MXPA01005915A - The process for manufacturing formulation of topical beta blockers with improved efficacy - Google Patents

Abstract

Beta blockers are used as topical ophthalmic preparation for reducing Intra Ocular Pressure. B-blocker used for this purpose include timolol, levobunolol, carteolol, metipranalol. They reduce the aqueous production and thereby reduce I.O.P. They are commonly used as drops. Efficacy of topical B-blockers is dependent on concentration of drug in formulation. However, increasing the concentration of drug beyond approved dosage forms does not increase the efficacy significantly e.g. Timolol 0.5%has identical pressure lowering capacity as 1%Timolol. The attempts to improve pressure reduction efficiency of B-blockers has not met with success so far. The sustained release formulation of Timolol (Timolol XE) has resulted in amount of drug to achieve same therapeutic effect. However, none of the formulation has improved efficacy of drug for reducing I.O.P. The present invention relates to the process of manufacturing such formulation of B-blocker which improves its I.O.P lowering effect. The formulation so prepared is non-irritating and well tolerated. The process of manufacturing new formulation with improved efficacy involves use of carboprolol and preservative. The timolol 0.5%gel formulated using process was evaluated in normal as well as glaucomatous eyes. The reduction in I.O.P. is found to be approx. 15%more than found with drops in normal individuals. Similar findings are also observed in glaucomatous eyes.

Description

PROCEDURE FOR THE ELABORATION OF A FORMULATION OF TOPICAL BETA-BLOCKERS WITH IMPROVED EFFICACY DESCRIPTIVE MEMORY The present invention relates to a process for preparing a formulation of beta-blockers with improved efficacy and tolerance. Beta-blockers are used as topical ophthalmic preparations to reduce intraocular pressure. The present invention is directed to the preparation of a formulation containing beta-blockers in such a way that the effects of lowering the pressure of beta-blockers are improved. It is necessary to use beta-blockers for prolonged periods to reduce P.I.O. (Intraocular pressure). Its prolonged use is associated with the instability of the tear film resulting in dry eye. The present invention is also directed to the preparation of a formulation containing beta-blockers in such a way that the tear film is stabilized. It is known that beta-blockers reduce P.l. O. mainly by reduction of aqueous secretion. This reduction in aqueous secretion depends on the dose. However, increasing the dosage beyond a point does not improve its ability to reduce P.l. O. For timolol, levobunolol and Betaxalol, this point is reached at a concentration of 0.5%, for carteolol at 1% and for metipranalol it is 0.3%. Increasing the concentration beyond these values does not result in a greater reduction in P.I.O. The attempts made to improve its effectiveness have not been successful. In clinical situation, when a greater reduction of P.l. O., another drug is added such as Pilocarpine, Dipivefrin hydrochloride, Dorzdamide, Brimonidine, Latanoprost, etc. The commonly used beta-blocker formulations are aqueous in nature. There are extended-release preparations available for beta-blockers. It is necessary to duplicate the pilocarpine formulation in the sustained release preparations, that is, to obtain the effects of P.l. O. of a 2% pilocarpine solution, a 4% pilocarpine gel is required. Betaxolol is available as Betopitic-s and timolol as Timoptic-XE. In both formulations the vehicle used is different. With this it is possible to reduce the concentration of Betaxolol used, but it is not possible to improve the effect on P.l. O. Similarly, it is possible to reduce the frequency of administration from twice a day to once a day with timoptic-XE. However, the effect of decreasing pressure remains the same. It has been found that formulations made with hydroxylpropylmethylcellulose have no advantage compared to the aqueous formulation.

Similarly, a prolonged release preparation of pilocarpine (Pilopina-HS gel) is also available. This contains Carbopol as a vehicle. The duration of the action is prolonged, but the effect of lowering the pressure is reduced. To obtain the pressure reducing effect similar to that of the aqueous solution, the concentration of pilocarpine in the prolonged release preparations should be doubled, that is, to reduce the P.l. O. As much as a 2% pilocarpine solution, a 4% gel is required. The aim of the present invention is to provide a formulation of beta-blockers with improved efficacy. Another objective of the present invention is to provide a formulation of beta-blockers that stabilizes the tear film. Another objective of the present invention is to provide a formulation of beta-blockers that are effective after long periods of storage. Another objective of the present invention is to reduce to the maximum / eliminate the introduction of Beta-blocker into the circulatory system. Another objective of the present invention is to increase acceptance by reducing / eliminating the side effects of beta-blockers. A further object of the present invention is to provide the formulation in a concentration known to provide the maximum diminution effect of P.l. O. in a conventional aqueous formulation.

