WO2022130033A1 - An aqueous sterile solution of atropine for ophthalmic use - Google Patents

An aqueous sterile solution of atropine for ophthalmic use Download PDF

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Publication number
WO2022130033A1
WO2022130033A1 PCT/IB2021/050925 IB2021050925W WO2022130033A1 WO 2022130033 A1 WO2022130033 A1 WO 2022130033A1 IB 2021050925 W IB2021050925 W IB 2021050925W WO 2022130033 A1 WO2022130033 A1 WO 2022130033A1
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solution
aqueous sterile
sterile solution
present
atropine
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PCT/IB2021/050925
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French (fr)
Inventor
Bhavikkumar SHAH
Sangaiah GANESH
Subhas Balaram Bhowmick
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Sun Pharmaceutical Industries Limited
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Priority to PCT/IB2021/061961 priority Critical patent/WO2022130337A1/en
Publication of WO2022130033A1 publication Critical patent/WO2022130033A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof

Definitions

  • the present invention relates to an aqueous sterile solution of atropine or its pharmaceutically acceptable salts for ophthalmic use, wherein the solution is filled in a light protective container.
  • Myopia is an ophthalmic condition affecting more than l/5 th of the world population, especially children.
  • Atropine is currently the most effective therapy for myopia control.
  • Berton et al “Stability of Ophthalmic Atropine Solutions for Child Myopia Control” teaches that 1% concentration atropine eye drops is effective in controlling myopic progression but causes important visual side effects resulting from cycloplegia and mydriasis.
  • Several clinical trials have evaluated the safety and efficiency of atropine eye drops at lower concentrations and demonstrated that low-dose atropine eye drops such as 0.01% resulted in retardation of myopia progression, with significantly less side effects compared to higher concentration preparation.
  • Atropine Sulfate is the sulfate salt of atropine, a naturally -occurring alkaloid isolated from the plant Atropa belladonna. It functions as a sympathetic, competitive antagonist of muscarinic cholinergic receptors, thereby abolishing the effects of parasympathetic stimulation.
  • atropine eye drops Several clinical trials have evaluated the safety and efficacy of atropine eye drops and have demonstrated that atropine eye drops helped in retardation of myopia progression, with significantly less side effects compared to higher concentration preparation.
  • the present invention provides an aqueous sterile solution for ophthalmic use fdled in a light protective container said solution comprising: a. atropine sulfate at a concentration ranging from 0.001 % to 0.05 % w/v, b. buffer consisting of sodium citrate and citric acid, and c. purified sterile water, wherein the pH of the solution ranges from 4.5 to 5.5, and the solution is to be instilled in the eye without dilution or reconstitution.
  • sterile as used in the context of the invention means a solution that has been brought to a state of sterility and has not been subsequently exposed to microbiological contamination, i.e. the sterility of the aqueous solution present in the container has not been compromised.
  • light protective container means a container that protects the contents from the effects of light by virtue of the specific properties of the material of which it is composed, including any coating applied to it, such as, for example, an opaque container or amber coloured container or a container coated with a light protective coating and the like.
  • the solution is to be instilled in the eye without dilution or reconstitution”as used herein refers to direct topical administration of the aqueous drug solution to the eye of patient without involving any intermediate steps of manipulation, dilution, reconstitution, dispensing, sterilization, transfer, handling or compounding before administration of the drug solution.
  • the aqueous drug solution is ready to use or ready to administer, which is meant for direct administration topically from the container to the eye of patient in need thereof, without dilution or reconstitution.
  • stable means that the aqueous solution filled in the container is physically as well as chemically stable when stored at room temperature for a period of at least 6 months, preferably 12 months or more.
  • the aqueous solution has been also found to be stable when stored at forced degradation conditions such as 60°C for 28 days.
  • the aqueous solution is stable upon storage at the accelerated stability condition of 40°C/25% relative humidity (RH) for at least 1 month, preferably 3 months, more preferably, 6 months.
  • RH relative humidity
  • physical stability it means that the solution remains clear and colourless and free of any visible particulate matter upon storage.
  • chemical stability it means that generation of tropic acid is controlled.
  • the level of tropic acid upon storage at 60°C for 28 days or upon storage at the accelerated stability condition of 40°C/25%RH for 1 month is not more than 0.2 % by weight of atropine.
  • tropic acid is not generated and the levels are not detected upon storage.
  • the level of tropic acid upon storage at room temperature (25 °C and 60 % relative humidity) for a period of 6 months is not more than 0.5 % by weight of atropine, preferably not more than 0.2 % by weight of atropine.
  • the assay of atropine remains within 93.0 % - 107.0 %, upon storage at room temperature for at least 6 months.
  • the present invention provides an aqueous sterile solution for ophthalmic use fdled in a light protective container said solution comprising: a. atropine sulfate at a concentration ranging from 0.001 to 0.05 % w/v, b. buffer consisting essentially of sodium citrate and citric acid, and c. purified sterile water, wherein the pH of the solution ranges from 4.5 to 5.5, and the solution is to be instilled in the eye without dilution or reconstitution.
