WO2005101982A2

WO2005101982A2 - A stable ophthalmic composition

Info

Publication number: WO2005101982A2
Application number: PCT/IN2005/000090
Authority: WO
Inventors: Subhas Balaram Bhowmick; Shrenik Popatlal Shah; Ajay Khopade
Original assignee: Sun Pharmaceutical Industries Limited
Priority date: 2004-03-24
Filing date: 2005-03-24
Publication date: 2005-11-03
Also published as: WO2005101982A3

Abstract

The present invention provides a stable ophthalmic composition comprising ketorolac or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipient(s), wherein the said pharmaceutically acceptable excipient(s) is not tocophersolan, and the said ophthalmic composition is nonirritating to the eye.

Description

A STABLE OPHTHALMIC COMPOSITION

FIELD OF THE INVENTION The present invention relates to a stable ophthalmic composition comprising ketorolac or its pharmaceutically acceptable salts, wherein the composition is nonirritating to the eye.

BACKGROUND OF THE INVENTION

A major cause of non-compliance of patients to ophthalmic preparations is the discomfort associated with instilling them into the eye. Discomfort in the form of irritation or pain may be caused due to various reasons, which includes compositions having unfavorable osmotic pressure or pH, or due to formulations containing an irritating component, which could be the drug, preservative, surfactant or any other excipient that may be used as a carrier.

Acidic drugs with carboxyl groups, including most nonsteroidal anti-inflammatory drugs, are inherently irritating to the eye and cause severe ocular discomfort including stinging and excessive tear generation when instilled into the eye.

United States Patent No. 4,089,969 claims ketorolac which is chemically 5-Benzoyl-2,3-dihydro- lH-pyrrolizine-1-carboxylic acid, and is a nonsteroidal anti-inflammatory drug of the pyrrolo- pyrrole group. United States Patent No. 4,454,151 claims its use in treating inflammation and treating corneal neovascularisation.

United States Patent No. 5,110,493 with a priority date of Sep 11, 1987 discloses an ophthalmic formulation of ketorolac tromethamine comprising benzalkonium chloride and ethoxylated alkyl phenol, the ethoxylated alkyl phenol being octoxynol 40, which has been added to obtain a stable formulation. This composition was approved for use in the United States in November 1992 and is marketed as ACULAR®. The label for this formulation mentions that transient stinging and burning of the eye were the most frequent adverse effects reported. These events were reported by up to 40% of patients participating in clinical trials. Subsequently, various attempts have been made to formulate comfortable ophthalmic compositions of nonsteroidal anti-inflammatory drugs.

United States Patent No. 5,886,030 with a priority date of May 6, 1994 claims an ophthalmic composition of a steroidal or non-steroidal anti-inflammatory drug comprising Vitamin E tocopherol polyethylene glycol succinate (Nit E TPGS) in an amount effective to reduce the discomfort and irritation associated with ocular application. This patent however does not specifically exemplify suitable ophthalmic formulations of ketorolac tromethamine.

United States Patent No. 5,558,876 with a priority date of Mar 29, 1995 also discloses an aqueous ophthalmic composition of an acidic drug, tocophersolan (Nit E TPGS) and caffeine wherein tocophersolan is used to reduce ocular discomfort and solubilise the drug, and caffeine reduces discomfort and also potentiates the preservative efficacy of benzalkonium chloride in the formulation. This patent also does not specifically exemplify suitable ophthalmic formulations of ketorolac tromethamine.

Thus the earlier known attempts to provide ophthalmic compositions of acidic drugs with reduced irritation or discomfort were directed towards the use of tocophersolan (Nit E TPGS). In the present invention an attempt has been made to provide a stable ophthalmic composition of ketorolac comprising pharmaceutically acceptable excipients that are nonirritating to the eye, wherein the pharmaceutically acceptable excipient is not tocophersolan.

Particularly in the present invention a stable ophthalmic composition of ketorolac or its pharmaceutically acceptable salts is provided comprising a cellulose or cellulose derivative such that the composition is nonirritating to the eye.

OBJECT OF THE INVENTION

The object of the present invention is to provide a stable ophthalmic composition comprising ketorolac or its pharmaceutically acceptable salts, and one or more pharmaceutically acceptable excipients, wherein the said composition is nonirritating to the eye.- SUMMARY OF THE INVENTION

The present invention relates to a stable ophthalmic composition comprising ketorolac or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, wherein the said pharmaceutically acceptable excipient is not tocophersolan, and the said, ophthalmic composition is nonirritating to the eye.

