Claims for Patent: 8,361,509

Summary for Patent: 8,361,509

Title:	Pharmaceutical dosage forms for the release of active compounds
Abstract:	Pharmaceutical form containing at least an active compound and a polymeric matrix, wherein said polymeric matrix comprises at least one polymer of cationic nature and at least one biodegradable polymer, process for the preparation thereof, pharmaceutical formulations comprising said pharmaceutical form, and their uses. The pharmaceutical form provides enhanced absorption of active compounds across the mucosa.
Inventor(s):	Lopez-Belmonte Encina; Ivan (Madrid, ES), Gutierro Aduriz; Ibon (Granada, ES), Maincent; Philippe (Nancy, FR)
Assignee:	Laboratorios Farmaceticos Rovi, S.A. (Madrid, ES)
Application Number:	13/355,763
Patent Claims:	1. A method for the prevention or treatment of a disease or disorder that is therapeutically responsive to one or more active principles, the method comprising: administering to a subject in need thereof a pharmaceutically effective amount of the one or more active principles, in a particulate vector, according to a predetermined dosing regimen, thereby providing a therapeutic response in the subject; wherein the particulate vector comprises at least one active principle and a polymeric matrix comprising a mixture of at least one biodegradable polymer and at least one non-water soluble polycationic polymer: the biodegradable polymer is selected from the group consisting of polyesters, lactic acid polymers, copolymers of lactic acid and of glycolic acid (PLGA), poly-.epsilon.-caprolactone (PCL), polyanhydrides, poly(amides), poly(urethanes), poly(carbonates), poly(acetals), poly(ortho-esters), polymers and copolymers derived from acrylic acid, polyethylene oxides, polypropylene oxides, polyethylene and polypropylene oxide copolymers, polycyanoacrylates, polydioxanones, poly(.alpha.-hydroxy acids), poly(.beta.-hydroxy acids), and polyphosphazenes; the non-water soluble polycationic polymer is selected from the group consisting of polycationic chitosan, polycationic polylysine, cholestyramine and the polycationic copolymers of acrylic and methacrylic acid esters with trimethylammonioethyl methacrylate chloride; the active principle is selected from the group consisting of insulin, heparin, unfractionated heparin, low molecular weight heparin, ultra low molecular weight heparin, heparinoid, heparin having a molecular weight between 2,500 D and 40,000 D, antibiotics, anti-inflammatory agents, anti-infectious agents, antiparasitic agents, hormones, substances with immunological activity, vaccines, immunomodulators, immunosuppressants, cytostatic agents, diuretics, agents with activity in the digestive system, agents with activity in the circulatory system, agents with activity in the respiratory system, human growth hormone, recombinant growth hormone, bovine growth hormone, growth-hormone releasing hormone, interferons, analgesics, agents with activity in the central nervous system, erythropoietin, somatostatin, gonadotropin-releasin hormone, follicle-stimulating hormone, oxytocin, vasopressin, parathyroid hormone, adrenocorticotropin, gonadotropin-releasing hormone, thrombopoietin, calcitonin, interferons, interleukins, dermatan, glucosamines, chondroitins, auricular natriuretic factor monoclonal antibodies, protease inhibitors, filgrastim, prostaglandins (PGE2 and PGI2), cyclosporin, cromolyn sodium cromoglycate and its salts, vasopressin, vancomycin, neomycin, desferrioxamine, antimicrobial agents, antifungals, cytostatics, immunomodulators, vitamins, antivirals, antigens, ribonucleic acid, deoxyribonucleic acid, oligonucleotides, CPG sequences, plasmids, active compounds of protein nature, active compounds of polysaccharide nature glucocerebrosidase, and derivatives and combinations thereof; the biodegradable polymer and the polycationic polymer are present in equivalent amounts; and the biodegradable polymer and the polycationic polymer are non-enteric. 2. The method of claim 1, wherein the disease is a thromboemoblic disease. 3. The method of claim 2, wherein the particulate vector is in the form of nanoparticles or microparticles. 4. The method of claim 3, wherein the particulate vector is a granule or pellet, having an average particle diameter in the range of 0.1 to 1.2 mm or of at least 1 mm. 5. The method of claim 1, wherein less than 20% wt. of the active compound is distributed on the surface of the particulate vector; and at least 80% wt. of the active compound is embedded within or surrounded by the polymeric matrix of the particulate vector. 6. The method of claim 1, wherein the particulate vector provides a release of at least 50% of active principle that is available for immediate release within 2 hours or less after the particulate vector is exposed to an aqueous environment; or wherein the particulate vector provides a release of at least 60% of active principle that is available for immediate release within 3 hours or less after the particulate vector is exposed to an aqueous environment. 7. The method of claim 6, wherein at least 20% of the active principle that is available for immediate release from the pharmaceutical form is absorbed via the mucosa of the subject following administration of the particulate vector to the subject. 8. The method of claim 7, wherein the mucosa is selected from the group consisting of oropharyngeal mucosa, gastrointestinal mucosa, pulmonary mucosa, nasal mucosa and vaginal mucosa. 9. The method of claim 1, wherein the vector further comprises one or more substances selected from the group consisting of enteric polymers and water-soluble or liposoluble substances. 10. The method of claim 1, wherein the at least one biodegradable polymer comprises at least one neutral polymer or at least one anionic polymer. 11. The method of claim 10, wherein at least one polymer of anionic or neutral nature and at least one polymer of cationic nature are present in a proportion of at least 10% each in relation to the weight of the polymeric matrix. 