ANTIPARASITIC NON-AQUEOUS FORMULATION CONTAINING AN AVERMECTIN OR MILBEMYCIN

Abstract: Ivermectin, an antiparasitic agent which is insoluble and unstable in water, and other avermectin and milbemycin com­ pounds, are formulated in glycerol formal and propylene glycol or in water and propylene glycol. These liquid formulations are suitable for parenteral administration for the treatment of parasitic infections and demonstrate improved efficacy and a broadened spectrum over previous formulations.

Description: ANTIPARASITIC NON-AQUEOUS FORMULATION CONTAINING AN AVERMECTIN OR MILBEMYCIN The present invention concerns the preparation of avermectin and milbemycin parenteral formulations. More particularly, but not exclusively, the avermectin is ivermectin, an anthelmintic agent. The avermectin family, of which ivermectin is a member, is a series of new and very potent antiparasitic agents which are useful against a broad spectrum of endoparasites and ectoparasites in mammals as well as having agricultural uses against various parasites found in and on crops and in soil. The basic avermectin compounds are isolated from the fermentation broth of the microorganism Streptomyces avermitilis. Such compounds are described in U.S. Patent US-A-4,310,519. In addition, certain derivatives of these basic fermentation products have been prepared. Some of the avermectins contain a 22,23-double bond. This may be selectively reduced to prepare the ivermectin compounds. In addition, the avermectins possess a disaccharide residue at the 13-position consisting of the -L-oleandrosyl-a-L-oleandrosyl group. One or both of these saccharide groups may be removed as described in U.S. Patent US-A-4,206,205. The thus produced aglycone derivatives have a hydroxy group at the 13-position. This group may be removed to form the 13-deoxy compound as described in U.S. Patents US-A-4,171,314 and US-A-4,173,571. On the avermectin compounds and derivatives are several hydroxy groups which may be acylated as described in U.S. Patent US-A-4,201,861. In addition, the milbemycin series of-sompounds have the same 16membered macrocyclic ring as the avermectin compounds, although they do not have the disaccharide residue and also differ in the nature of other substituent groups. These compounds are disclosed in U.S. Patent US-A-3,950,360. Ivermectin is disclosed in U.S. Patent US-A-4,199,569, issued 22 April 1980. Ivermectin is a mixture, in the ratio of approximately 80:20 of 22,23-dihydro C-076 Bla and Blb. In administering ivermectin to animals it is very convenient to use parenteral formulations to administer the drug. While an aqueous micelle formulation (see U.S. Patent US-A-4,389,397) is useful for parenteral administration, higher activity has been observed against endoparasites than ectoparasites. It is known that ivermectin can be useful against ectoparasites and it is desirable to have a parenteral formulation with high levels of both endo- and ectoparasiticidal activity. Thus, it is desirable to prepare a parenteral liquid formulation of ivermectin which has activity against internal and external parasites. Ivermectin has very poor solubility in water, at a level of about 0.005 mg per ml at room temperature, but is very soluble in many organic solvents. It was unexpectedly discovered during the investigation of organic parenteral formulations that both endo- and ectoparasiticidal activity was observed which was not observed with the aqueous micelle formulation. The invention is based on the unexpected discovery that the spectrum of activity of avermectin compounds is increased by the use of parenteral formulations described below. The parenteral formulations consist of glycerol formal and propylene glycol together with an avermectin or milbemycin compound. All such compounds share to an only slightly varying degree the spectrum of biological activity of ivermectin, which is the preferred compound. In the formulations of the present invention, the amount of the avermectin or milbemycin compound is 0.1 to 20 by weight, preferably about 1% by weight. The avermectin compound is dissolved in a solvent mixture of glycerol formal and propylene glycol which are in a ratio of from 10:90 to 90:10 by volume (V/V). It is preferred to use a ratio of about 40:60 V/V. A variation of this formulation replaces the glycerol formal with water at a lower concentration to achieve the same expanded profile of activity. The formulation uses ratios of propylene glycol to water of from 95:5 to 80:20 V/V, preferably about 90:10 V/V. To prepare the formulations the avermectin compound is dissolved in either the glycerol formal or propylene glycol and, when dissolution is complete, the remaining solvents are added to prepare the final concentration of drug and ratio of solvents. Since the formulation is for parenteral use it must be sterilized. The final step is sterilization by non-heating means, preferably by membrane filtration, since the active ingredient might be subject to decomposition at autoclave temperatures. The unexpected feature of this invention is realized in its comparison with other injectable formulations containing avermectin and milbemycin compounds. The aqueous micelle formulation provides dosages of the active compounds sufficient to eradicate substantially all internal parasites of the host animal. It was desired to obtain a parenteral formulation that also had high levels of activity against both internal and external parasites. The formulation of the invention achieves the desired result as demonstrated in the following test: A comparison of the efficacy of ivermectin when administered to cattle by means of the formulation of the invention or by an aqueous micelle formulation shows the superiority of the formulation of the invention, particularly towards ectoparasites. Cattle that had been infected with ticks (Boophilus microplus) were given a control placebo or equal doses of ivermectin via the formulation of Example 1, or an aqueous micelle formulation. The efficacy of the treatment was measured by counting the ticks in the manner described by Wharton et. al. in Australian Journal of Agricultural Research 21 pages 985-1006 (1970). The prolonged effects of the drug were observed by counting the ticks several times over a 4-week period with a constant natural exposure to tick infestation. The test showed that, to a statistically significant degree, both formulations had fewer ticks than the controls. At the end of the trial there were statistically significantly more ticks on the micelle-treated cattle than on the cattle treated with the formulation of the invention, thus demonstrating greater efficacy and duration of efficacy for the instant formulation. The following non-limiting examples are provided in order that the invention might be more fully understood. EXAMPLE 1 To prepare an ivermectin injectable solution containing 10 mg of active ingredient per ml of solution the following ingredients were used: Ivermectin 1.0% W/V Glycerol Formal 40.0% V/V Propylene Glycol q.s. 100.0% V/V The ivermectin was dissolved in either the glycerol formal, the propylene glycol or a mixture of the solvents. When the dissolution was complete the volume was adjusted to the final desired volume. The final solution was sterilized by membrane filtration and packaged aseptically providing 10 mg of ivermectin per ml of solution. EXAMPLE 2 To prepare an ivermectin injectable solution containing 10 mg of active ingredient per ml of solution, the following ingredients were used: Iver mectin 1.0% W/v Water for Injection 10.0% V/V Propylene Glycol q.s. 100.0% V/V The ivermectin was dissolved in a part of the propylene glycol. The water for injection was added in such a manner that precipitation of the ivermectin was avoided and the final volume was adjusted with propylene glycol to the desired final concentration. The solution was membrane filtered to sterilize it and packaged aseptically.

