UA105437C2 - Gel for topical treatment of inflammatory diseases of locomotor system based on apicultural products - Google Patents

Abstract

The invention relates to chemical-and-pharmaceutical industry, namely to the gels for the complex treatment of the mechanical injuries and post-traumatic inflammation of the soft tissues of the limbs, the diseases of the locomotor system (tendons, muscles, joints), the muscular-skeletal injuries in sport medicine and rehabilitation of sportsmen (ligament strains, dislocations, contusions, overloading, etc.). The gel for the topical treatment of the inflammatory diseases of the locomotor system contains the phenolic hydrophobic preparation of propolis, articaine hydrochloride, menthol, the essential oil of the rosemary, and the excipients – carbomer, propylene glycol, trometamol, ethanol 96 %, the preserving agent, and the purified water.

Description

The invention belongs to the chemical and pharmaceutical industry, namely to the creation of gels for use in the complex treatment of mechanical damage and post-traumatic inflammation of soft tissues of the limbs, diseases of the musculoskeletal system (tendons, muscles and joints), musculoskeletal injuries , typical for sports medicine and sports in the rehabilitation period: sprains, dislocations, blows, contusions, overloads, etc.

One of the important directions of modern medicine and pharmacy is the development of new and improvement of existing medicinal drugs on the pharmaceutical market, aimed at restoring the functional activity of various organs and systems, disrupted as a result of inflammatory and dystrophic processes or traumatic injuries. Special relevance in this regard is given to sports injuries of the musculoskeletal system, the growth of which in modern conditions not only affects achievements, but also generally worsens the quality of life of athletes even with high sports qualifications for a long time, or completely removes them from the training process and sports competitions .

Currently, soft medicinal forms in the form of liniments, ointments, creams, and gels are widely used in the rehabilitation of damaged joints. They are complex heterogeneous dispersed systems, the quality, effectiveness and safety of which depends on the type and composition of the base of the carrier, the dispersed state of medicinal substances, the expediency and correct selection of the introduction of auxiliary substances, the effectiveness of preservatives, conditions of production, storage, etc.

Therefore, ensuring the necessary pharmacological effect during the development of a soft dosage form can be carried out only under the conditions of the correct selection of active and auxiliary substances, rational technology, terms and conditions of storage.

Soft medicinal products are easy to use, can combine several active substances of multidirectional action in one dosage form, and also provide a long-term concentration of active substances directly at the place of application of the drug, etc. The gel form contributes to the penetration of the active substance into the deepest tissues, causes an additional cooling effect, is safe for the skin, convenient to use, and hygienic. The gel is able to form an even, non-slip continuous film on the surface of the skin, under which the active substances are well absorbed through the skin and penetrate into the source of inflammation in sufficient quantities.

Analysis of the pharmaceutical market of Ukraine shows that the range of anti-inflammatory drugs

Of the preparations in the form of gels, which are used locally for joint and muscle pain, it is only 9 95. Unlike other soft medicinal forms, preparations in the form of a gel have an additional moisturizing effect on the skin, and the slow diffusion of the active substance in the tissue allows achieve prolonged action. Therefore, the development of drugs for local use in the form of gels is more rational.

Considering the lack of domestic combined gels with simultaneous anti-inflammatory and local anesthetic action for the treatment of inflammatory diseases of the musculoskeletal system and the dependence of pharmacotherapy of the above-mentioned pathologies and microtraumas on imported drugs, the development and introduction into production of new drugs in the form of gels is an urgent task of medicine and pharmacy.

Beekeeping products have long been used in traditional medicine for the treatment of various pathologies. Their biological value is confirmed by fundamental research of domestic and foreign scientists. Currently, bee venom is widely used in the pharmacotherapy of a number of inflammatory joint diseases. There is information in the literature that beekeepers are less likely to suffer from rheumatism and gout, unlike people who have nothing to do with bees, and therefore are not susceptible to their stings.

Bee venom (apitoxin) is a secret of the venom glands of bees. The development of modern beekeeping has made it possible to expand scientific research on the study of the mechanism of action of this apiproduct produced by the honey bee on the human body and its introduction into medical practice, however, the use of apitoxin therapy (treatment with bee venom) is complicated by the fact that it must be carried out under the supervision of a special specialist - a doctor an apitherapist, who to date, according to the current legislation of our country, has not acquired an official status in the classification of medical professions.

In addition, it should be noted only a few drugs registered in Ukraine based on bee venom, which are prescribed for diseases of the musculoskeletal system and during sports activities: "Apizartron" ointment (Ezragta, Germany), "Virapin" ointment (Ziomakotagta,

Slovak Republic) and Ungapiven ointment (JSC "Khimpharmzavod "Chervona Zirka", Kharkiv,

Ukraine). They are also used for local disorders of peripheral blood circulation, functional disorders of muscles and ligaments, radiculitis, polyarthritis, arthrosis, rheumatism, neuralgia, etc.

