The synergistic composition containing benzimidazole anthelminthic agent and methylenedioxyaniline connection, the method of treatment

 

(57) Abstract:

The composition comprises anthelminthic effective amount of the benzimidazole or its prodrugs and methylenedioxyaniline synergist. Anthelminthic agent cannot be thiabendazole. The method of treatment of a human or animal includes the introduction of an effective amount of a benzimidazole or its prodrugs in conjunction with methylenedioxyaniline a synergist. The invention allows to enhance the effect of antihelminthic agent due to a synergistic effect. 2 C. and 12 C.p. f-crystals, 5 tab., 3 Il.

The present invention relates to pharmaceutical compositions containing benzimidazolone protivogelmintnye agents and, in particular, intended, although not necessarily, for use in veterinary medicine, and their potentiation by piperonylbutoxide or other methylenedioxyaniline insecticide synergist.

The benzimidazole are a well known class of antihelminthic agents, which are widely used for combating endoparasites, especially nematodes, Pets and farm animals. Albendazole is indicated for use in relation to the people. Although these agents are used successfully, row e, resulting in faster allocation of these loans, which may limit the effectiveness of their actions and to indicate the need for periodic introduction.

In addition, some parasites can be resistant to the effects of certain benzimidazole.

Piperonylbutoxide is a well-known insecticide synergist (Merck index 7446). His other methylenedioxyaniline insecticidal synergists are widely used in combination with a PYRETHROID insecticide.

It Was Reported (Food Chem. Toxicol. (1992 Dec); 30(12), 1021-30), that acute toxic effects of benzimidazole thiabendazole on kidneys mouse is enhanced by pretreatment with inhibitors of microsome monooxygenase system, namely, hydrochloride 2-diethylaminoethyl-2,2-diphenylacetate and piperonylbutoxide. The reported information is limited to consideration of toxicity and does not reveal any effects concerning the anthelminthic efficacy.

The present invention relates to the detection of amplification of antihelminthic effects of benzimidazole with a parallel introduction methylenedioxyaniline insecticide synergist, such as piperonylbutoxide.

The present isvee number benzimidazole or its prodrugs in conjunction with methylenedioxyaniline a synergist.

The benzimidazole especially readily undergoes oxidative destruction in vivo. When the benzimidazole contains tigroup, oxidation in a living organism usually goes with the transition sulfoxide metabolite (which can also have anthelminthic activity in inactive sulfon.

Other oxidation mechanism involves hydroxylation, for example, in position 5 of the benzimidazole ring.

The invention also concerns the application methylenedioxyaniline synergist for augmentation of such benzimidazole or its prodrugs.

In addition, the invention includes methods of treating animals and humans with endoparasite infections introduction benzimidazole or its prodrugs in conjunction with methylenedioxyaniline a synergist.

Methylenedioxyaniline the synergist is an inhibitor of the hepatic cytochrome P450 system. Many of these insecticidal synergists (which themselves do not have anthelminthic or pesticide activity) are known as synergists PYRETHROID group of insecticides, and they, in General, fall under the present invention. Specific synergists include piperonylbutoxide, piperacilline, carboxyethylpyrrole]benzene).

The pharmaceutical composition may include pharmaceutically acceptable inert carrier or diluent corresponding to the method of administration. Thus, the composition may be administered orally or parenterally (including subcutaneous, intramuscular and intravenous injection). For oral administration the pharmaceutical compositions may be prepared in the form of a solution or suspension in water. Packing, if necessary, may contain suspendresume agents, preservative agents, thickening agents, or emulsifying agents in accordance with well known methods of formulation. Oral administration can also be carried out through the inclusion of songs in the food or in a food cube. The composition may also be prepared in the form of tablets or granules. To introduce people to the composition may be prepared in the form of a solid standard dose (for example, in the form of tablets, capsules or wafers) or in the form of a liquid standard dose (for example, in the form of a capsule with liquid).

The composition can be introduced ruminant animal in the form of a bolus, which is retained in the rumen some animal and is the source of the composition over an extended sub is enteralnom the introduction of the composition may be in the form of a sterile solution or suspension and may contain preservatives and other materials make the composition isotonic with the blood of the proposed recipient. Such compositions can be prepared in the form of a roller or mnogochasovykh sealed packages.

The composition may be intended for topical administration (for example, in the form of pastes, viscous liquid or gel) or prepared in the form of so-called applied composition, when the active agents through the skin.

The composition may be intended for rectal, nasal, or vaginal administration.

The benzimidazole can be put together with methylenedioxyaniline a synergist in the form of a single composition or benzimidazole and methylenedioxyaniline the synergist can be entered separately immediately after each other, resulting in both agent will be mixed in the body of the recipient.

Or the composition may be introduced by other means, standard for protivogelmintnoe introduction.

