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.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Epidemiology (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Public Health (AREA)
• Ophthalmology & Optometry (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Engineering & Computer Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Inorganic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)

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• 2015
  • 2015-12-10 GR GR20150100539A patent/GR1008921B/el active IP Right Grant
• 2016
  • 2016-12-08 EP EP16819269.8A patent/EP3386482A1/en not_active Withdrawn
  • 2016-12-08 WO PCT/EP2016/025173 patent/WO2017097432A1/en active Application Filing

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