TR201615165A1 - OPHTHALMIC PHARMACEUTICAL COMPOSITIONS - Google Patents

Abstract

The present invention is a prophylactic and / or symptomatic treatment for the protection of the eye surface in cases of corneal epithelial injury due to eye irritation, dry eye syndrome (keratoconjunctivitis sicca) and also friction of the eyelids in all cases where tear secretion is inadequate or impaired. refers to a pharmaceutical composition (s) for monotherapy and / or combined treatment of a pharmaceutical composition (s) comprising a cellulose derivative water soluble polymer (s) and / or pharmaceutically acceptable derivatives thereof.

Description

DESCRIPTION OPHTHALMIC PHARMACEUTICAL COMPOSITIONS FIELD OF THE INVENTION The present invention applies to the eye in all conditions where tear secretion is insufficient or impaired. irritation, dry eye syndrome (keratoconjunctivitis sicca) and also eye In corneal epithelial injuries due to causes such as friction created on the eyeball prophylactic and/or symptomatic and/or therapeutic cellulose-derived water-soluble polymer/s and/or Monotherapy of pharmaceutical composition(s) containing pharmaceutically acceptable derivatives and/or pharmaceutical composition(s) used in combination therapy.

The present invention mainly focuses on the active ingredient, which is a cellulose-derived water-soluble polymer. Sodium Carboxymethylcellulose (Formula I) and/or pharmaceutically acceptable tears containing derivatives and suitable pharmaceutically acceptable excipients eye irritation, dry eye in all cases where secretion is insufficient or impaired syndrome (keratoconjunctivitis sicea) and also on the eyeball of the eyelids In the corneal epithelial injuries due to reasons such as friction created by the eye surface, prophylactic and/or symptomatic and/or therapeutic treatment relates to the pharmaceutical composition(s) used.

Formula 1: ROLE '9%' 09 R R = Horror **O-'iii front "ch3 In addition, the invention includes Sodium Carboxymethylcellulose and/or pharmaceutically acceptable ophthalmic preparations of pharmaceutical compositions containing monotherapy and/or combined treatment of its derivatives formulations suitable for administration and prophylactic, symptomatic or therapeutic includes their use. PRIOR ART (KNOWN STATE OF THE ART) Dry eye syndrome (KGS), Inflammation, tears with the potential to damage the ocular surface multifactorial disease characterized by increased film osmolarity, instability, and visual impairment. is a disease (Report of the Definition, Classification, Management aid Therapy Subeommittee is a state of inadequacy. Lacrimal secretion in the person to the extent that it provides comfort to the eye There is no quality in tears, or even though there is sufficient secretion of tears. has a disorder. Located in the tear layer; mucous layer, middle watery (aqueous) layer and deficiency or disorder of any of the outermost fatty (lipid) layer, dry eye causes complaints.

Tears prevent the nerves of the cornea, which is the transparent front surface of the eye, from being irritated.

Decreased production of fluids from your lacrimal glands, improving the strength of your tear membranes. breaking it down; rapidly rupture and cause irritation and decreased vision on the cornea. leads to the formation of dry spots. Lack of tears can cause serious long-term damage to the eye. to problems; In rare cases, it can even lead to blindness.

The treatment approach in dry eye syndrome is generally preventive methods, medical treatment. (topical lubricants and anti-inflammatories/immunomodulators, blood product tears supplements), interventional methods and surgical treatment.

artificial tear preparations; Lubricate with condoms and non-condoms artificial tears preparations, those with mild to moderate KGS in which the cornea and conjunctiva are not severely damaged. It is routinely used to control cases. artificial tear The purpose of applying the preparations is to moisten and lubricate the ocular surface. provide, eliminate the deficiency of tear components, pre-inflammation substances to provide dilution, reduce tear osmolarity and protect the eye against osmotic stress. to alleviate the symptoms of the disease by preserving it (Report of the Definition, Classification, Management and Therapy Subconimittee of the International Dry Eye WorkShop 2007; Ocul Surf.

Lenip MA. Management of dry eye disease. AmJ Manag Care.

The ocular surface, which forms the lacrimal functional unit, the main lacrimal gland, the blink reflex and The sensory and motor nerves connecting these structures are in mutual cooperation. (Stem et al., 2004). The main treatment for dry eye disease is to replace the missing It can be summarized as the reorganization of the lacrimal functional unit. Treatment “International Task Force Guidelines for Dry Eye” (Wilson et al., 2007).

