WO1994026266A1 - High dose formulations - Google Patents
High dose formulations Download PDFInfo
- Publication number
- WO1994026266A1 WO1994026266A1 PCT/US1994/005196 US9405196W WO9426266A1 WO 1994026266 A1 WO1994026266 A1 WO 1994026266A1 US 9405196 W US9405196 W US 9405196W WO 9426266 A1 WO9426266 A1 WO 9426266A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- mycophenolate mofetil
- active agent
- temperature
- pharmaceutical formulation
- liquefied
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 42
- 238000009472 formulation Methods 0.000 title claims abstract description 38
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 claims abstract description 72
- 229960004866 mycophenolate mofetil Drugs 0.000 claims abstract description 71
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000011049 filling Methods 0.000 claims abstract description 23
- 239000007788 liquid Substances 0.000 claims abstract description 17
- XKLMZUWKNUAPSZ-UHFFFAOYSA-N N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-1-yl}acetamide Chemical compound COC1=CC=CC=C1OCC(O)CN1CCN(CC(=O)NC=2C(=CC=CC=2C)C)CC1 XKLMZUWKNUAPSZ-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000002552 dosage form Substances 0.000 claims abstract description 15
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 claims abstract description 14
- 229960000213 ranolazine Drugs 0.000 claims abstract description 14
- 229960000951 mycophenolic acid Drugs 0.000 claims abstract description 13
- 238000004519 manufacturing process Methods 0.000 claims abstract description 12
- 239000002775 capsule Substances 0.000 claims description 41
- 239000013543 active substance Substances 0.000 claims description 36
- 238000002844 melting Methods 0.000 claims description 29
- 230000008018 melting Effects 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 26
- 239000007903 gelatin capsule Substances 0.000 claims description 25
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical group [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 23
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 22
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 22
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 238000001816 cooling Methods 0.000 claims description 15
- 239000000463 material Substances 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 11
- 239000007884 disintegrant Substances 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 239000013078 crystal Substances 0.000 claims description 6
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 4
- 239000000600 sorbitol Substances 0.000 claims description 4
- 239000012943 hotmelt Substances 0.000 abstract description 4
- 239000008203 oral pharmaceutical composition Substances 0.000 abstract 1
- 206010063344 microscopic polyangiitis Diseases 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- -1 morpholinoethyl ester Chemical class 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000004781 supercooling Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 4
- 229960001680 ibuprofen Drugs 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000007901 soft capsule Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 3
- 239000007902 hard capsule Substances 0.000 description 3
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- 239000012768 molten material Substances 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000006911 nucleation Effects 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000007711 solidification Methods 0.000 description 2
- 230000008023 solidification Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 229940032147 starch Drugs 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000009974 thixotropic effect Effects 0.000 description 2
- 238000011269 treatment regimen Methods 0.000 description 2
- GNXFOGHNGIVQEH-UHFFFAOYSA-N 2-hydroxy-3-(2-methoxyphenoxy)propyl carbamate Chemical compound COC1=CC=CC=C1OCC(O)COC(N)=O GNXFOGHNGIVQEH-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 0 CC(CCC(*)=O)=CCc(c(OC)c(C)c(CO1)c2C1=O)c2O Chemical compound CC(CCC(*)=O)=CCc(c(OC)c(C)c(CO1)c2C1=O)c2O 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 description 1
- HSRJKNPTNIJEKV-UHFFFAOYSA-N Guaifenesin Chemical compound COC1=CC=CC=C1OCC(O)CO HSRJKNPTNIJEKV-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 1
- 241000228145 Penicillium brevicompactum Species 0.000 description 1
- 201000001068 Prinzmetal angina Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000012864 cross contamination Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 238000005429 filling process Methods 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- 238000012395 formulation development Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960003627 gemfibrozil Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229960002146 guaifenesin Drugs 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000001746 injection moulding Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229960002330 methocarbamol Drugs 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 229960004270 nabumetone Drugs 0.000 description 1
- 239000011049 pearl Substances 0.000 description 1
- 229940098377 penicillium brevicompactum Drugs 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4833—Encapsulating processes; Filling of capsules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
Definitions
- the present invention relates to mycophenolate mofetil, mycophenolic acid, and ranolazine, particularly to improved formulations thereof, and specifically to high dose formulations.
- the invention is also directed to methods of manufacturing the formulations.
- MPA Mycophenolic acid
- 6- (1,3-dihydro-4- hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl) -4-methyl-4-hexenoic acid was initially described as a weakly-active antibiotic found in the fermentation broth of Penicillium brevicompactum, having the following structure.
