CA2047482A1 - Solid pharmaceutical composition - Google Patents
Solid pharmaceutical compositionInfo
- Publication number
- CA2047482A1 CA2047482A1 CA002047482A CA2047482A CA2047482A1 CA 2047482 A1 CA2047482 A1 CA 2047482A1 CA 002047482 A CA002047482 A CA 002047482A CA 2047482 A CA2047482 A CA 2047482A CA 2047482 A1 CA2047482 A1 CA 2047482A1
- Authority
- CA
- Canada
- Prior art keywords
- mass
- chlorophyll
- process according
- nifedipine
- capsule
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 25
- 239000007787 solid Substances 0.000 title claims abstract description 23
- 239000002775 capsule Substances 0.000 claims abstract description 51
- 239000004480 active ingredient Substances 0.000 claims abstract description 36
- 229960001597 nifedipine Drugs 0.000 claims abstract description 34
- 238000011049 filling Methods 0.000 claims abstract description 33
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 claims abstract description 33
- 235000013311 vegetables Nutrition 0.000 claims abstract description 28
- 239000007903 gelatin capsule Substances 0.000 claims abstract description 27
- 239000000203 mixture Substances 0.000 claims abstract description 25
- 238000002360 preparation method Methods 0.000 claims abstract description 24
- 239000012752 auxiliary agent Substances 0.000 claims abstract description 7
- 239000012050 conventional carrier Substances 0.000 claims abstract description 5
- 229930002875 chlorophyll Natural products 0.000 claims description 40
- 235000019804 chlorophyll Nutrition 0.000 claims description 40
- ATNHDLDRLWWWCB-AENOIHSZSA-M chlorophyll a Chemical compound C1([C@@H](C(=O)OC)C(=O)C2=C3C)=C2N2C3=CC(C(CC)=C3C)=[N+]4C3=CC3=C(C=C)C(C)=C5N3[Mg-2]42[N+]2=C1[C@@H](CCC(=O)OC\C=C(/C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@H](C)C2=C5 ATNHDLDRLWWWCB-AENOIHSZSA-M 0.000 claims description 40
- 238000000034 method Methods 0.000 claims description 33
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 32
- -1 nirudipine Chemical compound 0.000 claims description 22
- 108010010803 Gelatin Proteins 0.000 claims description 16
- 239000008273 gelatin Substances 0.000 claims description 16
- 229920000159 gelatin Polymers 0.000 claims description 16
- 235000019322 gelatine Nutrition 0.000 claims description 16
- 235000011852 gelatine desserts Nutrition 0.000 claims description 16
- 235000019501 Lemon oil Nutrition 0.000 claims description 10
- 239000010501 lemon oil Substances 0.000 claims description 10
- 239000003921 oil Substances 0.000 claims description 10
- 235000019198 oils Nutrition 0.000 claims description 10
- 229920001223 polyethylene glycol Polymers 0.000 claims description 9
- 240000009087 Crescentia cujete Species 0.000 claims description 7
- 235000005983 Crescentia cujete Nutrition 0.000 claims description 7
- 235000009797 Lagenaria vulgaris Nutrition 0.000 claims description 7
- 239000008158 vegetable oil Substances 0.000 claims description 7
- 125000004925 dihydropyridyl group Chemical class N1(CC=CC=C1)* 0.000 claims description 6
- 239000004006 olive oil Substances 0.000 claims description 6
- 235000008390 olive oil Nutrition 0.000 claims description 6
- 239000001593 sorbitan monooleate Substances 0.000 claims description 6
- 229940035049 sorbitan monooleate Drugs 0.000 claims description 6
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 5
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 claims description 4
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 claims description 4
- 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
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 claims description 4
- 239000000006 Nitroglycerin Substances 0.000 claims description 4
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 claims description 4
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 claims description 4
- 230000000340 anti-metabolite Effects 0.000 claims description 4
- 229940100197 antimetabolite Drugs 0.000 claims description 4
- 239000002256 antimetabolite Substances 0.000 claims description 4
- 229940085304 dihydropyridine derivative selective calcium channel blockers with mainly vascular effects Drugs 0.000 claims description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims description 4
- 239000008298 dragée Substances 0.000 claims description 4
- 239000000796 flavoring agent Substances 0.000 claims description 4
- 229960003711 glyceryl trinitrate Drugs 0.000 claims description 4
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000600 sorbitol Substances 0.000 claims description 4
- 235000019155 vitamin A Nutrition 0.000 claims description 4
- 239000011719 vitamin A Substances 0.000 claims description 4
- 229940045997 vitamin a Drugs 0.000 claims description 4
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 claims description 3
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 claims description 3
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 3
- 239000000194 fatty acid Substances 0.000 claims description 3
- 229930195729 fatty acid Natural products 0.000 claims description 3
- 235000013355 food flavoring agent Nutrition 0.000 claims description 3
- VKQFCGNPDRICFG-UHFFFAOYSA-N methyl 2-methylpropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)C)C1C1=CC=CC=C1[N+]([O-])=O VKQFCGNPDRICFG-UHFFFAOYSA-N 0.000 claims description 3
- 229960000715 nimodipine Drugs 0.000 claims description 3
- 229960000227 nisoldipine Drugs 0.000 claims description 3
- 229960005425 nitrendipine Drugs 0.000 claims description 3
- 239000002736 nonionic surfactant Substances 0.000 claims description 3
- 239000004014 plasticizer Substances 0.000 claims description 3
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 claims description 2
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 claims description 2
- UOTMYNBWXDUBNX-UHFFFAOYSA-N 1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxyisoquinolin-2-ium;chloride Chemical compound Cl.C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 UOTMYNBWXDUBNX-UHFFFAOYSA-N 0.000 claims description 2
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 claims description 2
- MIDXCONKKJTLDX-UHFFFAOYSA-N 3,5-dimethylcyclopentane-1,2-dione Chemical compound CC1CC(C)C(=O)C1=O MIDXCONKKJTLDX-UHFFFAOYSA-N 0.000 claims description 2
- FEBOTPHFXYHVPL-UHFFFAOYSA-N 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]-4-piperidinyl]-1H-benzimidazol-2-one Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCC(N2C(NC3=CC=CC=C32)=O)CC1 FEBOTPHFXYHVPL-UHFFFAOYSA-N 0.000 claims description 2
- VCCNKWWXYVWTLT-CYZBKYQRSA-N 7-[(2s,3r,4s,5s,6r)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2s,3r,4r,5r,6s)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)chromen-4-one Chemical compound C1=C(O)C(OC)=CC=C1C(OC1=C2)=CC(=O)C1=C(O)C=C2O[C@H]1[C@H](O[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 VCCNKWWXYVWTLT-CYZBKYQRSA-N 0.000 claims description 2
- 108010001478 Bacitracin Proteins 0.000 claims description 2
- 235000021537 Beetroot Nutrition 0.000 claims description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical class CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 2
- XUIIKFGFIJCVMT-LBPRGKRZSA-N L-thyroxine Chemical compound IC1=CC(C[C@H]([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-LBPRGKRZSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 229930192392 Mitomycin Natural products 0.000 claims description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 2
- 235000019486 Sunflower oil Nutrition 0.000 claims description 2
- 229940123445 Tricyclic antidepressant Drugs 0.000 claims description 2
- UFLGIAIHIAPJJC-UHFFFAOYSA-N Tripelennamine Chemical compound C=1C=CC=NC=1N(CCN(C)C)CC1=CC=CC=C1 UFLGIAIHIAPJJC-UHFFFAOYSA-N 0.000 claims description 2
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 claims description 2
- 229930013930 alkaloid Natural products 0.000 claims description 2
- BIVUUOPIAYRCAP-UHFFFAOYSA-N aminoazanium;chloride Chemical compound Cl.NN BIVUUOPIAYRCAP-UHFFFAOYSA-N 0.000 claims description 2
- 150000005010 aminoquinolines Chemical class 0.000 claims description 2
- 239000003263 anabolic agent Substances 0.000 claims description 2
- 229940070021 anabolic steroids Drugs 0.000 claims description 2
- 239000003242 anti bacterial agent Substances 0.000 claims description 2
- 230000000118 anti-neoplastic effect Effects 0.000 claims description 2
- 229940088710 antibiotic agent Drugs 0.000 claims description 2
- 229940054053 antipsychotics butyrophenone derivative Drugs 0.000 claims description 2
- 229940027988 antiseptic and disinfectant nitrofuran derivative Drugs 0.000 claims description 2
- 239000010692 aromatic oil Substances 0.000 claims description 2
- 229960003071 bacitracin Drugs 0.000 claims description 2
- 229930184125 bacitracin Natural products 0.000 claims description 2
- CLKOFPXJLQSYAH-ABRJDSQDSA-N bacitracin A Chemical compound C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2N=CNC=2)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 CLKOFPXJLQSYAH-ABRJDSQDSA-N 0.000 claims description 2
- 229960002507 benperidol Drugs 0.000 claims description 2
- 229960002537 betamethasone Drugs 0.000 claims description 2
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 claims description 2
- FFSAXUULYPJSKH-UHFFFAOYSA-N butyrophenone Chemical class CCCC(=O)C1=CC=CC=C1 FFSAXUULYPJSKH-UHFFFAOYSA-N 0.000 claims description 2