According to this, dry eye is divided into 4 stages and artificially artificial in common in each stage. tear preparations are preferred. Widely used artificial tear preparations According to pH, osmotic pressure, surface tension, viscosity, evaporation and preservative contents differs.

The chemical ingredients of artificial tear preparations are as follows: -Salt (to the eye/bell# Sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium bicarbonate, sodium phosphate, sodium thiophosphate, sodium borate, boric acid, hydrochloric acid, sodium hydroxide. The osmolarity of the drop according to the amount of salt solution changes. Since the tear is hyperosmolar in dry eye disease, the drops are isoosmolar or hypoosmolar (Murube et al., 1998).

-Glycerol, monosaccharides, disaccharides.

-Polysaccharides: Chios: The most widely used cellulose derivatives (Hydroxypropyl methylcellulose, carboxypropyl methylcellulose, sodium carboxymethylcellulose).

Dextrans: Dextran 85, 70, 60 or 40.

Mucopolysaccharides: It has been used in recent years. Healing ocular surface epithelium has an effect.

- Synthetic polymers: vinyl derivatives (polyvinyl alcohol, povidone, polyacrylic acid) and ethylene glycol (polyethylene glycol) derivatives.

- Gelatins.

- Lipids: paraffin, petrolatum. mineral oil and lanolin.

Protective agents (Preservatives); Traditionally, thiomersal, chlorobutanol sorbate and Benzalcholium chloride is used. Stabilized oxychloro, oxidative preservatives complex (SOC) and sodium perborate are other substances. Another condom in recent years The system is placed inside an artificial tear dropper of a sphere coated with silver ions. enhanced by its placement. Contact with air activates silver ions. has an antibacterial effect.

Electrolytes'; Bicarbonate and potassium are the most common and corneal epithelial play a role in metabolism.

osmolority; The most important electrolyte found in natural tears and providing osmolarity It is NaCl. Some of the tear preparations are isoosmolar and some are hypoosmolar. (Murube et al., 1998). pH; Dry eye patients have a higher tear count. Bicarbonate in tear film It combines with carbon dioxide in the air to buffer the alkaline environment on the ocular surface.

Viscosity enhancer, emulsion stabilizer in main food, pharmaceutical and cosmetic products, Carboxymethyl cellulose used as a thickener and to improve texture, chemical It is a modified cellulose derivative. Sodium carboxymethylcellulose (CMC) by the reaction of cellulose and sodium monochloroacetate in an aqueous solution of sodium hydroxide obtained. In detergent making, food industry, oil well mud, paints, paper It is used in manufacturing, pharmaceuticals, pollution control and textiles. Carboxymethyl cellulose also adds to microcrystalline cellulose, improving its solubility and changes its properties. Odorless, non-toxic and biodegradable it has a structure.

Some combinations of two polymeric components are described in the patent document EP2361610. Topically applicable ophthalmic compositions containing

In patent document U85518732, a cross-linked matrix gelatin from a non-bioacryl ophthalmic preservative containing glycosaminoglycan and carboxymethyl cellulose is mentioned.

DESCRIPTION OF THE INVENTION The present invention applies to the eye in all conditions where tear secretion is insufficient or impaired. irritation, dry eye syndrome (keratoconjunctivitis sicea) and also eye In corneal epithelial injuries due to causes such as friction created on the eyeball prophylactic and/or symptomatic and/or therapeutic cellulose-derived water-soluble polymer/s and/or Monotherapy of pharmaceutical composition(s) containing pharmaceutically acceptable derivatives and/or pharmaceutical composition(s) used in combination therapy.

Another aspect of the present invention is; cellulose derivative water soluble for ophthalmic use pharmaceutical containing polymer(s) and/or pharmaceutically acceptable derivatives where the compound(s) are used as monotherapy and/or combination therapy and relates to pharmaceutical composition(s) containing acceptable excipients.

