Application of pleuromutilin derivatives for transdermal treatment of bacterial disease

FIELD: medicine.

SUBSTANCE: the present innovation deals with application of pleuromutilin derivatives, that is valnemulin and thiamulin, for transdermal treatment of bacterial diseases, in particular those induced by Dichelobacter nodosus, Fusobacterium necrophorum, Bacteriodes nodosus and Bacteriodes melamnogenicus, for manufacturing medicinal preparation or as an active ingredient of medicinal preparation of the same indication and corresponding method for transdermal treatment of diseases, for example foot rot. It has been detected the capacity of antibiotics to penetrate skin and enter either plasma or blood at concentrations being efficient against systemic bacterial infections, so, medicinal preparation could be designed in the form of ointment, cream, solution, shampoo, powder and spray.

EFFECT: higher efficiency of application.

9 cl, 1 tbl

 

The present invention relates to a derivative pleuromutilin and valnemulin. More specifically it relates to the preparation of drugs for transdermal treatment of bacterial infections in humans and animals, containing the following compound of formula I. Such medicinal product used for the prevention or treatment of systemic bacterial infections, preferably infections in ungulates, such as digital dermatitis (stable hoof rot), digital disease such as laminitis (chronic inflammation between the front parts of the hoof; hoof rot) and digital microbatteries (digital abscess, hoof disease, clit-ill etc).

According to one of preferred embodiments of the invention to provide a system action or actions in a certain area of the body is injected by applying to the skin a compound of the formula

where R1denotes ethyl or vinyl;

Y denotes one of the groups selected from COOH, -CH2-R2and

R2denotes H, halogen, HE, NH2, SCN, N3, COOH, C(S)S-[C1-C5alkyl], -S,-pyridyl, -S-pyridyl, substituted with one or two hydroxyl groups, With1-C5alkylthio,1-C5-allylthiourea substituted one the th or more amino groups, hydroxyl or carboxyl groups, -O-SO2-(4-were), -S-(CH2)m-X -(CH2Z)r-(CH2)s-Q or-S-C(CH3)2-CH2-NH-C(O)-Q; or-S-(CH3)2-CH2-NH-C(O)-CH(NH2)-CH(CH3)2;

X denotes a saturated or unsaturated 5-6-membered heterocyclic ring, associated with the-S-(CH2)mgroup via a carbon atom, and which contains one or more heterogroup selected from the series comprising O, S, N, or-N(R3); and a heterocyclic ring is unsubstituted or substituted by one or more substituents selected from the group comprising halogen, hydroxy, mercapto, C1-C5alkyl, C1-C5alkanoyl,1With5alkylsulfonyl, nitro, formyl, C1-C5alkoxycarbonyl and C1-C5hydroxyalkyl;

R3denotes hydrogen or C1-C5alkyl;

Q denotes a group-N(R4)(R5), where R4and R5each independently from each other represents C1-C5alkyl or together with the nitrogen atom to which they are attached, form a saturated or unsaturated 5-6-membered heterocyclic ring, optionally containing a second heterotrimer representing sulfur or =N-(C1-C5alkyl);

Z represents O, S or =N(C1-the 5alkyl);

m is 0, 1, 2, 3, 4 or 5; r is 0 or 1; s is 2, 3, 4, or 5; in the form of a free base or as pharmaceutically acceptable salts for the treatment caused by bacterial infections of the human or animal diseases.

It should be understood that in the context of the present description, the term "alkyl" depending on the specified number of carbon atoms means, for example, the following groups with straight or branched chain: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, etc.

"Halogen" denotes chlorine, bromine, fluorine or iodine, preferably chlorine, bromine or fluorine, preferably chlorine.

Preferred heterocyclic rings are 5 - and 6-membered rings containing one or more heteroatoms selected from nitrogen and sulfur. More preferably the ring contains at least one nitrogen atom.

One group of such heterocyclic rings may contain as the only nitrogen heteroatoms, in particular 1, 2 or 3 nitrogen atom as the heteroatoms. Suitable 5 - or 6-membered heterocyclic ring containing one nitrogen atom, include pyridine, pyrrole and 4,5-dihydro-3H-pyrrole. Suitable 5 - or 6-membered ring containing 2 nitrogen atom include imidazole, pyridazine, pyrimidine. Such rings may be condensed, for example, with one or more of intalniri rings, for example, with the formation of the benzimidazole or pyrimidine. Suitable 5 - or 6-membered heterocyclic ring containing 3 nitrogen atom, include 1,2,4-triazole.

Another group of heterocyclic rings may contain 1 nitrogen atom and 1 sulfur atom, representatives of this group are, for example, thiazole, 4,5-dihydrothiazolo and benzothiazole. Another group of heterocyclic rings contains 2 atoms of nitrogen and 1 sulfur atom, a representative of this group is, for example, 1,3,4-thiadiazole.

In the context of the present invention, more preferred is the use of compounds of formula I, where R1denotes ethyl or vinyl; R2denotes the group-S-C(CH3)2-CH2-NH-C(O)-Q; where Q denotes the group-N(R4)(R5), where R4and R5each independently from each other represents C1-C5alkyl or together with the nitrogen atom to which they are attached, form a saturated or unsaturated 5-6-membered heterocyclic ring, optionally containing a second heterotrimer selected from the group comprising sulfur, or =N-(C1-C5alkyl; in free base form or in the form of pharmaceutically acceptable salts.

Even more preferred is the use of compounds of formula I, where R2denotes the group-S-(CH3)2-CH2-NH-C(O)-CH(NH2)-CH(CH3) ; in free base form or in the form of pharmaceutically acceptable salts.

Preferred is also the use of compounds of formula I, where R1denotes ethyl or vinyl; and Y represents a group -(CH2Z)r-(CH2)s-Q in which Z represents sulfur; r is 1; s is equal to 2; Q represents a group-N(R4)(R5), where R4and R3each independently from each other represents C1-C5alkyl or together with the nitrogen atom to which they are attached, form a saturated or unsaturated 5-6-membered heterocyclic ring, optionally containing a second heterotrimer selected from the group comprising sulfur, or =N-(C1-C5alkyl), where R4and R5most preferably represent ethyl; in free base form or in the form of pharmaceutically acceptable salts.