  • the term consisting essentially of as used herein means that the aqueous solution of the present invention contains a buffer having mainly sodium citrate and citric acid or hydrates thereof.
  • the aqueous sterile solution for ophthalmic use according to the present invention comprises atropine sulfate as a sole therapeutically active ingredient. It is present in an amount ranging from about 0.001 % to 0.05 % w/v, preferably from about 0.005 % to 0.015 % w/v, more preferably, 0.006, 0.065, 0.007, 00075, 0.008, 0.0085, 0.009, 0.0095, 0.01, and/or 0.015 % w/v. In one preferred embodiment, atropine sulfate is present in the ophthalmic solution in an amount of 0.01 % w/v.
  • the aqueous sterile solution for ophthalmic use according to the present invention comprises other pharmaceutically acceptable excipients, which may include, but are not limited to, pH adjusting agent/s, buffers, tonicity adjusting agents and preservatives.
  • the vehicle used for formulating the aqueous sterile solution of the present invention is purified/sterile water.
  • the active and inactive ingredients are dissolved in purified water to form a clear and colorless aqueous solution.
  • the aqueous sterile solution of the present invention is free of deuterated water.
  • the aqueous sterile solution for ophthalmic use according to the present invention has a pH in the range of about 3.5 to 6.0, preferably, from about 4.5 to 5.5, more preferably, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4 or 5.5 or intermediate values thereof.
  • the pH of the solution is 4.8 ⁇ 0.2, more preferably 4.89 ⁇ 0.2.
  • the pH of the solution may be adjusted using a pH adjusting agent/s and/or a buffer.
  • the pH adjusting agents that may be used in the ophthalmic solution according to the present invention include, but are not limited to, hydrochloric acid, sodium hydroxide or mixtures thereof.
  • the aqueous sterile solution for ophthalmic use according to the present invention comprises a buffer.
  • the buffer that is preferably used is a citrate buffer, which consists of a mixture of citric acid and sodium citrate or hydrates thereof.
  • the citrate buffer is present in the queous solution at a concentration ranging from 0.05 to 1.5 % w/vpreferably, 0.05%w/v, 0.1% w/v, 0.2% w/v, 0.3% w/v, 0.4% w/v, 0.5% w/v, 0.6% w/v, 0.7% w/v, 0.8% w/v, 0.9% w/v, 1.0% w/v, 1.1% w/v, 1.2% w/v, 1.3% w/v, 1.4 % w/v or 1.5 % w/v.
  • the citrate buffer consists of citric acid monohydrate and sodium citrate dihydrate.
  • Citric acid monohydrate may be present at a concentration ranging from 0.05 to 0.5 % w/v, preferably, at a concentration of 0.1 % to 0.3 % w/v,more preferably, 0.1 % w/v, 0.15% w/v, 0.2% w/v, 0.25 % w/v or 0.3% w/v
  • sodium citrate dihydrate may be present at a concentration ranging from 0.2 % to 1.0 % w/v, preferably, 0.3 % to 0.8 % w/v, more preferably, 0.3% w/v, 0.35% w/v, 0.4% w/v, 0.45% w/v, 0.5% w/v, 0.55% w/v, 0.6% w/v, 0.65% w/v, 0.7% w/v, 0.75% w/v or 0.8 % w/v.
  • the aqueous sterile solution for ophthalmic use according to the present invention comprises a tonicity adjusting agent.
  • the tonicity adjusting agent that may be used in the ophthalmic solution according to the present invention includes, but is not limited to, polyethylene glycol, propylene glycol, glycerol, sodium chloride, potassium chloride, sodium bromide, calcium chloride, mannitol, sorbitol, dextrose, sucrose, mannose and the like and mixtures thereof.
  • the tonicity adjusting agent used in the ophthalmic solution according to the present invention is sodium chloride.
  • Sodium chloride may be present in the solution at a concentration ranging from about 0.3 % to 0.9 % w/v.
  • a combination of sodium chloride and mannitol may be used as tonicity adjusting agent.
  • only sodium chloride is used as a tonicity adjusting agent at a concentration ranging from 0.7 to 0.9 % w/v.
  • the aqueous sterile solution of the present invention is characterized by osmolalities of 250 to 350 mOsm/kg, preferably, 270-350 mOsm/kg, more preferably, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340 or 345 mOsm/kg.
  • the aqueous sterile solution for ophthalmic use according to the present invention further comprises a preservative such as polyhexamethylene biguanide or its salt like hydrochloride salt, benzyl alcohol, cetrimide, chlorobutanol, mercurial preservatives like phenylmercuric nitrate, phenylmercuric acetate, thimerosal, phenylethyl alcohol, polyquad®, stabilized peroxides and perborates, stabilized oxychloro compounds, edetate disodium, boric acid, borates, parabens (such as methyl-propyl, isopropyl and butylparaben), pyruvates, sorbic acid/potassium sorbate, metal ions, and the like and mixtures thereof.
