Claims for Patent: 6,745,962

Summary for Patent: 6,745,962

Title:	Small-scale mill and method thereof
Abstract:	A small-scale or micro media-mill and a method of milling materials or products, especially pharmaceutical products, use a dispersion containing attrition milling media and the product to be milled. The milling media can be polymeric, formed of polystyrene or cross-linked polystyrene, having a nominal diameter of no greater than 500 microns. Other sizes include 200 microns and 50 microns and a mixture of these sizes. The mill has a relatively small vessel having an opening, an agitator, a coupling and a motor. The agitator can have a rotor and a shaft extending therefrom. The rotor can be cylindrical or have other configurations, and can have tapered end surfaces. The coupling can close the vessel opening, or attaching the coupling to the motor can close the opening. The coupling has an opening through which the rotor shaft extends into the motor. A sealing mechanism, such as a mechanical or lip seals the shaft while permitting the rotor shaft to rotate. The vessel can contain one or more ports for circulating the dispersion, where milling can be made in batches or recirculated through the milling chamber. The media can be retained in the vessel or recirculated along with the process fluid. The rotor is dimensioned so that its outer periphery is spaced with a small gap from an inner surface of the vessel. The vessel also can have a way of cooling the dispersion.
Inventor(s):	Reed; Robert Gary (Birdsboro, PA), Czekai; David A. (Spring City, PA), Bosch; Henry William (Bryn Mawr, PA), Ryde; Niels-Peter Moesgaard (Malvern, PA)
Assignee:	Elan Pharma International Limited (Shannon, IE)
Application Number:	10/037,566
Patent Claims:	1. A method of milling a non-soluble product, comprising: (a) providing a dispersion containing a non-soluble product to be milled and attrition milling media having a nominal size of no greater than about 500 microns; (b) inserting the dispersion into a cylindrical vessel; (c) providing an agitator and a coupling that closes the vessel, the coupling having an opening through which a portion of the agitator extends, the agitator comprising a cylindrical rotor and a shaft extending therefrom, wherein the cylindrical rotor is dimensioned so that an outer periphery is no greater than 3 mm away from an inner surface of the cylindrical vessel; (d) inserting the agitator into the cylindrical vessel and sealingly closing the coupling, wherein the vessel is filled so that the dispersion eliminates substantially all of the air in the vessel when the agitator is fully inserted into the vessel; and (e) rotating the agitator for a predetermined period. 2. The method according to claim 1, further including cooling the vessel. 3. The method according to claim 2, wherein the vessel is cooled by jacketing the vessel and flowing water between the jacket and the vessel. 4. The method according to claim 1, wherein the non-soluble product is selected from the group consisting of a pharmaceutical product, a human ingestable product, an animal ingestable product, and a cosmetic product. 5. The method of claim 4, wherein the pharmaceutical product is a heat sensitive product. 6. The method of claim 1, comprising milling the non-soluble product with the attrition media, wherein the attrition media is polymeric. 7. The method of claim 1, wherein the product is selected from the group consisting of analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives, astringents, beta-adrenoceptor blocking agents, blood products, blood substitutes, cardiac inotropic agents, contrast media, corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics, haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin, parathyroid biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones, anti-allergic agents, stimulants, anoretics, sympathomimetics, thyroid agents, vasodilators, and xanthines. 8. The method of claim 1, wherein the product is an NSAID. 9. The method of claim 8, wherein the NSAID is selected from the group consisting of nabumetone, tiaraide, proquazone, bufexamac, flumizole, epirazole, tinoridine, timegadine, dapsone, aspirin, diclofenac, alclofenac, fenclofenac, etodolac, indomethacin, sulindac, tolmetin, fentiazac, tilomisole, carprofen, fenbufen, flurbiprofen, ketoprofen, oxaprozin, suprofen, tiaprofenic acid, ibuprofen, naproxen, fenoprofen, indoprofen, pirprofen, flufenamic, mefenamic, meclofenamic, niflumic, oxyphenbutazone, phenylbutazone, apazone, feprazone, piroxicam, sudoxicam, isoxicam, and tenoxicam. 