The benzimidazole is usually injected in conventional non-toxic dosage amounts, though these amounts can be reduced taking into account the potentiation caused by the presence methylenedioxyaniline synergist. Typically, the benzimidazole is administered in a dose of from 1 to which aktivnosti action and on the nature of benzimidazole, usually it is in the region of 0.01 to 0.5 g per 1 kg of body weight. Usually the weight ratio of the contents methylenedioxyaniline synergist to the benzimidazole is located in the region of 10 to 500 to one in particular 30 - 120 to one.

The benzimidazole can be subdivided into different groups, such as groups containing tigroup, sulfoxide group, ether group, and the group, which is a complex of methyl esters carbamino acid. The benzimidazole containing thiazolidine group (such as thiabendazole and cambendazole), are less preferred.

The benzimidazole is usually a substance which undergoes oxidative destruction in vivo, and suggest that piperonylbutoxide or other methylenedioxyaniline synergist it reduces oxidative destruction that is accompanied by increasing levels of benzimidazole in plasma and possibly prolongation of the time of his stay. Especially preferred benzimidazole and their prodrugs are netobimin, febantel, albendazole, albendazole, fenbendazol, oxfendazole, triclabendazole, triclabendazole-sulfoxide, thiabendazol, cambendazole, oxibendazole, and typical animals include Pets or farm animals, particularly ruminants, and especially pigs, goats, horses, cattle, sheep, dogs, cats and poultry.

The composition is also suitable for the treatment of humans, especially against resistant of endoparasites. Especially effective against gastro-intestinal infections are compositions containing albendazole or albendazole in combination with piperonylbutoxide.

The composition is effective against of helminth endoparasites, especially gastrointestinal nematodes, cestodes and trematodes. Specific examples include krivohlavek, ascariasis, enterobiasis, Strongyloides and trichuris.

The term "prodrug" as it is used here, is a well-known term in the field of technology; it means the agent, which itself is not necessarily active, but which in vivo is converted into a de-worming active metabolite. Netobimin and febantel are prodrugs that in the living organism into the benzimidazole.

Embodiments of the present invention will now be described by way of examples.

First period: oral introduced fenbendazol (drug Panacur 2.5 percent) at a dose of 7.5 mg/kg blood Samples were taken before drug administration and after 0,25, 0,5, 1, 2, 4, 8, 12, 24, 32, 48, 72 and 96 h after its injection.

Second period: 1 h prior to the introduction of fenbendazol (7.5 mg/kg), the animals received a dose of piperonylbutoxide (0.5 g/kg), which was administered intramuscularly. Blood samples were taken as in the case of the first period.

Plasma samples were analyzed for the presence of fenbendazol through liquid chromatography high resolution.

From table. 1 one can see that the use of piperonylbutoxide in combination with fenbendazol leads to a significant increase in the area under the curve plasma concentration from time to time, as well as to a significant prolongation of residence time of fenbendazol.

In Fig. 1 shows the concentration of fenbendazol in plasma after administration of a single fenbendazol (squares) or in combination with piperonylbutoxide (diamonds).

In Fig. 2 shows the corresponding levels of active metabolitecheap (filled circles).

Example 2 (albendazole).

In this experiment used five sheep.

The experimental Protocol was the same as described above, except that used anthelminthic agent was albendazole (Valbazen 2,5%), which was administered at a dose of 7.5 mg/kg plasma Samples were analyzed for the presence of metabolic albendazolea conducting liquid chromatography high resolution.

The results are shown in table. 1 and shown in Fig. 3.

In Fig. 3 shows the concentration of albendazolea (active metabolite) in plasma after administration of a single albendazole (squares) or in combination with piperonylbutoxide (diamonds).

Example 3 (optimization of the dose).

To determine the optimal ratio of piperonylbutoxide and fenbendazol spent six-phase experiment.

Six year old tennamaram sheep were administered orally the fenbendazol (Panacur 2.5%) for a dose of 5 mg/kg in six cases. Piperonylbutoxide was introduced in parallel by gastric probe in accordance with the Protocol specified in table. 2. Each sheep received 0, 15, 31, 63, 125 and 250 mg/kg of piperonylbutoxide in combination with benzimidazole.

Was when the surveys duration of leaching was 4 weeks.

For an individual animal were combined analyses of all relations, and thereby it was found that the desired ratio of doses is 63 mg/kg piperonylbutoxide 5 mg/kg of fenbendazol (the ratio is 12.6 : 1).

At the end of the study, all animals were euthanized, and there was a thorough macroscopic and histopathological examination. Not have established the presence of an abnormal macroscopic damage. The results of histopathological examinations indicated no significant overdose causing toxicity.

Example 4 (effectiveness).

