing tube and then releasing the lid. The gellable liquid compositions of this invention can be supplied in bottles, or other suitable containers, and applied at the time of use by means of a conventional eye dropper.

The invention is illustrated by the Examples which follow: Example 1 The following gel was prepared under strictly aseptic conditions: % W/W Methazolamide micronised (sterile) 3.50 Chlorbutol B.P 0.50 Carbopol 934P 1.50 NaOH (4% w/v solution) 8.54 Water 85.96 Sterile micronised methazolamide powder, having an average particle size of 5 microns, with no particles in excess of 10 microns, was dispersed in a sterile unneutralised Carbopol dispersion in water containing dissolved chlorbutol. A sterile 4% w/v sodium hydroxide solution was then added with constant mixing to a final pH of 5.44. The resultant gel had a yield value of 3500-4100 dynes/cm2 by the Ferranti Shirley viscometer at 25 deg.

The gel was filled into epoxy resin-lined aluminium ophthalmic tubes and stored at temperatures of 23 C and 37 C. After three months storage there was no loss from initial methazolamide potency, as determined by HPLC, at either of these storage temperatures.

Example 2 The following gel was prepared under strictly aseptic conditions: % W/W Methazolamide micronised (sterile)* 3.50 Chlorbutol BP 0.50 Citric acid monohydrate** 0.117 Sodium citrate dihydrate 0.112 Sodium citrate 1% solution** qs Hydroxypropylmethylcellulose 2906 USP 4000 cps (sterile) 3.80 Water for Injection to -100.00 * average particle size of about 5 microns ** buffers Citric acid, sodium citrate and chlorbutol were dissolved in 95% of the total water for injection and the solution sterilised. Micronised sterile methazolamide powder was dispersed in the solution at ambient temperature using a high shear mixer. The hydroxypropylmethylcellulose, previously sterilized, was dispersed in the suspension and then allowed to hydrate over a period of about 15 minutes.The pH was adjusted to between 5.3 and 5.5 with a 1% solution of sterilized sodium citrate. The gel was adjusted to final weight with water for injection and mixed thoroughly.

The resultant gel had a viscosity of 21 poise at a shear rate of 380 second~1 and a yield value of 3050-3300 dynes/cm2, both measured on a Ferranti-Shirley viscometer at 25"C.

Example 3 The following suspension, gelling in situ at body temperature, was prepared.

% W/W Methazolamide micronised (sterile)* 3.50 Benzalkonium chloride BP 0.02 Citric acid monohydrate 0.117 Sodium citrate dihydrate 0.112 "Pluronic" F127** 19.000 Sodium citrate/citric acid solution qs Water for Injection to 100.000 * average particle size about 5 microns ** "Pluronic" F127 is a polyoxyethylene-polyoxypropylene block copolymer of average molecular weight about 11,500 Citric acid, sodium citrate and benzalkonium chloride were dissolved in 98% of the total water for injection. The "Pluronic" F127 was dispersed in this solution and left to hydrate overnight. The preparation was then thoroughly mixed and the pH adjusted to 5.30 to 5.50 with sodium citrate or citric acid solution as appropriate. The solution was made to 96.5% of the total weight and sterile filtered into a sterile container. The sterile micronised methazolamide was dispersed asceptically in the filtered solution using a high shear mixer.

The resultant suspension had a pH of 5.3 and on heating formed a gel with a sol-gel transition temperature of 29-33"C. The gel had a viscosity of 7.7 poise at a shear rate of 380 second'l and a yield value of 2200-2400 dynes/cm2, both measured at 34ec on a Ferranti-Shirley viscometer.

Example 4 The following gel was prepared under strictly asceptic conditions: % WIW Methazolamide micronised (sterile) 3.50 Chlorbutol BP 0.50 Ethylene maleic anhydride resin (EMA) type 91 (sterile) 0.80 Dilute ammonium hydroxide solution (3.50%) 3.66 Water for Injection 91.54 The sterile EMA resin was dispersed in 50% of the total water for injection, and the dilute ammonium hydroxide solution stirred in and heated at 95"C for 15 minutes. The resultant gel was allowed to cool to below 60eC The chlorbutol was dissolved in the remaining 50% of the water for injection, at a temperature not exceeding 60it, and sterile filtered into the gel which was mixed slowly.

