IPC분류정보
국가/구분 |
United States(US) Patent
등록
|
국제특허분류(IPC7판) |
|
출원번호 |
US-0431353
(2003-05-06)
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등록번호 |
US-8088415
(2012-01-03)
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발명자
/ 주소 |
- Wang, Chen-Chao
- Yoo, Jaedeok
- Bornancini, Esteban
- Roach, Willie J.
- Motwani, Monica Rewachand
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출원인 / 주소 |
- The Massachusetts Institute of Technology
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대리인 / 주소 |
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인용정보 |
피인용 횟수 :
2 인용 특허 :
17 |
초록
▼
The invention includes a core-and-shell dosage form or unit in which the core contains API and in which the shell substantially governs the release such as by controlling diffusion of API through the shell. The shell may comprise a release-blocking polymer, and particles of a release-regulating poly
The invention includes a core-and-shell dosage form or unit in which the core contains API and in which the shell substantially governs the release such as by controlling diffusion of API through the shell. The shell may comprise a release-blocking polymer, and particles of a release-regulating polymer. The shell may be substantially impervious but the release-regulating polymer may become suitable to allow diffusion through it when activated. The core may include a buffer region between the shell and the API-containing portion of the core. The dosage form may include multiple units. The dosage form of the invention is capable of providing a release profile whose time scale can be adjusted by adjusting powder composition, and which may be approximately zero-order release. The invention further includes methods of manufacturing such a dosage form, such as three-dimensional printing.
대표청구항
▼
1. A diffusion controlled dosage form having at least one unit providing a diffusion controlled release of Active Pharmaceutical Ingredient, the unit comprising: a powder comprising particles of release blocking-polymer and particles of release-regulating polymer, wherein the release-blocking polyme
1. A diffusion controlled dosage form having at least one unit providing a diffusion controlled release of Active Pharmaceutical Ingredient, the unit comprising: a powder comprising particles of release blocking-polymer and particles of release-regulating polymer, wherein the release-blocking polymer is substantially insoluble in water but is soluble at room temperature in a solvent other than water;a printed core comprising the powder and at least one Active Pharmaceutical Ingredient, wherein the powder particles are bound to each other by Active Pharmaceutical Ingredient; anda printed shell that surrounds the core, the shell comprising the powder, wherein the powder particles are bound to each other;wherein the unit provides a diffusion controlled release of Active Pharmaceutical Ingredient upon exposure to water or bodily fluid;the core has a core ratio of release-blocking polymer to release-regulating polymer in the core, the shell has a shell ratio of release-blocking polymer to release-regulating polymer in the shell, and the core ratio is substantially the same as the shell ratio; andthe core comprises the same release-blocking polymer and the same release-regulating polymer as contained in the shell. 2. The dosage form of claim 1 wherein at least some of the release-regulating polymer in the shell exists in the form of individual particles, which may touch other particles. 3. The dosage form of claim 1 wherein at least some of the release-regulating polymer in the shell exists in the form of tortuous continuous paths, which may include wider parts and narrower parts. 4. The dosage form of claim 1 wherein at least some of the release-regulating polymer in the shell exists in the form of a three-dimensionally interconnected network. 5. The dosage form of claim 1 wherein the shell is substantially free of microscopic defects. 6. The dosage form of claim 1 wherein the shell has a thickness of at least 100 microns. 7. The dosage form of claim 1 wherein the shell has a thickness of approximately 800 microns. 8. The dosage form of claim 1 wherein at least some of the release-regulating polymer in the shell exists in the form of individual particles having an average particle size dimension, and the shell has a thickness of at least 3 times the average particle size dimension. 