Cysteamine ophthalmic formulation with improved shelf life and in-use period

Abstract

The present invention relates to the pharmaceutical field, preferably to an ophthalmic formulation comprising, cysteamine or pharmaceutically acceptable salt thereof. The present invention also relates to an ophthalmic formulation wherein cysteamine or pharmaceutically acceptable salt thereof is in the form of ophthalmic solution or gel. The present invention further relates to an ophthalmic formulation for use in an ophthalmic disease therapy in an individual and enhances the shelf life and in-use period for the ophthalmic formulation.

Description

[0001] "CYSTEAMINE OPHTHALMIC FORMULATION WITH IMPROVED SHELF LIFE AND IN-USE PERIOD"

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to the pharmaceutical field, preferably to an ophthalmic formulation comprising, cysteamine or pharmaceutically acceptable salt thereof. The present invention also relates to an ophthalmic formulation wherein cysteamine or pharmaceutically acceptable salt thereof is in the form of ophthalmic solution or gel. The present invention further relates to an ophthalmic formulation for use in an ophthalmic disease therapy in an individual and enhances the shelf life and in-use period for the ophthalmic formulation.

[0004] BACKGROUND OF THE INVENTION

[0005] Cystinosis is a rare and very serious congenital condition that could be fatal. Cystinosis is characterized by a cysteine crystal build-up, causing damage to all the organs in the body, especially the kidneys and eyes.

[0006] Cysteine is a non-essential amino acid important for making protein, and for other metabolic functions. Deposition of cystine on the eye can cause significant discomfort throughout the day and require frequent treatment with eye drops, typically every waking hour.

[0007] Several ophthalmic preparations exist for the treatment of cystinosis manifestations, some in capsule form, and others in ophthalmic solution form. In particular, these ophthalmic preparations are used to treat cystine deposits on the eye.

[0008] Cysteamine is a chemical compound that can be biosynthesized in mammals, including humans, by the degradation of coenzyme A. Cysteamine acts as a cystine-depleting agent by converting cystine to cysteine and cysteine-cysteamine mixed disulfides and reduces corneal cystine crystal accumulation. The result is a reduction in cystine crystals.

[0009] Two cysteamine topical ophthalmic preparations (Cystaran® and Cystadrops®) have been approved for the treatment of corneal cystine crystal accumulation in patients with cystinosis. Both products use cysteamine hydrochloride as the salt form in the preparation.

[0010] Cystaran® is the first approved eye-drop preparation. It is composed of a sterile solution of cysteamine hydrochloride 0.65% w / v with benzalkonium chloride and sodium chloride. The product is very unstable and therefore must be kept frozen during long term storage. Once opened, it must be kept in a refrigerated condition and must be discarded after one week. Furthermore, due to the short duration of action, Cystaran® is recommended to be administered frequently to the eye every awake hour.

[0011] Cystadrops® is a viscous eye drop solution formulation composed of a sterile solution of cysteamine hydrochloride 0.55% w / v with benzalkonium chloride, disodium edetate, carmellose sodium, and citric acid monohydrate. The product is packaged in an amber glass and purged with nitrogen gas bubbling to protect cysteamine from oxidation degradation. While this viscous eye drop solution formulation is relatively more stable in the sealed glass container, its stability quickly diminishes over time once opened, and must be discarded after 7 days.

[0012] These were approved in the European Union in 2017 and in the USA in 2020 for the treatment of the ocular manifestations of cystinosis in adults and children from 2 years of age. Cystadrops® was designated an orphan drug by the European Commission with effect from November 2008.

[0013] A lyophilized cysteamine eye drop formulation was developed by Lucane Pharma with an attempt to overcome poor stability, but it failed to obtain regulatory approval for commercialization due to product contamination risk which may have occurred during assembly of the complex container system.

[0014] Therefore, there was a need to develop a new ophthalmic formulation with improved product stability, preferably from oxygen degradation and photo degradation and in-use period.

[0015] SUMMARY OF THE INVENTION

[0016] Main aspect of the present disclosure provides an ophthalmic formulation comprising, cysteamine or pharmaceutically acceptable salt thereof.

[0017] An aspect of the present disclosure provides an ophthalmic formulation comprising, cysteamine or pharmaceutically acceptable salt thereof; at least one polymer; at least one antioxidant; and / or a pharmaceutically acceptable excipients selected from chelating agent(s), antimicrobial agent(s), buffering agent(s), pH adjusting agent(s) and water; wherein cysteamine or pharmaceutically acceptable salt thereof is in the form of ophthalmic solution or gel.

