TR201606979A1 - TOPICAL THERAPEUTIC FORMULATIONS - Google Patents

Abstract

The present invention includes; acne, acne vulgaris, decubitus ulcer, blackhead (comedone), keratosis pilaris, mild and moderate acne vulgaris accompanied by inflammatory lesions, suitable for use in the symptomatic and / or therapeutic treatment of skin and soft tissue infections; and / or pharmaceutically acceptable derivatives thereof as monotherapy alone or in combination with other suitable active agent (s).

Description

DESCRIPTION TOPICAL THERAPEUTIC FORMULATIONS FIELD OF THE INVENTION The present invention; acne, acne vulgaris, decubitus ulcer, blackhead (comedone), keratosis pilaris, mild to moderate acne vulgaris accompanied by inflammatory lesions, skin and It can be used in the symptomatic and/or therapeutic treatment of soft tissue infections. as an anti-acne-like retinoid-like active ingredient and/or pharmaceutical acceptable derivatives are used alone as monotherapy or this agent pharmaceutical in which the substance is used as a combination therapy with other suitable active agent(s) relates to the composition/s.

The present invention; Adapalen, a retinoid-like agent with anti-acne properties, 6-[3-(1- adamantyl)-4-methoxy-phenyl] naphthalene-Z-carboxylic acid (Formula I) and/or pharmaceutical acceptable derivatives are used alone as monotherapy or this agent pharmaceutical where the substance is used in combination with other suitable active agent(s) relates to the composition/s.

Formula 1: In addition, the invention includes monotherapy of Adapalene and/or pharmaceutically acceptable derivatives. used alone or combined with other suitable active agent/s suitable for topical application of pharmaceutical compositions used as combination therapy formulations and symptomatic and/or therapeutic uses. PRIOR ART (KNOWN STATE OF THE ART) Acne is a skin condition that results from the embedding of hair follicles with oil and dead skin cells. is the disease. Acne lesions heal slowly, and when one lesion heals, another appears. it may come off. Acne is usually found on the face, neck, and sebaceous glands where the functional sebaceous glands are the most. appears on the chest, back, and shoulders.

Acne can take the following forms: l-Non-inflammatory lesions: Comedones (whiteheads and blackheads): Clay follicle openings, oil secretions, Dead skin cells and sometimes bacteria. Comedones are dark in color if they open to the skin surface. They are called black dots because they appear. When the comedones are closed, the skin slightly raised from the surface and skin-colored, these are called white dots.

Z-Inflammatory lesions: Papules: Small protrusions on the skin that indicate infection and inflammation.

Papules may be red and tender.

Pustules (pimples): These are red and sensitive protrusions with white pus at the tip.

Nodules: They are large, hard and painful lumps that form under the skin surface. in clay roots, It occurs as a result of the accumulation of secretions in the deep tissue.

Cysts: Painful, pus-filled lumps under the surface of the skin. These boil-like lesions are scars it can leave.

There are four goals in acne treatment: l-Reducing sebum production 2-Accelerating cell regeneration 3- Fight against bacterial infection 4-Reducing inflammation in the skin Topical retinoids inhibit microcomedone formation; formation of new lesions prolongs acne remission by inhibiting it; reduces mature comedones; prostaglandin, leukotriene, By inhibiting proinflammatory cytokines such as interferon-y, IL-loi and neutrophil chemotaxis It has an anti-inflammatory effect by preventing it; normal desquamation of the follicular epithelium and increases the penetration of other topical drugs into the skin (Krautheim A, Gollnick HP. topical and oral retinoids in the early treatment of acne. J Eur Acad Dermatol Venereol 2001;15 (Suppl 3):43-9), (Gollnick H, Cunliffe W, Berson D, Dreno B, Finlay A, Leyden JJ et al.

Management of acne: a report from a global alliance to improve outcomes in acne. J Am Acad Derniatol 2003;49(l): 1-37).

