EP3386482A1 - Preservative free pharmaceutical composition for ophthalmic administration containing dexamethasone - Google Patents

Preservative free pharmaceutical composition for ophthalmic administration containing dexamethasone

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Publication number
EP3386482A1
EP3386482A1 EP16819269.8A EP16819269A EP3386482A1 EP 3386482 A1 EP3386482 A1 EP 3386482A1 EP 16819269 A EP16819269 A EP 16819269A EP 3386482 A1 EP3386482 A1 EP 3386482A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
ophthalmic
composition according
ophthalmic pharmaceutical
dexamethasone
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP16819269.8A
Other languages
German (de)
French (fr)
Inventor
Evangelos Karavas
Efthymios Koutris
Vasiliki SAMARA
Anastasia Kalaskani
Loanna KOUTRI
Andreas KAKOURIS
Manolis FOUSTERIS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmathen SA
Original Assignee
Pharmathen SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmathen SA filed Critical Pharmathen SA
Publication of EP3386482A1 publication Critical patent/EP3386482A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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

Definitions

  • the present invention relates to a preservative-free pharmaceutical formulation for ophthalmic administration comprising a glucocorticoid and specifically Dexamethasone or ophthalmologically acceptable salts thereof.
  • a preservative-free pharmaceutical formulation for ophthalmic administration comprising a glucocorticoid and specifically Dexamethasone or ophthalmologically acceptable salts thereof.
  • Such preservative-free formulation is packed in container that ensures physical and chemical stability of the product.
  • Corticosteroids are a class of chemicals that includes the steroid hormones that are produced in the adrenal cortex of vertebrates as well as the synthetic analogues of these hormones. Corticosteroids are involved in a wide range of physiological processes, including stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior. More specifically, glucocorticoids control carbohydrate, fat and protein metabolism, and are anti-inflammatory by preventing phospholipid release, decreasing eosinophil action and a number of other mechanisms.
  • Dexamethasone is a corticosteroid, more precisely glucocorticoid, of high anti-inflammatory and immunosuppressant activity, which was introduced to ophthalmology in 1958.
  • Glucocorticoids are widely used today as effective and potent anti-inflammatory drugs. Glucocorticoids prevent the development of the inflammatory response, i.e. redness, swelling, tenderness. They also inhibit capillary dilation and phagocytosis and appear to prevent the hypersensitivity responses which occur after antigen-antibody reactions.
  • Dexamethasone suppresses the release of adrenocorticotrophic hormone (ACTH) from the pituitary, resulting in inhibition of endogenous corticotrophin secretion. Except for its use in the treatment of adrenal insufficiency, dexamethasone does not cure disease. Rather, the anti- inflammatory and immunosuppressant actions of dexamethasone suppress the symptoms associated with the disease.
  • ACTH adrenocorticotrophic hormone
  • Dexamethasone sodium phosphate is a water soluble inorganic ester of Dexamethasone. It is a synthetic corticosteroid with an anti-inflammatory and antiallergic action. It has more potent anti-inflammatory action compared to hydrocortisone, a naturally occurring glucocorticoid. Due to its hydrophilic properties, it is barely absorbed by the intact epithelium of the cornea. Following absorption via the eye and the nasal mucosa, Dexamethasone sodium phosphate is hydrolyzed in the system to Dexamethasone. Afterwards, Dexamethasone and its metabolites are mainly eliminated via the kidneys.
  • Dexamethasone phosphate (as sodium) is a white or slightly yellow, very hygroscopic, crystalline powder. It is odorless or has a slight odor of alcohol. It is freely soluble in water, slightly soluble in ethanol and practically insoluble in methylene chloride.