  • a preservative such as polyhexamethylene biguanide or its salt like hydrochloride salt, benzyl alcohol, cetrimide, chlorobutanol
  • the ophthalmic solution according to the present invention contains polyhexamethylene biguamde.
  • the polyhexamethylene biguamde may be present at a concentration ranging from 0.001 % to 0.5 % w/v, preferably, at a concentration ranging from 0.002 % to 0.5 % w/v, more preferably, 0.005 % w/v ,0.01% w/v, 0.015% w/v, 0.02% w/v, 0.025% w/v, 0.03% w/v, 0.035% w/v, 0.04 % w/v, 0.045% w/v , 0.05% w/v, 0.1% w/v, 0.15% w/v, 0.2% w/v, 0.25% w/v, 0.30% w/v, 0.35% w/v, 0.40% w/v, 0.45% w/v or 0.5 % w/v.
  • polyhexamethylene biguanide as a preservative has been found to be advantageous over other widely used preservative like benzalkonium chloride because an aqueous solution comprising polyhexamethylene biguanide shows lower mydriatic action than a solution which comprises benzalkonium chloride. It is noteworthy that mydriatic action, which leads to dilatation of pupil, is undesirable for the treatment of myopia.
  • the aqueous sterile solution for ophthalmic use according to the present invention is free of chelating agents, such as, ethylenediamine tetraacetic acid (EDTA), cyclohexanediamine tetraacetic acid (CDTA), hydroxyethylethylenediamine triacetic acid (HEDTA), diethylenetriamine pentaacetic acid (DTP A), dimercaptopropane sulfonic acid (DMPS), dimercaptosuccmic acid (DMSA), and aminotrimethylene phosphonic acid (ATP A).
  • chelating agents such as, ethylenediamine tetraacetic acid (EDTA), cyclohexanediamine tetraacetic acid (CDTA), hydroxyethylethylenediamine triacetic acid (HEDTA), diethylenetriamine pentaacetic acid (DTP A), dimercaptopropane sulfonic acid (DMPS), dimercaptosuccmic acid (DMSA), and aminotrimethylene
  • the aqueous sterile solution for ophthalmic use according to the present invention is free of water soluble polymers, for example, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone and the like.
  • the aqueous sterile solution for ophthalmic use according to the present invention is filled into a light protective container which protects the aqueous solution contained therein from the effects of light by virtue of the specific properties of the material of which it is composed, for example, a container being opaque or amber coloured or a container coated with a light protective coating.
  • Light protective containers that may be used include, but are not limited to, opaque polyethylene, polypropylene or low-density polyethylene containers.
  • the aqueous stable solution for ophthalmic use according to the present invention is filled into a light protective opaque polyethylene plastic bottle.
  • the light protective container may be in single-use format or multi -dose format.
  • the aqueous sterile solution for ophthalmic use according to the present invention comprises a low concentration of atropine sulfate (0.005 to 0.015 % w/v), citrate buffer to maintain the pH of the solution in the range of 4.6 to 5.0, polyhexamethylene biguanide as a preservative, a tonicity adjusting agent and a pH adjusting agent, wherein the solution is free of benzalkonium chloride, deuterated water and water soluble polymers.
  • the aqueous sterile solution for ophthalmic use is filled in a light protective container and comprises: a. atropine sulfate at a concentration of 0.01 % w/v, b. a buffer consisting essentially of sodium citrate and citric acid, and c. purified water, wherein the pH of the solution is 4.8 ⁇ 0.2, and the solution is to be instilled in the eye without dilution or reconstitution.
  • an aqueous sterile solution for ophthalmic use filled in a light protective container said solution consisting essentially of: a. atropine sulfate at a concentration of 0.01 % w/v, b. a buffer consisting essentially of sodium citrate and citric acid, c. polyhexamethylene biguanide at a concentration ranging from 0.001 % to 0.5 % w/v, d. a tonicity adjusting agent consisting essentially of sodium chloride, and e. purified water; wherein the pH of the solution is 4.8 ⁇ 0.2, and the solution is to be instilled in the eye without dilution or reconstitution.
  • an aqueous sterile solution for ophthalmic use filled in a light protective container said solution consisting essentially of: a. atropine sulfate at a concentration of 0.01 % w/v, b. a buffer consisting essentially of sodium citrate at a concentration ranging from 0.3 % to 0.8 % w/v and citric acid at a concentration ranging from 0.1 % to 0.3 % w/v, c. polyhexamethylene biguanide at a concentration ranging from 0.001 % to 0.5 % w/v, d. a tonicity adjusting agent consisting essentially of sodium chloride, and e. punned water, wherein the pH of the solution is 4.8 ⁇ 0.2, and the solution is to be instilled in the eye without dilution or reconstitution.