The study was conducted to determine the effectiveness of joint action piperonylbutoxide in combination with fenbendazol and compare it with the effectiveness of only one piperonylbutoxide and fenbendazol against resistant to benzimidazole abomasal (rennet) parasites.

Twenty-four free from parasites lamb lines Suffolk were divided into four groups of six. Each lamb received oral dose value 6000 resistant to benzimidazole species of Ostertagia circumcincta and dose size 2400 resistant to benzimidazole type At obrabotka not conducted.

Group 2. Piperonylbutoxide (63 mg/kg) by gastric probe.

Group 3. The fenbendazol (5 mg/kg) by gastric probe.

Group 4. Piperonylbutoxide (63 mg/kg) and fenbendazol (5 mg/kg) by gastric probe.

According to the Protocol used in example 1, all animals collected samples of blood.

All lambs were collected faeces and were killed 7 days after treatment (35th day). In the faeces was determined by the number of nematode eggs using the method of counting eggs on Mac-Master (Mc Macter) (Gordon and Whitlock (1939) J. Council for Scientific and Industrial Res., 12, 50), and the method of cultivation (Ritchie et al. (1966), Amer. J. Vet. Res. 27, 659-667) to determine the number of parasite species O. circumcincta. Determined the total number abomasal (rennet) parasites of the species H. contortus.

The results indicate a decrease in 79,7 and 98.4% in the number of eggs in the faeces, respectively, in the groups treated with only one fenbendazol and piperonylbutoxide in combination with fenbendazol (PL. 3). The combination is significantly (P<0,05) more effective in reducing the number of eggs in the faeces than one fenbendazol.

No piperonylbutoxide or fenbendazol entered individually, do not provide a significant reduction in the number of parasite species O. circumcincta, PA.cercumcincta on 84,9% (table. 4).

And fenbendazol itself, and product combinations significantly reduced the number of parasite species H. contortus found at autopsy. However, the combination is significantly (P<0.005 percent) are more effective than one fenbendazol. Piperonylbutoxide entered by itself, has no effect (table. 5).

Example 5 (hepatocyte studies).

Experiment using liver cells, cultured rats, carried out with the purpose of establishing metabolic interactions of piperonylbutoxide and fenbendazol (50 Microm). The concentration of fenbendazol in an environment with cell culture was about 2 μg/ml, when he introduced only one fenbendazol. Concentrations were significantly higher (approximately 3.7 μg/ml), when the fenbendazol was introduced together with piperonylbutoxide. Concentration sulfoxides and sulfonic metabolites are strongly reduced in the presence of piperonylbutoxide. Hence it was concluded that piperonylbutoxide inhibits the oxidative metabolism of fenbendazol, flowing under the influence of rat liver cells.

Example 6.

The procedure of example 5 was repeated, using oxfendazole, and found similar ENES similar results.

Example 8.

The procedure of example 5 was repeated, using triclabendazole, and similar results were obtained.

1. Pharmaceutical composition, characterized in that it contains anthelminthic effective amount of the benzimidazole or its prodrugs in conjunction with methylenedioxyaniline a synergist, provided that benzimidazole anthelminthic agent is not thiabendazole.

2. The composition according to p. 1, wherein the benzimidazole contains tigroup.

3. The composition according to p. 2, wherein the benzimidazole selected from the group consisting of albendazole, fenbendazol and triclabendazole.

4. The composition according to p. 1, wherein the benzimidazole contains sulfoxide group.

5. The composition according to p. 4, wherein the benzimidazole selected from the group consisting of albendazolea, oxfendazole and triclabendazole.

6. The composition according to p. 1, wherein the benzimidazole is a methyl ester carbamino acid.

7. The composition according to p. 6, wherein the benzimidazole selected from the group consisting of albendazole, albendazolea, fenbendazol, OK what about the benzimidazole selected from the group consisting of netobimin and febantel.

9. The composition according to any preceding paragraph, wherein methylenedioxyaniline synergist selected from the group consisting of piperonylbutoxide, piperacilline, carboxyethylpyrrole, stamina, n-probility and sulfoxide.

10. The composition according to any preceding paragraph, wherein the ratio of the benzimidazole or its prodrugs to methylenedioxyaniline the synergist is in the range from 1 : 10 to 1 : 500 by weight.

11. The composition according to any preceding clause, characterized in that further comprises a pharmaceutically acceptable carrier.

12. The method of antihelminthic treatment of the human or animal body, characterized in that it includes the introduction of anthelminthic effective amount of the benzimidazole or its prodrugs in conjunction with methylenedioxyaniline a synergist.

13. The method according to p. 12, wherein the benzimidazole is administered at a dose of 1 to 50 mg/kg of body weight of a person or animal.

14. The method according to p. 12 or 13, characterized in that methylenedioxyaniline synergist is administered in a dose of 0.01 - 0.5 g/kg body weight of a person or animal.

 

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