  • the chemical name of Dexamethasone sodium phosphate is 9-fluoro-l lb,17-dihydroxy-16a-methyl-3,20- dioxopregna-l,4-dien-21-yl disodium phosphate and its molecular formula is C 22 H 28 FNa 2 08P corresponding to a molecular weight of 516.41.
  • WO 2011/084473 Al discloses an ophthalmic preparation comprising a povidone-iodine at a concentration from about 0.1% to about 2.5%, at least one member selected from the group consisting of a lubricant and a cooling agent at a concentration which is not irritating to the eye; and optionally an anti-inflammatory compound.
  • EP 2129365 Al discloses pharmaceutical compositions for ophthalmic use comprising phospholipid component composed of zwitterionic phospholipids of natural origin and i oily component composed of oils of natural origin emulsified in water.
  • the main objective of the present invention is to develop a stable ophthalmic formulation that provides significant improvement over the prior art formulations.
  • an object of the present invention to provide an efficient ophthalmic Dexamethasone sodium phosphate product that contains no antimicrobial preservatives.
  • Such product is as effective in terms of therapy as products available with preservatives.
  • a further approach of the present invention is to provide ophthalmic solutions that are easily administrable in drop form.
  • an ophthalmic, preservative- free pharmaceutical formulation comprising Dexamethasone sodium phosphate as an active ingredient, a tonicity agent, a buffering agent and a chelating agent.
  • Dexamethasone sodium phosphate comprising the following stages:
  • a pharmaceutical composition comprising an active ingredient is considered to be “stable” if said ingredient degrades less or more slowly than it does on its own and/or in known pharmaceutical compositions.
  • Ocular administration of drugs is primarily associated with the need to treat ophthalmic diseases. Eye is the most easily accessible site for topical administration of a medication. Ophthalmic preparations are sterile products essentially free from foreign particles, suitably compounded and packaged for instillation into the eye. They are easily administered by the nurse or the patient himself, they have quick absorption and effect, less visual and systemic side effects, increased shelf life and better patient compliance.
  • Antimicrobial preservatives are added to aqueous preparations that are required to be sterile, such as in ophthalmic solutions.
  • the use of preservatives in topical ophthalmic treatments is ubiquitous for any product that is to be used more than once by the patient as they prevent any microbes that may enter into the product after its first use from allowing those microbes to grow and infect the patient on a later use of the product.
  • preservatives can cause serious inflammatory effects on the eye with long-term use in chronic conditions, such as glaucoma or potentially ocular allergies.
  • BFS blow-fill- seal
  • a further disadvantage is that, despite numerous technical improvements were made by some manufacturers, the edges around the tip of the opened dropper of disposable, single-dose container are still very sharp, which may cause an accident to the patients eye.
  • the present invention provides completely preservative-free ophthalmic formulations. Such formulations are packed in containers that enable to deliver preservative-free formulations while providing shelf life similar to traditional formulations.
  • the containers of the present invention ensure that medication is kept germ-free even after multiple uses. Patient compliance is greatly increased as the pumps of the present invention permit them to use preservative-free eye drops without worrying about the potential side effects caused by some preservatives and the related short- and long-term consequences, such as pain or discomfort, foreign body sensation, stinging or burning, dry eye sensation, ocular surface breakdown.
