WO1995025518A1

WO1995025518A1 - Aqueous solution of levocabastine for ophthalmic use

Info

Publication number: WO1995025518A1
Application number: PCT/IB1995/000143
Authority: WO
Inventors: Gene F. Tutwiler; Ramon L. Espino
Original assignee: Ciba-Geigy Ag
Priority date: 1994-03-18
Filing date: 1995-03-08
Publication date: 1995-09-28
Also published as: AU1716995A; IL112947A0; ZA952203B

Abstract

Levocabastine hydrochloride, (-)-[3S-[1(cis),3α,4β]]-1-[4-cyano-4-(4-fluorophenyl)-cyclohexyl]-3-methyl-4-phenyl-4-piperidinecarboxylic acid monohydrochloride, a potent hydrophobic antihistamine, has been prepared as a homogeneous aqueous solution containing hydroxypropyl-β-cyclodextrin as the solubilizing agent. The solution is useful in the treatment of allergic conjunctivitis.

Description

Aqueous solution of levocabastine for ophthalmic use

This invention relates to aqueous ophthalmic formulations for the treatment of ophthalmic allergic conditions. In particular, the invention relates to aqueous ophthalmic solutions for the treatment of ophthalmic allergic conditions wherein the active ingredient is levocabastine hydrochloride, whose chemical name is (-)-[3S-[l(cis),3α,4β]]-l-[4-cyano- 4-(4-fluorophenyl)-cyclohexyl]-3-methyl-4-phenyl-4-piperidinecarboxylic acid monohydrochloride, and whose molecular structure is the following:

Levocabastine is disclosed and claimed in Stokbroekx et al., U.S. Patent No. 4,369,184. EP 0 149 197 A2 discloses pharmaceutical preparations of cyclodextrin complexes with various pharmaceutical products, including levocabastine.

The characteristic signs and symptoms of ocular allergy include itching, swelling and red-eye and are induced by the local release of histamine. Levocabastine has been used to treat ophthalmic allergic conditions but only in the form of a suspension due to its limited solubility in aqueous media. The difficulties attendant to the use of suspensions in the treatment of ophthalmic conditions are well known. It is desirable, therefore, to provide a clear aqueous solution of levocabastine for the treatment of ophthalmic allergic conditions.

Levocabastine is a new, potent, and specific anti-histamine agent with a specific binding capacity on the HI -receptor. It is used in the treatment of ophthalmic allergic conditions in the form of its hydrochloride salt. It is a very hydrophobic compound with limited solubility in water. For this reason, a suspension, instead of a solution, of levocabastine has been employed for the treatment of ophthalmic conditions such as allergic conjunctivitis. However, given the heterogeneous nature of a suspension, vigorous shaking of the container before use is required to achieve a consistent dose for administration. It has been found that patient compliance decreases when a suspension is administered because of the inconvenience associated with such formulations. In contrast, a solution provides a homogeneous and consistent dosage with each application, which leads to better patient compliance. Moreover, suspensions are contraindicated for contact lens users, because of the particulate nature of the formulation. For these and others reasons, suspensions of levocabastine can not be universally employed in the treatment of ophthalmic allergic conditions.

One object of the present invention is to provide an aqueous ophthalmic solution for the treatment of ophthalmic conditions.

Another object of the present invention is to provide an aqueous ophthalmic solution for the treatment of ophthalmic conditions in which the active ingredient is levocabastine.

A further object of the present invention is to provide a method of treating ophthalmic allergic conditions which comprises the topical administration of an aqueous solution containing levocabastine as the active ingredient.

Another object of the present invention is an aqueous ophthalmic solution as defined in the main claim for the treatment of ocular allergic conditions.

Another object of the present invention is the use of an aqueous ophthalmic solution as defined in the main claim in the preparation of a pharmaceutical composition for the treatment of ocular allergic conditions.

The aqueous opthalmic solutions of the present invention are comprised of about 0.001 to about 2.0 % weight/volume of levocabastine, about 0.1 to about 20.0 % weight/volume of a solubilizing agent, about 0.001 to about 2.0 % weight/volume of a stabilizing agent, about 0.001 % to about 5.0 % weight/volume of a buffer, about 0.01 % to about 5.0 % weight/volume of a tonicity agent and sufficient water to adjust the formulation to 100 %.

