TR201603173A1 - OPHTHALMIC PHARMACEUTICAL COMPOSITIONS - Google Patents

Abstract

Open-angle glaucoma or ocular hypertension in the presence of dry eye syndrome (keratoconjunctivitis sicca) and tear deficiency, alone or in combination with the appropriate active substance and / or pharmaceutically acceptable derivatives of the stabilized oxychloro complex and / or pharmaceutically acceptable derivatives thereof and the use of the pharmaceutical composition and / or pharmaceutical composition for the prophylactic and / or symptomatic and / or therapeutic treatment of lowering intraocular pressure in patients with diabetes.

Description

DESCRIPTION OPHTHALMIC PHARMACEUTICAL COMPOSITIONS FIELD OF THE INVENTION The present invention is a stabilized oxychloro complex and/or pharmaceutically acceptable derivatives alone or as a suitable active ingredient and/or pharmaceutically acceptable dry eye syndrome (keratoconjunctivitis sicca) and lacrimation in combination with its derivatives in patients with open-angle glaucoma or ocular hypertension Prophylactic and/or symptomatic and/or therapeutic treatment for lowering intraocular pressure It relates to the pharmaceutical composition(s) intended for use and the use of the pharmaceutical product.

The present invention is also used for ophthalmic use in dry eye syndrome (keratoconjunctivitis). sicca) and lacrimation, open-angle glaucoma or ocular prophylactic and/or symptomatic reduction in intraocular pressure in patients with hypertension and/or stabilized oxychloro complex and/or pharmaceutically acceptable derivatives alone or with the appropriate active ingredient and/or Pharmaceuticals containing combination therapy with pharmaceutically acceptable derivatives relates to the composition/s. PRIOR ART (KNOWN STATE OF THE ART) Dry eye syndrome (KGS), inflammation with the potential to damage the ocular surface, tear film It is a multifactorial disease characterized by increased osmolarity, instability and visual impairment. (Report of the Definition, Classification, Management and Therapy Subcominittee of the International Dry Eye WorkShop 2007; Ocul Surf. 5(2): 1-163). Dry eye is a condition of insufficient tears.

The person does not have enough tear secretion to make the eye comfortable, or the tears are not enough. Although there is a secretion, there is a quality disorder in the tears. Located in the tear layer; mucus the absence or absence of any of the middle aqueous (aqueous) layer and the outermost fatty (lipid) layer. disorder causes sand eye complaints Tears prevent the nerves of the cornea, the transparent front surface of the eye, from being irritated. Tears decrease in the production of fluids from your glands, disrupting the strength of the tear membrane; quickly dry spots on the cornea that cause irritation and reduced vision causes it to occur. The lack of tears causes serious problems in the eye in the long term; even if rare can lead to blindness.

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

We prepare artificial tears; Condom and non-condom artificial tear with lubricant preparations 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 osinolarity 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 Subcoininittee of the International Dry Eye WorkShop 2007; Ocul Surf.

The ocular surface, which forms the lacrimal functional unit, the main lacrimal gland, the blink reflex and this The sensory and motor nerves connecting the structures are in mutual cooperation (Stem and et al., 2004). The main treatment of dry eye disease is to replace the missing and lacrimal can be summarized as the reorganization of the 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 artificial tears are common in each stage. preparations are preferred. Widely used artificial tear preparations pH, difference according to osmotic pressure, surface tension, viscosity, evaporation and preservative contents shows.

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

-Glycerol, monosaccharides, disaccharides.

-Polysaccharides: Gums: The most used cellulose derivatives (Hydroxypropyl methylcellulose and carboxypropyl methylcellulose).

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 benzal- colium chloride is used. Stabilized oxychloro complex, which are oxidative preservatives (SOC) and sodium perborate are other substances. In recent years, another preservative system is by placing a sphere coated with silver ions into an artificial tear dropper. developed. Antibacterial effect by activating silver ions in contact with air. forms.

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 NaCls. Some of the tear preparations are isoosmolar and some are hypoosmolar (Murube pH; In dry eye patients, the pH of tears is higher. Bicarbonate in tear film By combining with carbon dioxide in the air, the alkaline environment on the ocular surface is tainted by tainpon.

Purite (stabilized oxychloro complex), called soft preservative, polyquad (polyquaternium-1) containing oxidizing compounds (boric acid, propylene glycol, sorbitol and zinc chloride) Sonia and the preservative-free Comod system and disposable antiglaucoma medications Clinical and experimental studies with that it is more toxic than (Baudouin C, Riancho L, Warnet J M, et al. In vitro studies of antiglauconatous prostaglandin analogues: travoprost With and Without benzalkonium chloride and preserved of beiizalkonium chloride-preserved, polyquad-preserved, and sotZia-preserved topical glaucoma To provide an antimicrobial effect in multi-dose eye drops and to prevent the biodegradation of the active drug. Preservatives are used to prevent However, long-term treatment These substances are used in patients who see more than one drug and have to use more than one drug several times a day. they can accumulate and create cytotoxic effects (Noacker R. Effects of common ophtalmic The excretion of especially ammonium compounds is very slow and persists in tissue for up to 7 days. can stay.