  • a multi-use ophthalmic product comprising a container with an integral bacterial protection system and which has a dispensing tip, wherein the ratio of the inner to the outer diameter of the dispensing tip is from 1: 1 to 1:6, and the container having an ophthalmic composition that is dispensed from the tip into the eye of a patient wherein the ophthalmic composition is a preservative-free aqueous solution and contains pharmaceutically acceptable excipients.
  • Tonicity refers to the osmotic pressure exerted by salts in aqueous solution.
  • An ophthalmic solution is isotonic with another solution when the magnitudes of the colligative properties of the solutions are equal.
  • An ophthalmic solution is considered isotonic when its tonicity is equal to that of 0.9% sodium chloride solution (290 mOsm). This requires that a certain tonicity agent be added so that the total osmotic pressure is the same as the body fluid.
  • Sodium chloride, mannitol, dextrose, glycerine, potassium chloride are typical tonicity agents.
  • sodium chloride is used in the present invention as tonicity agent.
  • the aqueous formulation according to the present invention comprises sodium chloride in a range from 0.5% to 1% (w/v), preferably 0.66% (w/v).
  • compositions are prepared using a buffering system that maintains the composition at a pH of about 7 to a pH of about 8, preferably 7.5-7.7, and most preferably 7.6.
  • Suitable buffering agents include, but are not limited to, dibasic sodium phosphate, monobasic sodium phosphate, disodium phosphate dodecahydrate, hydrochloric acid, sodium hydroxide, sodium hydrogen carbonate.
  • disodium phosphate dodecahydrate is used in the present invention as buffering agent.
  • the composition of the present invention comprises disodium phosphate dodecahydrate as a buffering agent in a range of from 0.5% to 1% (w/v), preferably 0.75% (w/v).
  • Chelating agents are organic compounds that are used to trap metal ion in circular structures (chelate circles) by several coordination bounds. Most include oxygen, nitrogen and/or sulfur, and are bases on ethylenediamine, acetyl acetone, or oxine. EDTA is popular because it is very stable.
  • disodium edetate is used as a chelating agent typically at concentrations between 0.005-0.1% w/v.
  • the composition of the present invention comprises disodium edetate as a chelating agent in a range of from 0.09% to 0.1% (w/v), preferably 0.1% (w/v).
  • Example 1 Preservative-free ophthalmic compositions comprising Dexamethasone sodium phosphate according to the present invention are illustrated in Table 1 below:
  • compositions were prepared alternating either the disodium phosphate dodecahydrate content or the sodium chloride content. The manufacturing process followed in all compositions is described below:
  • Table 2 Physicochemical properties and Assay of Compositions 1-4.
  • the preferred composition of the present invention is Composition 4 as the physicochemical results of Composition 4 were acceptable and within specifications.
  • a filter study was performed. The procedure simulated the production filtration, by using different filter membranes. Samples of the solution of Composition 4 before and after filtration were collected and were analyzed under assay and impurities method determination. Totally, four membrane materials were tested-PVDF, PTFE, PES and NYLON.
  • the % Assay of API after filtration should be between ⁇ 2% of Assay before filtration.
  • the % difference in Total impurities after filtration should be not more than 5% compared to the Total impurities before filtration.
  • PVDF filter is selected to be used in the manufacturing process of Dexamethasone phosphate solution of the present invention.
  • a microbial challenge test has been performed for the optimized formulation.
  • a challenge suspension containing Brevundimonas Diminuta (ATCC 19146) was prepared.
  • the dropper of the multi-dose PF system was actuated by immersing the tip in challenge suspension and left at room temperature in order to simulate in use conditions.

