RU2635191C1 - Means for animal arachnoses treatment - Google Patents

Abstract

FIELD: veterinary medicine.

SUBSTANCE: ointment contains avermectins, isopropyl alcohol, dimexid, buckwheat melanins, polyhexamethyleneguanidine (PGMG), polyethylene oxide-400 (PEG-400) and polyethylene oxide-1500 (PEG-1500) as an active ingredient at a certain ratio of components, %: avermectins 0.06-0.1; isopropyl alcohol 8.0-9.0; dimexide 4.0-6.0; buckwheat melanin 0.01-0.02; polyhexamethyleneguanidine 0.005-0.006; PEG-400 45.0-80.0; PEG-1500 to 100.

EFFECT: reduced treatment time and increased therapeutic effect in animal arachnoses.

2 cl, 5 ex

Description

The invention relates to medicine, namely to pharmacy, and relates to the development of a veterinary agent in the form of an ointment for the treatment of animal arachnoses (demodicosis, otodectosis, notedrosis, sarcoptosis). The ointment contains avermectins, isopropyl alcohol, dimexide, buckwheat melanins, polyhexamethylene guanidine (PHMG), polyethylene oxide-400 (PEG-400) and polyethylene oxide-1500 (PEG-1500) with a certain ratio of components. EFFECT: invention increases the depth of penetration and the duration of the local action of the ointment, reduces the treatment time for arachnoses. Avermectin B1a hemisuccinate, which is part of the preparation, is a new compound from the class of avermectins - obtained by the authors of this application and protected by a patent (Zavarzin I.V., Dzhafarov M.Kh., Mirzaev MN, Kolobov A.V., Chernoburova E.I. ., Bobova T.A., Patent RU 2453553 C1, С07Н 19/01, С07Н 17/08, publ. 20.06.2012).

The relevance of improving measures to combat arachnoses is associated with the high contagiousness of dog and cat scabies mites for humans. There are known cases of papulocrustic lesions on the hands and body of a person (Nimand HG, Suter P.B. Diseases of dogs. - M .: Aquarium, 2001. - S. 303). Dog demodicosis is the most common and difficult to treat skin invasion. In the generalized form of demodicosis with the development of folliculitis, pathogens of bacterial infections penetrate the skin and cause pyoderma (Nimand HG, Suter P.B. Dog diseases. - M .: Aquarium, 2001. - P. 303), and against the background of a severe infection sepsis may result in death.

For the treatment of arachnoses in domestic dogs and cats, various forms of drugs are currently used - cutaneous, subcutaneous, oral. As the active substance, these preparations contain amitraz, ivermectin, milbemycin, etc. (Nimand HG, Suter P.B. Diseases of dogs. - M .: Aquarium, 2001. - P. 303-304; Chandler E.A. ., Gaskell K.J., Gaskell PM Cat Diseases. - M .: Aquarium, 2002. - S. 38-40). A disadvantage of the known drugs according to the available data is that when they are used, negative side effects are often observed - from amitrase vomiting, depression, diarrhea, etc., ivermectin and milbemycin are contraindicated in individual animal breeds.

Among the known preparations produced in the form of ointments and intended for the prevention and treatment of sarcoptidoses and demodicoses of animals, a composition including diazinon, dioctyl phthalate, animal fat, castor oil, stearin, beeswax deserves attention (Patent RU 2216327 C2, A61K 31/65, publ. . November 20, 2003). This drug has acaricidal and bactericidal effects, but does not have regenerative properties. The drug (Patent RU 2257209 C1, A61K 31/66, publ. 07/27/2005) contains hypodermine-chlorophos and sea-buckthorn oil, is characterized by high acaricidal, regenerating and anti-inflammatory activity, but does not have bactericidal activity.

Also known is the preparation “Ointment for the treatment of animal arachnoses” (Patent RU 2368377 C1, A61K 31/10, A61K 31/23, A61K 31/66, A61K 36/47, A61K 36/72, A61P 33/14, publ. 27.09. 2009), which has acaricidal, anti-inflammatory, regenerative, bactericidal and immunostimulating effects, which is important in the treatment of generalized forms of demodicosis and pyodemadecosis. The ointment contains an alcoholic solution of chlorophos, sea buckthorn oil, castor oil, dimexide and low molecular weight polyethylene (NMPE-2) in a certain ratio of ingredients. The disadvantage of the drug is that it does not have an antifungal effect and it contains an organophosphorus compound.

