Claims for Patent: 6,991,191

Summary for Patent: 6,991,191

Title:	Method of using a small scale mill
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 (Dublin, IE)
Application Number:	10/833,045
Patent Claims:	1. A method of milling a pharmaceutical product comprising: (a) providing a dispersion containing the product to be milled and attrition milling media, wherein the attrition milling media has a mean particle size of less than about 1000 microns; (b) inserting the dispersion into a 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 rotor and a shaft extending therefrom, wherein the rotor is dimensioned so that an outer periphery is no greater than 3 mm away from an inner surface of the wall of the vessel; (d) inserting the agitator into the 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, wherein the resulting milled pharmaceutical product has a submicron mean particle size. 2. The method of claim 1, wherein the pharmaceutical product is milled in the presence of at least one surface modifier. 3. The method of claim 2, wherein the at least one surface modifier is selected from the group consisting of gelatin, casein, lecithin, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates, colloidol silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethycellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, block copolymers of ethylene oxide and propylene oxide, a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylenediamine, dextran, a dioctyl ester of sodium sulfosuccinic acid, a sodium lauryl sulfate, and an alkyl aryl polyether sulfonate. 4. The method of claim 2, wherein the ratio of the distance between the outer periphery of the rotor and the inner surface of the wall to the attrition milling media nominal size is about 6 to about 1. 5. The method of claim 2, wherein the attrition media has a mean particle size selected from the group consisting of: (a) less than about 500 microns; (b) less than about 300 microns; (c) less than about 250 microns; (d) less than about 200 microns; (e) less than about 100 microns; (f) less than about 75 microns; (g) less than about 50 microns, (h) less than about 25 microns; (i) less than about 5 microns; and (j) a mixture thereof. 6. The method of claim 2, wherein the attrition media is selected from the group consisting of polymeric, zirconium oxide, zirconium silicate, glass, stainless steel, titania, alumina, and 95% ZrO stabilized with yttrium. 7. The method of claim 2, wherein the working volume of the vessel is about 12 mL to about 33 mL. 8. The method of claim 2, wherein the volume of the dispersion is about 5 ml to about 23 mL. 9. The method of claim 2, wherein the volume of the dispersion is less than about 10 mL. 10. The method of claim 2, wherein the method further comprises maintaining substantially uniform shear between the rotor and the and the cylindrical vessel. 11. The method of claim 2, wherein at the completion of the rotation period, the pharmaceutical product has an average particle size selected from the group consisting of less than about 500 nm, less than about 400 nm, less than about 300 nm, and less than about 100 nm. 12. The method of claim 11, wherein at least 90% of the milled pharmaceutical product particles have a size less than that selected from the group consisting of less than about 500 nm, less than about 400 nm, less than about 300 nm, and less than about 100 nm. 13. The method of claim 11, wherein at least 95% of the milled pharmaceutical product particles have a size less than that selected from the group consisting of less than about 500 nm, less than about 400 nm, less than about 300 nm, and less than about 100 nm. 14. The method of claim 11, wherein at least 99% of the milled pharmaceutical product particles have a size less than that selected from the group consisting of less than about 500 nm, less than about 400 nm, less than about 300 nm, and less than about 100 nm. 15. The method of claim 2, wherein the dispersion is recirculated through the vessel during rotation of the agitator. 16. The method of claim 2, wherein the pharmaceutical product is a heat sensitive product. 17. The method of claim 2, wherein the pharmaceutical 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. 18. The method of claim 2, wherein the product is an NSAID. 19. The method of claim 18, 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. 20. The method of claim 2, wherein the product is an anticancer agent. 21. The method of claim 20, wherein the anticancer agent is selected from the group consisting of alkylating agents, antimetabolites, natural products, hormones, and antagonists. 22. The method of claim 21, 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. 23. The method of claim 22, 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. 24. The method of claim 21, wherein the anticancer agent is selected from the group consisting of: (1) folic acid analogs; (2) pyrimidine analogs; and (3) purine derivatives. 25. The method of claim 24, 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. 26. The method of claim 21, wherein the anticancer agent is selected from the group consisting of vinca alkaloids, epipodophylotoxins, antibiotics, enzymes, biological response modifiers, camptothecin, taxol, and retinoids. 27. The method of claim 26, 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. 28. The method of claim 21, wherein the anticancer agent is selected from the group consisting of adrenocorticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. 29. The method of claim 28, 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. 30. The method of claim 21, wherein the anticancer agent is selected from the group consisting of radiosensitizers, platinum coordination complexes, anthracenediones, substituted ureas, adrenocortical suppressants, and an immunosuppressive drug. 31. A method of milling a human or animal ingestable product comprising: (a) providing a dispersion containing the product to be milled and attrition milling media, wherein the attrition milling media has a mean particle size of less than about 1000 microns; (b) inserting the dispersion into a 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 rotor and a shaft extending therefrom, wherein the rotor is dimensioned so that an outer periphery is no greater than 3 mm away from an inner surface of the vessel wall; (d) inserting the agitator into the 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, wherein the resulting human or animal ingestable product has a submicron mean particle size. 32. The method of claim 31, wherein the human or animal ingestable product is milled in the presence of at least one surface modifier. 