Abstract

The present invention relates to a preservative-free, ophthalmic formulation comprising Dexamethasone sodium phosphate.

Description

PRESERVATIVE FREE PHARMACEUTICAL COMPOSITION FOR OPHTHALMIC ADMINISTRATION CONTAINING DEXAMETHASONE
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a preservative-free pharmaceutical formulation for ophthalmic administration comprising a glucocorticoid and specifically Dexamethasone or ophthalmologically acceptable salts thereof. Such preservative-free formulation is packed in container that ensures physical and chemical stability of the product.
BACKROUND OF THE INVENTION
Corticosteroids are a class of chemicals that includes the steroid hormones that are produced in the adrenal cortex of vertebrates as well as the synthetic analogues of these hormones. Corticosteroids are involved in a wide range of physiological processes, including stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior. More specifically, glucocorticoids control carbohydrate, fat and protein metabolism, and are anti-inflammatory by preventing phospholipid release, decreasing eosinophil action and a number of other mechanisms.
Dexamethasone is a corticosteroid, more precisely glucocorticoid, of high anti-inflammatory and immunosuppressant activity, which was introduced to ophthalmology in 1958. Glucocorticoids are widely used today as effective and potent anti-inflammatory drugs. Glucocorticoids prevent the development of the inflammatory response, i.e. redness, swelling, tenderness. They also inhibit capillary dilation and phagocytosis and appear to prevent the hypersensitivity responses which occur after antigen-antibody reactions.
Dexamethasone suppresses the release of adrenocorticotrophic hormone (ACTH) from the pituitary, resulting in inhibition of endogenous corticotrophin secretion. Except for its use in the treatment of adrenal insufficiency, dexamethasone does not cure disease. Rather, the anti- inflammatory and immunosuppressant actions of dexamethasone suppress the symptoms associated with the disease.
Dexamethasone sodium phosphate is a water soluble inorganic ester of Dexamethasone. It is a synthetic corticosteroid with an anti-inflammatory and antiallergic action. It has more potent anti-inflammatory action compared to hydrocortisone, a naturally occurring glucocorticoid. Due to its hydrophilic properties, it is barely absorbed by the intact epithelium of the cornea. Following absorption via the eye and the nasal mucosa, Dexamethasone sodium phosphate is hydrolyzed in the system to Dexamethasone. Afterwards, Dexamethasone and its metabolites are mainly eliminated via the kidneys.
Dexamethasone phosphate (as sodium) is a white or slightly yellow, very hygroscopic, crystalline powder. It is odorless or has a slight odor of alcohol. It is freely soluble in water, slightly soluble in ethanol and practically insoluble in methylene chloride. The chemical name of Dexamethasone sodium phosphate is 9-fluoro-l lb,17-dihydroxy-16a-methyl-3,20- dioxopregna-l,4-dien-21-yl disodium phosphate and its molecular formula is C22H28FNa208P corresponding to a molecular weight of 516.41.
WO 2011/084473 Al discloses an ophthalmic preparation comprising a povidone-iodine at a concentration from about 0.1% to about 2.5%, at least one member selected from the group consisting of a lubricant and a cooling agent at a concentration which is not irritating to the eye; and optionally an anti-inflammatory compound.
EP 2129365 Al discloses pharmaceutical compositions for ophthalmic use comprising phospholipid component composed of zwitterionic phospholipids of natural origin and i oily component composed of oils of natural origin emulsified in water. Although each of the patents above represents an attempt to provide stable aqueous solutions of Dexamethasone sodium phosphate, there still remains the need in the art for alternative formulations providing as well adequate chemical and physical characteristics. Moreover, there is a need for a Dexamethasone sodium phosphate formulation that is free from preservatives to be provided in a multiple use container and provide efficient dosing of the solution to the patient, without wastage.
SUMMARY OF THE INVENTION
The main objective of the present invention is to develop a stable ophthalmic formulation that provides significant improvement over the prior art formulations.
It is, therefore, an object of the present invention to provide an efficient ophthalmic Dexamethasone sodium phosphate product that contains no antimicrobial preservatives. Such product is as effective in terms of therapy as products available with preservatives.
It is another object of the present invention to provide a preservative-free, thermodynamically stable and efficient product comprising Dexamethasone sodium phosphate suitable for ophthalmic administration.
A further approach of the present invention is to provide ophthalmic solutions that are easily administrable in drop form.
In accordance with the above objects of the present invention, an ophthalmic, preservative- free pharmaceutical formulation is provided comprising Dexamethasone sodium phosphate as an active ingredient, a tonicity agent, a buffering agent and a chelating agent.
According to another embodiment of the present invention, a process for the preparation of a preservative-free pharmaceutical formulation for ophthalmic administration containing
Dexamethasone sodium phosphate is provided, comprising the following stages:
-Adding the chelating agent into water for injection and dissolving;
-Adding to the solution formed the tonicity agent under stirring until dissolution;