- MPA and certain related compounds such as mycophenolate mofetil (the morpholinoethyl ester of MPA, chemically known as morpholinoethyl E-6-(l,3- dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl) -4-methyl-4- hexenoate) , having the following structure:
- Ranolazine known chemically ( ⁇ )N- (2,6-dimethylphenyl) -4- [2-hydroxy- 3- (2-methoxyphenoxy)propyl] -1-piperazine acetamide, is described in U.S. Patent No. 4,567,264 as having advantageous therapeutic properties, e.g., for cardiovascular disease including arrhythmias, variant and exercise induced angina and myocardial infarction and for treatment of tissues experiencing a physical or chemical insult, including treating cardioplegia, hypoxic and/or reperfusion injury to cardiac or skeletal muscle or brain tissue, and for use in transplants.
- ibuprofen a low-melting thermostable drug
- Smith, et al. "The filling of molten ibuprofen into hard gelatin capsules," Int . J. Pharm., Vol. 59, 115-119 at 115 (1990). There, ibuprofen (m.p. 77°C) was heated to 70-80°C, alone and v' l a variety of excipients, and filled into a variety of capsule sizes. . ⁇ .
- cimum approximate fill weights for ibuprofen alone of 450 mg (size 1) , 605 mg (size 0) , 680 mg (size 0 elongated) , and 825 mg (size 00) , were reported.
- Mycophenolate mofetil has a melting point of 95°C.
- MPA has a melting point of 141°C.
- Ranolazine free base has a melting point of 120°C. None is a low-melting drug that would be considered suitable for hot melt filling, particularly given an upper fill temperature of 80°C, preferably below 60°C, for hard gelatin capsules due to their own melting characteristics.
- mycophenolate mofetil once heated above its melting point, has the unexpected property of remaining liquid for sustained periods of time after cooling to significantly lower temperatures. Such a considerable delay in solidification even after cooling below melting point (a "supercooling” phenomena) was reported as "a problem" to be overcome in the preparation of medications in the form of pearls (see U.S. Patent No. 5,188,838).
- mycophenolate mofetil's ability to be suoercooled has been extended by the application of that discovery to hot melt filling, to produce previously unattainable high dose formulations. It has also been discovered that MPA exhibits the ability to be supercooled, and while the duration is shorter than that measured for mycophenolate mofetil, MPA's supercooling duration is sufficient for producing previously unattainable high dose formulations.
- mycophenolate mofetil, MPA,. and ranolazine can be conveniently manufactured into high dose oral formulations by the hot melt filling of a supercooled mycophenolate mofetil, MPA, or ranolazine liquid into a pharmaceutical dosage form.
- One aspect of the invention relates to a pharmaceutical formulation having a therapeutically effective amount of mycophenolate mofetil, the mycophenolate mofetil having been liquefied by heating to a first temperature above about 95°C, then cooled to a second temperature below about 80°C at which the mycophenolate mofetil remained liquefied, followed by filling the mycophenolate mofetil into a pharmaceutical dosage form while in said cooled liquefied state.
- the formulation includes a disintegrant such as croscarmellose sodium.
- the invention relates to high dose formulations of mycophenolate mofetil, having 500 mg in a size 1 capsule, 750 mg in a size 0 capsule, or 1000 mg in a size 00 capsule.
- Still another aspect of the invention relates to methods for manufacturing a pharmaceutical formulation of MPA or mycophenolate mofetil, including the steps of: liquefying the active agent by heating it to a first temperature above its melting point; cooling the liquefied active agent to a second temperature below its melting point, at which second temperature the active agent remains liquefied; and filling the liquefied active agent into a pharmaceutical dosage form.
- the manufacturing method includes the steps of: liquefying mycophenolate mofetil by heating it to a temperature above about 95 ⁇ C (preferably to about 95-120°C) ; admixing croscarmellose sodium, in an amount sufficient to serve as a dispersant in the formulation when finished, with the liquefied mycophenolate mofetil; cooling the admixed liquefied mycophenolate mofetil and croscarmellose sodium to a temperature below about 80°C (preferably below about 60°C) ; and filling the cooled, liquefied mycophenolate mofetil admixed with croscarmellose sodium into hard or soft capsules.
- the size and volume of the capsules employed in the formulations of the present invention include the following: SIZE VOLUME
- Mycophenolate mofetil can be made as described in U.S. Patent No. 4,753,935, previously incorporated by reference.
- Mycophenolic acid is commercially available, e.g., from Sigma Chemical Company, St. Louis, MO.