The most preferred compounds are valnemulin, tiamulin; primarily valnemulin; in free base form or in the form of pharmaceutically acceptable salts.

The most famous antibiotic among the compounds of the formula I is pleuromutilin (X indicates HE and R1denotes vinyl), which was dedicated in 1951 Kavanagh with employees [Proc. Natl. Acad. Soc. 37, 570-574 (1951)]. Another derived pleuromutilin formula (I), where R1denotes vinyl and X represents β,D-xylopyranosyl the second group, described in US-4247542. The most typical compounds of formula I are valnemulin, tiamulin.

Valnemulin available under the trademark Econor®and tiamulin under the trademark Tiamutin®. They have the following chemical structure

Valnemulin in free base form or in the form of physiologically acceptable salts are described, for example, in EP-0153277, primarily in example 12, and in WO 98/01127. Tiamulin and its derivatives, and other derivatives pleuromutilin in free base form or in the form of physiologically acceptable salts are described, for example, in US-4032530, US-4148890, US-5578585, US-4428953, 4060542, WO 98/01127 and ER-0153277.

In WO 99/51219 described the use pleuromutilin or certain of its pharmaceutically acceptable derivatives for the preparation of a medicinal product, adapted for introduction into the nasopharynx as a prophylactic agent for the treatment of infections caused by bacteria that colonises the nasopharynx. Thus the method is based on the absorption of the active substance membrane of the mucosa of the upper part of the nasopharynx. In contrast, the present invention is based on the transdermal absorption of the active substance, which is applied locally on the skin (epidermis) of the patient or the skin or coat of the animal.

Spectrum of activity valnemulin,tiamulin, and other derivatives pleuromutilin well known and described in the above reference patents and numerous scientific articles.

As follows from the quoted sources, the compounds of formula I possess antibacterial activity when their oral or parenteral administration. Treatment by oral administration, in which there is absorption of the active substance through the mucous membrane of the digestive tract, includes the prevention and therapy of bacterial infections. In the field of veterinary medicine active substances is preferably introduced pet along with food or drinking water.

With the invention it has been unexpectedly found that the compounds of formula I have the ability to penetrate the skin, in the context of the present description means to penetrate through the epidermis without metabolism and without losing its activity. It was absolutely impossible to predict what antibiotic having such a complex chemical structure that can pass through the skin barrier and penetrate into the fabric, and this can be achieved concentrations in blood and plasma, sufficient to effectively combat bacterial infections. These bacterial infections include systemic infection in which the bacteria colonise the cell, tissue or organ of the intestine, and non-systemic infection in which the bacteria colonise the small or having large dimensions of the area of the skin. This is one of the exceptional cases where for the treatment of systemic infections antibiotic can be applied to the skin, and not to apply using conventional systemic routes of administration, such as oral or dermal. This new application should not be confused with the application, consisting in the application of the antibiotic on the skin to disinfect areas contaminated with the pathogen. Unexpected is the fact that the compounds of formula I have the ability to penetrate the skin and destroy pathogens in the body of the animal and within the whole organism.

Representatives of the warm-blooded animal hosts, which can be treated using the method according to the present invention, are people, and also preferably domesticated animals such as cattle, horses, sheep, goats, poultry, pigs, dogs, cats and animals contained in the zoo.

This opens up new possibilities in the treatment of bacterial infections and especially systemic bacterial infections. Such new approaches may be more convenient and less time-consuming for farmers and veterinarians in comparison with the methods of treatment based on the use of tablets, bolus or injection.

Thus, this is the invention of a new way of dealing with bacterial infections in animals, who is that on the skin of the animal causing a certain amount of the antibiotic of the formula I, the compound is absorbed through the skin (epidermis) in the body of the animal.

The method according to the present invention is preferably used for the treatment of mammals, which preferably are of domestic or farm animals such as sheep, pigs, cows or cattle, horses, goats, dogs and cats. The method can be applied to treat people. It can also be used for animals used in laboratory experiments, such as rats, mice and Guinea pigs. The connection can be used for preventing or inhibiting infection or to treat an already existing infection.

In the method according to the present invention the compound is absorbed into the body of the animal through the skin. The connection is usually used in the composition containing a physiologically acceptable carrier. You can use numerous suited for this purpose the media. The composition may be a cream. However, it is particularly convenient to use a liquid composition, for which it is easier to measure certain doses and which is more easily absorbed through the skin. Therefore, the preferred are the solution or suspension of the compounds in liquid media. The most effective solutions in Rel is against the penetration of compounds through the skin and therefore they are the most preferred.

The compounds of formula I, intended for application to the skin/local applications when used in veterinary medicine and medicine, can be included in the composition such preparative forms, such as ointments, creams, lotions, shampoos, powders, sprays (for example, sprayed manually or by using an installation for processing a party animal), solutions for impregnation (for example, solutions for soaking in the tub), aerosols, drops (e.g., eye drops or nasal drops), drugs for treatment by irrigation/point drawing or drawing by hand (for example, by manual impregnation). For treatment of farm animals or pet animals, such as cows, horses, donkeys, camels, dogs, cats, poultry, sheep, goats, etc. preferred the so-called composition for treatment by irrigation" or "point of application"; such liquid or semi-liquid compositions have the advantage that they can be applied to small areas of hair or feathers, and, thanks to the properties of the oils governing the distribution, or the properties of other additives governing the distribution, they are distributed over a large area, which leads to strengthening them through the epidermis.

Ointments and creams can be prepared, for example, aqueous or oily base with the addition of suitable thickening agents and/or arousih agents. Ointment for introduction into the eye can be prepared under sterile conditions using sterile components. For example, the preparative form for processing by irrigation" or "point of application" for use in VETERINARII can, for example, prepared using oils containing organic solvents, optionally in combination with auxiliary substances for the composition, for example, stabilizers or solubilizers agents. Lotions can be prepared in water or oil-based and they usually contain one or more emulsifiers, stabilizers, leavening agents, suspendida agents, thickeners or dyes. Powders can be prepared using any acceptable powder Foundation. Drops can be prepared in an aqueous or nonaqueous basis, which also contains one or more dispersing agents, stabilizers, solubilizing agents or suspendida agents. They can also contain preservatives.