As the solubilizing agent any suitable surfactant may be employed. Suitable solubilizing agents are for example polysorbates such as polysorbate 20, polysorbate 60 or poly- sorbate 80; pluronics such as, for example, poloxamer 124, poloxamer 188, poloxa- mer 182 LF or poloxamer 331; or derivatives of cyclodextrin such as, for example, hydroxypiOpyl-β-cyclodextrin (HP-β-CD), α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, dimethyl, hydroxypropyl, glucosyl, maltosyl and maltotriosyl derivatives of β-cyclo- dextrin as well as dimethyl, hydroxyethyl, hydroxypropyl, glucosyl, maltosyl and maltotriosyl derivatives of α-cyclodextrin. In those cases where the solubilizing agent is a base, the base may be employed as the free base or as the pharmaceutically acceptable acid addition salt. Such pharmaceutically acceptable salts are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a hydrohalic acid, for example hydrochloric or hydrobromic acid. The preferred solubilizing agent is hydroxypropyl-β-cyclodextrin, in particular, hydroxypropyl- β-cyclodextrin having an MS (molar substitution - that is, number of substituents per glucose unit in the cyclodextrin molecule) of about 0.5. The solubilizing agent increases the solubility of levocabastine thus making the drug more bioavailable in the solution that it is in the known suspension formulations. The solubilizing agent is present in an amount of about 0.1 - 20.0 % weight/volume, preferably in an amount of about 0.5 - 15 % weight/volume and more preferably in an amount of about 1 - 10 % weight/volume.

As the stabilizing agent compounds such as the alkaline earth and the alkali metal salts of ethylenediaminetetraacetic acid (EDTA), edetate-disodium, edetate-dipotassium, sodium metabisulfite, ascorbic acid, acetyl crysteine, butylated hydroxyanisole, 2,6-di-tert- butyl-p-cresol and vitamin E may be employed. The purpose of the stabilizing agent is to prevent chemical degradation of the active ingredient. The stabilizing agent is present in an amount of about 0.001 - 2.0 % weight/volume, preferably in an amount of about 0.005 - 1.5 % weight/volume and more preferably in an amount of about 0.01 - 1.0 % weight/volume.

The pH of the ophthalmic formulation must be maintained preferably between 4.0 and 8.0, more preferably between 5.0 and 8.0 and even more preferably between 6.0 and 8.0. For this reason buffers are added to the formulation. Examples of buffer substances are acetate, ascorbate, borate, hydrogen carbonate/carbonate, citrate, gluconate, lactate, sulfate, phosphate, propionate and TRIS (tromethamine) buffers. Tromethamine and borate buffer are preferred buffers. The amount of buffer substance added is, for example, from about 0.001 - 5.0 % weight/volume, preferably from about 0.01 - 4.0 % weight/volume and more preferably from about 0.1 - 3.0 % weight/volume.

Tonicity agents are employed in the formulation in order to yield a final product which is physiologically isotonic. Suitable tonicity agents are, for example, ionic compounds, such as alkali metal or alkaline earth metal halides, such as, for example, CaCl₂, KBr, KC1, LiCl, Nal, NaBr or NaCl, or boric acid. Non-ionic tonicity agents are, for example, urea, glycerol, sorbitol, mannitol, propylene glycol, or dextrose. Such a tonicity agents is present in amount of about 0.01 - 5.0 % weight/volume, preferably in an amount of about 0.05 - 2.0 % weight/volume and more preferably in an amount of about 0.1 - 1.0 % weight/volume.

When the formulation of the present invention is packaged in a unit-dose container, the risk of microbial contamination is small and, therefore, the use of a preservative is not required. Ophthalmic products, however, are typically packaged in multiple-dose containers. Preservatives are often employed in multiple dose containers to prevent microbial contamination of the formulation during use or storage after use. Examples of preservatives which can be employed in the formulation of the present invention include benzalkonium chloride, thiomersal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, sorbic acid and sepazonium chloride. When employed as an ingredient in the formulation, the preservative will generally comprise from about 0.0001 to about 2.0 % and preferably from about 0.001 to about 1.0 % weight/volume of the formulation.

It may be desirable to add a viscosity agent to the formulation in order to prolong the residence time of the solution on the surface of the eye to gain an increased absorption and/or adsorption of the active ingredient, to decrease variability in dispensing the formulation and/or to otherwise improve the properties of the ophthalmic formulation. Suitable viscosity agents which can be employed in the formulation of the present invention include polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxy¬ propyl methylcellulose, hydroxyethyl cellulose, carboxymethylcellulose and hydroxy¬ propyl cellulose. Generally, the viscosity agent, when employed, will comprise from about 0.01 to about 2.0 % and preferably from about 0.1 to about 1.0 % weight/volume of the formulation.

The formulations of the present invention enhance the solubility of levocabstine and thus achieve a therapeutically active concentration of the drug in the aqueous solution. Moreover, the higher concentration of dissolved levocabastine in the solution of the present invention, when compared to that obtained in the suspension, provides greater availability of the drug for the treatment of the ophthalmic allergic condition. Thus, a higher level of the drug can be achieved in the eye in a relatively short time which results in rapid onset of the physiological effect. The compositions of the present invention are administered topically to the eye. The dosage range of the levocabastine administered is from about 0.0001 to about 5.0 mg per eye. The compositions can be administered directly or as solutions in a suitable ophthalmic vehicle. While the precise regimen to be employed is left to the discretion of the prescribing physician, it is generally recommended that the formulation be topically applied by placing one or two drops in each eye for about one to four times a day.

