Preparative form of solution for topical application for treatment of animals (options), method of production and method of processing animal (options)

 

(57) Abstract:

Preparative form of solution for topical application for the treatment of animals against endo - and ectoparasites includes avermectin as active ingredient and at least 50% glycol, glycerides or polymeric material. As embryo death contains a compound of the formula I, where the dashed line indicates a single or double bond in the 22 and 23 positions; R1is hydrogen or hydroxy; R2- C1-C6-alkyl or C3-C6alkenyl; R3is hydroxy, methoxy or =NOR5; R5is hydrogen or lower alkyl; R7Is h, hydroxy or lower alkyl; R4- H, hydroxy, C1-C6-polyalkoxy or a residue of formula (a), R6is hydroxy, amino, mono - or di(C1-C6)alkylamino or1-C6-alkanolamine. Preparative form provides excellent efficacy against endoparasites and ectoparasites in comparison with conventional preparative forms and maintains the concentration of the active compound in milk of dairy animals below are safe for human consumption levels. 7 C. and 11 C.p. f-crystals, 11 PL.

Connection group avermectins are potential antigenetically described in U.S. Pat. USA 4310519 AIbers - Shonberg et al., 22, 23 - dihydroavermectin described Chabala et al., in Pat. USA 4199569. The avermectins administered orally, parenteral or local way.

However, the usual formulation for local applications do not provide acceptable efficacy against ectoparasites, especially against Chorioptes, fleas and ticks. Often these formulations of failure due to loss of efficacy. Animals after processing the above-described preparative forms quickly re-infected fleas, ticks and parasites just when returning on Wednesday, infected fleas. In addition, preparative forms for local application currently used drugs show efficacy against endoparasites, such as heart worms and nematodes.

In veterinary medicine it is known that prolonged release of insecticide receive with the introduction of the insecticide in the polymer system. However, conventional polymer formulation is based on the evaporation of the active substance, but this type of system cannot be used for non vaporizing drugs, see U.S. Pat. USA NN 38525416 and 4172904. In addition, conventional formulations of existing drugs require lane is x can be used by man.

Brief description of the invention.

This invention relates to preparative forms of embryo death in the form of solution for topical application, which effectively kill ectoparasites, especially Chorioptes, fleas and ticks, and endoparasites, especially for heart worms and nematodes in animals, such as cattle, pigs and so on, for a long period up to the full four weeks, in particular, in domestic animals, such as cats and dogs. The claimed formulation also unexpectedly provide a zero delay time selection of milk for use in the case of local application of antiparasitic agents in dairy animals. Preparative form get when using as a carrier solvent such as water, alcohols, such as ethanol, methanol, isopropanol, and other esters of propylene glycol, glycerides or their derivatives.

In addition to active avermectines ingredient and solvent formulation may contain a polymer, such as polyvinylpyrrolidone. The drug is applied on the skin using a polymer that holds it on the surface of the skin after evaporation of the solvent after application. Thus, the object of this and is retene is the description of the compounds of embryo death, which can be used in the preparative form. An additional object of the invention is the description of the preservation of the concentration of the active compound in milk of dairy animals below the safe concentration for consumption of milk man.

Another object of the invention is to describe ways of obtaining long-term efficacy against fleas, ticks, and heart worms. Additional objects will be apparent after reading the following description.

Description of the invention.

This invention consists of a formulation in the form of solution for topical application on the basis of glycerides, glycol or their derivatives as a carrier and avermectins connection, which was found effective for the destruction of both ectoparasites and endoparasites. In addition to glycerides, glycol, or derivatives thereof, and embryo death preparative optional form may contain an antioxidant, such as bottled hydroxyanisol (BHA), bottled hydroxytoluene (EIT) and other additives, such as Crodamol CAP, glycerin usual, Tween 80, and the other, a mixture of water and/or solvents with a relatively high vapor pressure, such as ethanol, methanol, isope like that.