9. The dosage form of claim 1 wherein the release-blocking polymer and the release-regulating polymer are present in the shell in a proportion that is determined by a desired time scale of a release profile of the Active Pharmaceutical Ingredient from the dosage form. 10. The dosage form of claim 1 wherein the release-regulating polymer in the shell is in the range of 20% to 60% by volume of the combined total of release-regulating polymer and release-blocking polymer in the shell. 11. The dosage form of claim 1 wherein the release-blocking polymer is substantially unaffected by body fluids. 12. The dosage form of claim 1 wherein the release-blocking polymer is substantially impermeable to water. 13. The dosage form of claim 1 wherein the release-blocking polymer is hydrophobic. 14. The dosage form of claim 1 wherein the release-blocking polymer has at least one component that is soluble in at least one non-aqueous solvent. 15. The dosage form of claim 14 wherein the release-blocking polymer has at least one component that is soluble in ethanol. 16. The dosage form of claim 1 wherein the release-blocking polymer is selected from the group consisting of: a mixture of approximately 80% polyvinyl acetate; approximately 19% poylvinyl pyrrolidone; and less than approximately 1% of sodium lauryl sulfate and silica, other polyvinyl acetates, ethyl celluloses, and poly(ethyl acrylate, methyl methacrylate) trimethylammonioethyl methacrylate chloride. 17. The dosage form of claim 1 wherein the release-blocking polymer has at least one component that has a glass transition temperature in an unplasticized state that is less than a temperature that the Active Pharmaceutical Ingredient suffers thermal damage. 18. The dosage form of claim 1 wherein the release-blocking polymer has at least one component that has a glass transition temperature in a plasticized state that is less than a temperature that the Active Pharmaceutical Ingredient suffers thermal damage. 19. The dosage form of claim 1 wherein the release-regulating polymer, upon exposure to water, allows diffusion of aqueous solutions therethrough. 20. The dosage form of claim 1 wherein the release-regulating polymer is capable of forming a gel upon exposure to water. 21. The dosage form of claim 1 wherein the release-regulating polymer absorbs water in a manner which is approximately unaffected by the pH of the water. 22. The dosage form of claim 1 wherein the release-regulating polymer is hydrophilic. 23. The dosage form of claim 1 wherein the release-regulating polymer degrades or dissolves at least slightly upon exposure to body fluids. 24. The dosage form of claim 1 wherein the release-regulating polymer is selected from the group consisting of: hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, acrylate-methacrylate copolymers, polyethylene glycols, xanthan gum, gellan gum, locust bean gum, guar gum, tragacanth, and sodium alginate. 25. The dosage form of claim 1 wherein the shell has a uniform shell wall thickness. 26. The dosage form of claim 1 wherein the shell has a variable shell wall thickness. 27. The dosage form of claim 1 wherein the shell contains non-pharmaceutical materials. 28. The dosage form of claim 1 wherein the dosage form is a three-dimensionally printed dosage form having dimensional increments of a drop-to-drop-spacing and a line-to-line spacing and a powder layer thickness, and wherein the shell has a thickness of at least one drop-to-drop-spacing or one line-to-line spacing or one powder layer thickness. 29. The dosage form of claim 1 wherein the dosage form is a three-dimensionally printed dosage form has dimensional increments of a drop-to-drop-spacing and a line-to-line spacing and a powder layer thickness, and wherein the shell has a thickness of at least two drop-to-drop-spacings or two line-to-line spacings or two powder layer thicknesses. 30. The dosage form of claim 1 wherein the shell further includes a plasticizer. 31. The dosage form of claim 30 wherein the plasticizer and the release-blocking polymer are soluble in the same solvent. 32. The dosage form of claim 30 wherein the plasticizer is soluble in ethanol. 33. The dosage form of claim 30 wherein the plasticizer is selected from the group consisting of: triethyl citrate, triacetin, diethyl phthalate, acetyltriethyl citrate, acetyltributyl citrate, carboxylic acid esters, and phosphoric acid esters. 34. The dosage form of claim 30 wherein the plasticizer is present in the shell in the form of micelles dispersed in the release-blocking polymer. 35. The dosage form of claim 1 wherein the core includes unbound powder particles. 