Polymorph compositions, methods of making, and uses thereof
The described invention provides a biodegradable, biocompatible delivery system of flowable sustained release microparticulate composition of a substantially pure crystalline form of a bioactive agent such as, for example, nimodipine, a process of preparing a therapeutic form of a substantially pure crystalline form of the bioactive agent and a method for treating an interruption of a cerebral artery in a subarachnoid space at risk of interruption caused by brain injury in a mammal, which reduces signs or symptoms of at least one delayed complication associated with brain injury.
1. A semisolid, biodegradable, biocompatible delivery system capable of sustained release kinetics comprising:
(i) a flowable microparticulate formulation comprising a crystalline polymorphic Form I of Nimodipine characterized by a melting range of 122° C. to 127° C. as measured by Differential Scanning calorimetry (DSC), the microparticulate formulation being characterized by:
(a) a plurality of microparticles wherein each microparticle comprises a matrix;
(b) dispersal of the polymorphic Form I of Nimodipine throughout each microparticle, and
(c) a load of at least 70 percent by weight, relative to the total weight of Nimodipine, of Form I of Nimodipine;
(d) wherein said matrix comprises a biodegradable polymer selected from the group consisting of polylactide-polyglycolide, poly(orthoester), and poly(anhydride); and
(e) a pharmaceutically acceptable carrier,
the delivery system being characterized by delayed release of the polymorphic Form I of Nimodipine from the delivery system, wherein one half of the polymorphic Form I of Nimodipine is released from the delivery system within 1 day to 30 days in vivo.
2. The delivery system according to claim 1 , wherein the microparticulate formulation comprises a powder suspension of microparticles.
3. The delivery system according to claim 1 , wherein Nimodipine load of the formulation contained within the delivery system ranges from about 25% (by weight) to 75% by weight relative to the total weight of the formulation.
4. The semisolid, biodegradable, biocompatible delivery system capable of sustained release kinetics according to claim 1 , wherein the microparticulate formulation is characterized by a Nimodipine load of from about 25% to 75% by weight relative to the total weight of the formulation.
5. The semisolid, biodegradable, biocompatible delivery system capable of sustained release kinetics according to claim 1 , wherein the flowable microparticulate formulation is prepared by a process comprising:
(a) providing the polymorphic Form I of Nimodipine characterized by a melting range of 122° C. to 127° C. as measured by Differential Scanning calorimetry (DSC);
(b) adding the polymorphic Form I of Nimodipine to a polymer solution, thereby creating a mixture of the polymorphic Form I of Nimodipine and the polymer solution;
wherein the polymer solution comprises a solvent and a biodegradable polymer, the solvent in the polymer solution comprises ethyl acetate or dichloromethane or a mixture thereof and the biodegradable polymer is selected from the group consisting of polylactide, polylactide-co-glycolide, poly(orthoester), and poly(anhydride);
(c) homogenizing the mixture to form a disperse phase;
(d) mixing the disperse phase with a continuous phase comprising a continuous process medium, thereby forming an emulsion comprising the polymorphic Form I of Nimodipine;
(e) forming and extracting the microparticles comprising the polymorphic form of Nimodipine; and
(f) drying the microparticles for a time from 4 to 48 hours,
wherein the microparticulate formulation is characterized by:
(i) a plurality of microparticles;
(ii) dispersal of the polymorphic form I of Nimodipine throughout each microparticle; and
(iii) a load of at least 70% by weight relative to the total weight of Nimodipine of Form I of Nimodipine.