  • the aqueous sterile solution for ophthalmic use is filled in a light protective container, said solution consisting of: a. atropine sulfate at a concentration of 0.01 % w/v, b. a buffer consisting of sodium citrate dihydrate at concentration of 0.5 %w/v and citric acid monohydrate at the concentration of 0.2% w/v, c. polyhexamethylene biguanide at a concentration of 0.005 % w/v, d. sodium chloride, and e. purified water, wherein the pH of the solution is 4.8 ⁇ 0.2, and the solution is to be instilled in the eye without dilution or reconstitution.
  • the present invention provides a process of preparing the aqueous sterile solution for ophthalmic use involving the steps of:
  • Table 1 below gives composition details of an ophthalmic solution according to one preferred embodiment of the present invention.
  • Table 1 Composition details q.s.: quantity sufficient.
  • Method of preparation The dispensed quantity of the sodium citrate dihydrate and citric acid monohydrate were dissolved in water for injection. To this buffer solution, the dispensed quantity of polyhexamethylene biguanide was added under stirring and dissolved. The dispensed quantity of atropine sulfate was added to the solution containing the buffer and preservative. After that, the dispensed quantity of sodium chloride was added to the solution containing the buffer, preservative and atropine. The pH of the solution was 4.8. The volume was made up to 100 % with water for injection. The formulation was filtered through a membrane filter to get the sterile solution. The above solution was filled in opaque light protective polyethylene plastic bottles.
  • Example II The solution prepared as per Example I was tested for storage stability at room temperature (25°C and 60 % relative humidity) and was found to be physically and chemically stable upon storage. Stability results upon storage at room temperature are given below in Table 2.
  • Sulfate Ophthalmic solutions of atropine sulfate were prepared using the same procedure as explained in Example I.
  • the compositions were prepared using different buffer systems such as acetate, borate and phosphate as described in comparative Examples II, III and IV and without use of buffers as per comparative Example la.
  • Table 4 Compositions of Atropine with different buffer system. q.s.: quantity sufficient.
  • the above compositions of comparative examples were filled in opaque light protective polyethylene bottles. Stability testing was carried out at forced degradation condition of 60°C at different time points. The stability study was also carried out at the accelerated stability condition of 40°C/25%RH. The stability results upon storage are disclosed in Table 5 below.

Abstract

The present invention relates to an aqueous, sterile ophthalmic solution of low strength atropine sulfate, which is storage stable. Particularly, the present invention provides a stable, aqueous, sterile solution of atropine sulfate for ophthalmic use, filled in a light protective container, said solution comprising atropine sulfate and a buffer of sodium citrate 5 and citric acid, wherein the pH of the solution ranges from 4.5 to 5.5 and the solution is to be instilled in the eye without dilution or reconstitution.

Description

AN AQUEOUS STERIUE SOEUTION OF ATROPINE FOR OPHTHAEMIC USE FIELD OF THE INVENTION
The present invention relates to an aqueous sterile solution of atropine or its pharmaceutically acceptable salts for ophthalmic use, wherein the solution is filled in a light protective container.
BACKGROUND OF THE INVENTION
Myopia is an ophthalmic condition affecting more than l/5th of the world population, especially children. Atropine is currently the most effective therapy for myopia control. Berton et al, “Stability of Ophthalmic Atropine Solutions for Child Myopia Control” teaches that 1% concentration atropine eye drops is effective in controlling myopic progression but causes important visual side effects resulting from cycloplegia and mydriasis. Several clinical trials have evaluated the safety and efficiency of atropine eye drops at lower concentrations and demonstrated that low-dose atropine eye drops such as 0.01% resulted in retardation of myopia progression, with significantly less side effects compared to higher concentration preparation.
Atropine Sulfate is the sulfate salt of atropine, a naturally -occurring alkaloid isolated from the plant Atropa belladonna. It functions as a sympathetic, competitive antagonist of muscarinic cholinergic receptors, thereby abolishing the effects of parasympathetic stimulation. Several clinical trials have evaluated the safety and efficacy of atropine eye drops and have demonstrated that atropine eye drops helped in retardation of myopia progression, with significantly less side effects compared to higher concentration preparation.
Till date, however, there appears to be a need of an improved, stable aqueous solution of atropine that is robust in terms of chemical stability. In fact, the inventors of the present invention while developing a robust aqueous sterile solution of atropine that can be directly instilled into the eyes without any further need of dilution or reconstitution, faced with a problem of generation of unwanted degradation product of atropine, particularly tropic acid. Tropic acid is generated as a result of hydrolysis of atropine. The structure of the tropic acid is given in Formula I below:
Figure imgf000003_0001
Formula I
It is surprisingly found by the present inventors that when sodium citrate and citric acid are used as buffer, there occurs no substantial increase in the level of tropic acid upon storage. Surprisingly, other buffers such as acetate, borate and phosphate buffer was less effective at controlling tropic acid generation. Also, atropine solution prepared without using any buffer was similarly less effective at controlling tropic acid generation.
SUMMARY OF THE INVENTION
The present invention provides an aqueous sterile solution for ophthalmic use fdled in a light protective container said solution comprising: a. atropine sulfate at a concentration ranging from 0.001 % to 0.05 % w/v, b. buffer consisting of sodium citrate and citric acid, and c. purified sterile water, wherein the pH of the solution ranges from 4.5 to 5.5, and the solution is to be instilled in the eye without dilution or reconstitution.