The prototype of the invention is the drug "Aversectin Ointment", registration number No. PVR-2-4.5 / 01653 from 30.06.2006. As the active substance, the ointment contains aversectin-C (Golovkina L.P., Berezkina SV. Antiparasitic drugs based on aversectin C // Vetinform, 1998. - No. 1 - C. 4), related to avermectins (macrocyclic lactones) produced by the microorganism Streptomyces avermitilis, and auxiliary components are polyethylene oxide-1500, polyethylene enoxide-400, glycerol (distilled glycerin). The drug has a wide range of insect-acaricidal contact and systemic effects. It is effective against larval and mature phases of development of sarcoptoid ticks (Sarcoptes canis, Sarcoptes vulpis, Notoedres cati, Otodectes cynotis, Psoroptes cuniculi) and demodecid ticks (Demodex canis), insects (Ctenocephophis lephis canisisphelis canisphis felis canis), parasitic on dogs, cats and rabbits. The disadvantage of the drug is that it does not contain components that have a significant antimicrobial and regenerative effect, which is necessary for generalized forms of demodicosis.

The objective of the invention is to expand the range of drugs used in the treatment of arachnoses, the creation of an ointment form of a drug that has not only insectoacaricidal, but also anti-inflammatory, bactericidal and fungicidal effects, helping to reduce the treatment time of animals.

The technical result from the application of the claimed invention is to increase the depth of delivery of the active substance into the tissues, to overcome the possible resistance of invasive pathogens to known and already used avermectin-containing preparations, to prevent infection of microbial tissue damaged by ticks.

The technical result of the invention is achieved by the fact that the proposed preparation contains, as an active principle, a new derivative of avermectins - hemisuccinate Avermectin B1a or abamectin, isopropyl alcohol (IPA), dimexide, buckwheat melanin, polyhexamethylene guanidine (PHMG), polyethylene oxide-400 (PEG-400) and polyethylene -1500 (PEG-1500) in the following ratio of components, wt. %:

avermectin B1a hemisuccinate or abamectin 0.06-0.1 isopropyl alcohol 8.0-9.0 dimexide 4.0-6.0 buckwheat melanin 0.01-0.02 PHMG 0.005-0.006 PEG-400 45.0-80.0 PEG-1500 up to 100

When applied to affected skin, the ointment is well absorbed and provides high target effectiveness due to the selected combination of ingredients.

Avremectin B1a hemisuccinate and abamectin are highly active insectoacaricidal substances related to macrocyclic lactones. Their mechanism of action is to regulate the current of chlorine ions through the membranes of the muscle and nerve cells of the parasite. The target is glutamate-sensitive chlorine channels, as well as gamma-aminobutyric acid receptors. Disruption of the current of chlorine ions leads to a disorganization of the process of transmission of nerve impulses and, as a result, paralysis and death of the parasite.

Isopropyl alcohol (IPA) is widely used in pharmaceuticals, medicine, and cosmetics. It mixes well with water and organic solvents, dissolves many organic substances, for example, water-insoluble avermectins (avermectin hemisuccinate B1a, abamectin, etc.), wax, oil, etc. The antiseptic effect of isopropanol is higher than that of ethanol.

Dimexide (dimethyl sulfoxide, DMSO) is a sulfur-containing organic compound well known in the pharmaceutical industry. Having a high polarity and the ability to form associates, it easily dissolves medicinal substances of various chemical nature. A unique property of dimexide is its rapid penetration through the skin, facilitating the delivery of drugs. In addition, DMSO has an analgesic, anti-inflammatory and antibacterial effect. The mentioned properties and the established harmlessness of DMSO have become the basis for the fact that the substance is widely used in technologies for the production of various dosage forms - ointments, emulsions, liniments, etc. (Eliseev Yu.Yu. Pharmacist's full reference book. - M .: Eksmo-Press, 2006. - S. 285-286).

Buckwheat melanin obtained in accordance with TU No. 9169-001-35231285-13 Buckwheat husk extract “Melavit” dated 06/27/2013, is available in the form of a solution and dry powder. By its chemical nature, melanin is a polyphenolic nature pigment obtained by extraction from buckwheat husk. Recently, many works have been published that indicate the presence of a wide range of biological activities in melanins. This is immunomodulation, radioprotection, anti-inflammatory activity, pronounced antioxidant effect, etc.

Polyhexamethylene guanidine (PHMG) has a uniquely broad spectrum of antibacterial, fungicidal and antiviral effects at very low concentrations (Staphylococcus aureus dies at a concentration of 0.0015%, Pseudomonas aeruginosa at 0.007%). Therefore, this substance is in demand in the suppression of nosocomial infections in maternity hospitals and hospitals, in the production of disinfectants, water disinfection, and pre-sowing treatment of seeds of agricultural plants. In appearance, PHMG is a transparent glassy mass that dissolves in water and alcohol. Polyhexamethylene guanidine is a low-hazard substance: LD ₅₀ is 815 mg / kg for hydrochloride and 2500 mg / kg for phosphate (mouse, rat, oral), when exposed to the skin, respectively, 10,000 and 13,000 mg / kg; in water of reservoirs MPC 3 mg / l (Gembitsky P.A. Polyhexamethylene guanidine // Chemical industry. - 1984. - No. 2. - P. 18-19 .; Barkova N.P. Toxicological and sanitary-chemical studies of promising salts of polyhexamethylene guanidine // Hygiene and sanitation. - 1989. - No. 2. - S. 14-16).

