LONG ACTIVE INJECTABLE FORMULATIONS CONTAINING TRIACETIN

Abstract: There is disclosed an injectable formulation containing triacetin and an avermectin compound which has been discovered to provide an unexpectedly long duration of activity. The formulation contains the avermectin active ingredient and at least 50% triacetin and effective levels of the avermectin compounds have been maintained for up to 42 days. Prior injectable formulations provided only 14 days duration of activity.

Description: The avermectin series of compounds are potent anthelmintic and antiparasitic agents against internal and external parasites. The natural product avermectins are disclosed in US-A-4,310,519 to Albers Schonberg et al ., and the 22,23-dihydro avermectin compounds are disclosed in Chabala et al, US-A- 4,199,569. Triacetin (Triacetyl glycerine) is a known formulating agent which is generally recognized as safe by the US Food and Drug Administration. See Fragrance Raw Material Monographs pg 879-881 and Pattys Industrial Hygiene and Toxicology 3rd Ed. Vol 2A "Toxicology" Clayton et al , (Ed) pg 2321-2322. Triacetin has been disclosed as a stabilizing agent for prostaglandin compounds. See Yalkowsky US-A- 4,301,175 and 3,966,962 and Yalkowsky et al , Journal of Pharmaceutical Sciences , 68 , pg 114-115 (1979). Triacetin has also been disclosed as a component of a long acting antiperspirant composition for topical use, see Claukin US-A- 4,548,808; and in a formulation for the transdermal administration of psychostimulants, see Mahjour et al , US-A-4,666,926. This invention is concerned with the unexpectedly long duration of activity which is observed when avermectin injectable formulations are prepared using triacetin. Thus, it is an object of this invention to describe such a prolonged therapeutic effect. An additional object is to describe the avermectin compounds which may be employed in the long acting formulation. Additional objects will become apparent for a reading of the following description. This invention consists of 24 injectable formulation of triacetin and an avermectin compound which has been found to have a considerably prolonged duration of activity against internal and external parasites. Triacetin is the triacetic acid ester of glycerin, also referred to as glyceryl triacetate which has the following formula: The avermectin compounds may have the following structure: wherein the broken line indicates a single or a double bond at the 22,23-positions; R₁ is hydrogen or hydroxy provided that R₁ is present only when the broken line indicates a single bond; R₂ is alkyl of from 1 to 6 carbon atoms or alkenyl of from 3 to 6 carbon atoms; R₃ is hydroxy, methoxy or = NOR₅ wherein R₅ is hydrogen or lower alkyl; and R₄ is hydrogen, hydroxy or wherein R₆ is hydroxy, amino, mono-or di-loweralkyl amino or loweralkanoylamino. The preferred compounds are avermectin B1a/B1b (abamectin) and 22,23-dihydro avermectin B1a/B1b (ivermectin). Both abamectin and ivermectin are approved as broad spectrum antiparasitic agents. The structures of abamectin and ivermectin are as follows: wherein for abamectin the broken line represents a double bond and R₁ is not present and for ivermectin the double bond represents a single bond and R₁ is hydrogen; and R₂ is isopropyl or sec -butyl. The abamectin and ivermectin products are generally prepared as a mixture of at least 80% of the compound wherein R₂ is sec-butyl and no more than 20% of the compound where R₂ is isopropyl. In the injectable forms of the avermectin formulation it has not been possible to provide a long acting formulation since the avermectins are insoluble in water and generally of low solubility in the oil carriers usually used for injection. Heretofore, injectable formulations of a maximum of 14 days have been possible. The current long acting formulations of avermectins provided for unacceptably large volumes of the injection liquid, or resulted in irritation at the injection site. The instant formulations of an avermectin compound with triacetin provides the advantages of a readily injectable formulation which provides the animal with treatment and protection against internal and external parasites for up to 42 days. The injection material is maintained as a depot to provide the necessary reservoir of active ingredient for a long acting effect. No tissue damage has been observed at the site of injection either at the time of injection or during the 42 day course of therapy. In contrast to most oil based formulations, the formulation maintains a low viscosity even at high drug loads and even at temperatures as low as -5°C, a temperature at which most oil-based formulations become too viscous for practical use. The high solubility of the avermectins in triacetin, allows for a low dose volume, as low as 1 ml per 50 kg of body weight. Previous oil formulations provide a lowest dose volume of 1 ml per 30 kg of body weight. Since previous injectable formulations only provide 14 days duration, the improved current formulation with 42 days duration avoids two injections which would be necessary to obtain 42 days protection with a 14 day duration injection and also avoids the stress of the extra handling necessary for the extra injections which increses illness and weight loss. The triacetin formulation can contain the avermectin compound and the triacetin as the only ingredients. The formulations will generally be prepared to administer from 0.1 to 1 mg/kg preferably from 0.4 to 0.85 mg/kg and most preferably from about 0.6 to 0.7 mg/kg. At a preferred dose volume of about 1 ml to treat 50 kg of animal body weight the formulation contains from 5 to 50 mg of avermectin compound per ml of solution or about 0.5 to 10% w/v preferably 2.5 to 5% w/v. In addition to the triacetin and the avermectin the formulation can contain an antioxidant such as a propyl gallate, BHA (butylated hydroxy anisole), BHT, (butylated hydroxy toluene) and monothioglycerol. The antioxidants are generally added to the formulation at rates of from 0.01 to 2.0% (w/v). The formulation is prepared by dissolving the avermectin compound in approximately 80% of the intended volume of the triacetin. The antioxidant is then dissolved in the triacetin/avermectin mixture and the volume adjusted to 100% by the addition of the final volume of triacetin. Since the long acting formulation is intended for injection, it is necessary that it be sterilized. Heat sterilization is generally to be avoided since the avermectin compound would be unstable at autoclave temperatures. Rather, membrane sterilization is preferred. The sterile solution is then packaged a septically. The avermectin-triacetin long acting injectable formulation may be administered to warm blooded animals to provide up to 42 days of treatment and protection against external and internal parasites. Typically, the formulation is administered to domesticated animals such as cattle, sheep, pigs and horses. EXAMPLE OF THE INVENTION An ivermectin (22,23-dihydro avermectin B1a/B1b in a ratio of 80:20) formulation in triacetin for injection, 3.15% is prepared from the following ingredients. Ivermectin 3.15% w/v n-Propyl gallate 0.02% w/v Triacetin q.s. 100% w/v The ivermectin is dissolved in approximately 80% of the triacetin. When dissolved, the n-propyl gallate is added and dissolved. The volume is adjusted to 100% with triacetin and the solution sterilized by membrane filtrations and packaged aseptically.