DETAILED DESCRIPTION OF THE INVENTION
The term “sterile” as used in the context of the invention means a solution that has been brought to a state of sterility and has not been subsequently exposed to microbiological contamination, i.e. the sterility of the aqueous solution present in the container has not been compromised.
The term “light protective container” as used herein means a container that protects the contents from the effects of light by virtue of the specific properties of the material of which it is composed, including any coating applied to it, such as, for example, an opaque container or amber coloured container or a container coated with a light protective coating and the like.
The phrase “the solution is to be instilled in the eye without dilution or reconstitution”as used herein refers to direct topical administration of the aqueous drug solution to the eye of patient without involving any intermediate steps of manipulation, dilution, reconstitution, dispensing, sterilization, transfer, handling or compounding before administration of the drug solution. The aqueous drug solution is ready to use or ready to administer, which is meant for direct administration topically from the container to the eye of patient in need thereof, without dilution or reconstitution.
The term ‘stable’ as used herein means that the aqueous solution filled in the container is physically as well as chemically stable when stored at room temperature for a period of at least 6 months, preferably 12 months or more. The aqueous solution has been also found to be stable when stored at forced degradation conditions such as 60°C for 28 days. Also, the aqueous solution is stable upon storage at the accelerated stability condition of 40°C/25% relative humidity (RH) for at least 1 month, preferably 3 months, more preferably, 6 months. By the term “physical stability”, it means that the solution remains clear and colourless and free of any visible particulate matter upon storage. By the term “chemical stability”, it means that generation of tropic acid is controlled. The level of tropic acid upon storage at 60°C for 28 days or upon storage at the accelerated stability condition of 40°C/25%RH for 1 month is not more than 0.2 % by weight of atropine. In preferred embodiments, tropic acid is not generated and the levels are not detected upon storage. The level of tropic acid upon storage at room temperature (25 °C and 60 % relative humidity) for a period of 6 months is not more than 0.5 % by weight of atropine, preferably not more than 0.2 % by weight of atropine. Also, the assay of atropine remains within 93.0 % - 107.0 %, upon storage at room temperature for at least 6 months.
The present invention provides an aqueous sterile solution for ophthalmic use fdled in a light protective container said solution comprising: a. atropine sulfate at a concentration ranging from 0.001 to 0.05 % w/v, b. buffer consisting essentially of sodium citrate and citric acid, and c. purified sterile water, wherein the pH of the solution ranges from 4.5 to 5.5, and the solution is to be instilled in the eye without dilution or reconstitution. The term consisting essentially of as used herein means that the aqueous solution of the present invention contains a buffer having mainly sodium citrate and citric acid or hydrates thereof.
The aqueous sterile solution for ophthalmic use according to the present invention comprises atropine sulfate as a sole therapeutically active ingredient. It is present in an amount ranging from about 0.001 % to 0.05 % w/v, preferably from about 0.005 % to 0.015 % w/v, more preferably, 0.006, 0.065, 0.007, 00075, 0.008, 0.0085, 0.009, 0.0095, 0.01, and/or 0.015 % w/v. In one preferred embodiment, atropine sulfate is present in the ophthalmic solution in an amount of 0.01 % w/v.
The aqueous sterile solution for ophthalmic use according to the present invention comprises other pharmaceutically acceptable excipients, which may include, but are not limited to, pH adjusting agent/s, buffers, tonicity adjusting agents and preservatives.
The vehicle used for formulating the aqueous sterile solution of the present invention is purified/sterile water. The active and inactive ingredients are dissolved in purified water to form a clear and colorless aqueous solution.
The aqueous sterile solution of the present invention is free of deuterated water.
The aqueous sterile solution for ophthalmic use according to the present invention has a pH in the range of about 3.5 to 6.0, preferably, from about 4.5 to 5.5, more preferably, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4 or 5.5 or intermediate values thereof. According to preferred embodiments, the pH of the solution is 4.8 ± 0.2, more preferably 4.89 ± 0.2. The pH of the solution may be adjusted using a pH adjusting agent/s and/or a buffer. The pH adjusting agents that may be used in the ophthalmic solution according to the present invention include, but are not limited to, hydrochloric acid, sodium hydroxide or mixtures thereof.
