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Solid-state form of amg 706 and pharmaceutical compositions thereofSolid-state form of amg 706 and pharmaceutical compositions thereof description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20080108664, Solid-state form of amg 706 and pharmaceutical compositions thereof. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001]This application claims the benefit of U.S. Provisional Application No. 60/753,909, filed Dec. 23, 2005, which is hereby incorporated herein by reference in its entirety. FIELD OF THE INVENTION [0002]The present invention relates to the compound AMG 706, and in particular to solid-state forms of that drug, to pharmaceutical compositions comprising such solid-state forms, and to processes for preparing them. The invention further relates to methods of treatment of angiogenesis mediated disorders comprising administering such solid-state forms or compositions thereof to a subject, and to use of such solid-state forms in the manufacture of medicaments. DETAILED DESCRIPTION OF THE INVENTION [0003]N-(2,3-Dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)ami- no]-3-pyridinecarboxamide, and its pharmaceutically acceptable salts including the diphosphate salt, also known as AMG 706, has a therapeutic and prophylactic anti-angiogenic effect. AMG 706 has utility in treatment and prevention of angiogenesis-mediated disorders, and of such disorders in general. [0004]A need for new forms of AMG 706, in particular forms suitable for preparing rapid-onset compositions, exists. Rapid-onset drug-delivery systems can provide significant benefits over conventional dosage forms. Generally, rapid-onset preparations provide a short period to therapeutic or prophylactic response compared to conventional immediate-release or sustained-release dosage forms. [0005]However, AMG 706 presents certain challenges for formulation as a rapid-onset dosage form, particularly as a rapid-onset oral dosage form. For example, AMG 706 has low solubility in aqueous media and therefore may not have rapid absorption in the gastrointestinal tract when administered orally, for example in tablet or capsule form. In addition, AMG 706 has a moderately high dose requirement further increasing difficulties of providing a sufficient therapeutically effective dose for rapid absorption. For these and other reasons, therefore, it is difficult to prepare an orally deliverable, rapid-onset composition containing AMG 706 that has the desired blend uniformity. [0006]The bioavailability of an orally administered drug, as measured by its entry into systemic circulation in the bloodstream, depends on at least two fundamental processes: drug dissolution in gastrointestinal fluids (in vivo drug release) and subsequent absorption of the dissolved drug. Several factors influence dissolution of a drug from its carrier, including surface area of the drug presented to the dissolution solvent medium, solubility of the drug substance in the solvent medium, and driving forces of the saturation concentration of dissolved materials in the solvent medium. [0007]When the process of in vivo drug release is slower than the process of absorption, absorption is said to be dissolution rate-limited. Since dissolution precedes absorption in the overall process, any change in the drug release or dissolution process will subsequently influence drug absorption. See for example, Lieberman et al., Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, New York, 1, 34-36 (1989). It is clear, therefore, that dissolution time determined for a composition is one of the important fundamental characteristics for consideration when evaluating compositions intended for fast-onset delivery, particularly where drug absorption is dissolution rate-limited. [0008]Crystalline solids, due to their highly organized, lattice-like structures, typically require a significant amount of energy for dissolution. The energy required for a drug molecule to escape from a crystal, for example, is greater than is required for the same drug molecule to escape from a non-crystalline, amorphous form. Importantly, however, crystalline drug forms which have been transformed into amorphous forms tend to revert to a steady state of low energy, namely the crystalline form, over time and thus may not have an adequate shelf life. An amorphous form of AMG 706 has not hitherto been known in the art. [0009]As indicated hereinbelow, treatment with AMG 706 is indicated in a very wide array of angiogenesis-mediated conditions and disorders. Therefore, if an amorphous form of AMG 706 could be prepared, and in particular if a storage-stable composition comprising such an amorphous form of AMG 706 could be developed exhibiting enhanced bioavailability, for example through rapid dissolution of the drug, a significant advance would be realized in treatment of angiogenesis mediated conditions and disorders. [0010]AMG 706 provides better solubility or a more rapid onset of therapeutic effect if, upon oral administration of a composition comprising AMG 706, pharmacokinetic properties are exhibited leading to a greater maximum blood serum concentration (C.sub.max) and/or a shorter time following the administration to reach that maximum (T.sub.max). It is contemplated that a greater C.sub.max and/or a shorter T.sub.max can result from faster dissolution of AMG 706 when provided in amorphous form than in crystalline form. [0011]Accordingly, the present invention provides amorphous AMG 706. There is also provided AMG 706 drug substance wherein the AMG 706 is present, in at least a detectable amount, as amorphous AMG 706. The term "AMG 706 drug substance" as used herein means AMG 706 per se as qualified by the context in which the term is used, and can refer to unformulated AMG 706 or to AMG 706 present as an ingredient of a pharmaceutical composition. [0012]Alternatively, there is provided an AMG 706-crystallization inhibitor composite comprising particles of amorphous AMG 706 or AMG 706 drug substance of the invention in intimate association with one or more crystallization inhibitors. The crystallization inhibitors are selected and present in an amount sufficient to substantially reduce conversion of amorphous AMG 706 to crystalline AMG 706. Preferred crystallization inhibitors are polymers that form with the AMG 706 an AMG 706-polymer composite. [0013]Also provided are processes for preparing amorphous AMG 706, and for preparing AMG 706 drug substance of the invention. [0014]AMG 706 drug substance or powder thereof, prepared according to such processes can be further formulated to provide a pharmaceutical dosage form. [0015]Also provided is a method of treating a medical condition or disorder in a subject where treatment with an angiogenesis inhibitor is indicated, comprising administering, for example orally, a composition of the invention in a therapeutically effective amount. Such method is particularly useful where the medical condition or disorder is angiogenesis. [0016]Other features of this invention will be in part apparent and in part pointed out hereinafter. BRIEF DESCRIPTION OF THE DRAWINGS [0017]FIG. 1 shows a powder X-ray diffraction (XRPD) profile of AMG 706 drug substance prepared by a spray drying method of Example 1. [0018]FIG. 2 shows a differential scanning calorimetry (DSC) thermogram of AMG 706 drug substance prepared by a spray drying method of Example 1. [0019]FIG. 3 shows a powder X-ray diffraction (XRPD) profile of AMG 706 drug substance prepared by the lyophilization method described in Example 2. [0020]FIG. 4 shows a differential scanning calorimetry (DSC) thermogram of crystalline AMG 706 drug substance. [0021]FIG. 5 shows a powder X-ray diffraction (XRPD) profile of crystalline AMG 706 drug substance. Continue reading about Solid-state form of amg 706 and pharmaceutical compositions thereof... Full patent description for Solid-state form of amg 706 and pharmaceutical compositions thereof Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Solid-state form of amg 706 and pharmaceutical compositions thereof patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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