The preferred embodiment of the present invention are compositions intended for processing by irrigation" or "point of application". They differ in that the active substance is dissolved, emuleret or suspended in a suitable solvent or mixture of solvents, which are portable, the La leather, optional with the addition of other auxiliary substances, and they are applied using a suitable device, for example using a measuring Cup or vessel for spraying on the skin of the animal that is to be processed.

Methods of treatment by irrigation" or "point of application" is well known in veterinary medicine, but they are mainly used for the control of ecto - or endoparasites.

It is obvious that the prophylactic or therapeutic effect can be achieved also by inhalation medicines. With this purpose in medicine and veterinary active substances according to the invention can be introduced in the form of an aerosol or by using insufflator.

In addition to the compounds of formula I and the media, promoting the effective penetration of compounds through the skin, the composition may also contain additives which, for example, facilitate the use of animals. For example, the composition may contain additives designed to facilitate contact with the skin of the animal, protect the skin from unwanted actions, such as irritation, which otherwise causes the media, or to improve the ability of the composition to remain on the animal's body.

The viscosity of the liquid composition can be improved in comparison with the inherent initial viscosity by the addition of thickening agents that increase the viscosity. This can be a VC is positive for to slow or prevent the swelling of the composition to the animal's body.

Additives may include, for example, surfactant, fat of animal origin or waxes, such as lanolin, mineral oil, for example liquid paraffin, vegetable oil such as peanut oil, olive oil, corn oil or castor oil, or a polymer, for example, a hydrocarbon polymer, such as polyisobutene.

Surfactant can be an anionic substances, such as Soaps, fatty sulphate esters such as sodium dodecyl sulphate, fatty aromatic sulfonates, such as alkylbenzenesulfonates or butylnaphthalene, more complex fatty sulfonates such as the amide condensation products of oleic acid and N-methyltaurine, or dioctylamine sulfonate sodium.

Compared with the treatment by oral administration or by injection of a composition intended for processing by irrigation" or "point of application", have the additional advantage of great importance in veterinary practice. We can note the following General advantages:

1) very easy to use;

2) ease of processing all animals in the herd;

3) less risk in respect of injury to animals and man, engaged in processing the weave;

4) is significantly less risk of infection with diseases transmitted by injection;

5) symptoms of local intolerance manifested significantly less than in the case of injection; and

6) the costs of production equipment are lower.

Usually the effect of the compositions, administered orally or by injection, is more pronounced than in the case of appropriate treatment by irrigation or point of application. However, the above advantages can compensate for such a less pronounced effect. To achieve efficiency, comparable with the efficiency achieved in oral or dermal introduction, it is possible to increase the total amount of active substance of the formula I, and it is not accompanied by harmful side effects.

In the context of the present invention, tiamulin and primarily valnemulin represent the most preferred active ingredients for antibiotic compositions intended for processing by irrigation or point of application for the prevention or treatment of bacterial and preferably systemic bacterial infections, which involves penetration of the skin (epidermis) with a bactericidal effective amount of the compounds of formula I.

To broaden the spectrum of action of the compounds is of formula I can be administered in combination with other acceptable active ingredients, having pharmaceutical activity. The total dose for the same active substance can vary from one animal species to another, and also within the same species of animal, because it depends among other things on weight and Constitution of the animal. The total daily dose of the compounds according to the invention, which can be used both in veterinary medicine and medicine be from 0.01 to 2000 mg/kg body weight, preferably from 0.1 to 1000 mg/kg body weight, more preferably from 1 to 100 mg/kg of body weight, however they can be used as a single or divided doses. Thus they can be applied with an interval of one week, one month or even with large intervals. In such cases, the dose should be far greater than the daily dose and it should be chosen with consideration of the forms of introduction, body weight and specific indications. The appropriate dose can be determined by means of tests on models, preferably on models with animals. The most appropriate time intervals for the introduction of drugs can be determined on the basis of the experiment in each case.

Typically, such compositions contain a compound in combination with an acceptable carrier or diluent. These carriers may be liquid or solid, they are designed to ensure more effective application of the connection, what is that either they contribute to the fact that the compound is dispersed in the area on which you want to apply, or they provide a composition from which the consumer can obtain dispersible drug. Such compositions are well known in this field and they can be prepared by conventional methods, for example by mixing and/or grinding the active(it) substances(a) in combination with a carrier or diluent, for example with a solid carrier, solvent or surface-active agent.

Solid carriers which can be used in such compositions, as dusty, granules and powders may be selected, for example, from natural mineral fillers, such as diatomaceous earth, talc, kaolin, montmorillonite, profilit or attapulgite. Optionally, the composition can comprise a highly dispersed acid or highly dispersed polymer absorbents. Granular absorbent media that you can enter in the composition, can be porous (such as pumice, crushed brick, thick or bentonite) or non-porous (such as calcite or sand. Suitable pre-granulated materials that can be used may be organic or inorganic, they include dolomite and crushed remains of plants. Suitable as the e carriers or diluents solvents include, but are not limited to, aromatic hydrocarbons, aliphatic hydrocarbons, alcohols and glycols or their ethers, esters, ketones, amides, acids, highly polar solvents, optional epoxydecane vegetable oil and water. The compositions can be enabled individually or in combination with each other nonionic, cationogenic or anionic surfactants, such as ethoxylated alkyl phenols and alcohols, salts of alkali metals or alkaline earth metals and alkylbenzenesulfonic acids, lignosulfonic acids or sulfonating acids or sulfonates polymeric phenols having good emulsifying, dispersing and/or wetting properties.

Optionally, the composition can include stabilizers, agents, prevent caking, antifoams, viscosity regulators, binders and adhesives, photostabilization as well as fertilizers, substances that enhance appetite, or other active substances. Compounds according to the invention can be included in the preparative form in a mixture with other therapeutic active substances. Typically, the concentration of the active substance in the compositions ranges from 0.01 to 99 wt.%, more preferably from 0.01 to 40 wt.%. Marketed products are usually concentrated compositions, which before PR is the change must be diluted to the appropriate concentration, for example, to 0.1-0.01 wt.%.