The present invention particularly relates to a stable ophthalmic composition comprising ketorolac or its pharmaceutically acceptable salts and a cellulose or cellulose derivative, wherein the said composition is nonirritating to the eye.

DETAILED DESCRIPTION OF THE PRESENT INVENTION The present invention provides a stable ophthalmic composition comprising ketorolac or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, wherein the said composition is nonirritating to the eye.

A nonirritating ophthalmic composition according to the present invention is a composition which when instilled into the eye does not cause stinging or burning sensation, excessive tear generation, pain or any such kind of discomfort.

Ketorolac or any of its pharmaceutically salts including the tromethamine or an amide salt, can be used in the ophthalmic compositions of the invention. Ketorolac or its pharmaceutically acceptable salts maybe used in an amount ranging from about 0.005% to about 1% w/v.

The stable ophthalmic composition of the present invention may use one or more pharmaceutically acceptable excipients selected from groups such as an osmogent, surfactant, preservative, buffer, cellulose or cellulose derivative, a chelating agent and the like.

hi the stable ophthalmic compositions of the present invention, cellulose and cellulose derivatives that can be used, include, but are not limited, to hydroxy propyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), methyl cellulose (MC), ethyl cellulose (EC), hydroxyethyl cellulose (HEC) or carboxymethyl cellulose (CMC) and the like and mixtures thereof. Various grades of hydroxypropyl mefhylcellulose may be used in the present invention. The grades available are categorized depending upon the chemical substitution and hydration rates. Hydroxypropyl methylcellulose having methoxy content of 19-24 % and hydroxypropyl content of 7-12 % with a fastest relative rate of hydration is available commercially under the brand name of Methocel Grade K. Hydroxypropyl methylcellulose with 28-30 % methoxy content and 7-12 % of hydroxypropyl content with a faster relative hydration rate as compared to the above grade is available commercially under the brand name of Methocel Grade E. Hydroxypropyl methylcellulose with 27-30 % methoxy content and 4-7.5 % of hydroxypropyl content with a slow relative hydration rate is available as Methocel F grade and that with 27.5- 31.5 % methoxy content and 0 % hydroxypropyl content and with slowest rate of hydration is available as Methocel Grade A. The cellulose or its derivatives may be used in amounts ranging from about 0.01% to about 5%w/v, and more preferably in the amounts ranging from about 0.05% to about 1 %w/v and most preferably in an amount ranging from about 0.1% to about 0.5%w/v. hi preferred embodiments of the stable ophthalmic composition of the present invention, hydroxypropyl methylcellulose with a viscosity ranging from about 3500 mPas to about 5600 mPas of a 2% w/v aqueous solution, commercially available as Methocel E4 is used. i the stable ophthalmic composition of the present invention, any ophthalmically acceptable surfactant may be used. The opthalmically acceptable surfactants used include nonionic surfactants and cationic surfactants. The nonionic surfactant may be selected from the group comprising polyoxyethylene sorbitan esters, polyethoxylated castor oils, polyefhoxylated hydrogenated castor oils, ethoxylated alkyl phenol and the like or mixtures thereof. The cationic surfactants may be selected from the class of quaternary ammonium compounds comprising benzalkonium chloride, lauralkonium chloride, alkyl triethanol ammonium chloride, benzethonium chloride, cetyltrimethylammonium bromide, DYMED, POLYQUAD and the like, and mixtures thereof. The surfactant may be used in pharmaceutical compositions to enhance stability, aid solubility and achieve clarity of preparation in the concentrations and may be used in amounts ranging from about 0.05% to about 1.0%w/v. A preservative agent may be added in the stable ophthalmic composition of the present invention to protect the solution composition from microbial contamination. Examples of such preservatives include, but are not limited to, cationic surfactants such as quaternary ammonium compounds, organic mercurials, parabens, and their salts, organic alcohols, phenols, potassium sorbate, sodium benzoate and the like and mixtures thereof. The preferred preservatives are quaternary ammonium compounds. They may be used in amounts ranging from about 0.005% to about l%w/v.