Preservative substances used in glaucoma drugs are most commonly benzalkonium chloride (BAK). and less frequently benzododecinium bromide (BDD) and stabilized oxychloro complex-purite (SOC)°d1. BAK and BDD are ammonium compounds with similar action and are used as detergent preservatives. they are called; These cells cause damage by settling in liposomes or intracellular vacuoles. substances cannot be neutralized by cells (Noackcr R. Effects of common ophtalrnic detergent effect disrupting the film layer, weakening of the mucin layer on the corneal epithelium, oxidative stress at the cell level and apoptosis at low concentration - at high concentration such as necrotic effect, toxic effect on cornea, conjunctival epithelium and immunoallergic reactions. different mechanisms are held responsible.

Studies have shown that compared to ophthalmic solutions containing other preservatives, Purit-containing ophthalmic solutions have a lower corneal epithelial cytotoxicity and increased cell viability. proves that he has the ratio.

DESCRIPTION OF THE INVENTION The present invention is a stabilized oxychloro complex and/or pharmaceutically acceptable derivatives alone or as a suitable active ingredient and/or pharmaceutical dry eye syndrome (keratoconjunctivitis sicca) and lacrimation in combination with its derivatives in patients with open-angle glaucoma or ocular hypertension Prophylactic and/or symptomatic and/or therapeutic treatment for lowering intraocular pressure It relates to the pharmaceutical composition(s) intended for use and the use of the pharmaceutical product.

The present invention is also used for ophthalmic use in dry eye syndrome (keratoconjunctivitis). sicca) and lacrimation, open-angle glaucoma or ocular prophylactic and/or symptomatic reduction in intraocular pressure in patients with hypertension and/or stabilized oxychloro complex for use in the therapeutic treatment and/or pharmaceutically acceptable derivatives alone or with the appropriate active ingredient and/or combination with pharmaceutically acceptable derivatives and pharmaceutically acceptable It relates to pharmaceutical composition(s) containing suitable excipients.

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, acids, ethers, crystal and one or more of amorphous forms or free forms are expressed.

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

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

During the formulation of eye drops, besides the active ingredient(s), tonicity adjusting the viscosity, bringing 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 It should contain an antimicrobial substance. 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 in eye drops may irritate. In such cases, those who are sensitive to preservatives or contact lenses People who use it can use eye drops that do not contain preservatives. In addition to being sterile, the drops with water solvent are free of particles and clear. Occurrence, the suspension of eye drops can be homogeneously mixed again by shaking. dispersion (redispersion) and the homogeneity of the dose given with each instillation is correct and must be sufficient. Eye drops prepared in multi-dose containers Unless recommended in the figure, its volume should be no more than 10 ml. Eye preparations, a special If it does not contain any packaging material, it will be released into the container shortly after opening for use. It is possible. For this reason, the maximum usage times after unpacking are stated in the packages. should be specified.

Pharmaceutical formulation for ophthalmic administration used in the invention; stabilized oxychloro complex and/or pharmaceutically acceptable derivatives or suitable active ingredient(s) In addition to its combination with, but not limited to; at least one viscosity agent, at least a surfactant, at least one tonicity agent, at least one emulsifier, at least one isotonia adjuster, at least from the group consisting of a pH adjusting agent, solvent and at least one preservative. describes a composition that may contain one or more selected excipients.

In the invention, the term “viscosity agent” is an agent that increases the thickness of the liquid and makes it flow slowly. or agent mixture. Carbomer, xanthan gum, guar gum, acacia, povidone, alginic acid, ethylcellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, hydroxypropyl methylcellulose (HPMC), polydextrose, carrageenan, methyl cellulose, sucrose, sorbitol, xylitol, polyvinyl alcohol, ketaryl alcohol, colloidal silicon dioxide, sodium carboxymethylcellulose and their mixtures can be used.

In the invention, the term "surfactant" increases the surface tension when dissolved in water or an aqueous solution. refers to the chemical compound that affects it. Sodium lauryl sulfate as surfactant, sodium Long Chain alkyl sulfonate esters such as cetostearyl sulfate and sodium tetradecyl sulfate salts of long-chain carboxylic acids such as stearates, benzalkonium chloride, pyridinium compounds such as tetradecyltrimethyl ammonium bromide and cetylpyridinium chloride, or quaternary ammonium, lecithins such as soy lecithin and lauryl-1-carboxyglycine, polysorbate, glyceryl glycerol esters such as inioiostearate and glycol, sorbitan and mannitane such as sorbitan tristearate esters (polyoxyethylene sorbitan mono-oleate), polyoxyethylene derivatives of sorbitan esters or mixtures of these can be used.