Connection embryo death used in data formulation, have the following General structure:

< / BR>
where the dashed line indicates a single or double bond 22, 23 - positions;

R1is hydrogen or hydroxy, provided that R1present only when the broken line shows a simple connection;

R2is alkyl with from one to six carbon atoms or alkenyl with from 3 to 6 carbon atoms, or cycloalkyl with from 3 to 8 carbon atoms;

R3represents hydroxy, methoxy or =NOR5where R5means hydrogen or lower alkyl;

R7describes hydrogen, hydroxy or lower alkyl;

R4represents hydrogen, hydroxy, policy C1- C6-alkoxy or

< / BR>
where

R6means hydroxy, amino, mono - or di-C1-C6alkylamino or C1-C6alkanolamine.

The term "lower alkyl", as used in this application reflects alkyl group with straight or branched chain, containing 1 to 5 carbon atoms. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, pentyl and other such.

The term "nisei chain. Examples of such alkanoglu are formyl, acetyl, propanyl, butyryl, valeryl and other such.

The term "halogen" includes atoms of halogen: fluorine, chlorine, bromine and iodine.

The term "polyalkoxy" includes methoxyethoxy, 2-methoxyethoxy, (2 methoxyethoxy) - methoxy, [2-(2-methoxyethoxy)ethoxy]methoxy; and other similar.

Used in the present invention is related family of natural products known as milbemycin. Milbemycin have the same macrocyclic ring structure, and that the avermectins, but they do not contain the substituent at position 13 (R4= hydrogen), and contain methyl or italgroup in position 25 (R2= methyl or ethyl is preferable isopropyl or sec-butyl, as avermectins). Milbemycin in the fermentation conditions used in their preparation, are described in U.S. Pat. USA N 3950360. Closely related 13 - deoxycoformycin the aglycones receive chemical modification of natural avermectins, they are described in U.S. Pat. USA N 4173571.

One preferred embodiment (EI) this invention contains preparative form for local application in the form of a solution when using glycerides, glycol or their derivatives as a carrier and avermectines, the concentration of the active compound in milk of dairy animals remains less than adequate concentrations suitable for human consumption, i.e. it gives a zero delay time for the consumption of milk in the local application of endectocides (concentration in milk 4"acetylamine-4" - deoxyadenosine BI (L-653648) at zero retention in milk is (48 ng/ml).

Carriers are oleography alcohol, propylene glycol and its ethers, such as propylene dicaprylate/dicaprylate, propylene glycol laurate and the like, glycol ethers such as monoethylamine ether of ethylene glycol, monobutyl ether of diethylene glycol, diethyl ether of ethylene glycol and the like, and glycerides such as PEG-6 triglyceride Caprylic/Caproic acid, dipicolylamine Caprylic/capric acids, poliglecaprone glycerides and the like, preferably propylene kaprilat/kaprilat or kaprilat/karinat the glycerides available under such trade names as Miglyol 810 (triglycerides of Caprylic/capric acids), Miglyol 812 (triglyceride Caprylic/capric acids), Miglyol 818 (triglycerides of Caprylic/capric/linoleic acid), Miglyol 829 (triglycerides of Caprylic/capric/diantar is) and Labrasol (PEG-8 kaprilat/karinat the glycerides). Mark (/) in the propylene dicaprylate/dicaprate and PEG-6 in triglyceride Caprylic/capric acid is a mixture of the two components in the ratio of 65-80/15-30.

The above media give preparative form good penetration ability and namasivaya the ability of the active compounds, even at low temperatures.