- 235000013736 caramel Nutrition 0.000 claims description 2
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 claims description 2
- 229960000623 carbamazepine Drugs 0.000 claims description 2
- 150000003943 catecholamines Chemical class 0.000 claims description 2
- 229960003677 chloroquine Drugs 0.000 claims description 2
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 claims description 2
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 claims description 2
- 229960003771 cocaine hydrochloride Drugs 0.000 claims description 2
- PIQVDUKEQYOJNR-VZXSFKIWSA-N cocaine hydrochloride Chemical compound [Cl-].O([C@H]1C[C@@H]2CC[C@@H]([NH+]2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 PIQVDUKEQYOJNR-VZXSFKIWSA-N 0.000 claims description 2
- 229960001338 colchicine Drugs 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 239000003246 corticosteroid Substances 0.000 claims description 2
- 229960001334 corticosteroids Drugs 0.000 claims description 2
- 229960003638 dopamine Drugs 0.000 claims description 2
- 229960000394 droperidol Drugs 0.000 claims description 2
- RMEDXOLNCUSCGS-UHFFFAOYSA-N droperidol Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CC=C(N2C(NC3=CC=CC=C32)=O)CC1 RMEDXOLNCUSCGS-UHFFFAOYSA-N 0.000 claims description 2
- 229960001903 ergotamine tartrate Drugs 0.000 claims description 2
- 229940011871 estrogen Drugs 0.000 claims description 2
- 239000000262 estrogen Substances 0.000 claims description 2
- 150000002224 folic acids Chemical class 0.000 claims description 2
- 229960003878 haloperidol Drugs 0.000 claims description 2
- 150000002462 imidazolines Chemical class 0.000 claims description 2
- 229930005303 indole alkaloid Natural products 0.000 claims description 2
- 150000002475 indoles Chemical class 0.000 claims description 2
- 229960001317 isoprenaline Drugs 0.000 claims description 2
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 claims description 2
- 229960000991 ketoprofen Drugs 0.000 claims description 2
- 229950008325 levothyroxine Drugs 0.000 claims description 2
- 229960000485 methotrexate Drugs 0.000 claims description 2
- 229960004857 mitomycin Drugs 0.000 claims description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical class O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 2
- 229960004715 morphine sulfate Drugs 0.000 claims description 2
- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 claims description 2
- IAIWVQXQOWNYOU-FPYGCLRLSA-N nitrofural Chemical class NC(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 IAIWVQXQOWNYOU-FPYGCLRLSA-N 0.000 claims description 2
- NXFQHRVNIOXGAQ-YCRREMRBSA-N nitrofurantoin Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)NC(=O)C1 NXFQHRVNIOXGAQ-YCRREMRBSA-N 0.000 claims description 2
- 229960000564 nitrofurantoin Drugs 0.000 claims description 2
- 229960003207 papaverine hydrochloride Drugs 0.000 claims description 2
- 229940083254 peripheral vasodilators imidazoline derivative Drugs 0.000 claims description 2
- 150000004885 piperazines Chemical class 0.000 claims description 2
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 claims description 2
- 229960000624 procarbazine Drugs 0.000 claims description 2
- 229940083618 sodium nitroprusside Drugs 0.000 claims description 2
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 claims description 2
- 229960004306 sulfadiazine Drugs 0.000 claims description 2
- 239000002600 sunflower oil Substances 0.000 claims description 2
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 239000005495 thyroid hormone Substances 0.000 claims description 2
- 229940036555 thyroid hormone Drugs 0.000 claims description 2
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 claims description 2
- 239000003029 tricyclic antidepressant agent Substances 0.000 claims description 2
- ZEWQUBUPAILYHI-UHFFFAOYSA-N trifluoperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 ZEWQUBUPAILYHI-UHFFFAOYSA-N 0.000 claims description 2
- 229960002324 trifluoperazine Drugs 0.000 claims description 2
- 229960003223 tripelennamine Drugs 0.000 claims description 2
- 235000019166 vitamin D Nutrition 0.000 claims description 2
- 239000011710 vitamin D Substances 0.000 claims description 2
- 235000005282 vitamin D3 Nutrition 0.000 claims description 2
- 239000011647 vitamin D3 Substances 0.000 claims description 2
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 claims description 2
- 229940021056 vitamin d3 Drugs 0.000 claims description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical class NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims 1
- 239000002202 Polyethylene glycol Substances 0.000 claims 1
- XEYBHCRIKKKOSS-UHFFFAOYSA-N disodium;azanylidyneoxidanium;iron(2+);pentacyanide Chemical compound [Na+].[Na+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].[O+]#N XEYBHCRIKKKOSS-UHFFFAOYSA-N 0.000 claims 1
- 239000003053 toxin Substances 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 22
- 239000000969 carrier Substances 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000010348 incorporation Methods 0.000 abstract description 3
- 239000000975 dye Substances 0.000 description 21
- 239000000243 solution Substances 0.000 description 19
- 238000000354 decomposition reaction Methods 0.000 description 10
- 235000011187 glycerol Nutrition 0.000 description 10
- 239000003605 opacifier Substances 0.000 description 10
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 8
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 235000015112 vegetable and seed oil Nutrition 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000005562 fading Methods 0.000 description 3
- 235000010445 lecithin Nutrition 0.000 description 3
- 239000000787 lecithin Substances 0.000 description 3
- 229940067606 lecithin Drugs 0.000 description 3
- 229920003023 plastic Polymers 0.000 description 3
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- 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 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
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- 238000005429 filling process Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 208000013469 light sensitivity Diseases 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 150000002832 nitroso derivatives Chemical class 0.000 description 2
- RWNNRGBCWXOVAC-UHFFFAOYSA-N 1,4-bis[bis(aziridin-1-yl)phosphoryl]piperazine Chemical compound C1CN1P(N1CCN(CC1)P(=O)(N1CC1)N1CC1)(=O)N1CC1 RWNNRGBCWXOVAC-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 239000004150 EU approved colour Substances 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 241001082241 Lythrum hyssopifolia Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 229930182559 Natural dye Natural products 0.000 description 1
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 244000274883 Urtica dioica Species 0.000 description 1
- 235000009108 Urtica dioica Nutrition 0.000 description 1
- 241001464837 Viridiplantae Species 0.000 description 1
- 239000001089 [(2R)-oxolan-2-yl]methanol Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 244000285940 beete Species 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- XRKMNJXYOFSTBE-UHFFFAOYSA-N disodium;iron(4+);nitroxyl anion;pentacyanide;dihydrate Chemical compound O.O.[Na+].[Na+].[Fe+4].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].O=[N-] XRKMNJXYOFSTBE-UHFFFAOYSA-N 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- IINNWAYUJNWZRM-UHFFFAOYSA-L erythrosin B Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=C(I)C(=O)C(I)=C2OC2=C(I)C([O-])=C(I)C=C21 IINNWAYUJNWZRM-UHFFFAOYSA-L 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 229960003580 felodipine Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000001034 iron oxide pigment Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 239000000978 natural dye Substances 0.000 description 1
- 229960001783 nicardipine Drugs 0.000 description 1
- 229950000109 niludipine Drugs 0.000 description 1
- VZWXXKDFACOXNT-UHFFFAOYSA-N niludipine Chemical compound CCCOCCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCOCCC)C1C1=CC=CC([N+]([O-])=O)=C1 VZWXXKDFACOXNT-UHFFFAOYSA-N 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000003836 peripheral circulation Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000006303 photolysis reaction Methods 0.000 description 1
- 230000015843 photosynthesis, light reaction Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920002523 polyethylene Glycol 1000 Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- 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
- A61K9/4816—Wall or shell material
- A61K9/4825—Proteins, e.g. gelatin
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
SOLID PHARMACEUTICAL COMPOSITIONS
A b s t r a c t The present invention relates to solid pharma-ceutical compositions, preferably soft gelatin capsules, comprising a light-sensitive active ingredient optionally being hardly soluble in water, preferably nifedipine [4-(2'-nitrophenyl)--2,6-dimethyl-3,5-dimethoxycarbonyl-1,4-dihydro-pyridine], together with conventional carriers and/or auxiliary agents, wherein said composition incorporates a vegetable dye. Furthermore the invention is concerned with the preparation of such compositions.