Claims: CLAIMS 1. An endoparasiticidal and ectoparasiticidal parenteral formulation comprising an avermectin or milbemycin compound dissolved in a combination of propylene glycol and either glycerol formal or water. 2. A formulation as claimed in Claim 1 in which the avermectin or milbemycin compound is ivermectin. 3. A formulation as claimed in Claim 1 or 2 in which 0.1 to 20% W/V of the avermectic or milbemycin compound is dissolved in a 10:90 to 90:10 V/V mixture of glycerol formal and propylene glycol. 4. A formulation as claimed in Claim 1 or 2 in which 0.1 to 20% W/V of the avermectic or milbemycin compound is dissolved in a 95:5 to 80:20 V/V mixture of propylene glycol and water. 5. A formulation as claimed in Claim 2 containing 1% W/V of ivermectin dissolved in an about 40:60 V/V mixture of glycerol formal and propylene glycol. 6. A formulation as claimed in Claim 2 containing 1% W/V of ivermectin dissolved in an about 90:10 V/V mixture of propylene glycol and water. 7. A method of preparing a formulation as claimed in any one of Claims 1 to 6 comprising dissolving the avermectin or milbemycin compound in a sufficient quantity of glycerol formal, propylene glycol or a mixture thereof, then adjusting the solvent concentration to the desired level. 8. A method of preparing a formulation as claimed in any one of Claims 1, 2, 4 and 6, comprising dissolving the avermectin or milbemycin compound in a sufficient quantity of propylene glycol to dissolve it, adding water and if necessary adjusting the concentration to the desired level with propylene glycol.

Inventors: NESBITT, RUSSELL U., WILLIAMS, JAMES B.
Applicants: MERCK & CO. INC.
Application year: 1984
Main classification: A61K31
IPC codes: A61K31, A61K47, A61P33, C07D493, C07H19, C07H17, A61K9