Preferred avermectin connection E1 have preferred structural formula:

< / BR>
where a dotted line indicates a simple relationship;

R1represents hydrogen;

R2is isopropyl or sec-bootrom;

R6means hydroxy, amino, mono - or di-(C1-C6)alkylamino or1-C6alkanolamine;

Examples of preferred compounds of the current EI preparative forms are:

4"-metavarsity B1;

4"-metavarsity P2;

4"-keto-22,23-dihydroavermectin B1;

4"-keto-22,23-dihydroavermectin B2;

4"-deoxy-4"-aminoadenosine B1;

4"-deoxy-4"-aminoadenosine B2;

4"-deoxy-4"-amino-22,23-dihydroavermectin B1;

4"-deoxy-4"-amino-22,23-dihydroavermectin B2;

4"-deoxy-4"-acetylaminofluorene B1;

4"-deoxy-4"-acetylaminofluorene B2;

4"-deoxy-4"-acetylaminofluorene B1;

4"-deoxy-4"-diethylaminocoumarin B2;

4"-deoxy-4"-dimethylamino-22,23-dihydroavermectin B1;

4"-deoxy-4"-dimethylamino-22,23-dihydroavermectin B2;

4"-deoxy-4"-p-chlorobenzenesulfonamide-22,23 - dihydroavermectin B1;

4"-deoxy-4"-p-chlorobenzenesulfonamide-22,23 - dihydroavermectin B2;

4"-deoxy-4"-(2-methylbenzenesulfonamide)avermectin B1;

4"-deoxy-4"-(2-methylbenzenesulfonamide)avermectin B2.

Connection "b",containing 25-isopropylate, there is no need to separate from the corresponding "a" connection with the 25-torbutrol. Connections usually are in the form of a mixture of two compounds containing at least 80% verboselog connection and not more than 20% of the isopropyl compound. Thus, references in the current application for "a" compounds, such as B1a, A1a, and other similar, shall be construed in fact as containing some of the corresponding "b" connections. Or sometimes a mixture represented by the reference to B1 or B2 connection or separation "a connection" and "b" connected by a pipe (/), for example, so B1a/B1b; B2a/B2b and other similar. In addition, the products of synthetic methods, such as realizacija or epimerization, techniques known from previous works, can made, representing or -, or -, which are located, respectively, below or above the main plane of the molecule. In each case, as-and - configuration and other provisions included in the scope of this invention.

In the case of preparative forms of embryo death for local use, it is impossible to provide preparative form, which would have acceptable efficacy against ectoparasites, especially against Chorioptes. In addition, the currently available formulation for topical application does not provide zero time for retaining the consumption of milk when using endectocides, which thus prevents the use of such compounds in animals producing milk.

E1 current invention provides advantages preparative forms as solutions for local applications, which provide efficient processing of animals and protect them from the endoparasites and ectoparasites, especially Chorioptes, and at the same time maintain the concentration of the active substance in milk of dairy animals below safe for human consumption levels. Additional advantages of this invention include: new form is not flammable, not washed off quickly Doge currently dosing devices.

E1 may contain ivermectine connection and glycolic or glyceridae media as the only ingredients. Preparative form usually get the introduction of safe and effective amount of 0.005 to 10 wt.% avermectines component, more preferably from 0.01 to 5 wt. %. It is most preferable to use preparative form containing approximately 0.5% ivermectina. When using the preferred dose of about 5 ml to handle animal weighing 50 kg preparative form contains from about 1.0 to 50 mg avermectin compound per ml of solution. Glycolic or glycerides media add to preparative form from about 40 to 100% q.s. about/about (q.s.=the amount needed to achieve total 100% V/V).

The preferred preparative form E1 contains in addition to the glycol, glycerides or their derivatives and the connection embryo death, antioxidant, such as propylgallate BHA (bottled hydroxyanisole), BHT (bottled hydroxytoluene), monothioglycerol and other similar, preferably BHT. Antioxidants are usually added to the preparative form in the amount of 0.005 to 1.0% (wt/about). You can also use supplements, still is where it is refuelled add to preparative form up to 60% of the volume of the medium, glycol or glycerides, preferably up to 40% of the volume of the media.