-Adding the buffering agent into solution of previous step under stirring until dissolution; -Adding Dexamethasone sodium phosphate and stirring the solution until complete dissolution;
-Adjusting the pH of the solution to 7.60 by adding either sodium hydroxide or hydrochloric acid;
-Adjusting final solution volume using water for injections and checking again pH of solution;
-Adjusting again the pH of the solution to 7.60, if necessary, by adding either sodium hydroxide or hydrochloric acid. Other objects and advantages of the present invention will become apparent to those skilled in the art in view of the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION For the purposes of the present invention, a pharmaceutical composition comprising an active ingredient is considered to be "stable" if said ingredient degrades less or more slowly than it does on its own and/or in known pharmaceutical compositions.
Ocular administration of drugs is primarily associated with the need to treat ophthalmic diseases. Eye is the most easily accessible site for topical administration of a medication. Ophthalmic preparations are sterile products essentially free from foreign particles, suitably compounded and packaged for instillation into the eye. They are easily administered by the nurse or the patient himself, they have quick absorption and effect, less visual and systemic side effects, increased shelf life and better patient compliance.
Antimicrobial preservatives are added to aqueous preparations that are required to be sterile, such as in ophthalmic solutions. The use of preservatives in topical ophthalmic treatments is ubiquitous for any product that is to be used more than once by the patient as they prevent any microbes that may enter into the product after its first use from allowing those microbes to grow and infect the patient on a later use of the product. Although providing effective biocidal properties with well tolerated short-term use at low concentrations, preservatives can cause serious inflammatory effects on the eye with long-term use in chronic conditions, such as glaucoma or potentially ocular allergies. Antimicrobial preservatives are not found in single use vials of ophthalmic solutions since they are manufactured aseptically or are sterilised and the products are used once and the dispenser is thrown away. Preservative-free single dose containers most often are presented as blow-fill- seal (BFS) containers. The user takes the plastic vial and tears or cuts the plastic tip, inverts the vial and squeezes the ophthalmic liquid into the eye. Disadvantages of these systems are linked to the quite complicated filling technology, the need to overfill and amount of material needed for each dose. With an average drop size of ~35μ1 and the standard commercial volume of 400- 500 μΐ, five times the required drug quantity ends up being discarded in case of single dose containers. Additionally, a big amount of packaging material is required associated with high manufacturing costs. A further disadvantage is that, despite numerous technical improvements were made by some manufacturers, the edges around the tip of the opened dropper of disposable, single-dose container are still very sharp, which may cause an accident to the patients eye.
As the use of preservative containing eye drops has been implicated in the development or worsening of ocular surface disease, there is a tendency to limit their use by reducing their concentration as much as possible in eye drops. The present invention provides completely preservative-free ophthalmic formulations. Such formulations are packed in containers that enable to deliver preservative-free formulations while providing shelf life similar to traditional formulations. The containers of the present invention ensure that medication is kept germ-free even after multiple uses. Patient compliance is greatly increased as the pumps of the present invention permit them to use preservative-free eye drops without worrying about the potential side effects caused by some preservatives and the related short- and long-term consequences, such as pain or discomfort, foreign body sensation, stinging or burning, dry eye sensation, ocular surface breakdown.
We have found that the design of the tip of the container produce a highly accurate drop size with low variability of drop volume between each drop dispensed. Therefore, we present as a feature of the present invention a multi-use ophthalmic product comprising a container with an integral bacterial protection system and which has a dispensing tip, wherein the ratio of the inner to the outer diameter of the dispensing tip is from 1: 1 to 1:6, and the container having an ophthalmic composition that is dispensed from the tip into the eye of a patient wherein the ophthalmic composition is a preservative-free aqueous solution and contains pharmaceutically acceptable excipients.
Tonicity refers to the osmotic pressure exerted by salts in aqueous solution. An ophthalmic solution is isotonic with another solution when the magnitudes of the colligative properties of the solutions are equal. An ophthalmic solution is considered isotonic when its tonicity is equal to that of 0.9% sodium chloride solution (290 mOsm). This requires that a certain tonicity agent be added so that the total osmotic pressure is the same as the body fluid. Sodium chloride, mannitol, dextrose, glycerine, potassium chloride are typical tonicity agents. Preferably, sodium chloride is used in the present invention as tonicity agent.
The aqueous formulation according to the present invention comprises sodium chloride in a range from 0.5% to 1% (w/v), preferably 0.66% (w/v).