The incorporation of a vegetable dye into the capsule filling and optionally into the capsule wall ensures a reliable light protection during the manufacturing and filling operations and improves the solubility of nifedipine in certain carriers.
A b s t r a c t The present invention relates to solid pharma-ceutical compositions, preferably soft gelatin capsules, comprising a light-sensitive active ingredient optionally being hardly soluble in water, preferably nifedipine [4-(2'-nitrophenyl)--2,6-dimethyl-3,5-dimethoxycarbonyl-1,4-dihydro-pyridine], together with conventional carriers and/or auxiliary agents, wherein said composition incorporates a vegetable dye. Furthermore the invention is concerned with the preparation of such compositions.
The incorporation of a vegetable dye into the capsule filling and optionally into the capsule wall ensures a reliable light protection during the manufacturing and filling operations and improves the solubility of nifedipine in certain carriers.
Description
SOLID PHARMACEUTICAL COMPOSITIONS
This invention relates to solid pharmaceutical compositions and a process for the preparation thereof. More partlcularly it is concerned with solid pharmaceutical compositions comprising a light--sensitive active ingredient optionally being soluble in water, furthermore with a process for the prepara-tion of such compositions.
It is known that the preparation of pharmaceutical compositions comprising as active ingredient a light--sensitive substance involves serious difficulties.
Under effect of light decomposition products are formed which may be inactive or even harmful from therapeutical point of view. At the same time there are more and more severe pharmacopoeial requirements concerning the quantity of the decomposition products. It is also known ` 20 that active ingredients which do not dissolve readily in water can be formulated only by overcoming great difficulties. On the one hand, the sparingly water--soluble ingredients are barely soluble in the carriers and additives used for the preparation of pharmaceutical compositions and, on the other hand, owing to the poor water-solubility of the molecule, the release of the active ingredient is of slight degree.
From the above facts it follows that formulation of `~ light-sensitive and hardly water-soluble active ingredi-ents into solid pharmaceutical compositions is a hard A4745-62/PT/Ju - .., ,: .
.. ~
task for skilled artisans which, at the same time, is a more and more urgent demand for the pharmaceutical industry.
The above problems arise especially when making pharmaceutical preparations from dihydropyridine derivatives which are hoth light-sensitive and barely soluble in water. One of the most important represen-tative of these compounds is nifedipine [4-(2l-nitro-phenyl)-2,6-dimethyl-3,5-dimethoxycarbonyl-1,4-di-i 10 hydropyridine], a widely used calcium antagonist, which is highly useful in the treatment of acute and chronic ischemic heart diseases, hypertension, cerebral and peripheral circulation disorders.
It is known that nifedipine is highly light--sensitive and does not readily dissolve in water (British patent specification No. 1,362,627). Owing to the high light-sensitivity of the molecule, decomposi-tion products, especially nitro and nitroso derivatives, are formed very readily. The allowable maximum amount ` 20 of the decomposition products is determined by severe pharmacopoeial regulations. Thus, according to the requirements specified in USP XXII the allowable maximum amount of the nitro compound may not exceed 2.0 % by mass, while in case of the nitroso decomposition product this value may not exceed 0.5 % by mass.
Furthermore, owing to its hard solubility in water, nifedipine does not readily dissolve in the carriers and auxiliary agents usually applied in the pharma-ceutical industry for the preparation of solid pharmaceutical compositions; at the same time, due to its bare solubility in water, the release of the active ingredient is of very slight degree whereby the proper absorption is hindered.
Preferred representakives of the pharmaceutical compositions comprisiny nifedipine are soft yelatin capsules, but the preparation thereof gives rise to difficulties because of the light-sensitivity and .~ .
.
slight water-solubility of the active ingredient.
Several methods have been published for the prepara-tion of soft gelatin capsules of such a kind. ~ccord-ding to British patent specification No. 1,362,~27 one or more opacifier(s) (e.g. titanium dioxide or calcium carbonate) and optionally a synthetic dye absorbing light in a certain wavelength range (e.g.
Gelborange, Erythrosin) are incorporated into the gelatin shell of the capsule. The presence of the opacifier is obligatory, while that of the synthetic dye is only preferable. Coloured opacifiers, e.g.
iron oxide pigments, give an aesthetic exterior and colour to the capsule shell. Said coloured pigments are incorporated into the gelatin shell of the capsule in an amount of 2 to 3 % by mass to ensure the desired anti-fading effect. The amount of the ` opacifier can be reduced to about 0.5 to 1.5 % by mass by adding a dye to the composition, but the addition thereof can not be omitted. Synthetic dyes by themselves can not ensure an infallible anti-fading effect, only when applied with an opacifier.
However, light protection ensured by the capsule ; wall involves serious drawbacks. Namely, the anti-fading effect is provided only by the ready-to-use capsule which involves already the filling solution ` containing the active ingredient. This latter is completely unprotected against light during the manufacturing and filling processes, consequently expensive and cumbersome precautionary measures requiring strict technological and labour disci-plines have to be effectuated to avoid de-composition caused by light (e.g. the operations have to be carried out under indifferent red ; lighting etc.). The protection of the filling solution from the effect of light is particularly important when filtering the ready solution. Light protection has to be ensured during each of the -- ~ .
,::
.
I . .
encapsulating operations (e.g. black foil, special devices to exclude light, light filters etc.).
A further drawback of the light protection ensured by the capsule wall is that the incorpora-tion of the finely dispersed solid opacifier intothe capsule wall requires a separate operation and separate instruments. The finely powdered opacifier has to be smoothly suspended in the viscous gelatin mass constituting the capsule wall, which is a lengthy and cumbersome process. During the manufacturing process the possibility of an accidental inhomogeneity can not be precluded, ` the gelatin mass may become bubbled upon stirring, which may lead to the formation of inclusions, ; 15 and these latter may cause inhomogeneity and de-sortment inside the capsule wall.
The published European patent application No.
143,857 discloses soft gelatin capsules comprising nifedipine as active ingredient. The capsule wall consists of glycerol, one or more dye(s) absorbing light in the desired wavelength range and an opacifier, while the mixture constituting the filling of the capsule contains a solution of nife~
dipine in an organic solvent. A characteristic feature of this patent application is that the filling of the capsule contains nifedipine and polyvinylpyrrolidone (PVP) dissolved in a solution of a polyetheralcohol in tetrahydrofurfurylalcohol, and it does not contain glycerol at all, this latter being present only in the capsule wall. This method also involves the disadvantages specified above. Namely, the opaci~ying agent is admixed exclusively to the material of the capsule wall, consequently the filling of the capsule is un-protected against light during the manufacturingand filling operations, furthermore the above-specified difficulties arising when incorporating , .
.
, the opacifier into the capsule wall have to be surmounted, too.
The aim of the present invention is to elaborate a simple manufacturing process for the preparation of solid pharmaceutical compositions comprising as active ingredient a light-sensitive substance optionally being hardly soluble in water which ensures reliable light-protection and eliminates the drawbacks of the hitherto known processes.
The aim of the present invention is especially to provide an easily feasible process, ensuring reliable light protection, for the preparation of solid pharmaceutical compositions, particularly soft gelatin capsules, containing light-sensitive and slightly water-soluble nifedipine as active in-gredient.
The invention is based on the recognition that vegetable dyes in themselves, that is wi~hout the presence of opacifying components, are able to prevent the photolysis of light-sensitive active ingredients.
According to an aspect of the present invention there is provided a process for the preparation of solid pharmaceutical compositions comprising a light-sensitive and optionally hardly water-soluble active ingredient together with conventiona~ carriers and/or auxiliary agents, which comprises incorporating a vegetable dye into khe composition.