10. The method of claim 1, wherein the product is an anticancer agent. 11. The method of claim 10, wherein the anticancer agent is selected from the group consisting of alkylating agents, antimetabolites, natural products, hormones, and antagonists. 12. The method of claim 11, wherein the anticancer agent is selected from the group consisting of: (1) alkylating agents having the bis-(2-chloroethyl)-amine group; (2) alkylating agents having a substituted aziridine group; (3) alkylating agents of the alkyl sulfonate type; (4) alkylating N-alkyl-N-nitrosourea derivatives; (5) alkylating agents of the mitobronitole type; (6) alkylating agents of the dacarbazine type; and (7) alkylating agents of the procarbazine type. 13. The method of claim 12 wherein the anticancer agent is selected from the group consisting of chlormethine, chlorambucile, melphalan, uramustine, mannomustine, extramustinephoshate, mechlore-thaminoxide, cyclophosphamide, ifosfamide, trifosfamide, tretamine, thiotepa, triaziquone, mitomycine, busulfan, piposulfan, piposulfam, carmustine, lomustine, semustine, streptozotocine. 14. The method of claim 11, wherein the anticancer agent is selected from the group consisting of: (1) folic acid analogs; (2) pyrimidine analogs; and (3) purine derivatives. 15. The method of claim 14, wherein the anticancer agent is selected from the group consisting of methotrexate, fluorouracil, floxuridine, tegafur, cytarabine, idoxuridine, flucytosine, mercaptopurine, thioguanine, azathioprine, tiamiprine, vidarabine, pentostatin, and puromycine. 16. The method of claim 11, wherein the anticancer agent is selected from the group consisting of vinca alkaloids, epipodophylotoxins, antibiotics, enzymes, biological response modifiers, camptothecin, taxol, and retinoids. 17. The method of claim 16, wherein the anticancer agent is selected from the group consisting of vinblastine, vincristine, etoposide, teniposide, adriamycine, daunomycine, doctinomycin, daunorubicin, doxorubicin, mithramycin, bleomycin, mitomycin, L-asparaginase, alpha-interferon and retinoic acid. 18. The method of claim 11, wherein the anticancer agent is selected from the group consisting of adrenocorticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. 19. The method of claim 18, wherein the anticancer agent is selected from the group consisting of prednisone, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, diethylstilbestrol, ethinyl estradiol, tamoxifen, testosterone propionate, fluoxymesterone, flutamide, and leuprolide. 20. The method of claim 11, wherein the anticancer agent is selected from the group consisting of radiosensitizers, platinum coordination complexes, anthracenediones, substituted ureas, adrenocortical suppressants, and an immunosuppressive drug. 21. The method of claim 1, comprising milling the non-soluble product, wherein the ratio of the distance between the outer periphery of the cylindrical rotor and the inner surface of the cylindrical vessel to the attrition milling media nominal size is about 6 to about 1. 22. The method of claim 21, wherein the attrition media has a particle size selected from the group consisting of: (1) a mixture of about 50 microns and about 200 microns; (2) a mixture of about 50 microns and about 500 microns; (3) a mixture of about 50 microns, about 200 microns, and about 500 microns; (4) no greater than about 500 microns; (5) no greater than about 200 microns; (6) about 50 microns up to about 500 microns; (7) about 500 microns; (8) about 200 microns; and (9) about 50 microns. 23. The method of claim 21, comprising milling the non-soluble product in the cylindrical vessel, wherein the working volume of the vessel is about 12 mL to about 33 mL. 24. The method of claim 21, wherein the volume of the dispersion is about 5 ml to about 23 mL. 25. The method of claim 21, wherein the volume of the dispersion is less than about 10 mL. 26. The method of claim 21, wherein the method further comprises maintaining substantially uniform shear between the rotor and the cylindrical vessel. 27. The method of claim 21, wherein at the completion of the rotation period, the product has a particle size in the range of microns to nanometers. 28. The method of claim 27, wherein at the completion of the rotation period, the product has a particle size of less than about 500 nm. 29. The method of claim 27, wherein at the completion of the rotation period, the product has an average particle size of less than about 400 nm. 30. The method of claim 27, wherein at the completion of the rotation period, the product has an average particle size of less than about 300 nm. 31. The method of claim 27, wherein at the completion of the rotation period, the product has an average particle size of less than about 100 nm. 32. The method of claim 21 wherein the cylindrical vessel is horizontally orientated when the agitator is inserted into the vessel. 