With the invention it has been unexpectedly found that the compounds of formula I in free base form or in the form of pharmaceutically acceptable salts have a pronounced activity against digital dermatitis (stable hoof rot), which is often found in agricultural animals such as sheep, goats, horses, dairy cows and beef cattle. They also have a pronounced activity against digital disease such as laminitis or foot rot, occurring mainly in sheep, which usually is a chronic inflammation of the skin in the area between the front parts of the hooves on the feet (digital crack). This infection is caused by the bacterium Dichelobacter nodosus. The skin in the area of digital slit becomes swollen, it appear dry secretions, which leads to the formation of a scab. This condition can sometimes cause lameness or cracks in the heel of the hoof/the erosion of the heel of the hoof and usually results in a change of the gait of the animal. Usually occurs secondary infection with Fusobacterium necrophorum, which leads to the fact that the hoof can not fully be used when running, causing you receive a serious limp.

Digital necrobacillosis (digital abscess, hoof disease, clit-ill etc) is an acute infection the first disease of ungulates, first of all cattle. This disease is characterized by swelling and lameness in one or more legs. If treatment is not performed or is delayed, the disease becomes chronic. It is caused by the bacterium Fusobacterium necrophorum. In the development of the disease could also involve other organisms, such as Bacteroides melaninogenicus. Both the body are not capable to move independently of anaerobic gram-negative bacteria, which normally breed in areas of damage. While Fusobacterium necrophorum can cause hoof rot, if these bacteria for experimental purposes is injected in the digital area. In the development of the disease may also participate Bacteroides nodosus, the agent that causes foot rot in sheep. Digital necrobacillosis is characterized by a sudden onset of lameness of moderate to severe severity, accompanied by swelling in the area of ungulate and whisk in the digital area. Digital region is often necrotic and there are cracks, it emits a characteristic purulent smell, but it has a small amount of discharge. Body temperature is often raised, your appetite is reduced and the reduced fatness. The infected animals often lack appetite and grazing animals reduced attention. Tribes who haunted the bulls lose their ability especially if damaged hind leg.

Digital dermatitis, especially in dairy cattle, is a disease identified in recent years. Its etiology is unknown, however, there is the assumption that it is caused by a spirochete, possibly in combination with other bacteria. It is characterized by superficial inflammation of the skin in the digital area, primarily in the area of the hoof, leading to lameness and reduced milk yield.

Such infectious diseases of the hoof widespread in most countries of the world and they are the most common cause of lameness. The incidence varies from one or two animals in a herd or pen to a very large level with a sudden outbreaks. Diseases occur at any time of the year. Disease prone animals at any age, but most often diseases occur in animals during weaning and at an older age. The same animals can be infected again. In the past, digital dermatitis, digital disease such as laminitis and digital necrobacillosis mistakenly called interdigital dermatitis, interdigital a disease such as laminitis and interdigital necrobacillosis.

When creating the present invention it has been unexpectedly found that the introduction of the compounds of formula (I) in free base form is whether in the form of a pharmaceutically acceptable salt leads to a rapid response to treatment and rapid recovery, however, it does not exert any harmful effects on milk. In mild cases it is enough to make one treatment. In more serious cases, when the microorganism penetrates into the adjacent tendon sheath, joint capsules and/or bone tissue, it may be necessary to re-processing. You can easily implement preventive measures by using a foot bath, composed of one or more compounds of formula I in free base form or in the form of pharmaceutically acceptable salts.

Thus, another object of the present invention is an antibacterial composition intended for the prevention or treatment of infectious diseases of the legs, preferably diseases caused by one or more species of bacteria from the group comprising Dichelobacter nodosus, Fusobacterium necrophorum, Bacteroides nodosus and Bacteroides melaninogenicus, and the composition contains as active ingredient the compounds of formula I in free base form or in the form of a pharmaceutically acceptable salt and a physiologically acceptable carrier. The composition and method according to the present invention are effective against a wide variety of conditions, while they can be used in different dilutions. The compositions of the present invention may also comprise other additives, to the that can be any connection, improving the characteristics of the composition, enhancing the solubility or dispersion ability of the other components, enhance the adhesion of the composition to the affected area of the hoof, allow you to adjust the characteristics of wettability and increase stability, which may be related, among other things, with such characteristics as surface tension and viscosity. The composition of the present invention may also include dyes, which allows to obtain well-resolved composition that ensures the adequate and full use.

The compounds of formula I in free base form or in the form of pharmaceutically acceptable salts can be administered in a number of ways, for example, be applied to the skin or enter the system. Most preferred is applied to the skin. In accordance with this under the scope of the present invention is subject method of prevention or treatment of infectious diseases of the hoof in animals, namely, that the antibacterial composition of the present invention applied to the skin, preferably near the infected area. More preferably the composition is used for the treatment of foot rot. The composition can be applied by irrigation, by means of a jet, by washing, wiping with a sponge or spray the infected or the nearby area, or by making the mother of the l to shim the legs. In a preferred embodiment, the compositions of the present invention is applied by spraying. In an alternative embodiment, the processing of the hooves of the animal produced by washing composition according to the invention, by immersing or dipping into it.

From the above description, the person skilled in the art should be clear main characteristics of the invention and it can without deviating from the essence and scope of the invention to make various changes and modifications of the invention to acephali to different tasks and conditions. Thus, other embodiments of also fall under the scope of the invention.

It is assumed that the person skilled in the art based on this description without additional research may implement the present invention in its entirety. Therefore, the following specific example should be considered only as illustrations, he in no way limits the scope of the invention. The above publications are included in the present description by reference.

The following examples of the preparation and application serve to explain the invention, the specific aspects of these examples do not limit the scope of the invention.

Examples of compositions

Dusty:

valnemulin:from 0.1 to 10%, preferably from 0.1 to 1%
solid carrier:of 99.9 to 90%, preferably from about 99.9 to 99%

Suspension concentrates:

valnemulin:from 5 to 75%, preferably from 10 to 50%
water:from 94 to 24%, preferably 88 to 30%
surfactant:from 1 to 40%, preferably from 2 to 30%

Composition with delayed release:

valnemulin:0.1 to 1.0 g
peanut butter:to 100 ml

or

valnemulin:0.1 to 1.0 g
sesame oil:to 100 ml

Receiving: the Active substance is partially dissolved in the oil with stirring and, if necessary, at low heat, then bring to the desired volume and sterile-filtered through a suitable membrane filter with a pore size of 0.22 μm.