As vegetable dyes preferably chlorophyll, caramel, saffron yellow or beetroot dye (Rote Beete, Dragocoo~
can be used. According to a preferred form or realiza-tion of the process of the present invention, chloro~
phyll, the natural dye of green plants, is applied.
Both the lipophilic and hydrophilic forms of chlorophyll are suitable for accomplishing the process according to the invention with the desired result. The - , ~ .
. ~ .
, :' ,- ' : ' lipophilic form of chlorophyll is extracted from nettle with an orqanic solvent. The lipophilic form of chlorophyll is a dark-green honey-like prod~ct. The hydrophilic chlorophyll is a dye of natural origin, wherein the central magnesium atom of the molecule is exchanged for a copper atom, and the water-soluble sodium salt is obtained with sodium hydroxide. The potassium salt can be prepared in an analogous manner with potassium hydroxide. The hydrophilic chlorophyll is a finely dispersed green powder.
The vegetable dye can be used in an amount of 0.1 to 10 % by mass related to the total mass of the product.
According to our investigations the following light-sensitive compo~lnds optionally sparingly soluble in water can be used as active ingredients for the solid pharmaceutical compositions according to the invention:
vitamins D, preferably colecalciferol;
vitamin A;
imidazoline derivatives, preferably methynazol;
piperazine derivatives, preferably tripolydine hydrazine hydrochloride;
ergot and indole alkaloids, preferably dihydroergo-25toxin methanesulfonate or ergotamine tartrate;
butyrophenone derivatives, preferably haloperidol, droperidol or benperidol;
nitroglycerin; 0 dihydropyridine derivatives, preferably nifedipine, nirudipine, nitrendipine, nisoldipine, nimodipine, nicarbipine or phenodipine;
anabolic steroids, preferably phenoxymesteron;
thyroid hormones, preferably levothyroxine; 5 folic acid analogue antimetabolites, preferably methotrexate;
purine-analogue antimetabolites, preferably azathoprine;
.
~ `
nitrofuran derivatives, preferably nitrofurantoin;
antineoplastic methylhydroxines, preferably pro-carbazine;
corticosteroids, preferably betamethasone;
sodium nitroprusside;
morphine derivatives, preferably morphine sulfate or papaverine hydrochloride;
catecholamines, preferably dopamine or isoprenaline;
estrogens, preferably hexosterol;
sulfadiazine;
alkaloids, preferably colchicine;
profen derivatives, preferably ketoprofen;
antibiotics, preferably mitomycin or bacitracin;
; tricyclic antidepressants, preferably carbamazepine;
phenthiazines, preferably hibernal or trifluoperazine;
mustardnitrogens;
cocaine hydrochloride;
ethylenediami.ne derivatives, preferably tripelenamine;
or aminoquinoline derivatives, preferably chloroquine.
According to a particularly preferred embodiment of the present invention a light-sensitive dihydropyridine derivative hardly soluble in water such as vitamin A
or nitroglycerin is used as active ingredient.
According to an other particularly preferred embodiment of the present invention dihydropyridine derivatives showing a water-solubility not exceeding 20 gll at 25 C are used as active ingredients. Thus .` nifedipine, niludipine, nitrendipine, nisoldipine, nimodipine, nicardipine and felodipine have prooved to be particularly preferred as active ingredients.
According to the process of the present invention light-sensitive and optionally hardly water-soluble active ingredients can be formulated preferably into ~ 35 soft gelatin capsules, tablets, dragées or hard ~ gelatin capsules, particularly into soft gelatin ~ capsules.
:` :
!, ' ' : i l ' . . . :'. . ~, . ` : :
~` ~
`:
` :
When preparing soft gelatin capsules a vegetable dye, especially chlorophyll, is incorporated into the filling of the capsule. Consequently, the filling con~aining the light-sensitive active ingredient is already protected from light during the manu-facturing and filling processes, and not only after having been enclosed into the capsules. ~y this means expensive and cumbersome measures ensuring light-protection during the working up o~
the filling, which encloses the light-sensitive active ingredient, can be eliminated.
The lipophilic form of chlorophyll is admixed to the filling in an amount of 1 to 10 % by mass, preferably 1 to 5 % by mass, particularly preferably 1.5 to 3.5 % by mass. The hydrophilic colloid content of the filling may vary between 0.5 and 10 % by mass, preferably 1 to 7 % by mass, particularly preferably 1.5 to 5 % by mass. If nifedipine is used as active ingredient, the active ingredient content of the filling may vary between 0.5 and 7 % by mass, preferably 1 to 5 % by mass, particularly preferably 1.5 to 3 % by mass.
As a further component, the filling contains also a solvent suitable for oral administration and compatible with the wall material of the soft gelatin capsule. For this purpose the following solvents can be used: vegetable and aromatic oils (such as sun-flower oil, calabash oil, olive oil, lemon oil etc.), non-ionic surfactants [e.g. poly(ethylene oxide)--sorbitan fatty acid esters, preferably poly(ethylene oxide)-sorbitan monooleate], lecithin or polyethylene glycols (e.g. Carbowax 300). The filling of the capsule may optionally contain flavouring agents (e.g.
flavourings or essential oils), too.
When using lipophilic chlorophyll, the filling of the capsule may contain as solvent preferably a poly(ethylene oxide)-sorbitan fatty acid ester, , ' ' particularly poly(ethylene oxide)-sorbitan monooleake.
When applying hydrophilic chlorophyll, preferably polyethylene glycols (e.g. Carbowaw 300) are used as solvent.
The preparation of the capsule ~illing is carried out by conventional methods of the pharmaceutical industry. One proceeds preferably by dissolving the active ingredient in a solvent heated to the appropriate temperature. The lipophilic or hydrophilic chlorophyll and the other components are added to this solution either while it is still warm or after cooling it and, if necessary, the solution thus obtained is filtered on a sieve.
The filling prepared as specified above containing a vegetable dye is then filled into soft gelatin capsules. The wall of the capsule may contain plasticizers of gelatin base (e.g. glycerin or sorbite) and a conserver (e.g. Nipagin). One may also proceed by adding a vegetable dye, preferably chlorophyll, to the material of the capsule wall, too. In this case ; the chlorophyll content of the capsule wall is 0.1 to 5 % by mass, preferably 0.2 to 3 % by mass, particularly preferably 0.3 to 1.5 % by mass. The capsule wall may contain the hydrophilic form of chlorophyll.
The preparation of the capsule wall containing a vegetable dye is carried out as follows: the plasticizer (e.g. glycerol or sorbitol~ and the optionally applied further component(s) (e.g. polyvinylpyrrolidone or a ~ conserver) are dissolved in warm (70 to 90 C) water `~ 30 and gelatin is added to the solution. The mass thus obtained is treated in vacuo under continuous vigorous ' stirring until a translucid, honey-like mass has been formed. Chlorophyll is dissolved separately in a small portion of water and then admixed to the ready, cooled mass.
Encapsulation is carried out mechanically by methods known ~ se. The tablets, dragées and hard :
~ . ' ' -; ~
gelatin capsules may contain the following conventional carriers and/or auxiliary agents:
Disintegrants such as starch, modified starch, cellulose, cellulose derivatives, cross-linked PVP
(PvPp)l sodium alginate and colloidal silicon dioxide;
binding materials such as gelatin, tragacanth, glucose syrup, starch, PVP, cellulose derivatives, polyethylene glycols (PEG 1000-5000) and alginates; lubricants such as magnesium stearate, stearic acid, paraffin, talk, vegetable or animal fats, oils and waxes, silicones, polyethylene glycols (e.g. PEG 1000~5000); carriers and fillers such as starch, cellulose, PVP, PVPP, colloidal silicon dioxide, lactose, magnesium stearate, calcium stearate; diluents such as lactose, mannitol, starch, microcrystalline cellulose; colouring and flavouring agents and conventional coatings.
The pellet of the above-listed solid pharmaceutical compositions may contain 0.1 to 5 % by mass, preferably 0.5 to 3 % by mass of a vegetable dye, while the coating thereof may incorporate 0.1 to 1 ~ by mass, preferably 0.3 to 0.7 % by mass of the same substance.
The preparation o~ the tablets, dragées and hard gelatin capsules according to the invention is carried out by methods known ~E se.
