Injectable compositions for the controlled delivery of pharmacologically active compound

#The present invention relates to methods and compositions for extending the release times and decreasing the toxicity of pharmacologically active compounds.

#The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the present invention.

#It is often desirable to extend the release time of an injected drug to increase its duration of action, or to reduce its toxic effects. Formulations that are readily soluble in the body are usually absorbed rapidly and provide a sudden burst of available drug as opposed to a more desirable and gradual release of the pharmacologically active product. A variety of attempts have been made to provide controlled and extended release pharmaceutical compounds, but have not succeeded in overcoming all of the problems associated with the technology, such as achieving an extended release time, maximum stability and efficacy, reduced toxicity, maximum reproducibility in preparation, and the elimination of unwanted physical, biochemical, or toxicological effects introduced by undesirable matrix materials.

#FIG. 1 is a graphical illustration showing that oxytetracycline prepared according to the present invention is released into saline at a rate slower than that of the free drug. The solvent is DMSO, and the lipophilic counterion is lauric acid.

#FIG. 2 is a graphical illustration showing that metoprolol prepared according to the present invention is released into saline at a rate slower than that of the free drug. Fatty acid and solvent are lauric acid and N-methylpyrrolidone.

#FIG. 3 is a graphical depiction illustrating that the rate of release of the pharmacologically active compound (tilmicosin) is affected by the chain length of the fatty acid selected. Solvent: N-methyl pyrrolidone; lipophilic counterion: decanoic acid and lauric acid.

#The compositions of the present invention may be prepared using salts of pharmacologically active compounds with basic functionalities. These can be made using a variety of lipophilic acids, saturated or unsaturated fatty acids, cholic acids, phosphatidic acids, dicarboxylic acids such as sebacic acid or any acid that, when combined with the pharmacologically active compound, renders the resulting salt insoluble in water, but soluble in a water soluble solvent. By “salt” is meant two compounds that are not covalently linked but are chemically bound through ionic attractions. By “water miscible” is meant that the solvent is capable of mixing in any ratio in water without separation of two phases. By “water soluble” is meant that the solvent has some significant level of solubility in aqueous solutions, e.g., triacetin is considered a water soluble solvent since it is soluble in water at a ratio of about 1:14. By a “lipophilic counterion” is meant an ionic form of a fat soluble molecule. The lipophilic counterion may preferably be a fatty acid, but may also be another fat soluble molecule. The counterion has at least one charge opposite to that of a chemical group on an opposing salt member, thereby causing an ionic attraction between the two molecules. By “injectable formulation” or “injectable composition” is meant a formulation or composition that can be drawn into a syringe and injected subcutaneously, intraperitoneally, or intra-muscularly into a mammal without causing adverse effects due to the presence of solid materials in the composition. Solid materials include, but are not limited to, crystals, a gummy mass, and a gel. By “pharmacologically active compound” is meant a chemical compound that causes a pharmacological effect in the treated mammal. For example, the effect may be to destroy or prevent growth of bacteria or parasites, reduce inflammation, or another pharmaceutical and measurable effect in the treated mammal.

#By the verb “precipitate” is meant that the compound forms a precipitate, or solid. A precipitate is an insoluble solid formed in solution at room temperature in vitro or in a physiological (in vivo) environment. The precipitate can take many forms such as, for example, a solid, a crystal, a gummy mass, or a gel. By “pharmaceutically effective amount” is meant an amount that exerts a measurable and medically significant effect on the treated mammal, resulting in progress towards curing or preventing the subject disease, or alleviating or preventing the condition that was the reason for treatment. A “pharmaceutically acceptable solvent” is a liquid that dissolves a salt of the pharmacologically active compound and a lipophilic counterion, and that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.

#The compositions of the present invention offer several advantages. The compositions are injectable compositions that contain high concentrations of the active compound. In preferred embodiments, the pharmacologically active compound may be loaded into the composition in the range of 10%-60% (w/v). But the person of ordinary skill in the art will realize this range may be varied widely, depending on the solubility or insolubility of the pharmacologically active compound, the lipophilic counterion selected, the solvent selected, the injectability of the final product, and any other relevant needs of the particular application. Active compound may also be loaded as low as 10%, or 5%, or even 1% and still provide a useful effect. Similarly, active compound may be loaded at 70%, or even higher as needs require. No exotic excipients or carriers are required. The compositions are easily filtered, thereby simplifying the manufacturing process. It is believed that the exclusion of water from the formulation should impart greater stability to the formulations, and inhibit the growth of microorganisms. The processes for preparing the compositions, as described herein, are simple, and administration according to the present invention should result in milder reactions at the injection site due to the neutralization of the pharmacologically active compound.