Preferred compositions are prepared using a buffering system that maintains the composition at a pH of about 7 to a pH of about 8, preferably 7.5-7.7, and most preferably 7.6.
Suitable buffering agents include, but are not limited to, dibasic sodium phosphate, monobasic sodium phosphate, disodium phosphate dodecahydrate, hydrochloric acid, sodium hydroxide, sodium hydrogen carbonate. Preferably, disodium phosphate dodecahydrate is used in the present invention as buffering agent.
The composition of the present invention comprises disodium phosphate dodecahydrate as a buffering agent in a range of from 0.5% to 1% (w/v), preferably 0.75% (w/v). Chelating agents are organic compounds that are used to trap metal ion in circular structures (chelate circles) by several coordination bounds. Most include oxygen, nitrogen and/or sulfur, and are bases on ethylenediamine, acetyl acetone, or oxine. EDTA is popular because it is very stable. In pharmaceutical formulations disodium edetate is used as a chelating agent typically at concentrations between 0.005-0.1% w/v. The composition of the present invention comprises disodium edetate as a chelating agent in a range of from 0.09% to 0.1% (w/v), preferably 0.1% (w/v). EXAMPLES
Example 1: Preservative-free ophthalmic compositions comprising Dexamethasone sodium phosphate according to the present invention are illustrated in Table 1 below:
Table 1: Compositions 1 to 4
A range of alternative compositions were prepared alternating either the disodium phosphate dodecahydrate content or the sodium chloride content. The manufacturing process followed in all compositions is described below:
-Adding disodium edetate into water for injection and dissolving;
-Adding to the solution formed sodium chloride under stirring until dissolution;
-Adding disodium phosphate dodecahydrate into solution of previous step under stirring until dissolution;
-Adding Dexamethasone sodium phosphate and stirring the solution until complete dissolution;
-Adjusting the pH of the solution to 7.60 by adding either sodium hydroxide or hydrochloric acid;
-Adjusting final solution volume using water for injections and checking again pH of solution;
-Adjusting again the pH of the solution to 7.60, if necessary, by adding either sodium hydroxide or hydrochloric acid. The physicochemical properties and assay of Compositions 1-4 are presented in table 2 below:
Table 2: Physicochemical properties and Assay of Compositions 1-4.
The preferred composition of the present invention is Composition 4 as the physicochemical results of Composition 4 were acceptable and within specifications. In order to ensure that the filter used during the manufacturing process does not retain the drug substance Dexamethasone sodium phosphate and does not cause impurities to the final product, a filter study was performed. The procedure simulated the production filtration, by using different filter membranes. Samples of the solution of Composition 4 before and after filtration were collected and were analyzed under assay and impurities method determination. Totally, four membrane materials were tested-PVDF, PTFE, PES and NYLON.
The % Assay of API after filtration should be between ±2% of Assay before filtration.
The % difference in Total impurities after filtration should be not more than 5% compared to the Total impurities before filtration.
Table 3: Results of filter study for Dexamethasone phosphate lmg/ml, eye drops, solution. Assay
Impurities
After filtration Assay
From the results of all filters studied, there is no indication of drug absorption on any filter membrane since the assay seems to be stable before and after filtration.
As NYLON, PES and PTFE filters are susceptible to increase the related substances level upon the filtration process, they are not indicated for the current product development. Consequently, PVDF filter is selected to be used in the manufacturing process of Dexamethasone phosphate solution of the present invention.
Storage of the final product at zero time, 1, 3, 6 and 9 months under long term (25°C / 60% RH), intermediate (30°C / 65% RH) and accelerated storage conditions (40°C / 75% RH ) did not alter significantly the related substances profile conforming to the specification limits. Consequently, the multi-dose PF system of the present invention is indicated for the current development since the related substances of Dexamethasone phosphate are within the specifications in all storage conditions.
In order to investigate the potential contamination of the tip during use, i.e. by accidently touching the eye, a microbial challenge test has been performed for the optimized formulation. A challenge suspension containing Brevundimonas Diminuta (ATCC 19146) was prepared. The dropper of the multi-dose PF system was actuated by immersing the tip in challenge suspension and left at room temperature in order to simulate in use conditions.
The sterility of the optimized formulation was also checked upon storage in the multi-dose PF container for 6 months at 40°C. The results of these tests are presented in table 4 below. Table 4: Results of sterility tests for Dexamethasone phosphate lmg/ml PF eye drops solution in the multi-dose PF container.
Sterility upon storage
In use sterility test
In use sterility challenge test
It is obvious that the multi-dose PF container meets the sterility requirements for Dexamethasone phosphate lmg/ml PF eye drops solution.
While the present invention has been described with respect to the particular embodiment, it will be apparent to those skilled in the art that various changes and modifications may be made in the invention without departing from the spirit and scope thereof, as defined in the appended claims.