According to a further aspect of the present invention there are provided solid pharmaceutical compositions comprising a light-sensitive active ingredient optionally being hardly soluble in water together with conventional carriers and/or auxiliary agents, wherein said composition comprises a vegetable dye.
~, The preferred forms of the solid pharmaceutical compositions according to the invention, the vegetable dyes, furthermore the light-sensitive and hardly water--soluble active ingredients preferably used for the solid pharmaceutical compositions according to the invention have already been specified above.
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According to a pre~erred aspect of the present invention there are provi~ed solid pharmaceutical compositions, particularly soft gelatin capsules, comprising nifedipine as active ingredients.
According to a still further aspect of the present invention there are provided soft gelatin capsules comprising nifedipine as active ingredient, wherein the filling and/or the capsule wall incorporate(s) a vegetable dye, preferably chlorophyll, in an amount of 0.1 to 10 % by mass.
The photolytic decomposition of the active ingredient of the soft gelatin capsules according to the present invention was investigated by the so-called "sun test" during 4 hours. The results are given in Table I.
Table I
Photolytic decomposition Sample used Concentration Concentration of Example No. of the initial the decomposition active ingre- products (% by dient mass) (% by mass) nitro nitroso other Filling solution:
Example 2 25 98.50 1.00 0.23 0.27 Capsule wall:
Example 4 Filling solution:
- Example 1 98.00 0.90 0.24 0.86 Capsule wall:
` Example 5 According to USP XXII the amount of the nitro decomposition product may not exceed 2.0 % by mass, while that of the nitroso compound may not be more than 0.5 % by mass. From the data of Table I it can be established that the soft gelatin capsules prepared according to the present invention contain the decomposition products in a considerably lower amount than the allowed one. It is highly remarkable that - . ~ , .
; ~ -.
, `: , even in case of soft gelatin capsules containing a vegetable dye only in the filling a light protection satisfying the requirements of USP XXII has been achieved without the incorporation of a colouring agent into the capsule wall. On the other hand, the capsule wall does not contain any opacifier.
Surprisingly it has been found that not only a proper light protection can be achieved by the process according to the invention but the vegetable dyes improve the solubility of nifedipine in certain carriers (e.g. in vegetable oils). It is known that - nifedipine is barely soluble in vegetable oils.
At the same time the latter are, owing to their compatibility with the gelatin capsule wall, excellent carriers, but their applicability is hindered by the slight solubility of nifedipine.
The following experiment proves that under effect of vegetable dyes both the solubility of nifedipine ` in di~ferent vegetable oils and its release are improved.
` The drug release from the capsules was determined in a rotating paddle equipment according to USP XXII by using distilled water as dissolving medium within 15 minutes, at a temperature of 37 + 0.5 C (revolutions per minute = 50). The results are summarized in Table II.
, .
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Release of the active ingredient Vegetable oil Chlorophyll content Release o the used as solvent of the filling active ingre-solution dient from the (~ by mass) capsule within 15 minutes (% by mass) (demand: 80 %) lO Calabash oil - 82.30 Calabash oil 1.5 92.40 Calabash oil 3.0 97.02 Lemon oil - 90.76 Lemon oil 1.5 95.37 15 Lemon oil 3.0 100.14 Olive oil - 86.38 Olive oil 1.5 90.50 ` Olive oil 3.0 96.40 According to the requirements specified is USP
XXII the degree of the release of nifedipine has to amount at least to 80 %. From the data of Table II
it can be seen that the release of nifedipine from the vegetable oils used as solvent tcalabash oil, lemon oil, olive oil) considerably exceeds this value. Furthermore it is remarkable that in the presence of chlorophyll the release of nifedipine is significantly better than in case of using '; 30 besically the same carrier but without any vegetable dye. The recognition that vegetable dyes promote drug release could not be aforeseen and so it is fully surprising.
Further details of the present invention are ;~ 35 to be found in the following Examples, without limiting the scope of protection to these Examples.
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Example 1 A capsule filling having the following composition is prepared:
ComponentAmount, % bY mass 5 Nifedipine 3.00 Poly(ethylene oxide)-sorbitan monooleate 22.85 Lemon oil 14.65 Lecithin 57.00 10 Chlorophyll (lipophllic) 2.50 100 . 00 Preparation: poly(ethylene oxide)-sorbitan mono-oleate is warmed to about 70 C and nifedipine is dissolved in it. When the dissolution has been completed, lecithin and lipophilic chlorophyll are added to the solution while it is still warm, then the mixture is cooled to room temperature and lemon oil is introduced to it. If necessary, the solution is filtered through a plastic sieve (pore size: 120 mesh).
Example 2 A capsule filling having the following composition is prepared:
ComponentAmount. % by mass 25 Nifedipine 2.80 Poly(ethylene oxide)-sorbitan monooleate 82.50 Calabash oil 11.50 Chlorophyll (lipophilic) 3.20 100.00 Preparation: poly(ethylene oxide)-sorbitan mono-oleate is warmed to about 70 C and nifedipine is dissolved in it. When the dissolution has been completed, the solution is cooled to about 45 C
and calabash oil and lipophilic chlorophyll are added to it. If necessary, the solution is filtered . through a plastic sieve (pore size: 120 mesh).
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- , ` ' ~, , - . . :, Example 3 A capsule filling having the following composition is prepared:
Component Amount, % by mass Nifedipine 4.00 Carbowax 300 88.00 Lemon oil 3-00 Chlorophyll (hidrophilic) 5.00 100. 00 Preparation: Carbowax 300 is warmed to 60 C and nifedipine is dissolved in it. When the dissolutio~
has been completed, the solution is cooled to ~ 25-30 C and hydrophilic chlorophyll and lemon oil ; are added to it. If necessary, the solution is filtered through a plastic sieve (pore size: 120 mesh).
Example 4 A capsule wall having the following composition is prepared:
Component Amount, % bY mass 20 Gelatin 50.00 Glycerin 27.00 Sorbitol 70 % 6.00 Distilled water 17.00 100. 00 Preparation: water is warmed to 80 C and sorbitol and glycerol are added to it. Then gelatin is introduced to the mixture under vigorous stirring and the stirring is continued under vacuum until the mixture has turned i into a translucid, honey-like mass. This latter is * 30 covered into capsules mechanically by methods known se.
Example 5 A capsule wall having the following composition is prepared:
, ' . - : ' ~ ,'' ' ' . ' Component Amount, % bv mass Gelatin ~5.00 Glycerin 36.30 Conserver 0.20 5 Chlorophyll (hydrophilic)0.50 Distilled water 18.00 100.00 Preparation: water is warmed to 80 C and a conserver is dissolved in it. Then glycerol is added to the solution, and gelatin is introduced to it under vigorous stirring. The stirring is continued under vacuum until the mixture has turned into a translucid, honey-like mass. Chlorophyll is dissolved separately in a small portion of water and the aqueous solution is admixed with the above-specified mass cooled to 60 C. This latter is converted into capsules mechanically by methods known ~ se.
Example 6 A capsule wall having the following composition 20 is prepared:
Component Amount, % by mass Gelatin 45.00 Glycerin 37.00 Polyvinylpyrrolidone 5.00 25 Chlorophyll (hydrophilic) 1.00 Distilled water 12.00 100 . 00 Preparation: water is warmed to 80 C, polyvinyl-pyrrolidone is dissolved in it and glycerol is added to the solution. Then gelatin is introduced to the mixture under continuous vigorous stirringu The mass is stirred under vacuum until it has turned into a translucid, honey-like product. Chlorophyll is dissolved " separately in a small portion of water, and the aqueous solution is admixed with the above-specified mass cooled to 60 C. This latter is converted into capsules mechanically by methods known per se.
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This invention relates to solid pharmaceutical compositions and a process for the preparation thereof. More partlcularly it is concerned with solid pharmaceutical compositions comprising a light--sensitive active ingredient optionally being soluble in water, furthermore with a process for the prepara-tion of such compositions.
It is known that the preparation of pharmaceutical compositions comprising as active ingredient a light--sensitive substance involves serious difficulties.
Under effect of light decomposition products are formed which may be inactive or even harmful from therapeutical point of view. At the same time there are more and more severe pharmacopoeial requirements concerning the quantity of the decomposition products. It is also known ` 20 that active ingredients which do not dissolve readily in water can be formulated only by overcoming great difficulties. On the one hand, the sparingly water--soluble ingredients are barely soluble in the carriers and additives used for the preparation of pharmaceutical compositions and, on the other hand, owing to the poor water-solubility of the molecule, the release of the active ingredient is of slight degree.