The most commonly used topical retinoids today are all-trans retinol (retinol), all-trans retinoic acid (tretinoin), adapalene, tazarotene, retinaldehyde, l3-cis retinoic acid (isotretinoin), motretinide and ß-retinol glucuronide (Tüzün Y, Dolar N. Current!' acne treatment. Derinatose Adapalene is a retinoid-like drug used topically in the treatment of acne vulgaris.

It is usually used in gel form. Adapalene, unlike tretinoin, is a naphtholytic acid. derivative and less irritating to the skin.

Benzoyl peroxide is used in the treatment of mild to moderate acne cases, It is effective in reducing comedones. It also has a mild keratolytic effect. Benzoyl peroxide shows antibacterial effect. Its antibacterial effect is especially in oily follicles and comedones. It is more common against Propionibacterium acnes, which is the dominant microorganism.

It is a drying, mild desquamating and It also shows keratolytic effect.

In the patent document EP2049068 n0”1u, it has retinoid, antibiotic and/or keratolytic properties. topical antiacne formulations are mentioned. and pharmaceutical compositions containing benzoyl peroxide.

DESCRIPTION OF THE INVENTION The present invention; acne, acne vulgaris, decubitus ulcer, blackhead (comedone), keratosis pilaris, mild to moderate acne vulgaris accompanied by inflammatory lesions, skin and For use in the symptomatic and/or therapeutic treatment of soft tissue infections as an anti-acne-like retinoid-like active ingredient and/or pharmaceutical acceptable derivatives are used alone as monotherapy or this agent pharmaceutical in which the substance is used as a combination therapy with other suitable active agent(s) relates to the composition/s.

Another aspect of the present invention is; retinoid with anti-acne properties for topical use similar excipients and/or pharmaceutically acceptable derivatives When it is used alone as inonotherapy or when this active substance is used in other suitable active including the treatment of pharmaceutical composition(s) used in combination therapy with agent(s) relates to the preparation of pharmaceutical composition(s).

Appropriate anti-acne-like retinoid-like active substance adapalene used in the invention, isotretinoin, motretinide, tazarotene, tretinoin, and/or pharmaceutically acceptable it is preferably selected as adapaleii among its derivatives.

Other suitable active agent(s) used in the invention; preferably antibacterial benzoyl selected as peroxide.

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 compositions prepared for topical application include creams, gels, ointments, lotions, liniment (liquid ointment), suspension, emulsion (water/oil, oil/water), liquid solution, oils, such as paste, foam, solution, paste, stick, spray, soap, shampoo, powder, suppositories and eneina available in dosage forms.

Gels are suspensions of small inorganic particles or large swelled with liquid. They are semi-solid systems consisting of macromolecules. Small inorganic particles gel structure They form a three-dimensional network inside. Large inorganic polymers, natural and synthetic On the other hand, macromolecules form the gel structure in contact with each other's chain. Gels too as a carrier/sivag, such as ointments, for the application of active ingredients to the skin they can be used. Gels are composed of small solids or insoluble particles in a liquid medium. they were formed by the dispersion.

Many different substances are used to form gels. These: Gel-forming agents; l-Proteins: Collagen, gelatin 2-Polysaccharides: Alginates, agar, Carrageen, Chitosan, Glycyrrhizin 3-Yar1 synthetic polymers: Sodium carboxymethylcellulose (NawCMC), Methyl cellulose (MC), Hydroxypropylcellulose (HPC) and Hydroxypropylmethylcellulose (HPMC) 4-Synthetic polymers: Polyvinyl alcohol (PVA), Polyacrylic acid copolymers (CarbopoP Carbomer), Polyacrylamides, Poloxamers The term cream is generally used for soft and emulsion type preparations. Generally oil in water (oil/water) (Y/S) systems. There are also S/Y type ones, but the oil ratio less than ointment. Although the pH of the preparation is not decisive, it is more dependent on the skin pH. close, that is, slightly acidic. Pharmaceutical creams prepared for external application emulsion preparations; There are also suspension ones and they contain active substance.

