RU2162699C1 - Aqueous-dispersed medicinal form of ivermectin for treatment of ecto- and endoparasitosis - Google Patents

Abstract

FIELD: veterinary science, medicine. SUBSTANCE: preparation has water as a solvent, dimethylamide or propylene glycol or glyceroformal as a cosolvent, surface-active substances as for Tween-80, solutol, cremophore or other polyhydroxylated derivatives of natural oils as micelle-forming agent, benzyl alcohol or parabenes as preserving agents, phosphate-citrate buffer and, additionally, vitamin E (tocopherol) in the following ratio of components, wt.%: active substance, 0.1-7.5; cosolvent, 10-60; micelle-forming agent (surface-active substance), 4-20; preserving agent, 0.5-2.0; phosphate-citrate buffer (pH 6.0-7.0), up to 0.9; vitamin E, 0.7-7.0; distilled water, the balance. Developed medicinal form of ivermectin is suitable for using, it has no toxicity in therapeutic doses, makes effective concentration in body that is sufficient for recovery after a single preparation injection. EFFECT: improved properties of preparation. 2 tbl, 3 ex

Description

 The invention relates to the field of veterinary medicine and can be used to treat endo-and ectoparasitoses.

Ivermectin is a 22.23-dihydro derivative of avermectin B ₁ , a macrocyclic lactone that is obtained by microbiological synthesis.

Anhydrous injectable dosage forms of ivermectin are known (Ivermectin & Abamectm. W. Campbell eds. Springer Verlag., 1989) containing, as auxiliary components, substances such as glyceroformal, propylene glycol and polyvinylpyrrolidone, in the following component ratios, wt.%:
Ivermectin or Avermectin - 0.1-7.5
Propylene glycol - 50-90
Glyceroformal - 10-50
Polyvinylpyrrolidone - 0-5
These dosage forms have a high viscosity, which makes it difficult to inject, cause irritation and swelling at the injection site, are toxic (the presence of non-aqueous solvents and precipitation of ivermectin in the tissues of the body). In addition, the course of treatment of most parasitoses with these dosage forms of ivermectin always consists of at least two injections of the drug, since after one injection an effective concentration of ivermectin in the body tissues is maintained for 7-9 days, and this is not enough for a full recovery. The full course of development of most parasites under optimal conditions is 14-20 days, the drug does not act on parasite eggs (F. A. Volkov, V. A. Apalkin. Ivermectins in veterinary medicine, Novosibirsk, 1995).

The prototype of this invention is US patent N 4389397, IPC A 61 K 31/70, "Solution of ivermectin in water." This patent claims a stabilized aqueous (micellar) dosage form of avermectin or ivermectin in a concentration of from 0.1% to 7.5% weight / volume, containing the following auxiliary components:
- surfactant - tween 80 or polyoxyethylene sorbitol monostearate or polyoxyethylene sorbitol monoisostearate in a concentration of from 0.5% to 25% weight / volume;
- co-solvent (stabilizer of the active substance) - glyceroformal or glycerin, or propylene glycol in a concentration of from 10% to 60% weight / volume;
- preservative - benzyl alcohol or paraben in a concentration of from 1% to 5% weight / volume.

 The disadvantage of this dosage form is the high general toxicity associated with a high concentration of ivermectin in the blood in the first hours after administration. In effective concentration, this dosage form is identical to the preparation with non-aqueous solvents.

 The objective of the invention is the creation of a dosage form of ivermectin, convenient to use, non-toxic in therapeutic doses and with an effective concentration in the body, sufficient to completely cure after a single injection of the drug.

The essence of the invention lies in the fact that a water-dispersed dosage form of ivermectin or avermectin for the treatment of ecto- and endoparasites, containing as a solvent water, dimethylamide or propylene glycol, or glyceroformal as a cosolvent, surfactants such as tween 80, solutol, cremophor or other polyoxyethylated derivatives of natural oils as a micelle forming agent, benzyl alcohol or parabens as preservatives, phosphate-citrate buffer, additionally contains vitamin E (tocopher ol) at the following content of components (wt.%):
Active substance - 0.1 - 7.5
Co-solvent - 10 - 60
Micelle forming agent (surfactant) - 4 - 20
Preservative - 0.5 - 2.0
Phosphate-citrate buffer pH 6-7 - up to 0.9
Vitamin E - 0.7 - 7.0
Distilled Water - Else
Studies of the metabolism of ivermectin in the body showed that its degradation is carried out by the monooxygenase system of the liver, after which the oxidized products in the form of conjugates are excreted by the kidneys. (Ivermectin & Abamectin. WC Campbell eds. Springer Verlag., 1989). This process leads to a rapid decrease in the effective concentration of ivermectin in the body and, accordingly, incomplete cure. We suggest that the rate of degradation of ivermectin, converted into a water-dispersed (micellar) form in the liver, can be reduced by the administration of tocopherol (vitamin E). This phenomenon has been used by us in this invention.

