EA002628B1 - Water dispersed ivermectin dosage form for curing ecto- endoparasitic diseases - Google Patents

Abstract

1. A water dispersed ivermectin dosage form for curing ecto-endoparasitic diseases, comprising an active substance co-solvent, a surfactant, a preservative agent, a phosphato-citrated buffer and distilled water as a solvent, characterized in that further comprises vitamin E with the following content of the components: ivermectin or avermectin 0.1 - 7.5 co-solvent 10 - 60 micella-forming agent (PAV) 4 - 20 preservative agent 0.5 - 2.0 phosphato-citrated buffer Ph 6.0-7.0 up to 0.9 vitamin E 0.7 -.7.0 distilled water remaining

Description

The invention relates to the field of veterinary medicine and medicine and can be used for the treatment of endo - and ectoparasites.

Ivermectin-22,23 -dihydro derivative of avermectin B !, macrocyclic lactone, which is obtained by microbiological synthesis. Anhydrous injectable ivermectin dosage forms are known (ksgtsssbp & LatssCplus Satrybe11 ebk. 8ppedeg Weg1ad., 1989), containing such substances as auxiliary components such as glyceroformal, propylene glycol, and polyvinylpyrrolidone, with the following ratios, I have to use i'm using imeraformal, propylene glycol and polyvinylpyrrolidone. wt.%); propylene glycol - 50-90% (wt.%); glycerol formal - 10-50% (wt.%); polyvinylpyrrolidone - 0-5% (wt.%).

These dosage forms have a high viscosity, which makes the injection difficult, causes irritation and swelling at the injection site, is 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 parasitosis with these dosage forms of ivermectin always consists of at least two injections of the drug, since after one injection the effective concentration of ivermectin in the body tissues is maintained for 7-9 days, and this is not enough for complete recovery. The full course of development of most parasites under optimal conditions is 14–20 days, the drug does not act on the eggs of parasites (F. A. Volkov, V. Apalkin Ivermectins in veterinary medicine, Novosibirsk 1995).

The prototype of this invention is US patent No. 4389397 IPC AC61 / 70 A 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% w / v, containing the following auxiliary components:

surfactant - tween 80 or polyoxylethylenesorbit monostearate or polyoxyethylene sorbitol monoisostearate in a concentration from 0.5 to 25% w / v;

co-solvent (active substance stabilizer) - glycerol formal 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 a high overall toxicity associated with a high concentration of ivermectin in the blood during the first hours after administration. By effective concentration, this dosage form is identical to the drug with non-aqueous solvents.

The objective of this 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 for complete cure after a single injection of the drug.

The essence of the invention lies in the fact that water-dispersed dosage form of ivermectin or avermectin for the treatment of ecto-and endoparasitosis, containing water, dimethylacetamide or propylene glycol or glycerol-formal as a cosolvent, as a solvent, surface-active substances such as Tween 80, soltol, cremofor 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 (t . Koferol) at the following component ratio, wt%:

Active ingredient 0.1-7.5

Co-solvent 10-60

Micelle-Forming Agent (Surfactant) 4-20 Preservative 0.5-2.0

Phosphate-citrate buffer pH 6.0-7.0 To 0.9

Vitamin E 0.7-7.0

Distilled water Else

Studies of the metabolism of ivermectin in the body have shown that its degradation is carried out by the liver monooxygenase system, after which the oxidized products in the form of conjugates are eliminated by the kidneys. (Guegtesbp & Abatesy. XVC Satre11 ebk. 8pideg Ug1ad., 1989). This process leads to a rapid decrease in the effective concentration of ivermectin in the body and, accordingly, incomplete cure. We assume that the rate of degradation of ivermectin, translated into a water-dispersed (micellar) form in the liver, can be reduced by administering tocopherol (vitamin E). This phenomenon is used by us in this invention.

Cooking method

The co-solvent, ivermectin or avermectin, surfactant, vitamin E is mixed until completely dissolved at a temperature of 30-50 ° C. To the resulting solution add buffer pH 6.0-7.0 with the calculated amount of water. After complete mixing, the pH is monitored, then the resulting dosage form is sterilized by membrane filtration and aseptically filled into a suitable container.