Solutions:

15% valnemulin 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane

10% valnemulin in monoethylene ether of diethylene glycol

10% valnemulin in polyethylene glycol (mol. weight 300)

5% VA is nebulin in glycerol

The composition for treatment by irrigation/spot application:

(i)(ii)(ii)(iv)
valnemulin10,65 g10,65 g10,65 g21,00
vaseline oil with high viscosity--10,00 g----
vegetable oil------30 ml
isopropylmyristate----10,00 g--
trimethylbenzene------10,00 g
isopropanolto 100 mlto 100 mlto 100 mlto 100 ml

Biological examples

1. Pre-test: Evaluation of transdermal injection for pigs

Experimental animals: pigs (animal 1 and animal 2)

Test composition for animal No. 1: aqueous solution containing 10% valnemulin

Test composition for animal No. 2: a 40%solution of ethanol in water containing 10% valnemulin

Test dose: 2×25 mg/kg of body weight

The test solution is applied to the skin of the animal and determine the concentration in the liver, lung, skin, bile and plasma. The results are presented in table 1.

Table 1Animal No. 1Animal No. 2
Liver0,1750,132
Easy0,9160,353
Leather39,0566,965
Bile0,155<detection limit
Plasma, after 3 h after the 1st injection<detection limit<detection limit
Plasma 6 hours after the 1st injection<detection limit0,07

For determination of the concentration (μg/ml plasma or in µg/g of tissue) using a calibration curve of concentration valnemulin in the plasma. Such studies are not intended to define exact values, they can only get an answer like Yes or no. They serve to illustrate the ability of the test product to penetrate the skin.

2. Assessment of systemic absorption of compounds of the type valnemulin when applied to the skin of cattle

Disease: hoof rot

Method of application: foot bath, or it can be directly applied in spray form

Test Protocol: the Study was performed on four adults giving milk cows with clinically the ski symptoms of bovine digital dermatitis. Samples of blood and milk were collected prior experience and at certain intervals after application of ethanol-water solution containing 10% valnemulin, or by using a foot bath, or by directly spraying the legs.

The test composition: water-ethanol solution containing 10% valnemulin

valnemulin10,65 g*
propyl ester of para-hydroxybenzoic acid0.02 g
methyl ester of para-hydroxybenzoic acid0.18 g
ethanol5,00 g
water (purified)to 100 ml

*the initial mass for a product containing 93.9 per cent valnemulin (in the form of base)

Solutions for foot baths prepared anew each day of treatment. The calculated amount of the product being tested is added to a specific amount of water that is pre-filled in a footbath.

Each of the cows individually led into the footbath and made to stand in covering the feet of the solution for a foot bath for 2 minutes spraying the legs are produced using a handheld sprayer that make 100 ml of the test product. These 100 ml of the product is sprayed on the legs of each cow, dealing directly on the bottom of the feet and in the Rog and on the bottom of each hoof.

Content valnemulin in the samples is determined using widely known method of high performance liquid chromatography (IHVR). Day 1 until noon selected milk samples (50 ml/sample) before the first treatment, these data serve as control. During the experiment, each cow nine times to take samples of blood (20 ml/sample) from the coccygeal vein.

Graph processing (D = day) (a.m. = in the morning; RM. = after noon)

Day (D) 1 Individual processing using a foot bath with a volume of 150-200 l containing 10%solution valnemulin in the ratio of 3 l per 100 l of water.

Day (D) 3 Individual processing using a foot bath with a volume of 150-200 l containing 10%solution valnemulin in the ratio of 3 l per 100 l of water.

Day (D) 5 Affected and healthy feet sprayed with 25 ml of aqueous 10%solution valnemulin.

Blood samples taken before the first treatment and after a certain period of time after the subsequent processing. Milk samples taken during processing and during subsequent milkings.

Unexpectedly revealed the presence valnemulin in most of the samples of milk and blood. It is obvious that the connection has the ability to penetrate the skin. It has not been established correlation between the severity of damage and the concentration of the substance in the blood or milk. After one week, none of the processing is the R cows, symptoms of foot rot.

Additional experiments on pigs and cattle the cattle were allowed to establish that after the local point of application valnemulin quite significant quantities of active ingredients found in many tissues such as brain, liver, muscle, spleen and lung.

1. The use of the compounds of formula I

where R1denotes vinyl;

Y represents-CH2-S-(CH2)2-N(C2H5)2or-CH2-S-(CH3)2-CH2-CH(NH2)-CH(CH3)2,

in the form of a free base or as pharmaceutically acceptable salts for the preparation of drugs for transdermal treatment of bacterial infections in humans and animals.

2. The use according to claim 1, where the drug is intended for application by irrigation, point of application, for application by dipping or spraying.

3. The use according to claim 1 or 2, where bacterial infections are infectious diseases of the foot of a hoofed animal.

4. The use according to claim 1, where the medicinal product after application to the skin provides the penetration of the compounds of formula I through the skin.

5. The use of the compounds of formula I, characterized in claim 1, as an active ingredient pharmacist the political composition, intended for transdermal treatment of bacterial infections in humans and animals.

6. The use according to claim 3, where an infectious disease of a foot of a hoofed animal is called by one or more species of bacteria from the group comprising Dichelobacter nodosus, Fusobacterium necrophorum, Bacteriodes nodosus and Bacteriodes melaninogenicus.

7. The use according to claim 3, where an infectious disease of a foot of a hoofed animal is interdigital dermatitis, interdigital the disease such as laminitis or interdigitating necrobacillosis.

8. The transdermal method of treating bacterial infections in humans, including the application of a therapeutically effective amount of the compounds of formula I according to claim 1 to the skin or coat.

9. The use of the compounds of formula I, characterized in claim 1, for the transdermal treatment of bacterial infections in humans and animals.



 

Same patents:

FIELD: biotechnology, immunology.