In accordance with the foregoing, a method of preparing the topical beta-blocker formulation with improved efficacy is provided, which comprises the following steps: 1) The aqueous solution of Beta-blocker is made, which contains acceptable excipients, stabilizers and preservatives in distilled water. The pH of this solution is adjusted between 7.0 and 7.5. 2) In another vessel, Carbopol is dissolved in water and stirred well to form a gel. Gradually the stabilizers and preservatives are added maintaining the agitation. The pH of the solution is adjusted to a value between 6.5 and 7.5. 3) The solution containing the Beta-blocker, as formulated in step 1, is gradually added to the gel formed in step 2. 4) The volume is completed by adding distilled water as required. 5) Check the pH and adjust as necessary to maintain it on the 7.0 + 0.5 scale. The beta-blockers described in the previous lines can be: timolol 0.5%, Betaxolol 0.5%, Levobunolol 0.5%, Cartelol 1.0%, metipruanolol 0.3% or any other beta-blocker that can reduce P.l. O. in a therapeutic concentration. The carbopol can be carbopol 940, 932 970 or others that form a gel in aqueous solution. The concentration of carbopol in the final formulation can be from 0.5% to 5%.

The pH regulator that can be used can be any that is used in topical ophthalmic preparations, for example, dibasic sodium phosphate, monobasic sodium phosphate, etc. The preservative can be EDTA, benzalkonium chloride, Cetrimide, or any other that can be used in topical ophthalmic preparations, in a recommended dosage. The pH is usually acidic and it is necessary to adjust it with sodium hydroxide. The final product is autoclaved and placed in sterile containers.

EXAMPLE OF FORMULATION I. Timolol 0.5% Timolol Maleate 0.72 gm equivalent to 0.5gm timolol Benzalkonium Chloride 0.0107 gm Carbopol 940 2.0 gm Sodium hydroxide to adjust pH 6.5 to 7.5 Water for injection c.b.p. 100 ml II. Betaxolol 0.5% Betaxolol hydrochloride 0.56 gm equivalent to 0.5 gm of Betaxolol Benzalkonium chloride 0.01 gm Dibasic sodium phosphate 0.05 gm Sodium mono basic phosphate 0.025 gm Disodium EDTA 0.05 gm Sodium chloride 0.30 gm Propylene glycol 2.50 gm Carbopol 940 2.00 gm Water for cbp injection 100 ml of solution The pharmaceutical composition thus prepared is evaluated for its stability and efficacy. The pharmaceutical composition thus prepared is evaluated at different temperature and humidity test conditions (45 ° C, 37 ° C a 80% relative humidity and room temperature), for intervals that extend up to 12 months. Samples of the formulation were taken for study. The formulation of timolol 0.5% prepared as described (new formulation) was evaluated in healthy volunteers, as well as in eyes with elevated intraocular pressure.