[0018] Another aspect of the present disclosure provides an ophthalmic formulation wherein cysteamine or pharmaceutically acceptable salt thereof is in the form of ophthalmic solution or gel.

[0019] Yet another aspect of the present disclosure provides an ophthalmic formulation for use in an ophthalmic disease therapy in an individual and enhances in-use period for the ophthalmic formulation.

[0020] Still another aspect of the present disclosure provides the ophthalmic formulation, wherein ophthalmic Solution or Gel increases residence time and improves the drug permeation, increases bioavailability, improves patient usability, microbiological quality, and product stability in the presence of light and oxygen, for use in an ophthalmic disease therapy in an individual and enhances in-use period for the ophthalmic formulation.

[0021] DETAILED DESCRIPTION OF THE INVENTION

[0022] At the very outset of the detailed description, it may be understood that the ensuing description only illustrates a particular form of this invention. However, such a particular form is an only exemplary embodiment, and without intending to imply any limitation on the scope of this invention. Accordingly, the description is understood as an exemplary embodiment and teaching of invention and is not intended to be taken restrictively.

[0023] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art to which this invention belongs. Further, unless otherwise required by context, singular terms shall include pluralities, and plural terms shall include the singular. Main embodiment of the present disclosure provides an ophthalmic formulation comprising, cysteamine or pharmaceutically acceptable salt thereof; at least one polymer; at least one antioxidant; and / or a pharmaceutically acceptable excipients selected from chelating agent(s), antimicrobial agent(s), buffering agent(s), pH adjusting agent(s) and water; wherein cysteamine or pharmaceutically acceptable salt thereof is in the form of ophthalmic solution or gel.

[0024] An embodiment of the present disclosure provides an ophthalmic formulation, wherein cysteamine or pharmaceutically acceptable salt thereof is in the form of Ophthalmic Solution or Gel.

[0025] Yet another embodiment of the present disclosure provides the ophthalmic formulation, wherein pharmaceutically acceptable salt of cysteamine is selected from Cysteamine bitartrate, Cysteamine hydrochloride, Cysteamine phosphate, Cysteamine tartrate.

[0026] Still another embodiment of the present disclosure provides the ophthalmic formulation, wherein pharmaceutically acceptable salt of cysteamine is Cysteamine hydrochloride.

[0027] Yet another embodiment of the present disclosure provides the ophthalmic formulation, wherein ophthalmic solution or gel comprises of 3.2 to 4.6 mg / mL of Cysteamine or a pharmaceutically acceptable salt thereof.

[0028] Still another embodiment of the present disclosure provides the ophthalmic formulation, wherein ophthalmic solution or gel comprises of 3.6 to 4.4 mg / mL of Cysteamine or a pharmaceutically acceptable salt thereof.

[0029] Yet another embodiment of the present disclosure provides the ophthalmic formulation, wherein ophthalmic solution or gel comprises of 3.8 mg / mL of Cysteamine or a pharmaceutically acceptable salt thereof. Still another embodiment of the present disclosure provides the ophthalmic formulation, wherein the polymer is selected from a group comprising of Carmellose sodium, Polycarbophil, Hydroxypropyl methylcellulose, Polyvinyl alcohol, Chitosan, Gelatin, Alginate, Poly(acrylic acid), Carbomers, Pluronic F-127 and / or a combination thereof.

[0030] Yet another embodiment of the present disclosure provides an ophthalmic formulation, wherein the polymer can be mucoadhesive.

[0031] Still another embodiment of the present disclosure provides the ophthalmic formulation, wherein the antioxidant is selected from Sodium metabisulfite (SMBS), Sodium sulfate, Sodium sulfite, Sodium thiosulfate, Ascorbic acid, citric acid, Sodium ascorbate, Glutathione, Propyl gallate, Alpha-tocopherol, Butylated hydroxyanisole (BHA) and / or a combination thereof.

[0032] Y et another embodiment of the present disclosure provides an ophthalmic formulation, wherein the antioxidant is Sodium metabisulfite (SMBS).

[0033] Still another embodiment of the present disclosure provides the ophthalmic formulation, wherein ophthalmic solution or gel comprises of 0.1% to 5% of an antioxidant agent.

[0034] Yet another embodiment of the present disclosure provides the ophthalmic formulation, wherein ophthalmic solution or gel comprises of 0.5% to 3% of an antioxidant agent.

[0035] Still another embodiment of the present disclosure provides the ophthalmic formulation, wherein ophthalmic solution or gel comprises of 0.2% of an antioxidant agent.