The following examples are used to illustrate the present invention but are not intended to limit the scope of the invention.

Example 1: Levocabastine hydrochloride (269.82 mg) and hydroxyprOpyl-β-cyclodextrin (HP-β-CD) (37.507 g) are dissolved in distilled water (475 ml). Boric acid (5.015 g) sodium chloride (1.258 g) and EDTA-disodium (51.15 mg) are added and the pH is adjusted to 7.20 with 10 % sodium hydroxide. The final volume of the preparation is adjusted to 500 ml by the addition of distilled water to give the composition shown in Table 1.

Table 1

Composition of 0.05 % aqueous levocabastine solution

Levocabastine.HCl 0.054 %

HP-β-CD 7.5 %

Boric acid 1.0 %

NaCl 0.25 %

Edetate-disodium 0.01 %

Water q.s. 100 %

Example 2: Levocabastine hydrochloride (81.52 mg) and HP-β-CD (12.5 g) are dissolved in distilled water (230 ml). Boric acid (2.5 g) sodium chloride (0.7 g) and EDTA disodium (25 mg) are added and the pH is adjusted to 7.11 with 10 % sodium hydroxide. The final volume of the preparation is adjusted to 250 ml by the addition of distilled water to give the composition shown in Table 2. Table 2

Composition of 0.03 % aqueous levocabastine solution

Levocabastine-HCl 0.033 %

HP-β-CD 5.0 %

Boric acid 1.0 %

NaCl 0.28 %

Edetate-disodium 0.01 %

Water q.s. 100 %

Example 3: LevocabastincHCl (27.25 g) and HP-β-CD) (8.75 g) are dissolved in distilled water (230 ml). Boric acid (2.5 g), sodium chloride (0.75 g) and EDTA-disodium (25 mg) are added and pH is adjusted to 7.2 with 10 % sodium hydroxide. The final volume of the preparation is adjusted to 250 ml by distilled water to give the composition shown in Table 3.

Table 3

Composition of 0.01 % aqueous levocabastine solution

Levocabastine-HCl 0.0109 %

HP-β-CD 3.5 %

Boric acid 1.0 %

NaCl 0.30 %

Edetate-disodium 0.01 %

Water q.s. 100 %

Example 4: Bioavailability Study

Method: Two trops of an 0.05 % aqueous levocabastine suspension and two trops of an 0.05 % aqueous levocabastine solution are applied to the lower cul de sac of NZW rabbits (2.5-3 kg body weight). At various time points rabbits are sacrificed (n=5/time point) and the aqueous humor and the blood are collected. Plasma is fractionated by centrifugation. The concentration of levocabastine in these biological fluids is measured using a radio- immuno assay. The area under the concentration-time curve (AUC) between 0 and 24 hours is determined by the trapezoidal rule. The maximum concentration (Cmax) and the time needed to reach the Cmax (Tmax) are estimated by visual approximation. Results

Table 4. Pharmacokinetic parameters from the aqueous humor and plasma concentration- time profiles obtained after the topical administration of a single dose of levocabastine solution and a levocabastine suspension.

Formulation Cmax Tmax AUCQ-24 (ng ml) (hr) (hr-ng/ml)

Aqueous Humor

Solution 53.48* 0.5 96.13*

Suspension 20.44* 0.5 - 1 65.35*

Plasma

Solution 4.81^* 2 38.84*

Suspension 1.61^* 3 - 4 26.32*

: Significant difference (P > 0.05) between solution and suspension applications using the unpaired Student's t test

From the results, it is noted that the bioavailability and Cmax in the aqueous humor and plasma are increased by 1.5-2 times with administration of the solution over the administration of the suspension. In addition, the time needed to reach the Cmax is shorter for the solution.

Example 5: Pharmacological Efficacy study

Method: Two drops each of aqueous levocabastine solutions, at 0.01 %, 0.03 % and 0.05 %, two drops of an aqueous levocabastine suspension at 0.05 % are administered to one eye of NEW rabbits (n=8/treatment). The contralateral eye is treated with the corresponding placebo. One drop of histamine solution (25 mg/ml) is applied to each eye at 15 minutes after the drug/placebo dosing to induce the allergic reactions. Palpebral and bulbar chemosis are evaluated using a scale from 0 to 3 according to the severity of the response at the various time points after the histamine challenge. The difference beween the score obtained from drug treatment and placebo treatment is obtained by subtracting the score of the drug treatment from that of each corresponding placebo treatment.