In a parallel study of unit doses with 11 patients, 0.5% timolol drops (conventional formulation) were applied to one eye and the new formulation was applied to the other eye. Timolol droplets produced a decrease in P.l. O. of 23.49%, while the new formulation produced a decrease in P.I.O. 38.7% In a single-dose crossover study (10 eyes) the new formulation, as well as the conventional formulation (eye drops) were put in the same eye on different days, but at the same time of day. It was found that the reduction of P.l. O. with the conventional formulation was 22.36%, while with the new formulation it was 37.7%. In this way the improved efficacy of the new formulation is established as well as the efficacy in healthy volunteers. Similarly, in glaucomatous eyes (14), both formulations were evaluated (conventional and new). Even in glaucomatous eyes the reduction of P.l. O. observed was much higher than that observed with the conventional formulation. With the conventional formulation, the reduction was 33.35%, while with the new formulation, the decrease in P.l. O. was 44.4% The effect on the reduction of P.l. O. observed in glaucomatous eyes was further evaluated by long-term applications in 14 eyes. It was found that the effect is maintained even in a long-term application. The decrease in P.l. O. in glaucomatous eyes was 44.4% in 15 days, 43.6% in one month and 43.6% in a three-month interval. In this way it was found that the new formulation has an improved efficacy in glaucomatous eyes. This improved efficiency was found to persist even in a long-term application. Like the eye drops of timolol, when increasing the concentration of timolol in the new formulation from 0.5% to 1.0%, no greater decrease in P.l. O. However, the above did result in a longer duration of its action. When other anti-glaucoma drugs were added to therapy, in people using the new formulation it was found that P.l. Or it was reduced even more. This additional reduction of P.l. O. was as good as that observed with the combination of antiglaucoma drugs with eye drops of timolol. Similarly, when the formulation was made with other beta-blockers, such as Betaxolol, according to the procedure described in this invention, it was also found that they produced a greater decrease in P.l. O. compared with the conventional formulation. It is known that viscous formulations traditionally made to be used as topical ophthalmic preparations cause alterations in vision. However, none of the people with whom the new formulation was used complained of visual disturbances 5 minutes after the application of the new formulation.

Claims (8)

NOVELTY OF THE INVENTION CLAIMS

1. - A method of making the topical formulation of beta-blockers with improved efficacy comprising the following steps: i) preparing an aqueous solution of Beta-blocker with or without physiologically acceptable excipients, stabilizers and preservatives; i) b preparing a gel of a known substance that forms gel with or without physiological excipients, stabilizers and preservatives in another container; ii) add the aqueous solution of beta-blockers from step (a) in the gel prepared from step i (b) while stirring slowly; Ii) adjust the pH and volume before giving the final treatment in the autoclave and packing it.

2. The method according to claim 1, further characterized in that the beta-blockers can be selected from the topical beta-blockers used to reduce the intraocular pressure, for example Timolol, Betaxolol, Carteoiol, Metipranalol.

3. The process according to any of claims 1 and 2, further characterized in that the gel-forming agent can be carbopol.

4. The process according to any of claims 1 to 3, further characterized in that the concentration of carbopol can be from 0.5% to 5%.

5. - The method according to any of claims 1 to 4, further characterized in that physiologically acceptable stabilizers, excipients and preservatives are used.

6. The process according to any of claims 1 to 5, further characterized in that the pH of the formulation is finally adjusted to values between 6.0 and 8.0, preferably between 6.5 and 7.5.

7. The process according to any of claims 1 to 6, further characterized in that the formulation is processed in an autoclave before being packaged.

8. The process according to claim 1 and substantially described herein in examples I and II in the attached specification. SUMMARY OF THE INVENTION Beta-blockers are used as a topical ophthalmic preparation to reduce intraocular pressure; The B-blocker used for this purpose includes timolol, levobunolol, carteolol, metipranalol; reduce the aqueous production, so that the P.l. OR.; They are usually used as drops; the effectiveness of topical B-blockers depends on the concentration of drug in the formulation; however, increasing the concentration of the drug beyond the approved dosage forms does not increase efficacy significantly, for example, timolol 0.5% has an identical capacity of pressure decrease, like timolol 1%; Attempts to improve the effectiveness of pressure reduction of B-blockers have not been met successfully so far; the sustained release formulation of timolol (Timolol XE) has resulted in an amount of drug to achieve the same therapeutic effect; however, none of the formulations have improved drug efficacy to reduce P.l. OR.; The present invention relates to the process of making said B-blocker formulation which improves the diminution effect of P.l. OR.; the formulation thus prepared does not irritate and is of optimum tolerance; the procedure to elaborate the new formulation with improved efficacy covers the use of carbopolol and conservative; 0.5% timolol gel formulated by using the procedure was evaluated in normal as well as glaucomatous eyes; The reduction in P.I.O. it is approximately 15% more than what is found with drops in normal individuals; similar findings are also observed in glaucomatous eyes. RR / cgt * P01 / 939F