SUBSTANCE: invention proposes preparation that comprises the immunoelectrophoretically pure secretory immunoglobulin A isolated from whey milk and/or colostrum of immunized ungulate animals and pharmaceutically acceptable vehicles. The base preparation (substance) comprises 6-12% of secretory immunoglobulin A at pH 4-8, an anti-complementary activity at least 10 mg of protein, not activating 2 CH50, protects in >70% against corresponding infections (in infection macroorganism in doses ≥10 ID50), shows areactogenic property in intravenous administration, can comprise stabilizing additives in the total concentration 4%, not above. The preparation possesses high purity, low anti-complementary activity, stable in storage, useful for oral, parenteral and topical using and possesses therapeutic activity with respect to microorganisms and viruses against which humans and animals immunization have been carried out. Invention can be used in treatment and prophylaxis of immunodeficiency states, bacterial and viral infections in humans and animals.

EFFECT: valuable medicinal and veterinary properties of preparation.

9 cl, 1 tbl, 10 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel heterocyclic compounds comprising 2-aminopyridin-3-sulfonic fragment of the general formula (1) or their pharmaceutically acceptable salts, N-oxides or hydrates possessing properties of antagonists of glutamate-induced calcium ions transport, in particular, neuroprotective effect. Also, invention relates to the focused library for the search of biologically active leader-compounds comprising at least one heterocyclic compound of the general formula (1) and to pharmaceutical composition if form of tablets, capsules or injections placed into pharmaceutically acceptable package containing compounds of invention as an active substance. In compound of the general formula (1) R1 represents hydrogen atom; R2 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; or R1 and R2 in common with nitrogen and sulfur atoms to which they are bound form optionally substituted and optionally condensed with other cycles 1,1-dioxo-4H-pyrido[2,3-e][1,2,4]thiadiazine or optionally substituted and optionally condensed with other cycles 5,5-dioxo-5,6,7,9-tetrahydro-5-thia-1,6,9-triazabenzocyclohepten-8-one. Also, invention discloses methods for preparing different compounds of the general formula (1).

EFFECT: improved preparing methods, valuable medicinal properties of compounds.

10 cl, 4 sch, 4 tbl, 9 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new heterocyclylsulfonyl alkylcarboxylic acids and their derivatives of the general formula (1): or their pharmaceutically acceptable salts, N-oxides or hydrates possessing the inhibitory effect on kinase activity and to the focused library for search of active leader-compounds comprising at least abovementioned compound. In the general formula 91) W represents optionally substituted heterocyclic radical, among them: pyrrole-3-yl, thiophene-2-yl, isooxazole-4-yl, pyrazole-4-yl, imidazole-4-yl, pyridine-3-yl, 1H-2,4-dioxopyrimidine-5-yl, 2,3-dihydro-1H-indole-5-yl, 2,3-dihydro-1H-indole-7-yl, 1,3-dihydro-2-oxoindole-5-yl, 2,3-dioxo-1H-indole-5-yl, 2-oxo-3H-benzoxazole-6-yl, benzothiazole-6-yl, 1H-benzimidazole-5-yl, benzo[1,2,5]oxadiazole-4-yl, benzo[1,2,5]thiadiazole-4-yl, 1,2,3,4-tetrahydroquinoline-6-yl, 3,4-dihydro-2-oxo-1H-quinoline-6-yl, quinoline-8-yl, 1,4-dihydro-2,3-dioxoquinoxaline-6-yl, 3-oxo-4H-benzo[1,4]oxazine-7-yl, 3-oxo-4H-benzo[1,4]thiazine-7-yl, 2,4-dioxo-1H-quinazoline-6-yl, 2,4-dioxo-1,5-dihydrobenzo[b][1,4]diazepine-7-yl or 2,5-dioxo-3,4-dihydrobenzo[b][1,4]diazepine-7-yl; Y represents optionally substituted methylene group; R1 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; n = 1, 2 or 3; or Yn represents carbon atom of optionally substituted (C3-C7)-cycloalkyl or optionally substituted (C4-C7)-heterocyclyl. Also, invention relates to a pharmaceutical composition in form of tablets, capsules or injections placed into pharmaceutically acceptable package.

EFFECT: valuable properties of compounds.

5 cl, 3 sch, 5 tbl, 6 ex

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: derivative of 9-deoxo-9a-aza-9a-homoerythromycin A of the formula (3) wherein R4 represents hydroxyl protecting group is prepared by protection of 2'-hydroxy-group of compound of the formula (5) to form compound of the formula (4)

and by oxidation of C-4''-hydroxy-group of compound of the formula (4) that is carried out by addition of dimethylsulfoxide to solution containing compound of the formula (4) and a solvent followed by cooling the mixture up to about -70°C, activation of dimethylsulfoxide in situ and defoaming the reaction mixture. Compound of the formula (4) is converted to the oxidation stage directly without its isolation. Also, invention proposes additive salt of trifluoroacetic acid of compound of the formula (3) and a method for its preparing by treatment of compound of the formula (3) with trifluoroacetic acid. Invention provides increasing yield and improving purity of the end product.

EFFECT: improved preparing method.

11 cl, 6 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with infecting macrophages and cells of macrophagous cell lines with pathogenic microorganisms, their treatment with medicinal remedies followed by gamma-irradiation, immunization of disease-resistant and disease-sensitive animal lines and infecting vaccinated animals with alive pathogenic microorganisms that leads to improved immunity to pathogenic microorganisms.

EFFECT: higher efficiency.

4 cl, 1 dwg, 3 ex

FIELD: medicine, gynecology.

SUBSTANCE: one should perform laparoscopy, drain purulent foci, remove destructive tissues and wash abdominal cavity with great amount of "Baliz-2" introduced into abdominal cavity by fractional portions per 1-1.5 l at exposure up to 3 min either once or up to three times. The method provides complex impact as antibacterial, antioxidant and immunocorrecting actions of the preparation in area of lesion and, thus, quick interruption of acute stage by preventing the development of adhesions and saving reproductive function in this category of patients.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: biotechnology, microbiology, medicine, veterinary science.