It has a soft, easy-to-apply consistency. Creams are generally examined in three groups; l) Yag11 Creams (Cold Crem): Oily creams are also called Cold Crem (cooling cream). known. With the evaporation of the water in its formula, it gives a feeling of coolness on the skin. In the formula If the amount of water is more than 45%, the outer phase is water, and if it is less, an emulsion with outer phase oil is formed. 2) Semi-Oil Creams: These are also called cleansing creams and contain 20-30% oil.

It is rubbed into the skin. Then it is cleaned with a clean cloth or tampon. Usually oil/water It has a type of emulsion structure and cleaning agents with detergent structure and properties. 3) Oil-Free Creams: Matte creams, stearate creams, day cream and cleansing creams Also known as They are an oil/water emulsion prepared with an alkali and stearic acid. are the formulas in the structure. The pH of the cream prepared should be between 6.0 and 6.9. a thin When applied as a layer, it leaves a non-oily feel. By making the skin soft It allows the powder to penetrate the skin better.

Ointments or pomades, thick, oily, hard to apply to the skin, watery They are semi-solid preparations that cannot be removed. Staying for a long time when applied to the skin, active they provide the effect of the substance for a long time. Ointments have gastrointestinal effects. Stubborn, They are used in chronic, dry lesions.

Ointments consist of active substance and carrier (sivag, vehicle). in ointment The active substance can be dissolved or suspended/solid. single ointment It can be either phased or emulsion. Solubility problem of active substance If there is, it will be dissolved in the phase in which it is more dissolved and in an emulsion form of ointment. can also be presented to the patient.

There are two main parts in the formula of an ointment: -Active substance or substances: It is the effective substance of the drug that provides the purpose of treatment and diagnosis.

It is added in order for the active substance to be easily taken by the patient or to be dosed well, chemical substances that do not have a physiological effect (such as paraffin, glycerin).

-Sivag (excipent) and its properties: Sivag is formulated as a single substance or as a mixture. is done. Sivag should have some features according to the place of use and purpose.

Sivag chosen for the formula; 0 Should not harm the skin, 1› It should be easy to prepare, i Easy to clean, 0 Must be able to mix with water and oil soluble drugs, o Must be an appropriate phii (neutral is best), o Melting point should be close to body temperature, 0 Must be resistant to air, light and drugs, 0 It should not leave a feeling of watering or lubrication on the skin, It should not stain, o It should not inactivate or affect the active substance used together. should not delay.

Classification of Ointment Liquids o Oily ointment plasters o Absorption ointment plasters o Emulsion ointment plasters o Water-soluble sivags Ointment Preparation Methods: -Cold mixing method: The active ingredient and Sivag are placed on a clean glass plate or on glass. It is placed in a mortar and mixed with a spatula or pestle.

- Melting method: Oily substances in a container, the substances forming the aqueous phase in a separate container with water. It is mixed on the bath until it becomes homogeneous. The inner phase, on top of the outer phase, in the same While it is at the temperature, it is poured and mixed, after waiting for a while, it is mixed and cooled.

It is then filled into tubes.

Pharmaceutical formulation prepared for topical application in the present invention; pharmaceutical at least one binding agent, at least one glidant, at least one softening agent, at least one thickening agent, at least one chelating agent agent, at least one emulsifier, at least one gelling agent, at least one pH adjusting agent, at least one cooling agent, at least one penetration enhancing agent, at least one microbial preservative and one or more excipients selected from the group consisting of solvent Defines a composition that can contain

In the invention, pregelatinized corn starch, pregelatinized starch, hydroxypropyl starch, gelatin, microcrystalline cellulose, cellulose, gums, polyvinyl pyrrolidone, polymethacrylates, sodium carboxymethyl cellulose, starch, paratins, stearic acid, gums, methyl cellulose, ethyl cellulose, polyethyleneglycol, magnesium aluminum silicate, carboxy methylcellulose, hydroxy propylcellulose, hydroxy ethylcellulose, propylene glycol, polyoxyethylene- polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, polysaccharides, poloxamers, alginic acids, collagen, albumin, crospovidone, povidone, Copovidone, maltodextrin, hypromellose or mixtures of these can be used.

