Applications of Tulathromycin

Mar. 12, 2021

The present invention relates to pharmaceutical compositions comprising a substantially pure isomer of an azalide antibiotic compound and to methods for preparing them. This invention further relates to methods for treating a mammal comprising administering to a mammal in need of such treatment a pharmaceutical composition of the invention.

 

Draxxin® (tulathromycin) is a semi synthetic microcline antibiotic indicated e.g. for the treatment of swine respiratory disease, for the treatment of bovine respiratory disease and for the control of respiratory disease in cattle at high risk to develop bovine respiratory disease as well as for the treatment of infectious bovine keratoconjuctivis.

Compound of formula II can be formed from a translactonization reaction of isomer I. Draxxin® is marketed as an injectable solution comprising an equilibrium mixture of about 90%±4% of isomer A and about 10%±4% of isomer B.

 

Solutions of pharmaceutical ingredients have a limited chemical stability compared to solid forms, as solvents, especially water, slowly degrades the active pharmaceutical ingredient. In addition, in order reach the equilibrium mixture in Draxxin®, critical parameters have to be watched very carefully as pH, temperature and time heavily influence the quality of the equilibrated mixture with respect to impurities. One approach to overcome the problem comprises adding a colsolvent to the formulation in order to improve the stability of the equilibrated mixture in solution, see e.g. U.S. Pat. No. 6,667,393 or U.S. Pat. No. 6,514,945.

 

However, a solid formulation which is reconstituted with a solvent just before injection, is preferred to a solution. Development of a solid pharmaceutical composition comprising a single Tulathromycin isomer in high purity is therefore desirable.

 Tulathromycin Injection

The present invention relates to a solid pharmaceutical composition comprising essentially pure Tulathromycin A in form of an addition salt with one or more acids. Upon the addition of a solvent or diluent the solid formulation may be transferred to a ready-to-use injectable before injection.

 

Essentially pure Tulathromycin A means pure with respect to the presence of Tulathromycin B including a high chemical purity of Tulathromycin. Within the present invention “essentially pure” means the presence of more than about 97%, more preferably more than 98%, e.g. 99% of Tulathromycin A and less than about 3%, preferably less than about 2%, e.g. about 1% of Tulathromycin B in said composition.

 

Suitable acids for forming an addition salt with Tulathromycin A are, for example, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, methanesulfonic acid, hydrochloric acid, D- and L-lactic acid, succinic acid, sulfuric acid, D- and L. tartraric acid, malic acid, malonic acid, fumaric acid, palmitic acid, benzoic acid and phosphoric acid, preferably citric acid or a mixture of citric acid and hydrochloric acid.

 

Preferably, the compositions of the invention contain Tulathromycin A in form of an addition salt with citric acid or as addition salt with two different acids selected from the acids as mentioned above, in particular with citric acid and hydrochloric acid. The solid compositions of the invention may contain, in addition, some free acid, preferably selected from the one or more acids used to prepare the addition salt with Tulathromycin A, for example, for adjusting the pH value after reconstitution.

The information is provided by the veterinary medicine manufacturer.