SUBSTANCE: for preparing vaccine toxigenic strains of S. dysenteriae R-forms are grown, cells are subjected for lysis by treatment with chloroform, mixture is centrifuged and prepared supernatant is treated with saturated monobasic carboxylic acid or their derivatives and pH value is brought about to 3.0-5.0. Mixture if centrifuged and precipitate containing corpuscular antigens and shigellosis exotoxin are obtained. Precipitate is dissolved in buffer and pH value is brought about to 7.5-9.0. Then formalin is added in the amount 0.4-0.8% of the solution volume, or benzoic acid or benzoic acid salts are added in the amount 0.07-4.0% of the solution volume, or a mixture consisting of formalin and benzoic acid or benzoic acid salt solutions in the amount 0.10.3% and 0.03-2.5% of the solution volume, respectively. The solution is kept at temperature 30-60°C for 2 h - 60 days to provide the conversion of exotoxin to anatoxin and vaccine is prepared. Another variant of the claimed invention involves additional treatment with formalin or benzoic acid or benzoic acid salts to provide conversion of exotoxin to anatoxin, vaccine is prepared followed by its bagging and corking. For preparing immunoglobulin preparation animals are immunized with vaccine prepared by abovementioned methods followed by taking off blood, milk and/or colostrums, and/or blood, immunoglobulin fraction is prepared, sterilized, bagged and corked. This preparation is a component of the immunobiological preparation. The immunobiological preparation comprises the immunoglobulin preparation and at least one component taken among the following row: human and/or animal immunoglobulin preparations, lactoferrin, enzymes, inhibitors of proteolytic enzymes, human and/or animal normoflora preparations, yeast, vitamins, vitamin-like substances, human and/or animal proteins of acute phase, human and/or animal cytokines, higher plants components, lower plants components, components of natural origin products, apiculture products, enterosorbents, antibiotics, antibacterial chemopreparations, sulfanilamide drugs, antibacterial, anti-tuberculosis, antiviral preparations, antifungal antibiotics, synthetic antifungal preparations, stimulators of metabolic processes, antioxidants, mineral supplements, carbohydrates, lipids, replaceable and/or essential amino acids, organic acids, alkaloids, glycosides, taste supplements, aromatic supplements, base for suppositories, base for ointment formulations, technological additives for tableting, or their mixture. Invention provides preparing preparations eliciting antigenic activity with respect to broad species of pathogenic and opportunistic gram-negative microorganisms of intestine group and their exotoxins and therefore eliciting with prophylactic and curative effect with respect to diseases causing with these microorganisms.

EFFECT: improved preparing method, valuable properties of vaccine.

13 cl, 112 ex

Antibacterial agent // 2262346

FIELD: biotechnology, microbiology.

SUBSTANCE: invention proposes applying Flavobacterium odoratum culture as an antibacterial agent isolated from drinking mineral water "Ust-Kachkinskaya" from the hole 1/99. Microorganism Flavobacterium odoratum inhibits growth of Staphylococcus aureus, colon bacillus and yeast-like fungi Candida albicans that allows using microorganism Flavobacterium odoratum as an antibacterial agent. Invention can be used as an antibacterial agent.

EFFECT: valuable medicinal properties of agent.

2 ex

FIELD: biotechnology, medicine, antibiotics.

SUBSTANCE: invention proposes to the new compound amycomycin of the molecular formula C65H115NO18 (structural formula is given on the invention claim) that shows an antibacterial activity. Amycomycin, its pharmaceutically acceptable salts and derivatives in all their stereoisomeris and tautomeric forms can be obtained by culturing microorganism Amycolatopsis sp. ST 101170 (DSM 12216) under aerobic conditions on the nutrient medium containing the necessary nutrient components. The end product is isolated and purified and converted if necessary to its pharmacologically acceptable salt, ester, ether and other chemical derivatives and eliciting the same spectrum of antibacterial activity. Amycomycin is a component of the pharmaceutical composition eliciting an antibacterial activity. Amycomycin acts as an antibiotic. Invention provides inhibition of microorganisms with resistance to vancomycin and teicoplanin used in treatment of infections caused by Staphylococcus aureus.

EFFECT: improved preparing method, valuable medicinal properties of amycomycin.

7 cl, 2 tbl, 4 ex

FIELD: biochemistry, medicine.

SUBSTANCE: invention relates to two forms of peptide isolated from annelid worm (Arenicola marina) eliciting the broad spectrum of antibacterial effect. Indicated forms differ by a single amino acid residue at position 10 wherein at position 10 arenicin-1 has Val and arenicin-2 has Ile. Invention provides expanding assortment of antibacterial agents.

EFFECT: valuable medicinal properties of peptides.

1 tbl, 3 dwg, 4 ex

FIELD: medicine, hematology, cardiology, endocrinology.

SUBSTANCE: invention relates to a method for correction of disturbances at thrombocyte hemostasis in patients with metabolic syndrome. Method involves prescription of hypocaloric diet and lovastatin in the dose 20 mg before sleeping. Method provides normalization of primary hemostasis in these patients.

EFFECT: improved treatment method.

2 ex

FIELD: medicine.

SUBSTANCE: method involves applying tetradecylthioacetic acid as fatty acid analog for treating inflammatory disorders. Method for stimulating endogenous interleukine-10 production is suggested. Fatty acid analogs are applied for suppressing stimulated mononuclear cells proliferation in peripheral blood.

EFFECT: enhanced effectiveness of anti-inflammatory action.

17 cl, 5 dwg

FIELD: medicine, toxicology, pharmacy.

SUBSTANCE: according with the first variant the composition contains neutral lipid and therapeutically effective amount of cholanic acid or cholanic acid salt and phospholipid. Neutral lipid presents in the amount from 3% to 50% by mass relatively to the total amount of lipid. According with the second variant the composition contains from 3% to 30% by mass of bile acid or bile acid salt, from 3% to 50% by mass of neutral lipid and from 10% to 95% by mass of phospholipid. Composition is designated for treatment in poisoning with endotoxins. Composition no containing peptides and proteins but containing the combination of phospholipid with cholanic acid proves effective relief or prophylaxis of endotoxemia.

EFFECT: enhanced effectiveness and valuable medicinal properties of composition.