In the invention, talc, magnesium stearate, hydrogenated vegetable oil, calcium stearate, stearic acid, colloidal silicon dioxide, sodium stearylfumate, polyoxyethyleneglycol, leucine, sodium benzoate, sodium chloride, sodium acetate, sodium fumarate, silica, colloidal anhydrous silica, colloidal silica in aqueous form, polyethyleneglycol, cellulose derivatives, starch or their mixes can be used.

The term "softening agent" in the invention; water by forming a thin film on the skin It is expressed as substances that prevent it from flying. Vaseline as emollient, solid petrolatum, liquid paraffin, sorbitol, glycerin, hydrocarbons, lanolin, waxes, fatty acids, cet] alcohol, octyldodecanol, caprylic/capric triglyceride, cetyl stearyl alcohol, cocoa butter, diisopropyl adipate, polyhydric alcohols and polyether derivatives, polyhydric alcohol esters, glyceryl monooleate, glyceryl stearate, linoleic acid, oleic acid, polypropylene glycol-1S stearyl ether (PPG- stearyl ether), polyethylene glycol, polyoxyethylene glycol fatty alcohol ethers, polyoxypropylene stearyl ether, propylene glycol stearate, stearic acid, stearyl alcohol, phospholipids, lecithin, steorols, cholesterol, cholesterol fatty acid esters and amides, urea, glyceryl monostearate, isopropyl myristate, isopropyl palmitate, ketostearyl alcohol, dimethicone, mineral oils, white solid paraffin, cetearyl alcohol or mixtures thereof can be used. Also castor oil, coconut Vegetable softening agents such as oil, olive oil and vegetable waxes can also be used.

As a "thickening agent" in the invention; cetyl alcohol, aluminum stearate, dimethicone, cetearyl alcohol, stearyl alcohol, gum arabic, gum tragacanth, alginate, carrageenan, xanthan gum, guar gum, cetostearyl alcohol, ceti] wax of esters, dextrin, glyceryl inonostearate, hydroxypropyl cellulose, kaolin, polyethylene white vaseline, propylene glycol stearate, starch, inum, white wax, bentonite, beeswax, white wax, synthetic wax, paraffin, white solid paraffin, white soft paraffin, solid petrolatum, pectin, carbomer, polyvinylpyrrolidone or their mixes can be used.

EDTA (ethylene diamine tetraacetic acid), disodium EDTA as chelating agent in the invention (disodium ethylene diairin tetraacetic acid) or calcium EDTA (calcium ethylene diamine) tetraacetic acid) or mixtures thereof can be used.

In the invention, the term "emulsifier" means homogeneous between two immiscible liquid phases. are expressed as substances that provide dispersion. Polyethylene glycol as emulsifier stearate, polysorbate, polyglyceryl oleate, polyoxyethylene lauryl ether, ethoxylated lanolin, stearyl alcohol, cetostearyl alcohol, macrogol cetostearyl, glyceryl monostearate, cetostearyl alcohol, polyoxyethylene lauryl alcohol, polyoxy ethylene sorbitan monostearate, polyoxyethylene stearate, sorbitan monostearate, propylene glycol stearate, aluminum starch octenylsuccinate, ammonium hydroxide, a white balinuin, a synthetic balinuin, carbomer, cetearyl alcohol, cyclomethicone, diglycerides, dimethicone, disodium monooleamido sulfosuccinate, pentaerythritol, glycerides, glyceryl monooleate, glyceryl stearate, lanolin, hydrogenated magnesium stearate, mineral oil, monoglycerides, polyethylene glycol, polyethylene glycol distearate, polyethylene glycol monocetyl ether, polyethylene glycol monostearate, polyoxyethylene glycol, polyoxy] cetostearyl ether, polyoxy] stearate, simethicone, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan palmitate, stearic acid, disodium lauryl sulfosuccinate, triethanolamine, sodium lauryl sulfate or mixtures thereof can be used.