12. The method of claim 10, wherein the polymeric matrix comprises poly-.epsilon.-caprolactone as a polymer of anionic or neutral nature and a polymer derived from methacrylic acid with quaternary ammonium groups as a polymer of cationic nature, and the polymer derived from methacrylic acid with quaternary ammonium groups is a trimethylammonioethyl methacrylate chloride copolymer. 13. The method of claim 10, wherein the cationic polymer is a polymer derived from methacrylic acid with quaternary ammonium groups, and the biodegradable polymer is a polyethylene and polypropylene oxide copolymer, PLGA, or poly-.epsilon.-caprolactone. 14. The method of claim 1, wherein the at least one active principle is encapsulated within the polymeric matrix. 15. The method of claim 1, wherein the polymeric matrix comprises the at least one active principle, and the mixture of the at least one biodegradable polymer and the at least one non-water soluble polycationic polymer. 16. The method of claim 4, wherein the particulate vector is a granule comprising a core and the polymeric matrix, wherein said core comprises the at least one active compound. 17. The method of claim 16, wherein the polymeric matrix forms part of the core, or the polymeric matrix forms a coating layer on or over the core. 18. The method of claim 17, wherein the particulate vector further comprises an intermediate layer between the core and the coating layer. 19. The method of claims 17, wherein the core comprises an inert seed and a coating layer comprising the active compound. 20. The method of claim 19, wherein the particulate vector further comprises an intermediate layer between the inert seed and the layer comprising the active compound. 21. The method of claim 4, wherein the particulate vector is a pellet manufactured by a granulation process which comprises the step of subjecting a composition comprising at least one active compound to a granulation process to produce a core. 22. The method of claim 21, wherein the manufacturing process further comprises the step of coating the core with a composition comprising the at least one cationic polymer. 23. The method of claim 1, wherein the particulate vector has a surface potential in the range of -17.3.+-.1.35 mV to -37.2.+-.3.3 mV. 24. The method of claim 23, wherein the particulate vector has a surface potential of -17.3.+-.1.35, -20.+-.0.67, -29.9.+-.0.39, -30.7.+-.2.02, -33.6.+-.1.93, -37.2.+-.3.30. 25. The method of claim 1, wherein the particulate vector comprises: a) a copolymer of methacrylic acid polyesters with a proportion of trimethylammonioethyl methacrylate chloride, and a copolymer of lactic acid and of glycolic acid; b) a copolymer of lactic acid and of glycolic acid; c) a copolymer of methacrylic acid polyesters with a proportion of trimethylammonioethyl methacrylate chloride, and poly-.epsilon.-caprolactone; or d) poly-.epsilon.-caprolactone. 26. The method of claim 1, wherein the at least one active principle is selected from the group consisting of enoxaparin, tinzaparin, bemiparin, fondaparinux and insulin. 27. The method of claim 1, wherein the particulate vector is included in a pharmaceutical composition comprising the particulate vector and a pharmaceutically acceptable excipient. 28. The method of claim 27, wherein the at least one active principle is standard heparin which is administered at a dose of between 2,000 IU/day and 20,000 IU/day, or is LMWH which is administered at a dose of between 600 IU/day and 4,200 IU/day. 29. The method of claim 27, wherein the pharmaceutical composition is adapted for oral, peroral, sublingual, intraduodenal, intrajejunal, intraileal, intracolonic, rectal, intravaginal, nasal, intrapulmonary, ocular and/or otic administration. 30. The method of claim 29, wherein the pharmaceutical composition is a non-extended release formulation. 31. The method of claim 29, wherein the pharmaceutical composition is an oral formulation. 32. The method of claim 1, wherein less than 95% of the active compound present in the particulate vector is degraded in the gastric region following oral administration of the particulate vector to a subject. 33. The method of claim 18, wherein the particulate vector is manufactured by a coating process which comprises the steps of: a) coating an inert seed with a composition comprising at lest one active compound to obtain a core, and b) coating the core prepared in a) with a composition comprising at least a polymer of cationic nature. 34. The method of claim 33, wherein the process further comprises in step a) coating the inert seed with a composition, to form an intermediate coating layer before performing the coating with a composition comprising at least one active compound. 35. The method of claim 33, wherein, in step b) the composition further comprises at least one polymer of anionic or neutral nature. 36. The method of claim 33 wherein, in the manufacture process, a spray method is used in step b). 37. The method of claim 33 wherein, the manufacture process further comprises coating the core with a composition to form an intermediate coating layer. 38. The method of claim 15, wherein the particulate vector is manufactured by an extrusion process which comprises the steps of: a) mixing at least one active compound with at least one polymer of cationic nature, and b) extruding the homogenized mixture. 39. The method of claim 38 wherein in step a) the active compound is further mixed with at least one polymer of anionic or neutral nature. 40. The method of claim 1, wherein the active compound is selected from the group consisting of insulin, heparin, unfractionated heparin, low molecular weight heparin, ultra low molecular weight heparin, heparinoid and heparin having a molecular weight between 2,500 D and 40,000 D.

Details for Patent 8,361,509

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Amgen, Inc.	NEUPOGEN	filgrastim	Injection	103353	02/20/1991		2020-07-07
Amgen, Inc.	NEUPOGEN	filgrastim	Injection	103353	06/28/2000		2020-07-07
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2020-07-07