23 cl, 10 dwg, 2 tbl, 10 ex

FIELD: medicine, ophthalmology.

SUBSTANCE: the suggested composition includes a steroid-free antiphlogistic preparation, plant and/or animal phospholipids, sodium chloride, monosodium phosphate, disubstituted sodium phosphate and purified water at certain quantitative ratio of components, weight%. The innovation provides prolonged antiphlogistic action.

EFFECT: higher efficiency of application.

3 ex

FIELD: pharmaceutical chemistry, in particular crystal form of pravastatine sodium salt.

SUBSTANCE: invention relates to new crystal form of pravastatine sodium salt known under chemical name of 1,2,6,7,8,8a-hexahydro-b,d,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobubutoxy)-haphtaleneheptane acid monosodium salt, obtained by a) preparation of solution containing pravastatine and sodium cations in lower aliphatic C1-C4-alcohol; b) addition ethylacetate to said solution; c) cooling of obtained alcohol/ethylacetate mixture; and d) crystallization. Characteristics of new crystal form of pravastatine sodium salt such as crystallogram and melting point (170-1740C) also are disclosed. The subject invention also pertains to method for pravastatine production as well as pharmaceutical composition containing the same. Pravastatine, its derivatives and analogs are well-known HMG-CoA reductase inhibitors and are useful as anticholesterenemic agents in treatment of hypercholesterenemia and hyperlypemia.

EFFECT: crystal form of pravastatine sodium salt and pharmaceutical composition with improved therapeutic action.

29 cl, 5 ex, 4 dwg

FIELD: medicine, pharmacology, biochemistry, pharmacy.

SUBSTANCE: invention relates to preparations reducing blood cholesterol level. Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin and their derivatives and analogs known as inhibitors of HMG-CoA-reductase are used as anti-hypercholesterolemic agents. Above mentioned active substances can be destabilized as result of effect of environment and their destruction can be accelerated in interaction with other pharmaceutical agents, such as excipients, binding agents, lubricating agents, substances promoting to slipping and disintegrating agents. Therefore, pharmaceutical components and a method for preparing a pharmaceutical preparation must be taken thoroughly to avoid above said undesirable interactions and reactions. Invention relates to inhibitor of HMG-CoA-reductase that stabilized by formation of a homogenous composition with buffer substance or an alkalinizing substance. This homogenous composition is used as an active substance in pharmaceutical preparation used for treatment of hypercholesterolemia and hyperlipidemia. Invention enhances the enhancement of stability and homogeneity of the preparation.

EFFECT: improved and valuable pharmaceutical properties of composition.

23 cl, 2 tbl, 3 dwg, 11 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to a method for preparing statin sodium salts that relate to enzyme inhibitors that inhibit biosynthesis of plasma cholesterol of different species of mammals and can be used in preparing medicinal preparations. Method involves preparing statin sodium salts of the general formula: , wherein R represents hydrogen atom (H), CH3 or OH. Method involves interaction of statins as an oxyacid with the stoichiometric amount of 2-ethylhexanoate sodium to obtain suspension. Statin sodium salts are prepared from this suspension by filtration and drying a precipitate in the form of dry powder. Invention provides preparing such statin sodium salts as compactin, lovastatin and pravastatin sodium salts.

EFFECT: improved preparing method.

11 cl, 5 ex

FIELD: medicine, pharmacology, pharmacy, medicinal biochemistry.

SUBSTANCE: invention proposes a pharmaceutical composition that comprises, in particular, N-(1-octyl-5-carboxymethyl-dimethylindolin-7-yl)-2,2-dimethylpropaneamid or its pharmacologically acceptable salts as inhibitor of enzyme ACAT and inhibitor of HMG-CoA-reductase that represents pravastatin, lovastatin, simvaststin, fluvastatin, rivastatin, atorvastatin, rosuvastatin or pitavastatin used as active component of the composition. The combination of active substances shows the expressed synergistic effect. Invention provides enhancing activity of the composition in clinical applying.

EFFECT: valuable medicinal properties of composition.

71 cl, 2 tbl, 3 ex

The invention relates to medicine, in particular to surgery

and tnf-" target="_blank">

The invention relates to new aminobenzophenone General formula (I)

where R1and R3designate one or more identical or different substituents selected from the group consisting of halogen, (C1-C3)-alkyl, (C1-C3)-alkoxy; provided that, if R1denotes one Deputy, he is in the ortho-position, and if R1refers to several substituents, at least one substituent R1located in the ortho-position; and R2denotes one substituent in the ortho-position, and this Deputy is selected from the group consisting of halogen, (C1-C3)-alkoxy; and R3can additionally denote hydrogen; R4represents hydrogen; X represents oxygen; Q represents -(CO)- or a bond; Y represents (C5-C15)alkyl, (C2-C15)olefinic group; and any of these groups may be optionally substituted by one or more identical or different substituents selected from the group consisting of substituents of formula R5defined below, except that when Q represents a bond, then Y appears lcil, substituted by one or more substituents selected from the group R5; or a group of formula - (Z-O)n- Z, where Z is a (C1-C3)alkyl, n is an integer >1, and the number of atoms in a continuous linear sequence of atoms in the group Y does not exceed 15; R5denotes halogen, hydroxy, amino, (C1-C6)-alkylamino, (C1-C3)alkoxycarbonyl, -COOH, -CONHR' or-COONR'R' R' means (C1-C3)alkyl; or its pharmaceutically acceptable salt

FIELD: medicine, pharmacology, pharmacy, medicinal biochemistry.

SUBSTANCE: invention proposes a pharmaceutical composition that comprises, in particular, N-(1-octyl-5-carboxymethyl-dimethylindolin-7-yl)-2,2-dimethylpropaneamid or its pharmacologically acceptable salts as inhibitor of enzyme ACAT and inhibitor of HMG-CoA-reductase that represents pravastatin, lovastatin, simvaststin, fluvastatin, rivastatin, atorvastatin, rosuvastatin or pitavastatin used as active component of the composition. The combination of active substances shows the expressed synergistic effect. Invention provides enhancing activity of the composition in clinical applying.

EFFECT: valuable medicinal properties of composition.

71 cl, 2 tbl, 3 ex

Up!