E1 receive by dissolving compounds and embryo death in about 50 - 100% of the amount above of the media, and then bring up the volume to 100% when adding a final volume of media or additives. Antioxidant and additives can be mixed with the above media before mixing with ivermectina or to add in a final volume of solvent.

In order for you to understand more fully E1 embodiment of the invention provides the following example. It does not limit the invention.

An example of the invention.

Formulations of this invention depend on the specific avermectines connections and processing. Ivermectin dissolved in about 50% glycolic or glycerides media. After dissolution optional add antioxidant and/or additive, then volume up to 100% with the final amount of glycolic or glycerides media. The solution is mixed to obtain a homogeneous solution. Typically, the mixture is sufficient to carry out at room temperature (15 - 25oC), however, if necessary, it may be useful to heat up to the 50oC. the Following examples without limiting the invention, offers the use.

Composition I

4"-acetylamino-4"-deoxycoformycin B1 - 0,5% wt/about

BHT is 0.01% wt./about

Crodamol CAP - 10.0% to about/on

MigIyol 840 (q.s.) - 100,0% about/on

Composition II

4"-acetylamino-4"-deoxycoformycin B1 - 0,5% wt./about

BHT is 0.01% wt./about

Miglyol 840 (q.s.) - 100,0% about/on

Composition III

4"-acetylamino-4"-deoxycoformycin B1 - 0,5% wt./about

BHT is 0.01% wt./about

Isopropylmyristate - 10.0% to about/on

Miglyol 840 (q.s.) - 100,0% about/on

Composition IV

4"-acetylamino-4"-deoxycoformycin B1 - 0,5% wt/about

Triacetin - 50,0% about/on

Miglyol 840 (q.s.) - 100,0% about/on

Composition V

4"-acetylamino-4"-deoxycoformycin B1 - 0,5% wt/about

Softigen 767 - 65,0% about/on

Miglyol 840 - 25,0% about/on

Ethanol (q.s.) - 100,0% about/on

Composition VI

4"-acetylamino-4"-deoxycoformycin to 0.5% wt/about

Softigen 767 - 65,0% about/on

isopropanol (q.s.) - 100,0% about/on

Composition VII

4"-acetylamino-4"-deoxycoformycin B1 - 0,5% wt/about

EIT is 0.01% wt/about

Dowano1 DB (q.s.) - 100,0% about/on

Crodamol CAP is a trade name mixture isopropylmyristate, tetrachromat and stereochrome; Dowanol DB - trade name butyl ether of diethylene glycol.

E1 example II.

The data below show the concentration of embryo death (ng/ml) in Malone remains below 48 ng/ml, what is the concentration of embryo death in the milk required for zero-retaining use of milk.

The concentration of 4"-acetylamino-4"-deoxyadenosine B1 (ng/ml) in milk of cows after local application of the drug. Treatment A: Miglyol 840/EIT/500 mcg/kg

Treatment B: Triacetin/Miglyol 840 (50/50) /500 mcg/kg (see table. 1-7).

E1 example III.

To evaluate some of the above preparative forms are testing their effectiveness with Chorioptes and key endoparasites. In each experiment, confirming Chorioptes, four cows infect Chorioptes bovis on day - 1 and carry out the treatment on day 0. In experiments evaluating the endoparasites of animals infected Oelophagosfamum and Trichuris, Dictyocaulus in 17,7 and 7th day before processing the preparative form. The results are shown in table. 8,9.