Polyethylene glycol (polyethylene oxide) -400 is a product of the polymerization of ethylene oxide with ethylene glycol. The unique properties of PEG-400 determine its wide industrial, biotechnological and clinical applications. PEG has a high solubility with respect to substances of both hydrophilic and hydrophobic nature, which allows it to be used as an effective basis for the creation of medicines in the form of ointments, foams and emulsions.

From the chemical point of view, the terms polyethylene glycol and polyethylene oxide are equivalent, but traditionally polyethylene glycols are called lower molecular weight adducts with M _r <20,000, and the term polyethylene oxide is applied to high molecular weight polymers.

Polyethylene glycol-1500 is used in pharmacology, medicine, cosmetics, the textile industry, etc. New ointments based on a polyethylene oxide base (combinations of PEG-400 and PEG-1500) have been introduced into clinical practice for the treatment of purulent wounds in phase I of the wound process. In a purulent wound, PEG-1500 actively binds the inflammatory exudate, giving it to the dressing with which the liquid evaporates, and the released PEG-1500 molecules reattach the exudate that accumulates at the bottom of the wound. Smaller PEG-400 molecules are able to penetrate deep into the tissue. Forming a complex with a biocide, PEG-400 conducts it into wound tissues where microbes are localized - this is a fundamental difference from the action of ointments on a lanolin-petrolatum base, which are able to exert an antimicrobial effect only for a short time and only on the surface of the wound.

Based on the analysis of the publication of scientific and patent information, the Applicant concludes that no means of a similar purpose are known in which the totality of the features of the proposed technical solution would be disclosed. Hence, the claimed invention undoubtedly meets the requirements of patentability conditions.

The practical implementation of the invention is demonstrated by the following examples and the ointment manufacturing algorithm: avermectin B1a hemisuccinate or abamectin is dissolved in isopropyl alcohol (IPA), the resulting solution is added with stirring to a polyethylene oxide melt cooled to 40 ± 1 ° C.

An important condition for dissolution is compliance with the temperature regime, as temperature above 41 ° C causes the destruction of avermectins and a decrease in their antiparasitic activity.

Stage 1. Dissolution of avermectins in IPA and DMSO, mixing the solution with PEG-400 (50-70% by weight of PEG-400 according to the recipe) at a temperature (not more than 41 ° C), adding melanins and PHMG when mixing.

Stage 2. Fusion of the remaining part of PEG-400 with PEG-1500 at a temperature of 80 ° C, cooling the alloy to a temperature of 41 ° C.

Stage 3. Mixing using a high-speed mixer of the solution obtained in stage 1, with the PEG alloy obtained in stage 2.

Stage 4. Homogenization of the ointment using a roll maser. The resulting preparation is a mass of uniform consistency, opaque with a brownish tint. The drug is stable during storage for at least 2 years.

When the PEG ratio changes in the direction of increasing the PEG-400 content, the ointment becomes too liquid, when the PEG-1500 content increases, it becomes too solid.

The invention is illustrated by the following examples.

Example 1. In a mixer with a capacity of 5.0 l with constant stirring, add 255 ml of IPA, add 2.5 g of hemisuccinate B1a, 150 ml of DMSO, 450 mg of melanins, 180 mg of PHMG and 1500 g of PEG-400. The rest of the PEG-400 in an amount of 600 g is fused at a temperature of 80 ° C with 660 g of PEG-1500, mixed for another 20-30 minutes, and after the temperature drops to 40-41 ° C, they are introduced into a container, mixed and approximately 3 kg of finished product is obtained form of the drug in the form of an ointment.

Example 2. All operations are carried out analogously to example 1, only abamectin is taken instead of avermectin hemisuccinate. Get 3 kg of ointment containing abamectin as the active substance.

The antiparasitic composition is tested on tick-infested dogs, cats, and rabbits. Therapy of sick animals using the proposed funds in the form of ointments is carried out in the usual way, i.e. the drug is applied to the lesions with the capture of adjacent healthy skin areas to a width of 2-3 cm. The ointment is applied with a spatula, glass rod or swab 1 time in 5-6 days until the animal is completely recovered.