The aqueous sterile solution for ophthalmic use according to the present invention comprises a buffer. The buffer that is preferably used is a citrate buffer, which consists of a mixture of citric acid and sodium citrate or hydrates thereof. In preferred embodiments, the citrate buffer is present in the queous solution at a concentration ranging from 0.05 to 1.5 % w/vpreferably, 0.05%w/v, 0.1% w/v, 0.2% w/v, 0.3% w/v, 0.4% w/v, 0.5% w/v, 0.6% w/v, 0.7% w/v, 0.8% w/v, 0.9% w/v, 1.0% w/v, 1.1% w/v, 1.2% w/v, 1.3% w/v, 1.4 % w/v or 1.5 % w/v. Preferably, the citrate buffer consists of citric acid monohydrate and sodium citrate dihydrate. Citric acid monohydrate may be present at a concentration ranging from 0.05 to 0.5 % w/v, preferably, at a concentration of 0.1 % to 0.3 % w/v,more preferably, 0.1 % w/v, 0.15% w/v, 0.2% w/v, 0.25 % w/v or 0.3% w/v and sodium citrate dihydrate may be present at a concentration ranging from 0.2 % to 1.0 % w/v, preferably, 0.3 % to 0.8 % w/v, more preferably, 0.3% w/v, 0.35% w/v, 0.4% w/v, 0.45% w/v, 0.5% w/v, 0.55% w/v, 0.6% w/v, 0.65% w/v, 0.7% w/v, 0.75% w/v or 0.8 % w/v.
It has been surprisingly found by the present inventors that when sodium citrate and citric acid are used as buffer, the generation of tropic acid is effectively controlled and there occurs no substantial increase in the level of tropic acid impurity generated upon storage. Surprisingly, other buffers such as acetate, borate and phosphate buffer fail to control tropic acid generation. Also, atropine solution prepared without using any kind of buffer failed to control tropic acid generation.
The aqueous sterile solution for ophthalmic use according to the present invention comprises a tonicity adjusting agent. The tonicity adjusting agent that may be used in the ophthalmic solution according to the present invention includes, but is not limited to, polyethylene glycol, propylene glycol, glycerol, sodium chloride, potassium chloride, sodium bromide, calcium chloride, mannitol, sorbitol, dextrose, sucrose, mannose and the like and mixtures thereof. In one preferred embodiment, the tonicity adjusting agent used in the ophthalmic solution according to the present invention is sodium chloride. Sodium chloride may be present in the solution at a concentration ranging from about 0.3 % to 0.9 % w/v. In some embodiments, a combination of sodium chloride and mannitol may be used as tonicity adjusting agent. In preferred embodiments, only sodium chloride is used as a tonicity adjusting agent at a concentration ranging from 0.7 to 0.9 % w/v. The aqueous sterile solution of the present invention is characterized by osmolalities of 250 to 350 mOsm/kg, preferably, 270-350 mOsm/kg, more preferably, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340 or 345 mOsm/kg.
The aqueous sterile solution for ophthalmic use according to the present invention further comprises a preservative such as polyhexamethylene biguanide or its salt like hydrochloride salt, benzyl alcohol, cetrimide, chlorobutanol, mercurial preservatives like phenylmercuric nitrate, phenylmercuric acetate, thimerosal, phenylethyl alcohol, polyquad®, stabilized peroxides and perborates, stabilized oxychloro compounds, edetate disodium, boric acid, borates, parabens (such as methyl-propyl, isopropyl and butylparaben), pyruvates, sorbic acid/potassium sorbate, metal ions, and the like and mixtures thereof. In preferred embodiments, the ophthalmic solution according to the present invention contains polyhexamethylene biguamde. The polyhexamethylene biguamde may be present at a concentration ranging from 0.001 % to 0.5 % w/v, preferably, at a concentration ranging from 0.002 % to 0.5 % w/v, more preferably, 0.005 % w/v ,0.01% w/v, 0.015% w/v, 0.02% w/v, 0.025% w/v, 0.03% w/v, 0.035% w/v, 0.04 % w/v, 0.045% w/v , 0.05% w/v, 0.1% w/v, 0.15% w/v, 0.2% w/v, 0.25% w/v, 0.30% w/v, 0.35% w/v, 0.40% w/v, 0.45% w/v or 0.5 % w/v. In preferred embodiments, the aqueous solution according to the present invention is devoid of benzalkonium chloride.
The use of polyhexamethylene biguanide as a preservative has been found to be advantageous over other widely used preservative like benzalkonium chloride because an aqueous solution comprising polyhexamethylene biguanide shows lower mydriatic action than a solution which comprises benzalkonium chloride. It is noteworthy that mydriatic action, which leads to dilatation of pupil, is undesirable for the treatment of myopia.
In preferred embodiments, the aqueous sterile solution for ophthalmic use according to the present invention is free of chelating agents, such as, ethylenediamine tetraacetic acid (EDTA), cyclohexanediamine tetraacetic acid (CDTA), hydroxyethylethylenediamine triacetic acid (HEDTA), diethylenetriamine pentaacetic acid (DTP A), dimercaptopropane sulfonic acid (DMPS), dimercaptosuccmic acid (DMSA), and aminotrimethylene phosphonic acid (ATP A).
In preferred embodiments, the aqueous sterile solution for ophthalmic use according to the present invention is free of water soluble polymers, for example, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone and the like.