From the above facts it follows that formulation of `~ light-sensitive and hardly water-soluble active ingredi-ents into solid pharmaceutical compositions is a hard A4745-62/PT/Ju - .., ,: .
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task for skilled artisans which, at the same time, is a more and more urgent demand for the pharmaceutical industry.
The above problems arise especially when making pharmaceutical preparations from dihydropyridine derivatives which are hoth light-sensitive and barely soluble in water. One of the most important represen-tative of these compounds is nifedipine [4-(2l-nitro-phenyl)-2,6-dimethyl-3,5-dimethoxycarbonyl-1,4-di-i 10 hydropyridine], a widely used calcium antagonist, which is highly useful in the treatment of acute and chronic ischemic heart diseases, hypertension, cerebral and peripheral circulation disorders.
It is known that nifedipine is highly light--sensitive and does not readily dissolve in water (British patent specification No. 1,362,627). Owing to the high light-sensitivity of the molecule, decomposi-tion products, especially nitro and nitroso derivatives, are formed very readily. The allowable maximum amount ` 20 of the decomposition products is determined by severe pharmacopoeial regulations. Thus, according to the requirements specified in USP XXII the allowable maximum amount of the nitro compound may not exceed 2.0 % by mass, while in case of the nitroso decomposition product this value may not exceed 0.5 % by mass.
Furthermore, owing to its hard solubility in water, nifedipine does not readily dissolve in the carriers and auxiliary agents usually applied in the pharma-ceutical industry for the preparation of solid pharmaceutical compositions; at the same time, due to its bare solubility in water, the release of the active ingredient is of very slight degree whereby the proper absorption is hindered.
Preferred representakives of the pharmaceutical compositions comprisiny nifedipine are soft yelatin capsules, but the preparation thereof gives rise to difficulties because of the light-sensitivity and .~ .
.
slight water-solubility of the active ingredient.
Several methods have been published for the prepara-tion of soft gelatin capsules of such a kind. ~ccord-ding to British patent specification No. 1,362,~27 one or more opacifier(s) (e.g. titanium dioxide or calcium carbonate) and optionally a synthetic dye absorbing light in a certain wavelength range (e.g.
Gelborange, Erythrosin) are incorporated into the gelatin shell of the capsule. The presence of the opacifier is obligatory, while that of the synthetic dye is only preferable. Coloured opacifiers, e.g.
iron oxide pigments, give an aesthetic exterior and colour to the capsule shell. Said coloured pigments are incorporated into the gelatin shell of the capsule in an amount of 2 to 3 % by mass to ensure the desired anti-fading effect. The amount of the ` opacifier can be reduced to about 0.5 to 1.5 % by mass by adding a dye to the composition, but the addition thereof can not be omitted. Synthetic dyes by themselves can not ensure an infallible anti-fading effect, only when applied with an opacifier.
However, light protection ensured by the capsule ; wall involves serious drawbacks. Namely, the anti-fading effect is provided only by the ready-to-use capsule which involves already the filling solution ` containing the active ingredient. This latter is completely unprotected against light during the manufacturing and filling processes, consequently expensive and cumbersome precautionary measures requiring strict technological and labour disci-plines have to be effectuated to avoid de-composition caused by light (e.g. the operations have to be carried out under indifferent red ; lighting etc.). The protection of the filling solution from the effect of light is particularly important when filtering the ready solution. Light protection has to be ensured during each of the -- ~ .
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encapsulating operations (e.g. black foil, special devices to exclude light, light filters etc.).
A further drawback of the light protection ensured by the capsule wall is that the incorpora-tion of the finely dispersed solid opacifier intothe capsule wall requires a separate operation and separate instruments. The finely powdered opacifier has to be smoothly suspended in the viscous gelatin mass constituting the capsule wall, which is a lengthy and cumbersome process. During the manufacturing process the possibility of an accidental inhomogeneity can not be precluded, ` the gelatin mass may become bubbled upon stirring, which may lead to the formation of inclusions, ; 15 and these latter may cause inhomogeneity and de-sortment inside the capsule wall.
The published European patent application No.
143,857 discloses soft gelatin capsules comprising nifedipine as active ingredient. The capsule wall consists of glycerol, one or more dye(s) absorbing light in the desired wavelength range and an opacifier, while the mixture constituting the filling of the capsule contains a solution of nife~
dipine in an organic solvent. A characteristic feature of this patent application is that the filling of the capsule contains nifedipine and polyvinylpyrrolidone (PVP) dissolved in a solution of a polyetheralcohol in tetrahydrofurfurylalcohol, and it does not contain glycerol at all, this latter being present only in the capsule wall. This method also involves the disadvantages specified above. Namely, the opaci~ying agent is admixed exclusively to the material of the capsule wall, consequently the filling of the capsule is un-protected against light during the manufacturingand filling operations, furthermore the above-specified difficulties arising when incorporating , .
.
, the opacifier into the capsule wall have to be surmounted, too.
The aim of the present invention is to elaborate a simple manufacturing process for the preparation of solid pharmaceutical compositions comprising as active ingredient a light-sensitive substance optionally being hardly soluble in water which ensures reliable light-protection and eliminates the drawbacks of the hitherto known processes.
The aim of the present invention is especially to provide an easily feasible process, ensuring reliable light protection, for the preparation of solid pharmaceutical compositions, particularly soft gelatin capsules, containing light-sensitive and slightly water-soluble nifedipine as active in-gredient.
The invention is based on the recognition that vegetable dyes in themselves, that is wi~hout the presence of opacifying components, are able to prevent the photolysis of light-sensitive active ingredients.
According to an aspect of the present invention there is provided a process for the preparation of solid pharmaceutical compositions comprising a light-sensitive and optionally hardly water-soluble active ingredient together with conventiona~ carriers and/or auxiliary agents, which comprises incorporating a vegetable dye into khe composition.
As vegetable dyes preferably chlorophyll, caramel, saffron yellow or beetroot dye (Rote Beete, Dragocoo~
can be used. According to a preferred form or realiza-tion of the process of the present invention, chloro~
phyll, the natural dye of green plants, is applied.
Both the lipophilic and hydrophilic forms of chlorophyll are suitable for accomplishing the process according to the invention with the desired result. The - , ~ .
. ~ .
, :' ,- ' : ' lipophilic form of chlorophyll is extracted from nettle with an orqanic solvent. The lipophilic form of chlorophyll is a dark-green honey-like prod~ct. The hydrophilic chlorophyll is a dye of natural origin, wherein the central magnesium atom of the molecule is exchanged for a copper atom, and the water-soluble sodium salt is obtained with sodium hydroxide. The potassium salt can be prepared in an analogous manner with potassium hydroxide. The hydrophilic chlorophyll is a finely dispersed green powder.
The vegetable dye can be used in an amount of 0.1 to 10 % by mass related to the total mass of the product.
According to our investigations the following light-sensitive compo~lnds optionally sparingly soluble in water can be used as active ingredients for the solid pharmaceutical compositions according to the invention:
vitamins D, preferably colecalciferol;
vitamin A;
imidazoline derivatives, preferably methynazol;
piperazine derivatives, preferably tripolydine hydrazine hydrochloride;
ergot and indole alkaloids, preferably dihydroergo-25toxin methanesulfonate or ergotamine tartrate;
butyrophenone derivatives, preferably haloperidol, droperidol or benperidol;
nitroglycerin; 0 dihydropyridine derivatives, preferably nifedipine, nirudipine, nitrendipine, nisoldipine, nimodipine, nicarbipine or phenodipine;
anabolic steroids, preferably phenoxymesteron;
thyroid hormones, preferably levothyroxine; 5 folic acid analogue antimetabolites, preferably methotrexate;
purine-analogue antimetabolites, preferably azathoprine;
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nitrofuran derivatives, preferably nitrofurantoin;
antineoplastic methylhydroxines, preferably pro-carbazine;
corticosteroids, preferably betamethasone;
sodium nitroprusside;
morphine derivatives, preferably morphine sulfate or papaverine hydrochloride;
catecholamines, preferably dopamine or isoprenaline;
estrogens, preferably hexosterol;
sulfadiazine;
alkaloids, preferably colchicine;
profen derivatives, preferably ketoprofen;
antibiotics, preferably mitomycin or bacitracin;
; tricyclic antidepressants, preferably carbamazepine;
phenthiazines, preferably hibernal or trifluoperazine;
mustardnitrogens;
cocaine hydrochloride;
ethylenediami.ne derivatives, preferably tripelenamine;
or aminoquinoline derivatives, preferably chloroquine.