Another preferred embodiment (E2) current formulation includes preparative form solution for local application on the basis of a mixture solvent of water and/or solvents with a relatively high vapor pressure, such as ethanol, methanol, isopropanol, acetone and the like, more preferably ethanol, a polymeric material, such as polyvinylpyrrolidone, polyvinyl alcohol, a derivative is s such that more preferably polyvinylpyrrolidone (molecular weight from about 20,000 to 65,000, preferably 45000), substituted derivatives of proteins of the skin or hair, such as hydrolyzed wheat protein, hydrolyzed animal proteins, gelatin derivatives, derivatives of collagen and other similar alcohol-soluble copolymers such as acrylate/tert-octyldiphenyl copolymer and the like, and cationic Quaternary amine salt and the like. The form has an efficiency, which is extended up to the full four weeks. Polymeric material helps to keep the drug on the skin surface over a long period by using the fact that the drug remains on the skin surface after the solvent warialda after application. The remaining avermectin and polymer do not change the appearance of the fur of animals and avermectin is released by diffusion and/or erosion of the polymer.

Preferred compounds of embryo death E2 have the following structural formula

< / BR>
where

R1, R2and R3described above;

R4is hydrogen, hydroxy or polyalkoxy;

the dashed line indicates a single or double bond at 22, is z.

Examples of preferred compounds of the present invention are:

4" - metavarsity B1;

4" - cutewriter B2;

4" - keto - 22, 23 - dihydroavermectin B1;

4" - keto - 22, 23 - dihydroavermectin B2;

4" - deoxy-4" - aminoadenosine B1;

4" - deoxy-4" - aminoadenosine B2;

4" - deoxy-4" - amino-22,23 - dihydroavermectin B1;

4" - deoxy-4" - acetylaminofluorene B1;

4" - deoxy-4" - acetylamino avermectin B2;

4" - deoxy-4" - acetylamino - 22,23 - dihydroavermectin B1;

4" - deoxy-4" - acetylamino - 22,23 - dihydroavermectin B2;

4" - deoxy-4" - diethylaminocoumarin B1;

4" - deoxy-4" - diethylaminocoumarin B2;

4" - deoxy-4" - dimethylamino - 22,23 - dihydroavermectin B1;

4" - deoxy-4" - dimethylamino - 22,23 - dihydroavermectin B2;

4" - deoxy-4" - p-chlorobenzenesulfonamide - 22,23 - dihydroavermectin B1;

4" - deoxy-4" - p-chlorobenzenesulfonyl - 22,23 - dihydro-13 - O-[(2-methoxyethyl) methyl] avermectin B1 aglycone (hereinafter referred to as 13-O-MEM AVM);

4" - deoxy-4" - (2 - methylbenzenesulfonamide) avermectin B1;

4" - deoxy-4" - (2 - methylbenzenesulfonamide) avermectin B2;

13-EPI-O- (methoxymethyl)-22,23 - dihydroavermectin B1 aglycone (hereinafter referred to as 13-O-MOM AVM).

Preparative form of embryo death in the forms for local application cannot provide preparative form, which provides excellent long-term efficacy against ectoparasites, especially against fleas and ticks. In addition, the currently used formulation for topical application does not provide enough effectiveness against endoparasites, especially against a heart of helminths and nematodes.

E2 embodiment of the current formulations of benefits preparative forms of solution for topical application, which provides treatment of animals with long effective action and protect them from the endoparasites and ectoparasites, especially fleas, ticks, scabby mites, hookworms, Ascaris and heart of a helminth. An additional advantage of this invention is that the new form is not replaced quickly when dealing with animals, it is well spread out and used even at low temperatures.

E2 embodiment of the present formulation may contain connection embryo death, alcohol, water and a polymer as the only ingredients. Preparative form usually get the introduction of embryo death in quantity is) about 5% wt. the active ingredient. In the preferred dose of about 0.5 - 50 mg/kg preparative form is used at a dose of 0.05 - 4.0 mg/kg of body weight. The polymer present in the compositions of the present invention in amounts varying from examples 0% to 20% wt./about., preferably from about 0.5 to 10% wt./about. by weight of the total composition, and up to 95% volume of alcohol, q.s. up to 100% of the water.