Claims

1. A preservative-free ophthalmic pharmaceutical composition comprising a therapeutically effective quantity of Dexamethasone sodium phosphate.
2. The preservative free ophthalmic pharmaceutical composition according to claim 1, wherein the quantity of Dexamethasone sodium phosphate is about 0.1% by weight.
3. The preservative free ophthalmic pharmaceutical composition according to claim 1, wherein it further comprises an effective amount of a chelating agent, a buffering agent and a tonicity agent.
4. The ophthalmic pharmaceutical composition according to claim 3, wherein the chelating agent is disodium edetate, the buffering agent is disodium phosphate dodecahydrate and the tonicity agent is sodium chloride.
5. The ophthalmic pharmaceutical composition according to claim 4, wherein the amount of disodium edetate in the composition is from 0.09% to 0.1% w/v.
6. The ophthalmic pharmaceutical composition according to claim 4, wherein the amount of disodium phosphate dodecahydrate in the composition is from 0.5% to 1% w/v.
7. The ophthalmic pharmaceutical composition according to claim 4, wherein the amount of sodium chloride in the composition is from 0.5% to 1% w/v.
8. The ophthalmic pharmaceutical composition according to any preceding claim, wherein the pH value is between 7.5 and 7.7.
9. The ophthalmic solution according to any preceding claim, wherein the solution is sterilized under filtration with hydrophilic modified PVDF membrane.
10. The ophthalmic pharmaceutical composition according to any preceding claim, wherein it is packed in a multi-use container equipped with an integral bacterial protection system.
EP16819269.8A 2015-12-10 2016-12-08 Preservative free pharmaceutical composition for ophthalmic administration containing dexamethasone Withdrawn EP3386482A1 (en)

Applications Claiming Priority (2)

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GR20150100539A GR1008921B (en) 2015-12-10 2015-12-10 A preservative-free formulation containing sodium phosphate dexamethasone for occular administration
PCT/EP2016/025173 WO2017097432A1 (en) 2015-12-10 2016-12-08 Preservative free pharmaceutical composition for ophthalmic administration containing dexamethasone

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CN113750041A (en) * 2020-06-04 2021-12-07 成都倍特药业股份有限公司 Dexamethasone sodium phosphate liquid preparation and preparation method thereof

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CN101861139A (en) * 2007-11-27 2010-10-13 爱尔康研究有限公司 Topical ophthalmic or otic solution formulations containing moxifloxacin hydrochloride and dexamethasone phosphate
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GR1008330B (en) * 2013-10-17 2014-10-20 "Φαρματεν Α.Β.Ε.Ε.", Preservative free pharmaceutical compositions for ophthalmic administration having improved physical characteristics and drop volume

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