According to a particularly preferred embodiment of the present invention a light-sensitive dihydropyridine derivative hardly soluble in water such as vitamin A
or nitroglycerin is used as active ingredient.
According to an other particularly preferred embodiment of the present invention dihydropyridine derivatives showing a water-solubility not exceeding 20 gll at 25 C are used as active ingredients. Thus .` nifedipine, niludipine, nitrendipine, nisoldipine, nimodipine, nicardipine and felodipine have prooved to be particularly preferred as active ingredients.
According to the process of the present invention light-sensitive and optionally hardly water-soluble active ingredients can be formulated preferably into ~ 35 soft gelatin capsules, tablets, dragées or hard ~ gelatin capsules, particularly into soft gelatin ~ capsules.
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When preparing soft gelatin capsules a vegetable dye, especially chlorophyll, is incorporated into the filling of the capsule. Consequently, the filling con~aining the light-sensitive active ingredient is already protected from light during the manu-facturing and filling processes, and not only after having been enclosed into the capsules. ~y this means expensive and cumbersome measures ensuring light-protection during the working up o~
the filling, which encloses the light-sensitive active ingredient, can be eliminated.
The lipophilic form of chlorophyll is admixed to the filling in an amount of 1 to 10 % by mass, preferably 1 to 5 % by mass, particularly preferably 1.5 to 3.5 % by mass. The hydrophilic colloid content of the filling may vary between 0.5 and 10 % by mass, preferably 1 to 7 % by mass, particularly preferably 1.5 to 5 % by mass. If nifedipine is used as active ingredient, the active ingredient content of the filling may vary between 0.5 and 7 % by mass, preferably 1 to 5 % by mass, particularly preferably 1.5 to 3 % by mass.
As a further component, the filling contains also a solvent suitable for oral administration and compatible with the wall material of the soft gelatin capsule. For this purpose the following solvents can be used: vegetable and aromatic oils (such as sun-flower oil, calabash oil, olive oil, lemon oil etc.), non-ionic surfactants [e.g. poly(ethylene oxide)--sorbitan fatty acid esters, preferably poly(ethylene oxide)-sorbitan monooleate], lecithin or polyethylene glycols (e.g. Carbowax 300). The filling of the capsule may optionally contain flavouring agents (e.g.
flavourings or essential oils), too.
When using lipophilic chlorophyll, the filling of the capsule may contain as solvent preferably a poly(ethylene oxide)-sorbitan fatty acid ester, , ' ' particularly poly(ethylene oxide)-sorbitan monooleake.
When applying hydrophilic chlorophyll, preferably polyethylene glycols (e.g. Carbowaw 300) are used as solvent.
The preparation of the capsule ~illing is carried out by conventional methods of the pharmaceutical industry. One proceeds preferably by dissolving the active ingredient in a solvent heated to the appropriate temperature. The lipophilic or hydrophilic chlorophyll and the other components are added to this solution either while it is still warm or after cooling it and, if necessary, the solution thus obtained is filtered on a sieve.
The filling prepared as specified above containing a vegetable dye is then filled into soft gelatin capsules. The wall of the capsule may contain plasticizers of gelatin base (e.g. glycerin or sorbite) and a conserver (e.g. Nipagin). One may also proceed by adding a vegetable dye, preferably chlorophyll, to the material of the capsule wall, too. In this case ; the chlorophyll content of the capsule wall is 0.1 to 5 % by mass, preferably 0.2 to 3 % by mass, particularly preferably 0.3 to 1.5 % by mass. The capsule wall may contain the hydrophilic form of chlorophyll.
The preparation of the capsule wall containing a vegetable dye is carried out as follows: the plasticizer (e.g. glycerol or sorbitol~ and the optionally applied further component(s) (e.g. polyvinylpyrrolidone or a ~ conserver) are dissolved in warm (70 to 90 C) water `~ 30 and gelatin is added to the solution. The mass thus obtained is treated in vacuo under continuous vigorous ' stirring until a translucid, honey-like mass has been formed. Chlorophyll is dissolved separately in a small portion of water and then admixed to the ready, cooled mass.
Encapsulation is carried out mechanically by methods known ~ se. The tablets, dragées and hard :
~ . ' ' -; ~
gelatin capsules may contain the following conventional carriers and/or auxiliary agents:
Disintegrants such as starch, modified starch, cellulose, cellulose derivatives, cross-linked PVP
(PvPp)l sodium alginate and colloidal silicon dioxide;
binding materials such as gelatin, tragacanth, glucose syrup, starch, PVP, cellulose derivatives, polyethylene glycols (PEG 1000-5000) and alginates; lubricants such as magnesium stearate, stearic acid, paraffin, talk, vegetable or animal fats, oils and waxes, silicones, polyethylene glycols (e.g. PEG 1000~5000); carriers and fillers such as starch, cellulose, PVP, PVPP, colloidal silicon dioxide, lactose, magnesium stearate, calcium stearate; diluents such as lactose, mannitol, starch, microcrystalline cellulose; colouring and flavouring agents and conventional coatings.
The pellet of the above-listed solid pharmaceutical compositions may contain 0.1 to 5 % by mass, preferably 0.5 to 3 % by mass of a vegetable dye, while the coating thereof may incorporate 0.1 to 1 ~ by mass, preferably 0.3 to 0.7 % by mass of the same substance.
The preparation o~ the tablets, dragées and hard gelatin capsules according to the invention is carried out by methods known ~E se.
According to a further aspect of the present invention there are provided solid pharmaceutical compositions comprising a light-sensitive active ingredient optionally being hardly soluble in water together with conventional carriers and/or auxiliary agents, wherein said composition comprises a vegetable dye.
~, The preferred forms of the solid pharmaceutical compositions according to the invention, the vegetable dyes, furthermore the light-sensitive and hardly water--soluble active ingredients preferably used for the solid pharmaceutical compositions according to the invention have already been specified above.
:
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:
According to a pre~erred aspect of the present invention there are provi~ed solid pharmaceutical compositions, particularly soft gelatin capsules, comprising nifedipine as active ingredients.
According to a still further aspect of the present invention there are provided soft gelatin capsules comprising nifedipine as active ingredient, wherein the filling and/or the capsule wall incorporate(s) a vegetable dye, preferably chlorophyll, in an amount of 0.1 to 10 % by mass.
The photolytic decomposition of the active ingredient of the soft gelatin capsules according to the present invention was investigated by the so-called "sun test" during 4 hours. The results are given in Table I.
Table I
Photolytic decomposition Sample used Concentration Concentration of Example No. of the initial the decomposition active ingre- products (% by dient mass) (% by mass) nitro nitroso other Filling solution:
Example 2 25 98.50 1.00 0.23 0.27 Capsule wall:
Example 4 Filling solution:
- Example 1 98.00 0.90 0.24 0.86 Capsule wall:
` Example 5 According to USP XXII the amount of the nitro decomposition product may not exceed 2.0 % by mass, while that of the nitroso compound may not be more than 0.5 % by mass. From the data of Table I it can be established that the soft gelatin capsules prepared according to the present invention contain the decomposition products in a considerably lower amount than the allowed one. It is highly remarkable that - . ~ , .
; ~ -.
, `: , even in case of soft gelatin capsules containing a vegetable dye only in the filling a light protection satisfying the requirements of USP XXII has been achieved without the incorporation of a colouring agent into the capsule wall. On the other hand, the capsule wall does not contain any opacifier.
Surprisingly it has been found that not only a proper light protection can be achieved by the process according to the invention but the vegetable dyes improve the solubility of nifedipine in certain carriers (e.g. in vegetable oils). It is known that - nifedipine is barely soluble in vegetable oils.
At the same time the latter are, owing to their compatibility with the gelatin capsule wall, excellent carriers, but their applicability is hindered by the slight solubility of nifedipine.
The following experiment proves that under effect of vegetable dyes both the solubility of nifedipine ` in di~ferent vegetable oils and its release are improved.