The drug underwent clinical trials in 34 animals (11 dogs, 3 cats and 20 rabbits) with laboratory diagnoses: demodecosis, otodectosis, sarcoptosis, and notedrosis. The antiparasitic efficacy of the drug samples was evaluated based on the results of acarological studies of skin scrapings and the general condition of the animals. Tests have shown that the claimed drug has a pronounced acaricidal effect at various intensities of invasion. The use of the proposed ointment can reduce the treatment time for arachnoses (otodectosis, local demodicosis) up to 15-20 days, generalized form of demodicosis up to 30-65 days.

Example 3. Dogs (2 goals. - Caucasian shepherd dogs, 3 goals. - German shepherds, 6 goals. - Not purebred) contained in the vivarium of FSBEI HE MGAVMiB named after K.I. Scriabin with a diagnosis of demodicosis (in 2 animals a generalized form) was treated with preparations prepared in accordance with Example 1 and 2 and containing 0.08% avermectin B1a hemisuccinate (6 goals) and 0.08% abamectin (5 goals). As a result of the treatment with the proposed ointment, tick-affected areas on the body and limbs returned to normal in 9 goals in 18-20 days, and 2 dogs with generalized demodecosis were cured after 3 times of treatment after 35 days. Observations of animals were carried out for 4 months, repeated acarological studies confirmed complete release from ticks. Both drugs, containing both hemisuccinate and abamectin, showed the same acaricidal efficacy.

Example 4. Cats in the amount of 3 goals upon examination had squamous lesions in the head and back. Laboratory studies by microscopy of scrapings showed the presence of ticks - a diagnosis of demodicosis. The treatment with a drug containing abamectin was carried out. The treatment of wound surfaces of the skin was carried out 1 time 5 days. After 19 days, an improvement in the condition of the affected areas of the skin was recorded, and after 3 days there was no wound process on the affected surfaces of the skin.

Example 5. Of the 18 chinchilla rabbits infested with Psoroptes cuniculi (ear scabies), 6 groups of 3 heads each were formed. The animals of the first, second and third groups were treated with an ointment containing 0.06%, 0.08% and 0.1% of avermectin B1a hemisuccinate, respectively. The fourth and fifth groups of animals are treated with ointment containing 0.06% and 0.1% abamectin, respectively. The sixth group is treated with ointment containing 0.05% aversectin C (prototype) and serves as a control. The ointment was applied once after mechanical cleaning of the affected areas of the skin of the ears of rabbits from crusts. The treatment efficacy was evaluated on days 19-22 after treatment and at the same time a complete (100%) recovery of rabbits of groups 2, 3, 4, 5 was revealed, 66.66% recovery of rabbits was observed in groups 1 and 6 (prototype).

Thus, the above materials show the high antiparasitic efficacy of the proposed drug in the form of an ointment containing as an active substance a previously unknown substance - avermectin B1a hemisuccinate or abamectin in the above ratio of ingredients.

Information sources

1. Patent RU 2453553 C1, 06/20/2012.

2. Nimand H.G., Suter P.B. Dog Disease - M .: Aquarium, 2001 .-- 476 p.

3. Chandler E.A., Gaskell C.J., Gaskell P.M. Cat disease. - M .: Aquarium, 2002 .-- 712 p.

4. Patent RU 2216327 C2, 11.20.2003.

5. Patent RU 2257209 C1, 07.27.2005.

6. Patent RU 2368377 C1, September 27, 2009.

7. Golovkina L.P., Berezkina SV. Antiparasitic drugs based on aversectin C // Vetinform, 1998. - No. 1 - P. 4.

8. Eliseev Yu.Yu. A complete pharmacist reference. - M .: Eksmo-Press, 2006 .-- 767 p.

9. TU No. 9169-001-35231285-13. Buckwheat husk extract “Melavit” dated 06/27/2013

10. Gembitsky P.A. Polyhexamethylene guanidine // Chemical industry. - 1984. - No. 2. - S. 18-19.

11. Barkova N.P. Toxicological and sanitary-chemical studies of promising salts of polyhexamethylene guanidine // Hygiene and sanitation. - 1989. - No. 2. - S. 14-16.

Claims (3)

1. An agent for treating animal arachnoses containing avermectins, polyethylene oxide-400 (PEG-400) and polyethylene oxide-1500 (PEG-1500), characterized in that it additionally contains isopropyl alcohol, dimexide, buckwheat melanins and polyhexamethylene guanidine (PHMG) in the following the ratio of components, wt. %: avermectins 0.06-0.1 isopropyl alcohol 8.0-9.0 dimexide 4.0-6.0 buckwheat melanin 0.01-0.02 PHMG 0.005-0.006 PEG-400 45.0-80.0 PEG-1500 up to 100 2. A means for treating animal arachnoses according to claim 1, characterized in that the avermectin class contains avermectin B1a hemisuccinate or abamectin.