Claims: A long acting injectable formulation consisting of an avermectin compound as the only active agent and of triacetin as the only solvent. The formulation according to Claim 1 wherein the avermectin compound has the formula: wherein the broken line indicates a single or a double bond at the 22,23-positions; R₁ is hydrogen or hydroxy provided that R₁ is present only when the broken line indicates a single bond; R₂ is alkyl of from 1 to 6 carbon atoms or alkenyl of from 3 to 6 carbon atoms; R₃ is hydroxy, methoxy or = NOR₅ wherein R₅ is hydrogen or loweralkyl; and R₄ is hydrogen, hydroxy or wherein R₆ is hydroxy, amino, mono- or di-loweralkyl amino or loweralkanoylamino. The formulation according to Claim 2 wherein the avermectin compound has the formula: wherein for abamectin the broken line represents a double bond and R₁ is not present and for ivermectin the double bond represents a single bond and R₁ is hydrogen; and R₂ is isopropyl or sec -butyl. The formulation according to Claim 3 wherein the avermectin compound is ivermectin. The formulation according to Claim 3 wherein the avermectin compound is abamectin. The formulation according to Claim 1 which contains from 5 to 50 mg of the avermectin compound per ml of formulation. The formulation according to Claim 1 which contains from 0.5 to 10% w/v of the avermectin compound. A process for the preparation of the formulation according to Claim 1 which comprises dissolving the avermectin compound in about 80% of the volume of the triacetin; adding the remainder of the triacetin; and sterilizing the resultant formulation.

Inventors: WILLIAMS, JAMES B.
Applicants: MERCK & CO. INC.
Application year: 1990
Main classification: A61K31
IPC codes: A61K9, C07D493, A61K47, A61K31, C07H17