Examples of osmogents that may be used in the stable ophthalmic composition of the present invention include all pharmaceutically acceptable and pharmacologically inert water-soluble compounds referred to in the pharmacopoeias such as United States Pharmacopoeia, as well as in Remington: The Science and Practice of Pharmacy; edition 19; Mack Publishing Company, Easton, Pennsylvania (1995). Pharmaceutically acceptable water-soluble salts of inorganic or organic acids, or non-ionic organic compounds with high water solubility, e.g. carbohydrates such as sugars, or amino acids, are generally preferred. The examples of agents used for rendering the solution isoosmotic include inorganic salts such as magnesium chloride, magnesium sulfate, lithium, sodium or potassium chloride, lithium, sodium or potassium hydrogen phosphate, lithium, sodium or potassium dihydrogen phosphate, sodium carbonate, sodium bicarbonate and the like; salts of organic acids such as sodium or potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, sodium ascorbate and the. like; carbohydrates such as mannitol, sorbitol, arabinose, ribose, xylose, glucose, dextrose, fructose, mannose, galactose, sucrose, maltose, lactose, raffmose, inositol, xylitol, maltitol and the like; water-soluble amino acids such as glycine, leucine, alanine, me hionine and the like; urea and the like, and mixtures thereof. Preferred osmogent is sodium chloride, which may be added in an amount, which renders the solution isoosmotic.

Chelating agents that may be used in the stable ophthalmic composition of the present invention are selected from a group comprising edetic acid, edetic acid salts like disodium edetate, sodium edetate, edetate calcium disodium and trisodium edetate, malic acid and the like and mixtures thereof. The pH of the stable ophthalmic composition of the present invention may be adjusted using suitable pH adjusting agents, selected from a group of buffering agents, comprising lactic acid, citric acid, tartaric acid, phosphoric acid, acetic acid, hydrochloric acid, nitric acid, tromethamine, sodium or potassium metaphosphate, sodium or potassium phosphate, sodium or potassium acetate, ammonia, sodium carbonate, sodium or potassium hydroxide, dibasic sodium phosphate, sodium borate, and the like and mixtures thereof. Strong mineral acids like hydrochloric acid or strong bases such as sodium hydroxide may also be used for adjusting pH. The pH may be adjusted between 5.0 to 8.0 and more preferably between 7.0 to 8.0.

The stable ophthalmic compositions of the present invention may be in the form of a solution or a suspension. In preferred embodiments the stable ophthalmic compositions of the present invention may be prepared by dissolving the excipients such as chelating agent, preservative, surfactant, buffers and drug in water, dispersing or solubilising the cellulose polymer in a sufficient amount of water, mixing the two solutions and adjusting the pH between 7.00 - 7.40.

The invention is further illustrated by the following examples, which are by no means intended to limit the scope of the invention but are given by way of illustration.

Example 1

The stable ophthalmic composition of the present invention was obtained as per the formula given in Table 1. Table 1

Disodium EDTA, sodium chloride, tromethamine, benzalkonium chloride and Polysorbate 80 were dissolved one by one in 40% Water for Injection (WFI). The ketorolac tromethamine was added to this solution and stirred. HPMC E4M was dispersed in hot WFI (80-90°C) with constant stirring and allowed to cool to 40°C. Ice chilled water was added in it with stirring to get a clear solution. This HPMC phase was added to the drug phase and pH was checked. pH of solution was adjusted between 7.00 to 7.40 with sodium hydroxide solution and final volume was made up. Solution was stirred for 30 minutes. Example 2

The eye irritation potential of the formulation of example 1 and that of the commercially available ACULAR ophthalmic drops (Batch No 24907) were studied. A cell based cytotoxicity test for the assessment of eye irritation potential was used. The cell based test used was the Neutral Red Uptake assay (NRU assay), which has been widely used in the art and which measures the ability of a test substance to inhibit the uptake of neutral red dye, a marker of cell viability.

hi the current test, rabbit corneal cells (SIRC line) were cultured in presence of the test compounds, the irritation of which was determined by their effect upon cell viability which was in turn indicated by a decrease in cell number, as measured by the uptake of the neutral red dye.

The assay was performed as per the protocol known in the art. The typical procedure in brief is given below. The rabbit corneal cells (SIRC cells) were trypsinized and added to a 96-well micro titer plate such that the cell density was 3.4 X 10⁴ cells/well (lOOμl). The growth medium used was Minimum Essential Medium (MEM) along with New Born Calf Serum (NBCS). The plates were incubated for 24 hours at 37°C. The Neutral red dye solution (40μg/ml) was incubated overnight and centrifuged at 2500 rpm for 30 minutes and lOOμl/well of the supernatant was added to the plate. This plate with Neutral red dye was incubated for 3.0 hours at 37°C. Then the dye solution was decanted and the plate blotted on tissue paper and washed by phosphate buffer saline (PBS) (200ul/ml) and again blotted on tissue paper. The test samples, diluted appropriately, along with the positive and negative controls were added to the plate and incubated at 37°C + 5% CO for 30.0 minutes. MEM was used as the sample diluent medium. Then the plate was treated with fixation solution (0.5% formaldehyde & 1% calcium chloride), washed with PBS and treated with extractant solution (1% acetic acid & 50% ethanol). The plate was kept on rotatory-platform shaker for 10 minutes and absorbance read at 540 ran.