33. The method of claim 21, further including externally circulating the dispersion. 34. The method of claim 27, wherein the predetermined period of rotation of the agitator is a few hours or less. 35. The method of claim 21, further comprising minimizing vortexing during rotation of the agitator. 36. The method of claim 21, further comprising preventing the dispersion formulation from foaming. 37. The method of claim 21, wherein the dispersion is retained in the vessel during rotation of the agitator. 38. The method of claim 21, wherein the dispersion is recirculated through the vessel during rotation of the agitator. 39. A method of milling a product, wherein the product is selected from the group consisting of a pharmaceutical product, a human ingestable product, an animal ingestable product, and a cosmetic product, comprising: (a) providing a dispersion containing the product to be milled and attrition milling media having a nominal size of no greater than about 500 microns; (b) inserting the dispersion into a cylindrical vessel; (c) providing an agitator and a coupling that closes the vessel, the coupling having an opening through which a portion of the agitator extends, the agitator comprising a cylindrical rotor and a shaft extending therefrom, wherein the cylindrical rotor is dimensioned so that an outer periphery is no greater than 3 mm away from an inner surface of the cylindrical vessel; (d) inserting the agitator into the cylindrical vessel and sealingly closing the coupling, wherein the vessel is filled so that the dispersion eliminates substantially all of the air in the vessel when the agitator is fully inserted into the vessel; and (e) rotating the agitator for a predetermined period. 40. The method of claim 39, comprising milling the product, wherein the ratio of the distance between the outer periphery of the cylindrical rotor and the inner surface of the cylindrical vessel to the attrition milling media nominal size is about 6 to about 1. 41. The method of claim 40, wherein the pharmaceutical product is a heat sensitive product. 42. The method of claim 40, wherein the product is selected from the group consisting of analgesics anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives, astringents, beta-adrenoceptor blocking agents, blood products, blood substitutes, cardiac inotropic agents, contrast media, corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics, haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin, parathyroid biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones, anti-allergic agents, stimulants, anoretics, sympathomimetics, thyroid agents, vasodilators, and xanthines. 43. The method of claim 40, wherein the product is an NSAID. 44. The method of claim 40, wherein the NSAID is selected from the group consisting of nabumetone, tiaramide, proquazone, bufexamac, flumizole, epirazole, tinoridine, timegadine, dapsone, aspirin, diclofenac, alclofenac, fenclofenac, etodolac, indomethacin, sulindac, tolmetin, fentiazac, tilomisole, carprofen, fenbufen, flurbiprofen, ketoprofen, oxaprozin, suprofen, tiaprofenic acid, ibuprofen, naproxen, fenoprofen, indoprofen, pirprofen, flufenamic, mefenamic, meclofenamic, niflumic, oxyphenbutazone, phenylbutazone, apazone, feprazone, piroxicam, sudoxicam, isoxicam, and tenoxicam. 45. The method of claim 40, wherein the product is an anticancer agent. 46. The method of claim 45, wherein the anticancer agent is selected from the group consisting of alkylating agents, antimetabolites, natural products, hormones, and antagonists. 47. The method of claim 46, wherein the anticancer agent is selected from the group consisting of: (1) alkylating agents having the bis-(2-chloroethyl)-amine group; (2) alkylating agents having a substituted aziridine group; (3) alkylating agents of the alkyl sulfonate type; (4) alkylating N-alkyl-N-nitrosourea derivatives; (5) alkylating agents of the mitobronitole type; (6) alkylating agents of the dacarbazine type; and (7) alkylating agents of the procarbazine type. 48. The method of claim 45, wherein the anticancer agent is selected from the group consisting of chlormethine, chlorambucile, melphalan, uramustine, maimomustine, extramustinephoshate, mechlore-thaminoxide, cyclophosphamide, ifosfamide, trifosfamide, tretamine, thiotepa, triaziquone, mitomycine, busulfan, piposulfan, piposulfam, carmustine, lomustine, semustine, streptozotocine. 