The summarized results indicate that the 0.01 %, 0.03 %, and 0.05 % levocabastine solution and the 0.05 % levocabastine suspension effectively inhibit bulbar and palpebral chemosis after the histamine challenge.

The results further demonstrate that the levocabastine solutions and the levocabastine suspension effectively inhibit bulbar and palpebral chemosis within about 3 to 5 minutes after the histamine challenge. The maximum inhibiting effect for both the solutions and the suspension is obtained after about 20 to 40 minutes.

Claims

1. An aqueous ophthalmic solution comprising 0.001 - 2.0 weight % of levocabastine, 0.1 - 20.0 weight % of a solubilizing agent, 0.001 - 2.0 weight % of a stabilizing agent, 0.001 - 5 weight % of a buffer, 0.01 - 5.0 weight % of a tonicity agent and water to adjust the formulation to 100 %.

2. An aqueous ophthalmic solution according to claim 1, wherein the solubilizing agent is present in an amount of about 0.5 - 15 weight %.

3. The aqueous ophthalmic solution of claim 1 wherein the solubilizing agent is selected from polysorbate, pluronic, and derivatives of cyclodextrins.

4. The aqueous ophthalmic solution of claim 1 wherein the stabilizing agent is selected from edetate disodium, sodium metabisulfite, ascorbic acid, acetyl cysteine, butylated hydroxyanisole, 2,6-di-tert-butyl-p-cresol, vitamin E and cyclodextrins.

5. An aqueous ophthalmic solution according to claim 1, wherein the stabilizing agent is present in an amount of about 0.005 - 1.5 weight %.

6. The aqueous ophthalmic solution of claim 1 wherein the buffer is selected from alkali metal acetates, monobasic phosphates, dibasic phosphates, borates, citrates, sulfates and boric acid.

7. An aqueous ophthalmic solution according to claim 1, wherein the buffer is present in an amount of about 0.01 - 4.0 weight %.

8. The aqueous ophthalmic solution of claim 1 wherein the tonicity agent is selected from ionic compounds, such as alkali metal or alkaline earth metal halides, such as, for example, CaCl₂, KBr, KCl, LiCl, Nal, NaBr or NaCl, or boric acid; or wherein the tonicity agent is selected from non-ionic tonicity agents such as urea, glycerol, sorbitol, mannitol, propylene glycol, or dextrose.

9. The aqueous ophthalmic solution of claim 1 which comprises about 0.05 % of levocabastine, 7.5 % of hydroxypropyl-β-cyclodextrin, 0.01 % edetate disodium, 1.0 % boric acid and 0.25 % sodium chloride.

10. The aqueous ophthalmic solution of claim 1 which comprises about 0.03 % of levocabastine, 7.5 % of hydroxypropyl-β-cyclodextrin, 0.01 % edetate disodium, 1.0 % boric acid and 0.28 % sodium chloride.

11. The aqueous ophthalmic solution of claim 1 which comprises about 0.01 % of levocabastine, 3.5 % of hydroxypropyl-β-cyclodextrin, 0.01 % edetate disodium, 1.0 % boric acid and 0.3 % sodium chloride.

12. The aqueous ophthalmic solution of claim 1 wherein the pH is between 4.0 and 8.0.

13. The aqueous ophthalmic solution of claim 1, 9, 10 and 11 wherein a preservative is additionally present.

14. The aqueous ophthalmic solution of claim 13 wherein the preservative is selected from the group consisting of benzalkonium chloride, thiomersal, chlorobutanol, methylparaben, propyl- paraben, phenylethyl alcohol, sorbic acid and sepazonium chloride.

15. The aqueous ophthalmic solution of claim 14 wherein the preservative comprises 0.0001 to 2.0 weight % of the formulation.

16. The aqueous ophthalmic solution of claim 1, 9, 10 and 11 wherein a viscosity agent is additionally present.

17. The aqueous ophthalmic solution of claim 16 wherein the viscosity agent is selected from poly- vinyl alcohol, polyvinylpyrrolidone methylcellulose, hydroxypropylmethylcellulose, hydroxyethyl- cellulose, carboxymethylcellulose and hydroxypropylcellulose.

18. The aqueous ophthalmic solution of claim 17 wherein the viscosity agent comprises 0.01 to 2.0 weight % of the formulation.

19. A method of treating ocular allergic conditions which comprises administering topically to the affected eye an effective amount of an aqueous ophthalmic solution as defined in claim 1.

20. A method of treating allergic conjunctivitis which comprises administering topically to the affected eye an effective amount of an aqueous ophthalmic solution as defined in claim 1. PCMB95/00143 WO 95/25518

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21. Aqueous ophthalmic solution as defined in claim 1 for the treatment of ocular allergic conditions.

22. Use of an aqueous ophthalmic solution as defined in claim 1 in the preparation of a pharmaceutical composition for the treatment of ocular allergic conditions.