The well-known angioprotective agent "Troxevasint", gel produced by "Balkanfarma-Troyan"

AT", Bulgaria. The gel contains the active substance (troxerutin) and auxiliary substances: carbomer, triethanolamine, disodium edetate (Trilon B), benzalkonium chloride, purified water. Unlike ointments, the gel base of the drug is absorbed faster (pH is close to skin pH), it is more convenient to use (there are no feelings of greasiness and stickiness on the skin, it is easily washed off with water), and it also more fully provides the therapeutic properties of the active substances.

In addition, gels are a more economical and energy-efficient medicinal form, since a small amount of gelling agent and a much smaller number of technological stages are required for the manufacture of the gel base than for the manufacture of ointments.

The closest analog (prototype) is the gel for external use "Voltaren emulgel" (per:/Ltpedi.gy/20ОС/06125.пит), which includes the active substance - sodium diclofenac and auxiliary substances: diethylamine, carbopol 974 R ( carbomer), cetomacrogol 1000, cethiol C, isopropyl alcohol, liquid paraffin, aromatic cream, propylene glycol, purified water.

The basis of the invention is the task of improving the gel for external use, in which due to the optimal selection of components and their ratios, the most effective anti-inflammatory and analgesic effect will be achieved, as well as long-term preservation of the positive effect after the end of the treatment.

The task is solved in such a way that the developed gel for the local treatment of inflammatory diseases of the musculoskeletal system based on beekeeping products, which contains active substances, namely the standardized substance FGPP (Phenolic hydrophobic preparation of propolis), articaine hydrochloride, menthol, rosemary essential oil and auxiliary substances - carbomer (carbopol), propylene glycol, and additionally contains trometamol, ethyl alcohol 9695, preservative and purified water with the following ratio of components, wt. 9o: phenolic hydrophobic preparation of propolis (FGPP) 0.5-5.0 articaine hydrochloride 1.0-10.0 menthol 0.1-3.0 rosemary essential oil 0.1-3.0 carbomer 0.5-2, 0 trometamol 0.5-2.0 propylene glycol 1.0-30.0 preservative 0.1-2.0 ethyl alcohol 96 95 0.0-30.0 purified water the rest.

The pharmaceutical composition is mainly an anti-inflammatory agent for the treatment of joints.

The ratio of the components of the product is selected in such a way as to provide the pharmaceutical composition with the necessary analgesic and anti-inflammatory properties, as well as a quick

Effect and long-term effect when using the claimed composition. When the phenolic hydrophobic drug propolis is added to the product, the anti-inflammatory properties of the composition are enhanced, as well as the stimulating effect.

The domestic industry produces a biologically active standardized substance of propolis - phenolic hydrophobic preparation of propolis (PHPP), which exhibits high antimicrobial, anti-inflammatory and reparative properties. In view of the above, the creation of a soft medicinal form in the form of a gel based on FGPP, which meets all modern requirements for drugs for the local treatment of microtraumas in sports medicine, is relevant.

In the development of modern drugs for local use, a synthetic high-molecular liquid cross-linked thickener-copolymer of acrylic acid, obtained by polymerization in organic solvents - "Carbomer" (carbopol, BP: Sagroteg»x, RyEEig: Sagrotega, OBR: Sagroteg) is widely used as a gelling agent. Carbomer is the basis for gels and cream-gels, which provides optimal structural and mechanical properties and the necessary viscosity. Carbomer gels are transparent, do not create a sticky film on the surface of the skin, they can be obtained in a wide pH range from 4.0 to 11.0. They are also thermally and microbiologically stable, non-toxic, stable during storage and compatible with most natural and synthetic (including medicinal) substances.

It is known that the indicators of structural viscosity of gel bases with carbomer depend on the nature of the neutralizer. The most viscous systems are formed when trometamol is added, which, unlike other amino derivatives, is considered a non-toxic substance.

Articaine hydrochloride (Apisaipi pudgospiohyditis) is a local anesthetic that exhibits a rapid and relatively long-lasting local anesthetic effect in local, infiltrative, conductive, spinal and lumbar anesthesia. Causes weak surface anesthesia. Crystalline powder of white or almost white color. Easily soluble in water and 96 95 ethyl alcohol.

Menthol (MepipoYit) (from Latin Mepiga - mint), hexahydrothymol, mint camphor - colorless crystalline powder in the form of loose or agglomerates or prismatic or needle-like colorless shiny crystals, structurally belongs to monoterpene alcohols. Easily soluble in almost all organic solvents and fatty oils, practically insoluble in purified water. It is used as an active substance of medicines (validol, corvalol, menovazin, etc.), has a mild local anesthetic effect. Menthol is a means that eliminates irritation and dilates blood vessels. Local application of menthol is accompanied by the rapid appearance and preservation of the feeling of warmth. Irritation of sensitive nerve endings with menthol leads to a mild local anesthetic effect. Menthol has a weak irritating effect, which is accompanied by a comfortable feeling of pain relief in muscles, ligaments and joints due to the cooling effect. Menthol stimulates local blood circulation in tissues.