33. The method of claim 32, wherein the at least one surface modifier is selected from the group consisting of gelatin, casein, lecithin, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates, colloidol silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethycellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, block copolymers of ethylene oxide and propylene oxide, a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylenediamine, dextran, a dioctyl ester of sodium sulfosuccinic acid, a sodium lauryl sulfate, and an alkyl aryl polyether sulfonate. 34. The method of claim 32, wherein the ratio of the distance between the outer periphery of the rotor and the inner surface of the wall to the attrition milling media nominal size is about 6 to about 1. 35. The method of claim 32, wherein the attrition media has a mean particle size selected from the group consisting of: (a) less than about 500 microns; (b) less than about 300 microns; (c) less than about 250 microns; (d) less than about 200 microns; (e) less than about 100 microns; (f) less than about 75 microns; (g) less than about 50 microns, (h) less than about 25 microns; (i) less than about 5 microns; and (j) a mixture thereof. 36. The method of claim 32, wherein the attrition media is selected from the group consisting of polymeric, zirconium oxide, zirconium silicate, glass, stainless steel, titania, alumina, and 95% ZrO stabilized with yttrium. 37. The method of claim 32, wherein the working volume of the vessel is about 12 mL to about 33 mL. 38. The method of claim 32, wherein the volume of the dispersion is about 5 ml to about 23 mL. 39. The method of claim 32, wherein the volume of the dispersion is less than about 10 mL. 40. The method of claim 32, wherein the method further comprises maintaining substantially uniform shear between the rotor and the and the vessel. 41. The method of claim 32, wherein at the completion of the rotation period, the human or animal ingestable product has an average particle size selected from the group consisting of less than about 500 nm, less than about 400 nm, less than about 300 nm, and less than about 100 nm. 42. The method of claim 41, wherein at least 90% of the milled human or animal ingestable product particles have a size less than that selected from the group consisting of less than about 500 nm, less than about 400 nm, less than about 300 nm, and less than about 100 nm. 43. The method of claim 41, wherein at least 95% of the milled human or animal ingestable product particles have a size less than that selected from the group consisting of less than about 500 nm, less than about 400 nm, less than about 300 nm, and less than about 100 nm. 44. The method of claim 41, wherein at least 99% of the milled human or animal ingestable product particles have a size less than that selected from the group consisting of less than about 500 nm, less than about 400 nm, less than about 300 nm, and less than about 100 nm. 45. The method of claim 32, wherein the dispersion is recirculated through the vessel during rotation of the agitator. 46. A method of milling a cosmetic product comprising: (a) providing a dispersion containing the product to be milled and attrition milling media, wherein the attrition milling media has a mean particle size of less than about 1000 microns (b) inserting the dispersion into a 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 rotor and a shaft extending therefrom, wherein the rotor is dimensioned so that an outer periphery is no greater than 3 mm away from an inner surface of the vessel wall; (d) inserting the agitator into the 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, wherein the resulting cosmetic product has a submicron mean particle size. 47. The method of claim 46, wherein the cosmetic product is milled in the presence of at least one surface modifier. 48. The method of claim 47, wherein the at least one surface modifier is selected from the group consisting of gelatin, casein, lecithin, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates, colloidol silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethycellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, block copolymers of ethylene oxide and propylene oxide, a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylenediamine, dextran, a dioctyl ester of sodium sulfosuccinic acid, a sodium lauryl sulfate, and an alkyl aryl polyether sulfonate. 49. The method of claim 47, wherein the ratio of the distance between the outer periphery of the rotor and the inner surface of the wall to the attrition milling media nominal size is about 6 to about 1. 50. The method of claim 47, wherein the attrition media has a mean particle size selected from the group consisting of: (a) less than about 500 microns; (b) less than about 300 microns; (c) less than about 250 microns; (d) less than about 200 microns; (e) less than about 100 microns; (f) less than about 75 microns; (g) less than about 50 microns, (h) less than about 25 microns; (i) less than about 5 microns; and (j) a mixture thereof. 51. The method of claim 47, wherein the attrition media is selected from the group consisting of polymeric, zirconium oxide, zirconium silicate, glass, stainless steel, titania, alumina, and 95% ZrO stabilized with yttrium. 52. The method of claim 47, wherein the working volume of the vessel is about 12 mL to about 33 mL. 53. The method of claim 47, wherein the volume of the dispersion is about 5 ml to about 23 mL. 54. The method of claim 47, wherein the volume of the dispersion is less than about 10 mL. 55. The method of claim 47, wherein the method further comprises maintaining substantially uniform shear between the rotor and the and the vessel. 56. The method of claim 47, wherein at the completion of the rotation period, the cosmetic product has an average particle size selected from the group consisting of less than about 500 nm, less than about 400 nm, less than about 300 nm, and less than about 100 nm. 57. The method of claim 56, wherein at least 90% of the milled cosmetic product particles have a size less than that selected from the group consisting of less than about 500 nm, less than about 400 nm, less than about 300 nm, and less than about 100 nm. 58. The method of claim 56, wherein at least 95% of the milled cosmetic product particles have a size less than that selected from the group consisting of less than about 500 nm, less than about 400 nm, less than about 300 nm, and less than about 100 nm. 59. The method of claim 56, wherein at least 99% of the milled cosmetic product particles have a size less than that selected from the group consisting of less than about 500 nm, less than about 400 nm, less than about 300 nm, and less than about 100 nm. 60. The method of claim 47, wherein the dispersion is recirculated through the vessel during rotation of the agitator.

Details for Patent 6,991,191

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