Cellulose-derived water-soluble polymer/s used as active ingredient(s) in the invention Gura (Natural) gum (gum, gum), Arabic gum (natural), Tragacanth gum (natural), Locust Bean (grasshopper bean) Gum (natural), Methylcellulose and other alkylcelluloses (cellulose ethers), Sodium carboxymethylcellulose (CMC) and/or Among its pharmaceutically acceptable derivatives, preferably sodium selected as carboxymethylcellulose. Sodium used as active ingredient(s) in the invention amount of carboxymethylcellulose substance 0.01-10% w/v, preferably 0.1-1% w/v is in the ratio.

In the invention, the term "pharmaceutically acceptable derivatives" is defined as pharmaceutically acceptable. Suitable salts, esters, solvates, hydrates, complexes, polymorphs, enantiomers, prodrugs, acid addition salts, analogs, isomers, racemates, amides, enantiomer salts, basic salts, conjugates, tautomers, anhydrates, anhydrides, bases, one or more of acids, ethers, crystalline and amorphous forms or free forms is expressed.

Pharmaceutical composition(s) prepared for ophthalmic administration, drops (solution, suspension), cream, gel, ointment, lotion, liniment (liquid ointment), solution, suspension, emulsion It can be in dosage forms such as (sufyag, oil/water) and liquid solution.

Eye drops containing one or more active ingredient/s, used by local application, They are preparations in the form of sterile aqueous solution, oily solution and suspension. preparation If there is a stability problem, the mixture of active and auxiliary substances is packaged as sterile powder and into solution or suspension with suitable sterile solvent just before use. brought and applied.

During the formulation of eye drops, besides the active ingredient(s), tonicity adjust, adjust the viscosity, bring the preparation to the most stable pH and Some auxiliary substances are also used to increase the solubility of the substance/s. When eye preparations with water solvent are to be prepared in multi-dose containers, an appropriate should contain antimicrobial agents. If it is not appropriate to put an antimicrobial agent The preparation may be prepared in single-dose containers. For example; eye used in eye surgery The drops do not contain preservatives and are prepared in single-dose containers.

In addition, in some cases, protective (preservative) substances found in eye drops may irritate the eye. In such cases, those who are sensitive to preservatives or Contact lens wearers can use preservative-free eye drops. In addition to being sterile, the drops with water solvent are free of particles and clear, the suspension of eye drops is homogeneous again by shaking. dispersion (redispersion) and the homogeneity of the dose given with each dispersion. It must be accurate and sufficient. Eye drops prepared in multi-dose containers Its volume should not exceed 10 ml unless recommended otherwise. eye preparations, shortly after opening for use, unless it contains a special packaging material. becomes contaminated. Therefore, the maximum usage times after unpacking should be specified on the packaging.

Pharmaceutical eye drop formulation for ophthalmic administration used in the invention; In addition to the appropriate active ingredient/s, at least one isotonia adjusting agent, at least one buffering agent one or more selected from the group consisting of an agent, at least one pH-adjusting agent, and solvent. describes a composition that may contain more excipients.

Polyvinylpyrrolidone, sodium chloride, potassium as "isotonia adjusting agent" in the invention chloride, calcium chloride dihydrate, magnesium chloride hexahydrate, sodium dihydrogen phosphate monohydrate, disodium phosphate anhydrous, mannitol, sorbitol, glycerin, boric acid, potassium nitrate, glucose or their mixtures can be used. In the invention preferably sodium chloride and/or potassium chloride and/or calcium chloride dihydrate and/or magnesium chloride hexahydrate is used. The amount of isotonia adjusting agent used in the invention is 0.001-15% weight/volume, preferably 0.005-2% weight/volume.

In the invention, the term "buffering agent" is used to regulate the acidity and basicity of the composition. referred to as items. As a buffering agent; citric acid anhydrous, sodium citrate dihydrate, sodium phosphate, sodium dihydrogen phosphate, potassium citrate, phosphoric acid, ammonium hydroxide, citric acid, diisopropanolamine, sodium carbonate, sodium silicate, disodium orthophosphate, calcium carbonate, magnesium carbonate, magnesium hydroxide, magnesium aluminate, diethanol amine, sodium alginate, ethylenediamine, meglumine, hydrochloric acid, lactic acid, sodium citrate, sodium hydroxide, triethanolamine, trolamine, sodium benzoate, sodium hydrogen carbonate, sodium borate decahydrate, boric acid and/or their mixes can be used. In the invention preferably sodium borate decahydrate and/or boric acid is used. The amount of buffering agent used in the invention is 0.003-10% w/v, preferably at a rate of 0.01-2% weight/volume.