[0036] Yet another embodiment of the present disclosure provides the ophthalmic formulation, wherein ophthalmic solution or gel comprises of 0.1% to 5% of Sodium metabisulfite.

[0037] Still another embodiment of the present disclosure provides the ophthalmic formulation, wherein ophthalmic solution or gel comprises of 0.5% to 3% of Sodium metabisulfite.

[0038] Yet another embodiment of the present disclosure provides the ophthalmic formulation, wherein ophthalmic solution or gel comprises of 0.2% of Sodium metabisulfite. Still another embodiment of the present disclosure provides the ophthalmic formulation, wherein the formulation further comprises pharmaceutically acceptable excipients selected from antioxidants, polymers, preservatives, tonicity agents, viscosifying agents and / or combination thereof.

[0039] Yet another embodiment of the present disclosure provides the ophthalmic formulation, wherein the preservative is selected from Benzalkonium Chloride, Chlorobutanol, Polyquaternium- 1 , Thimerosal, Sodium Perborate, Purite and Phenylmercuric Nitrate / Acetate.

[0040] Still another embodiment of the present disclosure provides the ophthalmic formulation, wherein the tonicity agent is selected from Sodium Chloride, Mannitol, Glycerin, Potassium Chloride, Boric Acid, Dextrose and Sorbitol.

[0041] Yet another embodiment of the present disclosure provides the ophthalmic formulation, wherein the viscosifying agent is selected from Carboxymethylcellulose Sodium, Hydroxypropyl Methylcellulose (HPMC), Polyvinyl Alcohol (PVA), Polyethylene Glycol (PEG), Carbomers, Hyaluronic Acid (Sodium Hyaluronate), Hydroxyethyl Cellulose (HEC), Xanthan Gum, Guar Gum and Methylcellulose.

[0042] Still another embodiment of the present disclosure provides the ophthalmic formulation, wherein the Chelating agent is selected from Edetate Disodium Dihydrate, Tetrasodium EDTA, Citric Acid and Sodium Citrate.

[0043] Yet another embodiment of the present disclosure provides the ophthalmic formulation, wherein the Buffering agent is selected from Citric Acid Monohydrate, Hydrochloric Acid, Sodium Hydroxide, Sodium Phosphate (Monobasic and Dibasic), Sodium Acetate, Boric Acid, Sodium Borate, Sodium Bicarbonate, Potassium Phosphate, Sodium Citrate and Tromethamine (Tris Buffer).

[0044] Still another embodiment of the present disclosure provides the ophthalmic formulation which addresses the patient usability, microbiological quality, and better product stability in the presence of light and oxygen. Yet another embodiment of the present disclosure provides the ophthalmic formulation, wherein ophthalmic Solution or Gel increases residence time and improves the drug permeation, increases bioavailability, improves patient usability, microbiological quality, and product stability in the presence of light and oxygen, for use in an ophthalmic disease therapy in an individual and enhances in-use period for the ophthalmic formulation.

[0045] Still another embodiment of the present disclosure provides ophthalmic formulation for use in an ophthalmic disease therapy in an individual.

[0046] Yet another embodiment of the present disclosure provides the ophthalmic formulation which can offer improved convenience, ease of use, and protection against microbial contamination, light and oxygen to enhance the overall user experience and product stability, extended shelf life and in-use period for the ophthalmic formulation.

[0047] Still another embodiment of the present disclosure provides a method of treating an ophthalmic disease or condition, the method comprising administering an effective amount of formulation of the present invention to a patient in need thereof.

[0048] While the present invention is disclosed generally above, additional aspects are further discussed and illustrated with reference to the examples below. However, the examples are presented merely to illustrate the invention and should not be considered as limitations thereto.

[0049] EXAMPLES

[0050] Example -1 Process for preparation of Formulation 1:

[0051] Step 1: Collect Water for Injection; purge with nitrogen gas to achieve dissolved oxygen level less than 1 ppm.

[0052] Step 2: Separate 50% batch size water for injection in another manufacturing vessel.

[0053] Step 3: Add & dissolve weighed quantity of citric acid in step 2 Water for injection.

[0054] Step 4: Add & dissolve weighed quantity of sodium hydroxide in step 3 solution.

[0055] Step 5: Add & mix measured quantity of 0.1 N hydrochloric acid solution in step 4 solution. Step 6: Adjust the pH of step 5 solution to pH 4.4 with IN sodium hydroxide solution.

[0056] Step 7: Make up the batch quantity to 90% with previously nitrogen purged Water for Injection.