The cytotoxicity of the formulation of example 1 and the marketed formulation was calculated by using the following formula:

Percentage cytotoxicity = (Average A_540nm of Negative Control - Average A_540nrn Of samples) X 100 / Average A₅₄o_nm of Negative Control.

It was found that the formulation of example 1 showed 39% cytotoxicity as compared to the marketed formulation ACULAR, which showed 87% cytotoxicity. This shows that the eye irritating potential of the formulation of the present invention is less than that of the marketed formulation.

While the invention has been described by reference to specific embodiments, this was done for purposes of illustration only and should not be construed to limit the spirit or the scope of the invention.

Claims

Claims:

1. A stable ophthalmic composition comprising: (i) ketorolac or its pharmaceutically acceptable salts_^ (ii) pharmaceutically acceptable excipient(s), wherein the said pharmaceutically acceptable excipient(s) is not tocophersolan, and the said ophthalmic composition is nonirritating to the eye.

2. A stable ophthalmic composition as claimed in claim 1, wherein the pharmaceutically acceptable excipient comprises one or more of osmogent, surfactant, preservative, buffer, cellulose or cellulose derivative, and a chelating agent.

3. A stable ophthalmic composition comprising: (i) ketorolac or its pharmaceutically acceptable salts, (ii) a cellulose or cellulose derivative, wherein the said ophthalmic composition is nonirritating to the eye.

4. A stable ophthalmic composition as claimed in claim 3, wherein the cellulose or cellulose derivative is selected from a group comprising hydroxy propyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose and mixtures thereof.

5. A stable ophthalmic composition as claimed in claim 4, wherein the cellulose derivative is hydroxypropyl methyl cellulose.

6. A stable ophthalmic composition as claimed in claim 5, wherein 2% w/v aqueous solution of hydroxypropyl methylcellulose has a viscosity in the range of about 3500 mPas to about 5600 mPas.

7. A stable ophthalmic composition as claimed in claim 6, wherein the hydroxypropyl methyl cellulose is used in an amount ranging from about 0.01% to about 5%w/v.

8. A stable ophthalmic composition as claimed in claim 7, wherein the hydroxypropyl methyl cellulose is used in an amount ranging from about 0.05% to about l%w/v.

9. A stable ophthalmic composition as claimed in claim 8, wherein hydroxypropyl methyl cellulose is used in an amount ranging from about 0.1% to about 0.5%w/v.

10. A stable ophthalmic composition as claimed in claim 3, wherein the pharmaceutically acceptable salt of ketorolac is ketorolac tromethamine.

11. A stable ophthalmic composition as claimed in claim 10, wherein the ketorolac tromethamine is used in an amount ranging from about 0.005% to about 1% w/v.

12. A stable ophthalmic composition as claimed in claim 3, which further comprises a surfactant.

13. A stable ophthalmic composition as claimed in claim 12, wherein the surfactant is a nonionic surfactant, a cationic surfactant or mixtures thereof.

14. A stable ophthalmic composition as claimed in claim 13, wherein the nonionic surfactant is selected from the group comprising polyoxyethylene sorbitan esters, polyethoxylated castor oils, polyethoxylated hydrogenated castor oils, ethoxylated alkyl phenol and mixtures thereof.

15. A stable ophthalmic composition as claimed in claim 14, wherein the nonionic surfactant is a polyoxyethylene sorbitan ester.

16. A stable ophthalmic composition as claimed in claim 15, wherein the polyoxyethylene sorbitan ester is polysorbate 80.

17. A stable ophthalmic composition as claimed in claim 3, which further comprises a chelating agent selected from the group comprising edetic acid, edetic acid salts like disodium edetate, sodium edetate, edetate calcium disodium and trisodium edetate, malic acid and mixtures thereof.

18. A stable ophthalmic composition as claimed in claim 3, which further comprises sodium chloride as an osmogent.

19. A stable ophthalmic composition as claimed in claim 3, which further comprises a buffering agent.

20. A stable ophthalmic composition as claimed in claim 3, wherein the pH of the ophthalmic composition is about 5.0 to about 8.0.

21. A stable ophthalmic composition as claimed in claim 20, wherein the pH of the ophthalmic composition is about 7.0 to about 8.0.