Rosemary essential oil (OiIveit goztagipi) is part of the preparation "Alflutop gel" (manufactured by KO "Biotechnos" JSC, Romania), which exhibits anti-inflammatory, analgesic, regenerating, chondroprotective and pain-relieving effects in various forms of osteoarthritis, and also prevents the destruction of macromolecular structures of the connective tissue tissues, stimulates regeneration processes in the tissues of the articular cartilage and peri-articular area.

Rosemary essential oil is used externally for arthralgia, radiculitis, arthritis, arthrosis, rheumatism, muscle pains, blows, sprains of ligaments and tendons, as well as for preparing muscles for physical exertion. Colorless or with a yellow tint, with a pleasant refreshing smell, the essential oil is obtained from rosemary leaves, in which it is up to 2.5 90. Rosemary oil contains 3095 sa- and D-pinene, 2095 camphene, 1095 cineole, 1895

Of borneol, 7 96 camphors, sesquiterpene hydrocarbon - D-caryophyllene, bornyl acetate, up to 8 95 tannins, terpineol, limonene, ursolic acid, isoalantolactone, betulin. The presence of nicotinic acid, flavonoids, rosmaricin alkaloid in rosemary leaves has also been established.

Propylene glycol (RgoruiIepdiusOimt) is a viscous, transparent, colorless liquid with a weak characteristic smell, sweetish taste, which exhibits hygroscopic properties. Mixes with purified water and 96 95 ethanol. The relative density of propylene glycol is greater than the density of water and is from 1.035 to 1.040 g/l at 20 "C, the boiling point is from 184 "C to 1897C, the melting point is -60 "C. Aqueous solutions with a concentration of propylene glycol of 60 9o freeze at a temperature of -70" C. The exact definition of the freezing point was not found due to the high viscosity and tendency of its solutions to hypothermia. Both hydrophilic and hydrophobic substances dissolve well in propylene glycol, which allows mixing them together in its presence.

Thanks to the scientifically based selection of components, the gel base ensures the solubility of lipophilic substances that are difficult to dissolve in water, including active medicinal substances, in particular FGPP.

The method of preparation of the gel base consists in the following technological process.

Experimental samples of gels with carbomer were prepared according to the classic scheme: the preservative was dissolved in the calculated amount of purified water, carefully poured a thin layer of carbomer on its surface (to prevent the formation of lumps) and left to rest for 10-15 minutes. Then trometamol was added in several doses and slowly mixed (to prevent the formation of air bubbles) until the formation of a transparent gel base of the required viscosity. Menthol and rosemary essential oil were dissolved in 9695 ethyl alcohol. At the same time, FGPP was dissolved in propylene glycol, and articaine hydrochloride was dissolved in a portion of purified water.

The obtained solutions were added to the gel base in the following order: an alcoholic solution of menthol and rosemary essential oil was added to an aqueous solution of articaine hydrochloride, mixed with a solution of FGPP in propylene glycol, and then the resulting mixture was added to the gel base. The finished gel was homogenized for 10 minutes until a homogeneous product was obtained.

According to organoleptic (appearance, color, smell, uniformity) and physico-chemical (structural viscosity, pH, colloidal stability, mechanical stability, thermal stability)

indicators were used for quality control. After receiving positive results, the gel was transferred to a storage container.

The table shows examples of gel base formulations. An increase or decrease in the quantitative share of components leads to a change in the rheological (structural-mechanical properties) and consumer characteristics of the developed gel.

The gel base has a homogeneous, structured gel-like mass of light or dark brown color (depending on the FGPP substance) with a pleasant specific smell.

Thus, the proposed gel base, thanks to a successful combination of substances, exhibits clearly defined properties, and can be used in the technology of manufacturing medicines. The anti-inflammatory and local anesthetic gel based on beekeeping products, in particular the standardized substance of the phenolic hydrophobic preparation of propolis (PHGPP), can be prescribed for use in sports medicine.

Table

Phenolic hydrophobic drug

Claims (1)

FORMULA OF THE INVENTION Gel for the local treatment of inflammatory diseases of the musculoskeletal system based on beekeeping products, containing active substances and auxiliary substances - carbomer (carbopol), propylene glycol, which differs in that as active substances it contains - a standardized substance FGPP (phenolic hydrophobic preparation of propolis ), articaine hydrochloride, menthol, rosemary essential oil, and additionally contains auxiliary substances - trometamol, ethyl alcohol 96 95, preservative and purified water, with the following ratio of components, wt. 9: phenolic hydrophobic 0 5-50 propolis preparation (FGPP) Ot articaine hydrochloride 1.0-10.0 menthol 0.1-3.0 rosemary essential oil 0.1-3.0 carbomer 0.5-2.0 trometamol 0.5-2.0 propylene glycol 1.0-30.0 preservative 0.1-2.0 ethyl alcohol 96 95 0.0-30.0 purified water the rest.