[0057] Step 8: Divide the step 7 solution into two parts as below:

[0058] Part 1: Divide 80% solution from step 7 solution for polymer phase preparation.

[0059] Part 2: Divide 10% solution from step 7 solution for drug phase preparation.

[0060] Preparation of Polymer Phase Solution:

[0061] Step 9: To part 1 solution of step 8, add slowly and disperse sodium carboxymethyl cellulose.

[0062] Step 10: Autoclave the step 9 polymer phase solution at 121 °C for 20 mins and after autoclaving cool down the polymer phase solution to 2 - 8°C temperature condition.

[0063] Preparation of Drug Phase Solution:

[0064] Step 11: To part solution of step 8, add and dissolve weighed quantity of edetate disodium.

[0065] Step 12: Add and dissolve weighed quantity of BKC 50% solution in step 11 solution.

[0066] Step 13: Add and dissolve weighed quantity of cysteamine hydrochloride in step 12 solution.

[0067] Step 14: Aseptically filter the drug phase solution of step 13 through 0.22 pm filter.

[0068] Step 15: Aseptically mix the step 10 polymer phase and step 14 dug phase to get uniform viscous solution.

[0069] Step 16: Aseptically make up the step 15 solution batch size to 100% with previously nitrogen purged Water for Injection through 0.22 pm filter.

[0070] Step 17: Aseptically fill the sterilized bulk into amber color USP Type-1 glass vials, maintain the pre & post nitrogen environment in the glass vials and stopper with 20 mm butylated rubber stopper and seal with 20 mm aluminum flip-off seals. Step 18: Label the filled and sealed vials.

[0071] The ingredients and amount thereof for the preparation of Example 1 are summarized in Table 1 below.

[0072] Table 1: Ingredients and amount thereof used for Formulation 1 prepared in Example 1. Example 2: Process for preparation of Formulation 2 (Present Invention):

[0073] Step 1: Collect Water for Injection; purge with nitrogen gas to achieve dissolved oxygen level less than 1 ppm.

[0074] Step 2: Separate 50% batch size Water for injection in another manufacturing vessel. Step 3: Add & dissolve weighed quantity of citric acid in step 2 Water for injection.

[0075] Step 4: Add & dissolve weighed quantity of sodium hydroxide in step 3 solution.

[0076] Step 5: Add & mix measured quantity of 0.1 N hydrochloric acid solution in step 4 solution.

[0077] Step 6: Adjust the pH of step 5 solution to pH 4.4 with IN sodium hydroxide solution.

[0078] Step 7: Make up the batch quantity to 90% with previously nitrogen purged Water for Injection.

[0079] Step 8: Divide step 7 solution into two parts as below.

[0080] Part 1 : Divide 80% solution from step 7 solution for polymer phase preparation.

[0081] Part 2: Divide 10% solution from step 7 solution for drug phase preparation.

[0082] Preparation of Polymer Phase Solution:

[0083] Step 9: To part 1 solution of step 8, add slowly and disperse sodium carboxymethyl cellulose.

[0084] Step 10: Autoclave the step 9 polymer phase solution at 121 °C for 20 mins and after autoclaving cool down the polymer phase solution to 2 - 8°C temperature condition.

[0085] Preparation of Drug Phase Solution:

[0086] Step 11: To part solution of step 8, add and dissolve weighed quantity of edetate disodium.

[0087] Step 12: Add and dissolve weighed quantity of BKC 50% solution in step 11 solution.

[0088] Step 13: Add and dissolve weighed quantity of sodium metabisulfite in step 12 solution and cool down the solution to 2 - 8°C temperature condition.

[0089] Step 14: Add and dissolve weighed quantity of cysteamine hydrochloride in step 13 solution.

[0090] Step 15: Aseptically filter the drug phase solution of step 14 through 0.22 pm filter.

[0091] Step 16: Aseptically mix the step 10 polymer phase and step 15 dug phase to get uniform viscous solution. Step 17: Aseptically make up the step 16 solution batch size to 100% with previously nitrogen purged Water for Injection through 0.22 pm filter.

[0092] Step 18: Aseptically fill the sterilized bulk into amber color USP Type-1 glass vials, maintain the pre & post nitrogen environment in the glass vials and stopper with 20 mm butylated rubber stopper and seal with 20 mm aluminum flip-off seals.

[0093] Step 19: Label the filled and sealed vials.

[0094] The ingredients and amount thereof for the preparation of Example 2 are summarized in Table 2 below.