Cooking method
Co-solvent, ivermectin or avermectin, surfactant, vitamin E is stirred until complete dissolution at a temperature of 30 - 50 ^o C. To the resulting solution add a buffer pH 6-7 with the calculated amount of water. After complete mixing, pH control is carried out, then the resulting dosage form is sterilized by membrane filtration and packaged aseptically in a suitable container.

 The following active substances (substances) may be used in this dosage form: Avermectin Ala and Alb; Avermectin Bla and Blb; Ivermectin (22.23-dihydro avermectin Bla and Blb); Milbemycin.

 Examples of ratios of components in the micellar dosage form of ivermectin. In all examples, ivermectin can be replaced with the above substances without changing the physico-chemical and pharmacological properties of the drug.

Example N 1
The optimal ratios and the most preferred types of components, wt.%
Ivermectin - 1.0
Dimethylacetamide - 40.0
Solutol - 14.0
Benzyl alcohol - 1.0
Vitamin E - 4.0
Phosphate citrate buffer, pH 6.5 - 0.09
Distilled Water - Else
Example N 2
The formulation with the maximum amount of co-solvent and the corresponding amount of other components, wt.%:
Ivermectin or Avermectin - 1.0
Dimethylacetamide - 60.0
Solutol - 4.0
Benzyl alcohol - 0.5
Vitamin E - 0.7
Phosphate citrate buffer, pH 6.5 - 0.12
Distilled Water - Else
An increase in the amount of cosolvent up to 60% entails a decrease in such components as surfactants, preservatives, and vitamin E, due to the instability of the aqueous dispersion. With a further increase in the amount of cosolvent or an increase in the other components mentioned above, micelles (aqueous dispersion) are destroyed and the liquid stratifies.

Example N 3
The recipe with a minimum amount of cosolvent and the corresponding amount of other components, wt.%:
Ivermectin or Avermectin - 1.0
Dimethylacetamide - 10.0
Solutol - 20.0
Benzyl alcohol - 2.0
Vitamin E - 7.0
Phosphate citrate buffer, pH 6.5 - 0.2
Distilled Water - Else
In this case, add the maximum amount of surfactant, preservative and antioxidant, as with fewer of these components, the aqueous dispersion also becomes unstable. On the other hand, a further increase in the above components leads to a sharp increase in the viscosity of the dosage form and, as a consequence, the impossibility of injections.

 Tests have shown that a decrease or increase in the components in the formulation leads to a qualitative change in the properties of the dosage form.

 Experiments were carried out using the substances listed above as surfactants, cosolvent, and preservatives at the same percentages. In this case, almost identical results were achieved.

 Tests of the claimed dosage form conducted on agricultural and laboratory animals. Acute toxicity, the effect on the body of elevated doses of the drug, as well as the time spent in finding an effective concentration in blood plasma were determined. The therapeutic efficacy of the claimed dosage form for endo- and ectoparasitoses of farm animals was studied compared with the prototype and analogue (see tables. 1 and 2).

 Variants of the claimed dosage form are more convenient to use than the prototype and analogue - they can be administered intramuscularly, which is less time-consuming, especially in sheep. When administered both subcutaneously and intramuscularly, they do not cause irritation and local tissue reactions. The therapeutic efficacy of the claimed dosage form compared with the prototype and analogue for various endo- and ectoparasitoses of cattle is higher by 41.1-50.5%; sheep - by 36.6-43.4%, respectively.

 Thus, to achieve the maximum therapeutic effect with a single administration, it is necessary to use a dose of 1.5 ml per 50 kg of body weight. In this case, the claimed drug does not cause toxic effects, unlike the known ones.

Claims (1)

A water-dispersed dosage form of ivermectin for the treatment of ecto- and endoparasitoses, including an active substance, a co-solvent, a micelle-forming agent (surfactant), a preservative, phosphate-citrate buffer and distilled water as a solvent, characterized in that it additionally contains vitamin E at the following content components, wt.%:
Ivermectin or Avermectin - 0.1 - 7.5
Co-solvent - 10 - 60
Micelle forming agent (surfactant) - 4 - 20
Preservative - 0.5 - 2.0
Phosphate Citrate Buffer pH - Up to 0.9
Vitamin E - 0.7 - 7.0
Distilled Water - Else

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