The aqueous sterile solution for ophthalmic use according to the present invention is filled into a light protective container which protects the aqueous solution contained therein from the effects of light by virtue of the specific properties of the material of which it is composed, for example, a container being opaque or amber coloured or a container coated with a light protective coating. Light protective containers that may be used include, but are not limited to, opaque polyethylene, polypropylene or low-density polyethylene containers. In a preferred embodiment, the aqueous stable solution for ophthalmic use according to the present invention is filled into a light protective opaque polyethylene plastic bottle. The light protective container may be in single-use format or multi -dose format. In one preferred embodiment, the aqueous sterile solution for ophthalmic use according to the present invention comprises a low concentration of atropine sulfate (0.005 to 0.015 % w/v), citrate buffer to maintain the pH of the solution in the range of 4.6 to 5.0, polyhexamethylene biguanide as a preservative, a tonicity adjusting agent and a pH adjusting agent, wherein the solution is free of benzalkonium chloride, deuterated water and water soluble polymers.
In another preferred embodiment, the aqueous sterile solution for ophthalmic use is filled in a light protective container and comprises: a. atropine sulfate at a concentration of 0.01 % w/v, b. a buffer consisting essentially of sodium citrate and citric acid, and c. purified water, wherein the pH of the solution is 4.8 ± 0.2, and the solution is to be instilled in the eye without dilution or reconstitution.
In another preferred embodiment, there is provided an aqueous sterile solution for ophthalmic use filled in a light protective container, said solution consisting essentially of: a. atropine sulfate at a concentration of 0.01 % w/v, b. a buffer consisting essentially of sodium citrate and citric acid, c. polyhexamethylene biguanide at a concentration ranging from 0.001 % to 0.5 % w/v, d. a tonicity adjusting agent consisting essentially of sodium chloride, and e. purified water; wherein the pH of the solution is 4.8 ± 0.2, and the solution is to be instilled in the eye without dilution or reconstitution.
In another preferred embodiment, there is provided an aqueous sterile solution for ophthalmic use filled in a light protective container, said solution consisting essentially of: a. atropine sulfate at a concentration of 0.01 % w/v, b. a buffer consisting essentially of sodium citrate at a concentration ranging from 0.3 % to 0.8 % w/v and citric acid at a concentration ranging from 0.1 % to 0.3 % w/v, c. polyhexamethylene biguanide at a concentration ranging from 0.001 % to 0.5 % w/v, d. a tonicity adjusting agent consisting essentially of sodium chloride, and e. punned water, wherein the pH of the solution is 4.8 ± 0.2, and the solution is to be instilled in the eye without dilution or reconstitution.
In another preferred embodiment, the aqueous sterile solution for ophthalmic use is filled in a light protective container, said solution consisting of: a. atropine sulfate at a concentration of 0.01 % w/v, b. a buffer consisting of sodium citrate dihydrate at concentration of 0.5 %w/v and citric acid monohydrate at the concentration of 0.2% w/v, c. polyhexamethylene biguanide at a concentration of 0.005 % w/v, d. sodium chloride, and e. purified water, wherein the pH of the solution is 4.8 ± 0.2, and the solution is to be instilled in the eye without dilution or reconstitution.
In one embodiment, the present invention provides a process of preparing the aqueous sterile solution for ophthalmic use involving the steps of:
1. Dispensing and dissolving specified quantity of the sodium citrate dihydrate and citric acid monohydrate in water for injection to prepare a buffer solution;
2. Dispensing specified quantity of preservative such as polyhexamethylene biguanide, and adding it to the above buffer solution under stirring, until it is dissolved;
3. Dispensing specified quantity of atropine sulfate and adding in solution containing buffer and preservative;
4. Dispensing specified quantity of tonicity adjusting agent like sodium chloride and adding it to the solution containing buffer, preservative and atropine;
5. Adjusting the pH of the solution to 4.8±0.2 using pH adjusting agent/s if required and making the volume to 100 % with purified water;
6. Sterilizing the solution, preferably by filtering it through membrane filter to get sterile solution; and filling the solution in an opaque container like a light protective polyethylene plastic bottle. While the present invention is disclosed generally above, additional aspects are further discussed and illustrated with reference to the examples set forth below. However, the examples are presented merely to illustrate the invention and should not be considered as limitations thereto.
EXAMPLE I
Table 1 below gives composition details of an ophthalmic solution according to one preferred embodiment of the present invention.
Table 1 : Composition details
Figure imgf000010_0001
q.s.: quantity sufficient.
Method of preparation: The dispensed quantity of the sodium citrate dihydrate and citric acid monohydrate were dissolved in water for injection. To this buffer solution, the dispensed quantity of polyhexamethylene biguanide was added under stirring and dissolved. The dispensed quantity of atropine sulfate was added to the solution containing the buffer and preservative. After that, the dispensed quantity of sodium chloride was added to the solution containing the buffer, preservative and atropine. The pH of the solution was 4.8. The volume was made up to 100 % with water for injection. The formulation was filtered through a membrane filter to get the sterile solution. The above solution was filled in opaque light protective polyethylene plastic bottles.
The solution prepared as per Example I was tested for storage stability at room temperature (25°C and 60 % relative humidity) and was found to be physically and chemically stable upon storage. Stability results upon storage at room temperature are given below in Table 2.