- Ranolazine can be made as described in U.S. Patent No. 4,567,264, incorporated herein by reference.
- Pharmaceutically acceptable excipients, hard and soft gelatin capsules, cellulosic capsules (also referred to as starch based capsules, commercially available from Warner Lambert) and capsule filling machinery are commonly commercially available.
- Mycophenolate mofetil, MPA, or ranolazine can be employed as the active agent in the formulations of the present invention, either alone or in combination with pharmaceutically acceptable excipients and/or other medical agents.
- the formulation will contain about 90% to 100%, preferably about 95% to 96% by weight of active agent, the remainder being suitable pharmaceutical excipients, carriers, etc, preferably about 4% by weight of a disintegrant (most preferably croscarmellose sodium) .
- Normally employed excipients include, for example, disintegrants (such as croscarmellose sodium, sodium carboxymethylcellulose, crosspovidone, sodium starch glycolate or the like) , diluents (such as lactose, sucrose, dicalcium phosphate, or the like) , lubricants (such as magnesium stearate or the like) , binders (such as starch, gum acacia, gelatin, polyvinylpyrrolidine, cellulose and derivatives thereof, and the like) , viscosity aids (such as cellulose) and crystal modifying aids (such as sodium chloride) .
- disintegrants such as croscarmellose sodium, sodium carboxymethylcellulose, crosspovidone, sodium starch glycolate or the like
- diluents such as lactose, sucrose, dicalcium phosphate, or the like
- lubricants such as magnesium stearate or the like
- binders such as starch, gum
- a crystal retardant or poison such as sorbitol 5-7% w/w (e.g., as described by Thomas, et al., "The Use of Xylitol as a Carrier for Liquid-Filled Hard-Gelatin Capsules," Pharm. Tech. Int.. Vol. 3, 36, 38-40 (1991) incorporated herein by reference)' hydroxypropylmethyl cellulose, or hydroxypropylcellulose] can be added to an active agent that exhibits supercooling (stays liquid below its melting temperature) for a time period less than that optimally desired for dosage form filling, for example prior to or after the active agent has been liquefied.
- supercooling stays liquid below its melting temperature
- the mycophenolate mofetil formulations of the invention have a therapeutically effective amount of mycophenolate mofetil, the mycophenolate mofetil having been liquefied by heating to a first temperature above about 95°C, then cooled to a second temperature below about 80°C at which the mycophenolate mofetil remained liquefied, followed by filling the mycophenolate mofetil into a pharmaceutical dosage form, such as a capsule (e.g., a hard gelatin capsule, a soft gelatin capsule, or a cellulosic capsule) or a tablet mold (e.g., by injection molding) while in said cooled liquefied state.
- Tablets formulations of the invention are preferably coated with a pharmaceutically acceptable coating material (such as opadry, commercially available from Coloron, Inc. of West Point, PA) for example by spray coating or other coating methods conventionally employed in the field.
- a pharmaceutically acceptable coating material such as opadry, commercially available from Coloron, Inc. of West Point
- the formulations include croscarmellose sodium, admixed with liquefied mycophenolate mofetil prior to cooling in an amount sufficient to serve as a disintegrant.
- Preferred formulations include mycophenolate mofetil (95-100% w/w, most preferably 96% w/w) and croscarmellose sodium (0-5% w/w, most preferably 4% w/w) , filled into a gelatin capsule.
- the methods for manufacturing a pharmaceutical formulations of include the steps of: liquefying the active agent by heating it to a first temperature above its melting point; cooling the liquefied active agent to a second temperature below its melting point, the active agent remaining liquefied at the second temperature; and filling the liquefied active agent into a pharmaceutical dosage form. Once filled, the liquefied active agent is allowed to solidify.
- a preferred manufacturing method, where the active agent is mycophenolate mofetil includes the steps of: liquefying mycophenolate mofetil by heating it to a temperature above about 95°C (preferably about 95 to 120°C) ; admixing croscarmellose sodium (in an amount sufficient to serve as a disintegrant in the formulation when finished) with the liquefied mycophenolate mofetil; cooling the admixed liquefied mycophenolate mofetil and croscarmellose sodium to a temperature below about 80°C (preferably below about 60°C, most preferably about 35 to 45°C) ; and filling the cooled, liquefied mycophenolate mofetil admixed with croscarmellose sodium into hard or soft capsules (preferably using temperature controlled filling apparatus adjusted to the temperature of the cooled admixture) .