36. The dosage form of claim 1 wherein at least a portion of the core further includes a core binder substance. 37. The dosage form of claim 1 wherein, in the core, particles of the release-regulating polymer comprise API absorbed within them. 38. The dosage form of claim 1 wherein the core contains more Active Pharmaceutical Ingredient than can be contained in solution at body temperature in a volume of water equal to the void volume in the core. 39. The dosage form of claim 1 wherein the core contains less than or equal to the amount of Active Pharmaceutical Ingredient that can be contained in solution at body temperature in a volume of water equal to the void volume in the core. 40. The dosage form of claim 1 wherein the core contains less than or approximately equal to 0.34 milligrams of Active Pharmaceutical Ingredient per cubic millimeter of core region. 41. The dosage form of claim 1 wherein the Active Pharmaceutical Ingredient is water-soluble. 42. The dosage form of claim 1 wherein the Active Pharmaceutical Ingredient comprises at least one substance from the group consisting of pseudoephedrine hydrochloride, metoprolol, d-chlorpheniramine maleate, chlorpheniramine maleate, diphenhydramine hydrochloride, caffeine, d-brompheniramine maleate, brompheniramine maleate, aminophylline, and orphenadrine citrate. 43. The dosage form of claim 1 wherein the core comprises a central region comprising Active Pharmaceutical Ingredient, and comprises a buffer region, surrounding the central region, wherein the buffer region has at least some porosity and contains substantially no Active Pharmaceutical Ingredient. 44. The dosage form of claim 43 wherein the buffer region is sized so as to provide a desired delay time in a release of the Active Pharmaceutical Ingredient from the dosage form. 45. The dosage form of claim 43 wherein the buffer region is sized so as to prevent an initial burst release of the Active Pharmaceutical Ingredient. 46. The dosage form of claim 43 wherein the buffer region has a thickness of at least 200 micrometers. 47. The dosage form of claim 43 wherein the buffer region comprises the same release-blocking polymer and the same release-regulating polymer as are contained in the shell, and wherein the buffer region has a buffer region ratio of release-blocking polymer to release-regulating polymer in the buffer region and the shell has a shell ratio of release-blocking polymer to release-regulating polymer in the shell, and the buffer region ratio is substantially the same as the shell ratio. 48. The dosage form of claim 43 wherein the dosage form is a three-dimensionally printed dosage form having dimensional increments of a drop-to-drop-spacing and a line-to-line spacing and a powder layer thickness, and wherein the buffer region has a thickness of at least one drop-to-drop-spacing or one line-to-line spacing or one powder layer thickness. 49. The dosage form of claim 1 wherein the unit has a rectangular prismatic shape. 50. The dosage form of claim 1 wherein the unit has a cylindrical shape. 51. The dosage form of claim 1, further comprising at least one additional unit. 52. The dosage form of claim 51 wherein the additional unit or units are joined to the unit by a joining structure that comprises an inter-unit binding substance. 53. The dosage form of claim 52 wherein the inter-unit binding substance is soluble in water. 54. The dosage form of claim 52 wherein the inter-unit binding substance is soluble in aqueous solutions of a specified pH. 55. The dosage form of claim 51 wherein the additional unit or units are substantially identical to the first unit. 56. The dosage form of claim 51 wherein at least one additional unit differs from the first unit. 57. The dosage form of claim 51 wherein at least one additional unit does not comprise a shell. 58. The dosage form of claim 1, further including a capsule that encloses the unit or units. 59. The dosage form of claim 1 wherein the core has a void fraction of greater than 20%. 60. The dosage form of claim 1 wherein the unit or the dosage form has a void fraction less than 5%. 61. A method of forming a dosage form according to claim 1, comprising three-dimensionally printing a core and a shell each comprising a release-blocking polymer and particles of a release-regulating polymer. 62. The dosage form of claim 1 wherein the dosage form is manufactured by methods that include three-dimensional printing.
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