The sterile micronised methazolamide powder was thoroughly dispersed in the gel.

The resultant gel had a pH of 5.32. The viscosity and yield value, both measured by a Ferranti Shirley viscometer at 25"C, were 12.3-12.9 poise (at a shear rate of 380 second~1) and 2460-2800 dynes/cm2 respectively.

Example 5 The following gel was prepared under strictly asceptic conditions.

% W/W Methazolamide micronised (sterile) 3.50 Chlorbutol BP 0.50 Carbopol 934P 0.25 NaOH (4% W/V solution) 1.47 Water 94.28 Sterile micronised methazolamide powder, having an average particle size of 5 microns, with no particles in excess of 10 microns, was dispersed in a sterile unneutralised Carbopol dispersion in water containing dissolved chlorbutol. A sterile 4% W/V sodium hydroxide solution was then added with constant mixing to a final pH of 5.97. The resultant gel had a yield value of 770 dynes/cm2 and a viscosity of 3 poise at a shear rate of 380-1 second, both measured on a Ferranti-Shirley viscometer at 25 C 250C.

Claims (19)

CLAIMS:

1. A stable, ophthalmic aqueous composition for topical administration, comprising (a) methazolamide and either (b) a pre-formed, pharmaceutically acceptable, aqueous gel or (c) an aqueous gel-forming liquid capable of forming a pharmaceutically acceptable gel in situ when applied topically to a patient; said composition having a pH within the range of 4.5 to 6.8.

2. A composition according to Claim 1, having a pH in the range 5.2 to 5.6.

3. A composition according to Claim 2, having a pH in the range of 5.3 to 5.5.

4. A composition according to any preceding claim, wherein said methazolamide used has a particle size of 10 microns or less.

5. A composition according to any preceding claim, formulated as a pre-formed gel from a pharmaceutically acceptable high molecular weight gelforming polymer.

6. A composition according to Claim 5, wherein said high molecular weight gel-forming polymer is a carboxy vinyl polymer having a molecular weight above 1,000,000, a cellulose ether or an ethylene-maleic anhydride copolymer.

7. A composition according to Claim 6, wherein said pre-formed gel has a yield value of 700 to 7000 dynes/cm2.

8. A composition according to any one of Claims 1-4, formulated as a liquid capable of forming a gel in situ when warmed by the body of a patient.

9. A composition according to Claim 8, containing as gel-forming agent a polymer of "Pluronic" or "Tetronic" type.

10. A composition according to any preceding claim, comprising also an antimicrobial agent.

11. A composition according to Claim 10, wherein said antimicrobial agent is l,l,1-trichloro-2methyl-2-propanol hemihydrate.

12. A composition according to any preceding claim, comprising from 1 to 10% by weight of said methazolamide.

13. A sterile composition according to any preceding claim.

14. A method of preparing a stable ophthalmic aqueous pre-formed gel for topical administration, comprising preparing an aqueous suspension of methazolamide powder and a gel-forming acidic polymer, and thereafter partially neutralizing the polymer with a base to form a gel containing said methazolamide and having a pH in the range of 4.5 to 6.8.

15. A method according to Claim 14, wherein sufficient base is added to raise the pH to from 5.2 to 5.6.

16. A method according to Claim 15, wherein sufficient base is added to raise the pH to from 5.3 to 5.5.

17. A method according to any one of Claims 14-16, for the preparation of a sterile gel, wherein said polymer and said methazolamide powder are each separately pre-sterilized prior to admixture, and said base is added as a sterile aqueous solution.

18. A stable ophthalmic aqueous composition for topical administration, substantially as described in any one of the Examples herein.

19. A method of preparing a stable ophthalmic aqueous composition for topical administration, substantially as hereinbefore described.