- the cooling and mixing rates can be optimized depending upon the particular active agent, manufacturing process, size and equipment employed. While the underlying theory for formulating supercooled liquids is not completely understood (for example, it remains unpredictable whether a given active agent will exhibit supercooling at all, as illustrated below in Example 6) , particularly for larger scale manufacturing processes, some factors to be considered include stirring rate (e.g., for mycophenolate mofetil it can be advantageous to avoid causing sheer forces when stirring, or to eliminate stirring altogether), stirring equipment (e.g., overhead or magnetic bar) , cooling rate, cooling temperature, and filling equipment temperature.
- stirring rate e.g., for mycophenolate mofetil it can be advantageous to avoid causing sheer forces when stirring, or to eliminate stirring altogether
- stirring equipment e.g., overhead or magnetic bar
- Formulations prepared by the -above-described process of the invention may be identified by the solid (as opposed to compacted powder or granule) contents of a capsule.
- mycophenolate mofetil forms a friable, solid, off-white mass when cooled in a capsule.
- the presence of such a solid mass is a method of detecting a formulation made by the invention and/or use of a process of the invention.
- mycophenolate mofetil is liquefied by heating it to a temperature above about 95°C; croscarmellose sodium is admixed with the liquefied mycophenolate mofetil in an amount sufficient to serve as a disintegrant in the formulation when finished; the admixed liquefied mycophenolate mofetil and croscarmellose sodium are cooled to a temperature below about 80°C (most preferably below about 60°C) ; and the cooled, liquefied mycophenolate mofetil admixed with croscarmellose sodium is filled into hard or soft capsules.
- Preferred Formulations Presently preferred is the formulation of 96% w/w mycophenolate mofetil and 4% w/w croscarmellose sodium, most preferably in a size 1 hard gelatin capsule containing 500 mg active ingredient, in a size 0 hard gelatin capsule containing 750 mg active ingredient, or in a size 00 hard gelatin capsule containing 1000 mg active ingredient.
- the formulations of the present invention are useful for oral administration in any oral treatment regimen for MPA, mycophenolate mofetil, or ranolazine. While human dosage levels have yet to be finalized, generally, a daily dose of mycophenolate mofetil or mycophenolic acid is from about 2.0 to 5.0 grams, preferably about 2.0 to 3.5 grams. The amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.
- a treatment regimen for administering 3.0 grams of mycophenolate mofetil per day which previously entailed taking 6 size 1 capsules (250 mg) twice daily, when administered with a formulation of the present invention entails taking 2 size 0 capsules (750 mg) twice daily.
- Mycophenolate mofetil (50 g) was added to a 250 ml beaker and melted on a hot plate at low setting. The molten material was allowed to cool to 40 - 50°C, at which temperature it remained a liquid, which was drawn into a 20 ml disposable syringe using the plunger. The syringe was used to fill the body of a size 0 hard gelatin capsule using the luer connection as a fill nozzle. The material was dispensed bottom up, withdrawing the nozzle as fill proceeded. The capsule cap was then placed on the filled body and the closed capsule allowed to stand overnight, to give a high dose mycophenolate mofetil capsule.
- This example illustrates the preparation of a 2.0 kg batch of a representative high dose pharmaceutical formulation for oral administration containing mycophenolate mofetil as the active compound.
- Mycophenolate mofetil (1920 g; 96% w/w) is added to a jacketed kettle. The temperature is raised to a temperature between 95 and 120 ⁇ C.
- Croscarmellose sodium 80 g; 4% w/w is added to the jacketed kettle with mixing. The temperature is lowered to a temperature between 35 and 45 Z, with continued mixing.
- the cooled mixture (750 mg) is filled into the bodies of 2,500 size 0 hard gelatin capsules (allowing for a small amount of surplus) , the temperature of the filling apparatus being adjusted to between 35 and 45°C.
- Mycophenolic acid 90% w/w (90 g) is added to a 500 ml beaker and melted on a hot plate at a temperature of 145°C.
- croscarmellose sodium 4% w/w (4 g) and sorbitol 6% w/w (a 70% solution, added dropwise) with gentle mixing.
- the mixture is allowed to cool to 50 - 60°C, at which temperature it remains a liquid, which is drawn into a 20 ml disposable syringe using the plunger.
- the syringe is used to fill the body of a size 0 hard gelatin capsule using the luer connection as a fill nozzle.
- the capsule cap is then placed on the filled body and the closed capsule allowed to stand overnight, to give a high dose mycophenolic acid capsule.
- the formulations of the present invention contained significantly more mycophenolate mofetil per capsule (1058 mg/cc) than did conventional formulations such as 250 mg of mycophenolate mofetil in a size 1 capsule (520 mg/cc) .