Preferred E2 embodiment contains, in addition to the polymer, an alcohol, water and connection embryo death additional ingredients such as antioxidants and glycol, glycerides, glycol esters and derivatives thereof mentioned above. Antioxidants are usually added to the preparative form in the amount of 0.005 to 1.0% (wt./vol.), they can be propylgallate, BHA (butilirovannyh hydroxyanisole), BHT (butilirovannyh hydroxytoluene), monothioglycerol and other similar, preferably BHT.

E2 preparative form is received by dissolving compounds and embryo death in the required amount of alcohol. Then the antioxidant and one of the polymeric materials listed above, dissolved in a mixture of alcohol/avermectin, then the volume is brought to 100% add the remaining volume of water. The solution is stirred until a homogeneous state. Or BHT , or polymer, or Y, to most fully could be understood E2 embodiment of the invention. They do not limit the invention.

Examples E2 invention.

E2 formulations of this invention that can be used depend on the individual links embryo death and processing. To test the effectiveness of E2 preparative forms against fleas and ticks received the following songs:

Composition VIII

13-O - MEM AVM to 0.3% wt/about

Polyvinylpyrrolidone - 0,5% wt/about

Cremophor RH-40 - 1.0% wt/about

Anhydrous (denatured) ethanol - 40,0% vol/about

Softigen 767 - 20,0% about/on

Water (q.s.) - 100,0% about/on

Composition IX

13-O-MEM AVM to 0.3% wt/about

Polyvinylpyrrolidone to 5.0% wt/about

Water (q.s.) - 100,0% about/on

BHT is 0.01% wt/about

Composition X

13-About-MOM AVM to 5.0% wt/about

Polyvinylpyrrolidone to 5.0% wt/about

Anhydrous ethanol to 90.0 about/on

Water (q.s.) - 100,0 about/on

BHT - 0,01; wt/about

Song XI

13-O-MEM AVM - 0,6% wt/about

Polyvinylpyrrolidon to 5.0% wt/about

Anhydrous ethanol is 75.0% about/on

Water (q.s.) - 100,0% about/on

Vitamin E - a 0.02%/about

Composition XII

13-O-MEM AVM - 0,6% wt/about

Hydrolyzed wheat protein - 3.0 wt/about

Anhydrous ethanol to 90.0% about/on

Water (q.s.) - 100,0% about/on

Vitamin ER>
Water (q.s.) - 100,0% about/on

Vitamin E - a 0.02%/about

Composition XIV

13-O-MEM AVM - 0,6% wt/about

Polyvinylpyrrolidone to 5.0% wt/about

Anhydrous ethanol - 80,0% about/on

Water (q.s.) - 100,0% about/on

Vitamin E - 0,002% about/on

Miglyol is 0.5% about/on

Composition XV

13-O-MEM AVM - 0,6% wt/about

The acrylate/tert-octyldiphenyl copolymer - 1.0% wt/about

Polyvinylpyrrolidone - 2.0% wt/about

Anhydrous ethanol - 80,0% about/on

Water (q.s.) - 100,0% about/on

Vitamin E - a 0.02%/about

Softigen 767 trade name PEG-6 kaprilat/karinat glycerides, Cremophor RH-40 trade name of a mixture of polietilenglicoli and glycol oxystearate and Ethocel trade name ethyl cellulose.

The above composition X was used locally in many places, usually 2 to 6 points located Runestone between the neck and tail on the back of infected fleas dogs. Counting was performed by combing the hair, removing and counting of live parasites in the dog at a certain time. Witnessing the destruction of fleas with different number 13-O-MEM AVM is shown in table. 10, where 60 dogs were divided into four groups of treatment. Dogs were infected with 100 nearline adult fleas, is indicated by the lower arrow which is equivalent to three days before providentialist composition, containing 13-O-MEME AVE (called 2-MEM) in various forms, in the processing of ticks.

The present formulation can be used for local application on warm-blooded animals to ensure the long-term treatment and protection against endoparasites and ectoparasites or locally in the place of the infection, or in various locations, usually 2-6 points (multipoint application), along the back of domestic and pet animals, such as cattle, sheep, cats, dogs and other such.