[0095] Table 2: Ingredients and amount thereof used for Formulation 2 prepared in Example 2. After preparing two formulations i.e., Formulation 1 (Example 1) and Formulation 2 (Example 2), impurity Profile at long term storage condition were analysed. Result of said analysis are summarized in below Table 3.

[0096] Table 3: Impurity Profile at Long Term Storage Condition (5 ± 3°C): As can be seen from Table 3, Cysteamine dihydrochloride impurity in case of Formulation 2 is significantly lower than Cystadrops and Formulation 1 even after storage of 6 months. Similarly, other impurities are also very much low for Formulation 2 as compared to other formulations including originator Cystadrops. Thus, long term storage stability of the ophthalmic formulation of the present invention is better as compared to other formulations. Further, impurity Profile of Formulation 1 (Example 1) and Formulation 2 (Example 2) during In-use Storage were analysed. Result of said analysis are summarized in below Table 4.

[0097] Table 4: Impurity Profile at 25 ± 2°C / 60 ± 5% RH / Room Temperature (In-use Storage):

[0098] As can be seen from Table 4, Cysteamine dihydrochloride impurity in case of Formulation 2 is significantly lower than Formulation 1 even after in use storage of 2 weeks. Similarly, other impurities are also very much low for Formulation 2 as compared to other formulations. Thus, in use stability of the ophthalmic formulation of the present invention is better as compared to other formulations.

Claims

WE CLAIM1. An ophthalmic formulation comprising, cysteamine or pharmaceutically acceptable salt thereof; at least one polymer; at least one antioxidant; and / or a pharmaceutically acceptable excipients selected from chelating agent(s), antimicrobial agent(s), buffering agent(s), pH adjusting agent(s) and water; wherein cysteamine or pharmaceutically acceptable salt thereof is in the form of ophthalmic solution or gel.

2. The ophthalmic formulation as claimed in claim 1, wherein cysteamine or pharmaceutically acceptable salt thereof is in the form of Ophthalmic Solution or Gel.

3. The ophthalmic formulation as claimed in claim 1 or 2, wherein pharmaceutically acceptable salt of cysteamine is selected from Cysteamine bitartrate, Cysteamine hydrochloride, Cysteamine phosphate, Cysteamine tartrate.

4. The ophthalmic formulation as claimed in claims 1 to 3, wherein ophthalmic solution or gel comprises of 3.2 to 4.6 mg / mL of Cysteamine or a pharmaceutically acceptable salt thereof, preferably 3.6 to 4.4 mg / mL of Cysteamine or a pharmaceutically acceptable salt thereof, more preferably 3.8 mg / mL of Cysteamine or a pharmaceutically acceptable salt thereof.

5. The ophthalmic formulation as claimed in claims 1 to 4, wherein the polymer is selected from Carmellose sodium, Polycarbophil, Hydroxypropyl methylcellulose, Polyvinyl alcohol, Chitosan, Gelatin, Alginate, Poly(acrylic acid), Carbomers, Pluronic F-127 and / or a combination thereof.

6. The ophthalmic formulation as claimed in claim 1, wherein the antioxidant is selected from Sodium metabisulfite, Sodium sulfate, Sodium sulfite, Sodium thiosulfate,Ascorbic acid, citric acid, Sodium ascorbate, Glutathione, Propyl gallate, Alphatocopherol, Butylated hydroxyanisole (BHA) and / or a combination thereof.

7. The ophthalmic formulation as claimed in claims 1 to 6, wherein ophthalmic solution or gel comprises of 0.1% to 5% of antioxidant agent, preferably 0.5% to 3% of antioxidant agent, more preferably 0.2% of antioxidant agent.

8. The ophthalmic formulation as claimed in claims 1 to 7, wherein ophthalmic solution or gel comprises of 0.1% to 5% of Sodium metabisulfite, preferably 0.5% to 3% of Sodium metabisulfite, more preferably 0.2% of Sodium metabisulfite.

8. The ophthalmic formulation as claimed in claim 1 or 8, wherein the formulation further comprising pharmaceutically acceptable excipients selected from antioxidants, polymers, preservatives, tonicity agents, viscosifying agents, agents and / or combination thereof.

9. The ophthalmic formulation as claimed in claim 1 to 8, wherein ophthalmic Solution or Gel increases residence time and improves the drug permeation, increases bioavailability, improves patient usability, microbiological quality, and product stability in the presence of light and oxygen, for use in an ophthalmic disease therapy in an individual and enhances in-use period for the ophthalmic formulation.

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