- Mineral oil (15 ml) in a 50 ml beaker is heated to a predetermined temperature in excess of the melting point of the compound to be tested, using a hotplate.
- a 2-5 g sample of test compound (a solid at room temperature) is weighed into a scintillation vial, and the vial is placed into the preheated mineral oil.
- the test compound is allowed to melt, after which the scintillation vial is removed from the mineral oil and allowed to return to room temperature. Changes in the appearance of the test compound, including recrystallization, and the time before solidification are recorded.
- mycophenolate mofetil (m.p. 95 ⁇ C) was employed as the test compound in the above procedure, and heated to 120°C, the compound remained a liquid at room temperature for up to two hours.
- Mycophenolate mofetil heated to melting and filled into size 0 capsules, recrystallized in the capsule to form a solid mass when stored at room temperature conditions for approximately 12 hours.
- Mycophenolic acid (m.p. 141°C) , when tested in the above procedure and heated to melting, after cooling to room temperature did not exhibit crystal seed nucleation for about ten minutes, and remained a liquid for 35 minutes prior to complete recrystallization.
Abstract
Description
Claims
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
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HU9503224A HU226470B1 (en) | 1993-05-13 | 1994-05-10 | High dose formulations |
JP52565394A JP3584037B2 (en) | 1993-05-13 | 1994-05-10 | High dose formulation |
DK94916722T DK0697866T3 (en) | 1993-05-13 | 1994-05-10 | high dose formulations |
BR9406604A BR9406604A (en) | 1993-05-13 | 1994-05-10 | High dose formulations |
CA002162670A CA2162670C (en) | 1993-05-13 | 1994-05-10 | High dose formulations of mycophenolate mofetil, mycophenolic acid and ranolazine |
DE69421918T DE69421918T2 (en) | 1993-05-13 | 1994-05-10 | HIGH DOSE MEDICINAL COMPOSITIONS |
AU68301/94A AU674960B2 (en) | 1993-05-13 | 1994-05-10 | High dose formulations |
EP94916722A EP0697866B1 (en) | 1993-05-13 | 1994-05-10 | High dose formulations |
PL94311654A PL175583B1 (en) | 1993-05-13 | 1994-05-10 | High-dosage preparations |
KR1019950704984A KR100296214B1 (en) | 1993-05-13 | 1994-05-10 | High capacity formulation |
RU95122420A RU2135182C1 (en) | 1993-05-13 | 1994-05-10 | Medicinal forms of high dosage |
NO954546A NO308828B1 (en) | 1993-05-13 | 1995-11-10 | Pharmaceutical preparation |
FI955439A FI114286B (en) | 1993-05-13 | 1995-11-10 | Process for the preparation of pharmaceutical preparations containing mycophenolate mofetil, mycophenolic acid or ranolazine |
GR990401633T GR3032021T3 (en) | 1993-05-13 | 1999-12-02 | High dose formulations |
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US08/061,656 | 1993-05-13 | ||
US08/061,656 US5455045A (en) | 1993-05-13 | 1993-05-13 | High dose formulations |
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US (3) | US5455045A (en) |
EP (1) | EP0697866B1 (en) |
JP (1) | JP3584037B2 (en) |
KR (1) | KR100296214B1 (en) |
CN (1) | CN1045884C (en) |
AT (1) | ATE187067T1 (en) |
AU (1) | AU674960B2 (en) |
BR (2) | BR9406604A (en) |
CZ (1) | CZ285297B6 (en) |
DE (1) | DE69421918T2 (en) |
DK (1) | DK0697866T3 (en) |
ES (1) | ES2138661T3 (en) |
FI (1) | FI114286B (en) |
GR (1) | GR3032021T3 (en) |
HU (2) | HU226470B1 (en) |
IL (1) | IL109639A (en) |
NO (1) | NO308828B1 (en) |
NZ (1) | NZ266683A (en) |
PL (1) | PL175583B1 (en) |
PT (1) | PT697866E (en) |
RU (1) | RU2135182C1 (en) |
TW (1) | TW434010B (en) |
WO (1) | WO1994026266A1 (en) |
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Title |
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A.SMITH ET AL.: "THE FILLING OF MOLTEN IBUPROFEN INTO HARD GELATIN CAPSULES", INT. J. PHARM., vol. 59, no. 2, 1990, pages 115 - 119 * |
CHEMICAL ABSTRACTS, vol. 113, no. 2, 9 July 1990, Columbus, Ohio, US; abstract no. 12026 * |
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