The following active substances (substances) can be used in this dosage form:

Avermectin A1a and A1b;

Avermectin B1 a and B1 B;

Ivermectin (22,23-dihydroavermectin B1a and

B1c);

Milbemycin.

Examples of the ratios of components in micellar dosage form of ivermectin

In all examples, ivermectin can be replaced by the above named substances without changing the physicochemical and pharmacological properties of the preparation.

Example 1

The optimal ratios and the most preferred types of components are given.

Component Name Amount, 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 Rest

Example 2

A recipe with the maximum amount of co-solvent and corresponding amounts of other components is given.

Component Name Amount, 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 Rest

An increase in the amount of co-solvent to 60% entails a decrease in such components as surfactant, preservative, and vitamin E due to the instability of the aqueous dispersion.

With a further increase in the amount of co-solvent or an increase in the other components mentioned above, the destruction of micelles (aqueous dispersion) and separation of the liquid occurs.

Example 3

A recipe with a minimum amount of co-solvent and corresponding amounts of other components is given.

Component Name Amount, wt.% Ivermectin or avermectin 1.0 Dimethylacetamide 10.0 Solutol 20.0 Benzyl alcohol 2.0 Vitamin E 7.0 Phosphatio-citrate buffer, pH 6.5 0.2 Distilled water Rest

In this case, the maximum amount of surfactant, preservative and antioxidant is added, because with a smaller amount 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 conducting injections.

The 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 as the surfactant, a co-solvent and a preservative of the other substances listed above at the same percentage ratios. At the same time almost identical results were achieved.

Tests of the claimed dosage form conducted on agricultural and laboratory animals. The acute toxicity, the effect on the organism of increased doses of the drug, as well as the residence time of the effective plasma concentration were determined. The therapeutic efficacy of the claimed dosage form in endo- and ectoparasites of farm animals was investigated in comparison with the prototype and the analogue.

Table 1. Data on acute toxicity, effective concentration of variants of the claimed dosage form, prototype, and analog (ivermectin preparation on a non-aqueous basis).

Acute toxicity, mice (intraperitoneal administration), mg / kg body weight The retention time of the effective concentration of the active substance in the blood, days Cows Sheeps Example 1 43-46 13.8 12.8 Example 2 41-47 13.6 12.7 Example 3 40-45 13.7 12.6 Prototype 20-25 8.9 8.1 Analog 25-30 9.0 8.3

Table 2. Data on the therapeutic efficacy of variants of the claimed dosage form, prototype, and analog (ivermectin preparation on a non-aqueous basis) for endo-ectoparasites of farm animals.

A drug Dose and frequency of administration, ml per 50 kg of weight Therapeutic efficacy in endo - and ectoparasitosis,% Cattle Small cattle Example 1 1.0 double 100 100 1.0 one time 72.3-100 57.8-100 1.5 one time 100 95.2-100 Example 2 1.0 double 100 100 1.0 one time 65.7-100 53.3-100 1.5 one time 91.6-100 83.0-100 Example 3 1.0 double 100 100 1.0 one time 65.2-100 54.7-100 1.5 one time 89.4-100 81.5-100 Prototype 1.0 double 97.5-100 89.4-100 1.0 one time 21.8-100 16.2-100 Analog 1.0 double 96,8-100 87.3-100 1.0 one time 23.2-100 16.7-100

Variants of the claimed dosage form is easier to use than the prototype and the analogue can be administered intramuscularly, which is less time consuming, especially in sheep. With the introduction of both subcutaneously and intramuscularly, they do not cause irritation and local tissue reaction. The therapeutic efficacy of the claimed dosage form in comparison with the prototype and the analogue with various endo-and ectoparasites 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 injection, a dose of 1.5 ml per kg of body weight should be used. In this case, the claimed drug does not cause toxic effects, in contrast to the known.

Claims (1)

A water-dispersed dosage form of ivermectin for the treatment of ecto- and endoparasitoses, including an active substance, a co-solvent, a surfactant, a preservative, phosphate-citrate buffer and distilled water as a solvent, characterized in that it additionally contains vitamin E with the following 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 6.0-7.0 To 0.9 Vitamin E 0.7-7.0 Distilled water