Sustained-release compositions for parenteral administration

#Helminthiasis is a widespread disease found in many animals and is responsible for significant economic losses throughout the world. Among the helminths most frequently encountered are the group of worms referred to as nematodes. The nematodes are found in the gastrointestinal tract, heart, lungs, blood vessels and other body tissues of animals and are a primary cause of anemia, weight loss and malnutrition in the infected animals. They do serious damage to the walls and tissue of the organs in which they reside and, if left untreated, may result in death to the infected animals.

#The nematodes most commonly found to be the infecting agents of ruminants include Haemonchus and Ostertagia generally found in the abomasum; Cooperia, Trichostrongylus and Nematodirus generally found in the intestinal tract, and Dictyocaulus found in the lungs. In non-ruminant animals important nematodes include Toxocara and Ancylostoma in the intestine and Dirofilaria in the heart of dogs and cats; Ascaridae in the intestine of swine; and large and small strongyles in equines.

#Arthropod ectoparasites commonly infecting warm-blooded animals include ticks, mites, lice, fleas, blowfly, the ectoparasite Lucilia sp. of sheep, biting insects and migrating dipterous larvae such as Hypoderma sp. in cattle, Gastrophilus in horses and Cuterebra sp. in rodents.

#FIG. 1 is a graph depicting the blood concentration profile of moxidectin in calves treated with composition number 2.

#In accordance with the present invention, the sustained-release compositions comprise a macrolide compound; a low-HLB surfactant; a co-solvent selected from the group consisting of an aromatic alcohol and a cyclic amide and mixtures thereof; and a solvent selected from the group consisting of triglycerides of medium chain fatty acids and glycol esters of medium chain fatty acids and mixtures thereof. The invention also provides a method for preventing or treating helminth, acarid or arthropod endo- or ectoparasitic infection or infestation in warm-blooded animals.

#Preferred sustained-release compositions of this invention comprise on a weight to volume basis about 10% to 20% of the macrolide compound or mixture of macrolide compounds; about 1% to 10% of the low-HLB surfactant or mixture of low-HLB surfactants; about 1% to 15% of the co-solvent; and the solvent.

#Uniquely, it has been found that sustained-release compositions having relatively high loadings of macrolide compounds may be obtained when a low-HLB surfactant is used in combination with the co-solvent and solvent of the present invention. Advantageously, the rate of absorption of macrolide compounds from subcutaneous injection depots is controlled through the inventive combination of a low-HLB surfactant, co-solvent and solvent to achieve: (1) long lasting therapeutic efficacy; (2) relatively low peak blood levels; and (3) essentially complete absorption. Long lasting efficacy is advantageous because animals will need to be treated less frequently. By providing relatively low peak blood levels, the inventive compositions reduce the risk of systemic toxicity associated with high blood levels of certain macrolide compounds. Essentially complete absorption is highly desirable because it reduces the risk of unacceptable injection site irritation, and minimizes injection site and/or tissue residues.