Table 2: Results of Stability study at room temperature:
Figure imgf000010_0002
Stability testing of the solution of Example I was also carried out at forced degradation condition of 60°C at different time points. The stability study was also carried out at the accelerated stability condition of 40°C/25%RH. Stability results upon storage at different conditions are given below in Table 3. Table 3: Results of Stability:
Figure imgf000011_0001
COMPARATIVE EXAMPLES (la to IV)
Effect of various buffers on the stability of an aqueous sterile solution of Atropine
Sulfate Ophthalmic solutions of atropine sulfate were prepared using the same procedure as explained in Example I. The compositions were prepared using different buffer systems such as acetate, borate and phosphate as described in comparative Examples II, III and IV and without use of buffers as per comparative Example la.
Table 4: Compositions of Atropine with different buffer system.
Figure imgf000011_0002
q.s.: quantity sufficient. The above compositions of comparative examples were filled in opaque light protective polyethylene bottles. Stability testing was carried out at forced degradation condition of 60°C at different time points. The stability study was also carried out at the accelerated stability condition of 40°C/25%RH. The stability results upon storage are disclosed in Table 5 below.
Table 5: Stability Results for comparative Examples la to IV
Figure imgf000012_0001
From the stability data set forth in Tables 2, 3 and 5, it was surprisingly found that when a citrate buffer consisting of citric acid and sodium citrate was used, there occurs no increase in the tropic acid impurity levels and no levels were detected. In contrast, other buffers as described in comparative Examples II, III and IV surprisingly caused increase in the tropic acid levels. The atropine solution prepared without using any buffer also showed an increased tropic acid level.

Claims

Claims: I . An aqueous sterile solution for ophthalmic use filled in a light protective container, said solution comprising:
1. atropine sulfate at a concentration ranging from 0.001 % to 0.05 % w/v, ii. a buffer consisting essentially of sodium citrate and citric acid, and iii. purified water, wherein the pH of the solution ranges from 4.5 to 5.5and the solution is to be instilled in the eye without dilution or reconstitution.
2. The aqueous sterile solution as claimed in claim 1 , wherein atropine sulfate is present at a concentration of 0.01 % w/v.
3. The aqueous sterile solution as claimed in claim 1, wherein the buffer is present at a concentration ranging from 0.05 % to 1.5 % w/v.
4. The aqueous sterile solution as claimed in claim 1, wherein the buffer consists of citric acid monohydrate and sodium citrate dihydrate.
5. The aqueous sterile solution as claimed in claim 4, wherein citric acid monohydrate is present at a concentration ranging from 0.1 % to 0.3 % w/v and sodium citrate dihydrate is present at a concentration ranging from 0.3 % to 0.8 % w/v.
6. The aqueous sterile solution as claimed in claim 1, wherein the pH of the solution is 4.89 ± 0.2.
7. The aqueous sterile solution as claimed in claim 1, wherein the light protective container is an opaque polyethylene plastic bottle.
8. The aqueous sterile solution as claimed in claim 1, wherein the solution further comprises a preservative.
9. The aqueous sterile solution as claimed in claim 8, wherein the preservative is polyhexamethylene biguanide.
10. The aqueous sterile solution as claimed in claim 8, wherein the preservative is present at a concentration ranging from 0.002 % to 0.5 % w/v.
I I. The aqueous sterile solution as claimed in claim 1, wherein the solution is free of benzalkonium chloride and deuterated water.
12. The aqueous sterile solution as claimed in claim 1, wherein the solution further comprises a tonicity adjusting agent.
13. The aqueous sterile solution as claimed in claim 12, wherein the tonicity adjusting agent is present at a concentration ranging from 0.3 % to 0.9 % w/v.
14. The aqueous sterile solution as claimed in any one of claims 1 to 13, wherein the solution has no substantial increase in the level of tropic acid upon storage.
15. A method of treating myopia comprising administering to a patient in need thereof an aqueous sterile solution for ophthalmic use filled in a light protective container, said solution comprising: i. atropine sulfate at a concentration ranging from 0.001 % to 0.05 % w/v, ii. a buffer consisting essentially of sodium citrate and citric acid, and iii. purified water; wherein the pH of the solution ranges from 4.5 to 5.5 and the solution is to be instilled in the eye without dilution or reconstitution.
PCT/IB2021/050925 2020-12-17 2021-02-04 An aqueous sterile solution of atropine for ophthalmic use WO2022130033A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016172712A2 (en) * 2015-04-23 2016-10-27 Sydnexis, Inc. Ophthalmic composition
WO2018209051A1 (en) * 2017-05-11 2018-11-15 Nevakar Inc. Atropine pharmaceutical compositions

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016172712A2 (en) * 2015-04-23 2016-10-27 Sydnexis, Inc. Ophthalmic composition
WO2018209051A1 (en) * 2017-05-11 2018-11-15 Nevakar Inc. Atropine pharmaceutical compositions

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