1. Preparative form of solution for topical application for the treatment of animals against endo - and ectoparasites, including avermectins as the active ingredient, the carrier is a glycol or a glycerol ester and an antioxidant, wherein as embryo death contains a compound of the formula I

< / BR>
where the dashed line indicates a single or double bond at the 22,23-positions;

R1is hydrogen or hydroxy, provided that R1present only when the broken line represents a simple bond;

R2means alkyl from 1 to 6 carbon atoms, or alkenyl from 3 to 6 carbon atoms, or cycloalkyl from 3 to 6 carbon atoms;

R is hydrogen, hydroxy or lower alkyl,

R4means hydrogen, hydroxy, C1-C6-polyalkoxy or

< / BR>
where R6represents a hydroxy, amino, mono - or di (C1-C6)-alkylamino or (C1C6)-alkanolamine,

in the amount of 0.005-10 wt.%/about as glycolic or glycerides ether - Propylenediamine/dicaprylate or triglyceride Caprylic/ capric acid - 40-99%q.s.about/about. and 0.005-1 wt.%/about. the antioxidant.

2. Form p. 1, wherein R4represents a

< / BR>
3. Form p. 1, characterized in that it contains from 0.01 to 5 wt.%about. avermectines connection.

4. Form p. 1, characterized in that as an antioxidant contains n-propyl-gallate, bottled hydroxyanisol (BHA), bottled hydroxytoluene (EIT), monothioglycerol.

5. Form under item 4, characterized in that as an antioxidant contains bottled hydroxytoluene (EIT).

6. Form p. 1, characterized in that it contains a solvent belonging to the group comprising Crodamol Cap, glycerin usual, Tween 80 or propylene glycol up to 59%/about.

7. Form p. 1, characterized in that it contains 100% q.s.about/about. the nose is config hydroxytoluene (BHT) in an amount of 0.005 to 0.05 wt.%/about. from 0.01 to 5 wt.%/about. 4"-acetylamino-4" -deoxyadenosine B1.

8. Form under item 7, characterized in that it comprises 0.5 wt.%/about. 4"-acetylamino-4" -deoxyadenosine VI 0.01 wt.%/about. BHT.

9. The method of obtaining the preparative form under item 1, including the dissolution of 0.005 to 10 wt.%/about. connection embryo death under item 1 in 40-50% q.s.about/about. total media glycolic or glycerides ether followed by the addition of 0.005 to 1.0 wt.%/about. antioxidant and adding to the quality of the final volume of the remaining number of media.

10. Processing method and prevention of internal and external parasites of animals, including local application on the skin of the animal avermectines connection, characterized in that the skin of the animal put a solution formulation under item 1, in the calculation of from 1.0 to 50 mg ivermectina connection.

11. Preparative form local action for direct application on the skin of the animal, effective for the treatment and prevention of infection by ectoparasites and endoparasites within four weeks containing compounds embryo death, antioxidant and media, wherein the media contains 40-95%/about. ethanol and 100 vol.%/about. water and additionally contains b. n-propylgallate, bottled hydroxyanisole (BHA), butylated of hydroxytoluene (EIT) or monodiglyceride, and as embryo death contains 0.05-10 wt. %/about. the compounds of formula I

< / BR>
where the dashed line indicates a single or double bond 22, 23 - positions;

R1is hydrogen or hydroxy, provided that R1present only when the broken line represents a simple bond;

R2means alkyl from 1 to 6 carbon atoms, or alkenyl from 3 to 6 carbon atoms, or cycloalkyl from 3 to 6 carbon atoms;

R3represents hydroxy, methoxy or =NOR5where R5hydrogen or lower alkyl,

R7is hydrogen, hydroxy or lower alkyl;

R4means hydrogen, hydroxy, poly-C1-C6-alkoxy or

< / BR>
where R6represents a hydroxy, amino, mono - or dis1-C6-alkylamino or C1-C5-alkanolamine.