In the invention, the term "tonicity agent" means having the same osmotic pressure as the standard reference substance. means items. As a tonicity agent; mannitol, sorbitol, glycerin, boric acid, potassium iitrate, glucose, calcium chloride dihydrate, magnesium chloride hexahydrate, sodium borate decahydrate, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, zinc chloride or mixtures thereof may be used.

In the invention, the term "emulsifier" means a homogeneous mixture between two immiscible liquid phases. are expressed as substances that provide dispersion. Polyethylene glycol as emulsifier stearate, polysorbate, polyglyceryl oleate, polyoxyethylene lauryl ether, lanolin, ethoxylated lanolin, stearyl alcohol, cetostearyl alcohol, cetomacrogol, glyceryl monostearate, cetyl alcohol, polyoxyethylene lauryl alcohol, polyoxy ethylene sorbitan monostearate, polyoxyethylene stearate, sorbitan monostearate, sodium lauryl sulfate, disodium EDTA, polyoxyethylene hydrogenated castor oil or their mixes can be used.

In the invention, polyvinylpyrrolidone, sodium dihydrogen phosphate monohydrate, disodium phosphate anhydrous, mannitol, sorbitol, glycerin, boric acid, potassium nitrate, glucose, calcium chloride dihydrate, magnesium chloride hexahydrate, sodium borate decahydrate, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, zinc chloride or their mixes can be used.

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, calcium chloride dihydrate, magnesium chloride hexahydrate, potassium chloride, magnesium chloride, calcium chloride, zinc chloride or their mixtures can be 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, the term "preservative" refers to substances that protect against microbial activity. is doing. As a preservative; p-hydroxybenzoic acid ester, sodium beiizoate, sodium methyl para hydroxybenzoate, sodium propyl para hydroxybenzoate, benzoic acid, boric acid, Purite (stabilized oxychloro complex), ethylenediaminetetraacetic acid, sorbic acid, benzetonium chloride, benzododecinium bromide, phenylethyl alcohol, benzalkonium chloride, chlorobutanol, parabens, sodium propionate, propylene glycol, sorbates, polyquatemia or their mixes can be used.

The invention is primarily a stabilized oxychloro complex for ophthalmic use and/or pharmaceutically acceptable derivatives alone or with the appropriate active ingredient and/or combination with pharmaceutically acceptable derivatives and pharmaceutically acceptable It relates to the preparation of pharmaceutical composition(s) containing suitable excipients.

It is essential that the pharmaceutical compositions of the invention be in the form of ophthalmic eye drops. find it stabilized oxychloro complex for ophthalmic use and/or pharmaceutical acceptable derivatives and suitable pharmaceutically acceptable excipients. It relates to the preparation of pharmaceutical composition(s) containing boric acid as an ingredient. Also find stabilized oxychloro complex and/or pharmaceutically acceptable derivatives alone or with the appropriate active ingredient and/or pharmaceutically acceptable derivatives combination and suitable pharmaceutically acceptable excipients. dry eye syndrome (keratoconjunctivitis sieca) and lacrimation of a pharmaceutical product intraocular in patients with open-angle glaucoma or ocular hypertension for prophylactic and/or symptomatic and/or therapeutic treatment in lowering blood pressure related to its use. Thus, the obtained pharmaceutical product has low irritant properties. such as having a quick effect, not drying in the eyes, being easier to use. These pharmaceutical compositions have advantages in terms of physical and chemical stability. exhibited a very stable behavior.

Claims (1)

REQUESTS . It is used for prophylactic and/or symptomatic and/or therapeutic treatment in reducing intraocular pressure in patients with open-angle glaucoma or ocular hypertension in cases of dry eye syndrome (keratoconjunctivitis sicca) and lacrimation. stabilized oxychloro complex and/or pharmaceutically acceptable derivatives alone or in combination with the appropriate active ingredient and/or pharmaceutically acceptable derivatives and suitable pharmaceutically acceptable excipients. . Preparation of pharmaceutical composition(s) containing stabilized oxychloro complex and/or pharmaceutically acceptable derivatives alone or in combination with appropriate active ingredient and/or pharmaceutically acceptable derivatives and suitable pharmaceutically acceptable excipient(s) for ophthalmic use. . Preparation of pharmaceutical composition(s) containing stabilized oxychloro complex and/or its pharmaceutically acceptable derivatives and boric acid as suitable pharmaceutically acceptable excipient for ophthalmic use. . It is the pharmaceutical composition/s specified in claim 1 and its feature is; The dosage form is chosen among drops (solution, suspension), cream, gel, ointment, lotion, liniment (liquid ointment), solution, suspension, emulsion (water/oil, oil/water) and liquid solution. . It is the pharmaceutical composition/s specified in the request 4° and its feature is; The dosage form is preferably eye drops (solution, suspension).