As a pH adjusting agent in the invention; sulfuric acid, sodium hydroxide, sodium chloride, hydrochloric acid, acetic acid, boric acid, anhydrous sodium sulfite, sodium citrate, sodium carbonate or mixtures thereof can be used. In the invention preferably hydrochloric acid and/or sodium hydroxide is used.

As a solvent in the invention; purified water, water for injection, physiological saline, sterilized Suitable aqueous solutions such as distilled water may be used. In the invention preferably water for injection is used.

In the invention, Sodium Carboxymethylcellulose and/or pharmaceutically acceptable consideration for the ophthalmic application of pharmaceutical compositions using derivatives The dropper formulation contains the following; - approximately 001% -10% w/v Sodium Carboxymethylcellulose - about 000%] -15 weight/volume of one or more isotonia adjusting agents - one or more buffering agents at a weight/volume ratio of about 0003-10% - sufficient amount of pH adjusting agent - sufficient amount of solvent.

The invention is mainly used for ophthalmic use with Sodium Carboxymethylcellulose and/or Monotherapy of pharmaceutical composition(s) containing pharmaceutically acceptable derivatives and/or combined therapy and pharmaceutically acceptable adjuvant relates to the preparation of pharmaceutical composition(s) containing substances. Invention pharmaceutical It is essential that its compositions be in the form of ophthalmic eye drops. sodium Containing carboxymethylcellulose and/or its pharmaceutically acceptable derivatives pharmaceutical composition(s) are used as monotherapy and/or combined therapy, and pharmaceutical dosage containing suitable pharmaceutically acceptable excipients low form/s irritating properties, acting quickly, dry eye It has advantages such as not making it easy to use, being easier to use, and this pharmaceutical The compounds exhibited a very stable behavior in terms of physical and chemical stability.

The following examples illustrate the invention, but in no way limit it.

Sodium Carboxymethylcellulose and/or pharmaceutically acceptable derivatives eye drops for ophthalmic administration of pharmaceutical compositions Its formulation includes the following; - approximately 001% -10% w/v Sodium Carboxymethylcellulose - sodium chloride and/or potassium chloride at a weight/volume ratio of approximately 0001-15% and/or calcium chloride dihydrate and/or magnesium chloride hexahydrate - approximately 0003-10% w/v sodium borate decahydrate and/or boric acid - sufficient amount of hydrochloric acid and/or sodium hydroxide - Enough amount of water for injection.

Sodium Carboxymethylcellulose and/or pharmaceutically acceptable derivatives eye drops for ophthalmic administration of pharmaceutical compositions its formulation contains (mg/1mL); - about 0.1-25mg Sodium Carboxymethylcellulose - about 0.001-65mg sodium chloride and/or potassium chloride and/or calcium chloride dihydrate and/or magnesium chloride hexahydrate - about 0.01-45mg sodium borate decahydrate and/or boric acid - sufficient amount of hydrochloric acid and/or sodium hydroxide - Enough amount of water at the most injection. Production process: Sodium Carboxymethylcellulose, Sodium Borate Decahydrate, Sodium Chloride, Potassium Chloride, Calcium Chloride Dihydrate, Magnesium Chloride Hexahydrate and Boric Acid weighed in specified quantities. A certain amount of water for injection is taken into a boiler and Sodium Borate Decahydrate is added on it under stirring. Complete dissolution It is mixed until it is done. Boric Acid is added to the mixture and completely Stir until dissolution is achieved. Sodium Chloride and Potassium Chloride is added and mixed until complete dissolution is achieved. my wife's Calcium Chloride Dihydrate and Magnesium Chloride Hexahydrate are added on it, completely Stir until dissolution is achieved. The resulting mixture is sterile by filtration method. (Mixture 1). A certain amount of water for injection is taken to the main boiler and Sodium Carboxymethylcellulose is slowly added under stirring. Sodium Stirring is continued until the carboxyinethylcellulose is completely swollen. autoclave method It is sterilized with (Mix H). Mixture-I is added to Mixture-117 and homogeneous It is mixed until a mixture is obtained. The pH is checked (between pH 7.0-7.9, preferably pH completion is done. It is filled into special bottles for drops without preservatives.