49. The method of claim 45, wherein the anticancer agent is selected from the group consisting of: (1) folic acid analogs; (2) pyrimidine analogs; and (3) purine derivatives. 50. The method of claim 45, wherein the anticancer agent is selected from the group consisting of methotrexate, fluorouracil, floxuridine, tegafur, cytarabine, idoxuridine, flucytosine, mercaptopurine, thioguanine, azathioprine, tiamiprine, vidarabine, pentostatin, and puromycine. 51. The method of claim 45, wherein the anticancer agent is selected from the group consisting of vinca alkaloids, epipodophylotoxins, antibiotics, enzymes, biological response modifiers, camptothecin, taxol, and retinoids. 52. The method of claim 45, wherein the anticancer agent is selected from the group consisting of vinblastine, vincristine, etoposide, teniposide, adriamycine, daunomycine, doctinomycin, daunorubicin, doxorubicin, mithramycin, bleomycin, mitomycin, L-asparaginase, alpha-interferon and retinoic acid. 53. The method of claim 45, wherein the anticancer agent is selected from the group consisting of adrenocorticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. 54. The method of claim 45, wherein the anticancer agent is selected from the group consisting of prednisone, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, diethylstilbestrol, ethinyl estradiol, tamoxifen, testosterone propionate, fluoxymesterone, flutamide, and leuprolide. 55. The method of claim 45, wherein the anticancer agent is selected from the group consisting of radiosensitizers, platinum coordination complexes, anthracenediones, substituted ureas, adrenocortical suppressants, and an immunosuppressive drug. 56. The method of claim 40, wherein the attrition media has a particle size selected from the group consisting of: (1) a mixture of about 50 microns and about 200 microns; (2) a mixture of about 50 microns and about 500 microns; (3) a mixture of about 50 microns, about 200 microns, and about 500 microns; (4) no greater than about 500 microns; (5) no greater than about 200 microns; (6) about 50 microns up to about 500 microns; (7) about 500 microns; (8) about 200 microns; and (9) about 50 microns. 57. The method of claim 40, comprising milling the product with the attrition media, wherein the attrition media is polymeric. 58. The method of claim 40, comprising milling the product in the cylindrical vessel, wherein the working volume of the vessel is about 12 mL to about 33 mL. 59. The method of claim 40, wherein the volume of the dispersion is about 5 ml to about 23 mL. 60. The method of claim 40, wherein the volume of the dispersion is less than about 10 mL. 61. The method of claim 40, wherein at the completion of the rotation period, the product has a particle size in the range of microns to nanometers. 62. The method of claim 61, wherein at the completion of the rotation period, the product has a particle size of less than about 500 nm. 63. The method of claim 62, wherein at the completion of the rotation period, the product has a particle size of less than about 400 nm. 64. The method of claim 63, wherein at the completion of the rotation period, the product has a particle size of less than about 300 nm. 65. The method of claim 64, wherein at the completion of the rotation period, the product has a particle size of less than about 100 nm. 66. The method according to claim 40, further including cooling the vessel. 67. The method according to claim 66, wherein the vessel is cooled by jacketing the vessel and flowing water between the jacket and the vessel. 68. The method of claim 40, wherein the method further comprises maintaining substantially uniform shear between the rotor and the and the cylindrical vessel. 69. The method of claim 40, wherein the cylindrical vessel is horizontally orientated when the agitator is inserted into the vessel. 70. The method of claim 40, further including externally circulating the dispersion. 71. The method of claim 40, wherein the predetermined period of rotation of the agitator is a few hours or less. 72. The method of claim 40, further comprising minimizing vortexing during rotation of the agitator. 73. The method of claim 40, further comprising preventing the dispersion formulation from foaming. 74. The method of claim 40, wherein the dispersion is retained in the vessel during rotation of the agitator. 75. The method of claim 40, wherein the dispersion is recirculated through the vessel during rotation of the agitator.

Details for Patent 6,745,962

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2019-06-01