In the invention, carbopol, carbomer, hydroxy propylmethylcellulose, methylcellulose, hydroxy ethylcellulose, hydroxy propylcellulose, carboxy methylhydroxy ethylcellulose, sodium carboxy inethylcellulose, methoxypolyethyleneglycol, polyethyleneglycol, benzyl alcohol, ethyl alcohol, isopropyl alcohol, hyaluronic acid, carboxyvinyl polymers, polyacrylate polymers, polyethylene glycol ketostearyl ether or mixtures thereof may be used.

In the invention, the term "pH adjusting agent" is used to regulate the acidity and basicity of the composition. referred to as items. As a pH adjusting 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 bicarbonate, sodium hydroxide, sodium chloride, diethanolamine, diethylamine, triethanolamine, trolamine, tromethamine, sodium benzoate, sodium hydrogen carbonate or mixtures thereof can be used.

Menthol esters, menthylene, menthol crystal, eucalyptol, synthetic or natural levomenthol or their mixtures can be used.

The term "penetration enhancing agent" in the invention; substances from the skin or biological chemical compositions that allow better and higher penetration through membranes is expressed as. Polypropylene glycol-1S stearyl as penetration enhancing agent ether, dimethyl sulfoxide, pyrrolidones, azone, propylene glycol, fatty acids, terpenes, terpenoids, oxazolidinones, ureas, isopropyl myristate, linoleate, palmitate, palmitate stearate or mixtures of these can be used.

In the invention, the term "microbial preservative" protects against microbial activity. referred to as items. As a microbial preservative; sodium benzoate, sodium methyl para hydroxybenzoate, sodium propi] para hydroxybenzoate, benzalkonium chloride, boric acid, sorbic acid, ethyl alcohol or their mixtures can be used.

In the invention, alcohols such as pure water, ethyl alcohol, methyl alcohol, isopropyl alcohol, butyl alcohol as solvents, acetone, diacetone, polyols, polyethers, esters, alkyl ketones, methylene chloride, methyl acetate, ethyl acetate, isopropyl acetate, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether or mixtures thereof may be used.

The invention is mainly based on retinoid-like adapalene with anti-acne properties for topical use. and/or pharmaceutically acceptable derivatives alone as monotherapy used or combined with antibacterial benzoyl peroxide of this active ingredient. relates to the pharmaceutical composition(s) for which it is used as a treatment. The pharmaceutical in question Absorption and biocompatibility increase with the preparation of formulations at appropriate pH7. surprisingly observed. For topical use of said pharmaceutical composition Stable with its prepared form, long shelf life, high strength: positive rheological and thixotropic, easy to use, compatible with excipients, reliable and effective high pharmaceutical compositions were obtained.

Claims (1)

REQUESTS . Preparation of pharmaceutical composition(s) for topical use, in which appropriate active substance and/or pharmaceutically acceptable derivatives such as retinoid with anti-acne properties are used alone as monotherapy or in which this active substance is used in combination with other suitable active agent/s. . It is a pharmaceutical composition/s as in Claim 1 and its feature is; is to select the appropriate anti-acne retinoid-like active ingredient among adapalene, isotretinioiii, motretinide, tazarotene, tretinoin and/or pharmaceutically acceptable derivatives. . It is a pharmaceutical composition/s as in claim 1 and its feature is; Appropriate anti-acne retinoid-like active ingredient is preferably adapalene. . It is a pharmaceutical composition/s as in claim 1 and its feature is; Another suitable active agent/s used is preferably antibacterial benzoyl peroxide. . It is a pharmaceutical composition/s as in claim 1 and its feature is; cream, gel, ointment, lotion, liniment (liquid ointment), suspension, emulsion (water/oil, oil/water), liquid solution, oils, paste, foam, solution, paste, stick, spray, soap, shampoo, powder, drinking one or more pharmaceutical dosage forms selected from suppository and enema. . It is a pharmaceutical composition/s according to any of the above claims and its feature is; It is indicated for the symptomatic and/or therapeutic treatment of acne, acne vulgaris, decubitus ulcer, blackhead (comedone), keratosis pilaris, mild to moderate acne vulgaris accompanied by inflammatory lesions, skin and soft tissue infections.