12. The form under item 11, wherein R4represents hydrogen, hydroxy or polyalkoxy.

13. The form under item 11, characterized in that it contains from 0.1 to 5.0 wt. %/about. connection embryo death and from 5.0 to 10 wt.%/about. polyvinylpyrrolidine, and R is ecaudata fact, that contains polyvinylpyrrolidone (mol.m. 45000.

15. The form under item 11, characterized in that it contains an additive selected from the group consisting of propylene glycol, Tween 80, Crodamol Cap, vitamin E or glycerin usual, up to 50 vol.%/about.

16, preparative form local action for direct application on the skin of the animal for the effective treatment of infection by parasites containing compound embryo death, an antioxidant and a carrier, characterized in that embryo death contains 5.0 wt.%/about. 22,23-dihydro-13-0-[( 2-methoxyethoxy)methyl] embryo death, B1 aglycone, as the carrier contains about 90. %/about. ethanol q.s. up to 100% with water as an antioxidant contains 0.01 wt.%/about. bottled hydroxytoluene (EIT) and additionally contains 5.0 wt.%/about. polyvinylpyrrolidone (mol.m. 45000.

17. The method of obtaining the preparative form under item 11, comprising dissolving in the carrier of 0.005-10 wt.%/about. connection embryo death on p. 11, characterized in that as the carrier is used 40-95%/about. ethanol until a clear solution is formed, then add and dissolve of 0.005 to 1.0 wt.%/about. antioxidant and 0.01-20 wt.%/about. polyvinylpyrrolidone solution, add up to 50 vol.%/about. supplements, bring the volume to 100% by adding logical, Tween 80, Crodamol Cap, Vitamine E or glycerin usual.

18. The method of processing and control internal and external parasites of animals comprising applying to the skin of the animal a biologically active substance, characterized in that the biologically active substances are used preparative shape p. 1.

 

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The invention relates to medicine, namely to facilities for the treatment of purulent infected and burn wounds

The invention relates to pharmaceutical industry and relates to a method of making a stable aqueous suspension
The invention relates to the field of producing emulsions of organic substances (oil in water emulsion of the type oil-in-water M/V)

The invention relates to medicine , in particular to the prevention and treatment of atherosclerosis
The invention relates to medicine, for treatment of allergic and diatopically diseases of the eyes and nose
The invention relates to medicine, for treatment of allergic and diatopically diseases of the eyes and nose
The invention relates to medicine, in particular to the means, possessing tonic and tonic effect, and can be used for General strengthening of the body, as well as for treatment of the gastrointestinal tract, upper respiratory tract, strengthen the cardiovascular system

The invention relates to medicine and relates to a method of obtaining herbal substances with adaptogenic activity

The invention relates to pharmaceutical industry and relates to biologically active agents derived from plant materials

The invention relates to medicine and for the preparation for the local treatment of superficial changes on the skin and mucous membranes, as well as for the treatment of infections of the skin and mucous membranes on the basis of the reaction of interaction between the solution of 1 - 5.5 M nitric acid with 45 - 170 mmol of primary C1- C5-alkanol on 1 l of nitric acid, as well as the way to obtain the drug

The invention relates to pharmaceutical technology and relates to a new pharmaceutical composition with analgesic activity
The invention relates to pharmaceutical industry, and in particular to improving technologies for injection K(Na) salt of benzylpenicillin (BP), which is used in medicine to treat diseases caused by gram-positive organisms and gram-negative cocci, and for the manufacture of various dosage forms based on it, such as: benzylpenicillin procaine salt, economically-1, bicillin-1, bicillin-3, bicillin-5, spectrum of antimicrobial action of which is similar to the spectrum of benzylpenicillin

The invention relates to new biologically active chemical compound exhibiting the properties of activator germination of seeds of agricultural crops
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