` The drug release from the capsules was determined in a rotating paddle equipment according to USP XXII by using distilled water as dissolving medium within 15 minutes, at a temperature of 37 + 0.5 C (revolutions per minute = 50). The results are summarized in Table II.
, .
" ` ~ ': ' Table II
Release of the active ingredient Vegetable oil Chlorophyll content Release o the used as solvent of the filling active ingre-solution dient from the (~ by mass) capsule within 15 minutes (% by mass) (demand: 80 %) lO Calabash oil - 82.30 Calabash oil 1.5 92.40 Calabash oil 3.0 97.02 Lemon oil - 90.76 Lemon oil 1.5 95.37 15 Lemon oil 3.0 100.14 Olive oil - 86.38 Olive oil 1.5 90.50 ` Olive oil 3.0 96.40 According to the requirements specified is USP
XXII the degree of the release of nifedipine has to amount at least to 80 %. From the data of Table II
it can be seen that the release of nifedipine from the vegetable oils used as solvent tcalabash oil, lemon oil, olive oil) considerably exceeds this value. Furthermore it is remarkable that in the presence of chlorophyll the release of nifedipine is significantly better than in case of using '; 30 besically the same carrier but without any vegetable dye. The recognition that vegetable dyes promote drug release could not be aforeseen and so it is fully surprising.
Further details of the present invention are ;~ 35 to be found in the following Examples, without limiting the scope of protection to these Examples.
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Example 1 A capsule filling having the following composition is prepared:
ComponentAmount, % bY mass 5 Nifedipine 3.00 Poly(ethylene oxide)-sorbitan monooleate 22.85 Lemon oil 14.65 Lecithin 57.00 10 Chlorophyll (lipophllic) 2.50 100 . 00 Preparation: poly(ethylene oxide)-sorbitan mono-oleate is warmed to about 70 C and nifedipine is dissolved in it. When the dissolution has been completed, lecithin and lipophilic chlorophyll are added to the solution while it is still warm, then the mixture is cooled to room temperature and lemon oil is introduced to it. If necessary, the solution is filtered through a plastic sieve (pore size: 120 mesh).
Example 2 A capsule filling having the following composition is prepared:
ComponentAmount. % by mass 25 Nifedipine 2.80 Poly(ethylene oxide)-sorbitan monooleate 82.50 Calabash oil 11.50 Chlorophyll (lipophilic) 3.20 100.00 Preparation: poly(ethylene oxide)-sorbitan mono-oleate is warmed to about 70 C and nifedipine is dissolved in it. When the dissolution has been completed, the solution is cooled to about 45 C
and calabash oil and lipophilic chlorophyll are added to it. If necessary, the solution is filtered . through a plastic sieve (pore size: 120 mesh).
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.
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- , ` ' ~, , - . . :, Example 3 A capsule filling having the following composition is prepared:
Component Amount, % by mass Nifedipine 4.00 Carbowax 300 88.00 Lemon oil 3-00 Chlorophyll (hidrophilic) 5.00 100. 00 Preparation: Carbowax 300 is warmed to 60 C and nifedipine is dissolved in it. When the dissolutio~
has been completed, the solution is cooled to ~ 25-30 C and hydrophilic chlorophyll and lemon oil ; are added to it. If necessary, the solution is filtered through a plastic sieve (pore size: 120 mesh).
Example 4 A capsule wall having the following composition is prepared:
Component Amount, % bY mass 20 Gelatin 50.00 Glycerin 27.00 Sorbitol 70 % 6.00 Distilled water 17.00 100. 00 Preparation: water is warmed to 80 C and sorbitol and glycerol are added to it. Then gelatin is introduced to the mixture under vigorous stirring and the stirring is continued under vacuum until the mixture has turned i into a translucid, honey-like mass. This latter is * 30 covered into capsules mechanically by methods known se.
Example 5 A capsule wall having the following composition is prepared:
, ' . - : ' ~ ,'' ' ' . ' Component Amount, % bv mass Gelatin ~5.00 Glycerin 36.30 Conserver 0.20 5 Chlorophyll (hydrophilic)0.50 Distilled water 18.00 100.00 Preparation: water is warmed to 80 C and a conserver is dissolved in it. Then glycerol is added to the solution, and gelatin is introduced to it under vigorous stirring. The stirring is continued under vacuum until the mixture has turned into a translucid, honey-like mass. Chlorophyll is dissolved separately in a small portion of water and the aqueous solution is admixed with the above-specified mass cooled to 60 C. This latter is converted into capsules mechanically by methods known ~ se.
Example 6 A capsule wall having the following composition 20 is prepared:
Component Amount, % by mass Gelatin 45.00 Glycerin 37.00 Polyvinylpyrrolidone 5.00 25 Chlorophyll (hydrophilic) 1.00 Distilled water 12.00 100 . 00 Preparation: water is warmed to 80 C, polyvinyl-pyrrolidone is dissolved in it and glycerol is added to the solution. Then gelatin is introduced to the mixture under continuous vigorous stirringu The mass is stirred under vacuum until it has turned into a translucid, honey-like product. Chlorophyll is dissolved " separately in a small portion of water, and the aqueous solution is admixed with the above-specified mass cooled to 60 C. This latter is converted into capsules mechanically by methods known per se.
:, :
.
:~.
:: ~ , `-
Claims (19)
1. A solid pharmaceutical composition comprising a light-sensitive and optionally hardly water-soluble active ingredient together with conventional carriers and/or auxiliary agents, wherein said composition incorporates a vegetable dye.
2. A solid pharmaceutical composition according to claim l, prepared in the form of a soft gelatin capsule.
3. A soft gelatin capsule according to claim 2, comprising as active ingredient nifedipine and containing chlorophyll in the filling solution and optionally in the capsule wall.
4. A process for the preparation of a solid pharmaceutical composition as claimed in claim 1, w h i c h c o m p r i s e s incorporating a vegetable dye into the composition.
5. A process according to claim 4, w h i c h c o m p r i s e s using chlorophyll, caramel, saffron yellow or beetroot dye as vegetable dye.
6. A process according to claim 4 or 5, w h i c h c o m p r i s e s using chlorophyll in an amount of 0.1 to 10 % by mass related to the total mass of the composition.
7. A process according to any of claims 4 to 6, w h i c h c o m p r i s e s using as hardly water-soluble and/or light-sensitive active ingredient a compound selected from the group consisting of vitamins D, preferably colecalciferol;
vitamin A;
imidazoline derivatives, preferably methynazol;
piperazine derivatives, preferably tripolydine hydrazine hydrochloride;
ergot and indole alkaloids, preferably dihydtoergo-toxin methanesulfonate or ergotamine tartrate;
butyrophenone derivatives, preferably haloperidol, droperidol or benperidol;
nitroglycerin;
dihydropyridine derivatives, preferably nifedipine, nirudipine, nitrendipine, nisoldipine, nimodipine, nicarbipine or phenodipine;
anabolic steroids, preferably phenoxymesteron;
thyroid hormones, preferably levothyroxine;
folic acid analogue antimetabolites, preferably methotrexate;
purine-analogue antimetabolites, preferably azathoprine;
nitrofuran derivatives, preferably nitrofurantoin;
antineoplastic methylhydroxines, preferably pro-carbazine;
corticosteroids, preferably betamethasone;
sodium nitroprusside;
morphine derivatives, preferably morphine sulfate or papaverine hydrochloride;
catecholamines, preferably dopamine or isoprenaline;
estrogens, preferably hexosterol;
sulfadiazine;
alkaloids, preferably colchicine;
profen derivatives, preferably ketoprofen;
antibiotics, preferably mitomycin or bacitracin;
tricyclic antidepressants, preferably carbamazepine;
phenthiazines, preferably hibernal or trifluoperazine;
mustardnitrogens;
cocaine hydrochloride;
ethylenediamine derivatives, preferably tripelenamine;
or aminoquinoline derivatives, preferably chloroquine.
vitamin A;
imidazoline derivatives, preferably methynazol;
piperazine derivatives, preferably tripolydine hydrazine hydrochloride;
ergot and indole alkaloids, preferably dihydtoergo-toxin methanesulfonate or ergotamine tartrate;
butyrophenone derivatives, preferably haloperidol, droperidol or benperidol;
nitroglycerin;
dihydropyridine derivatives, preferably nifedipine, nirudipine, nitrendipine, nisoldipine, nimodipine, nicarbipine or phenodipine;
anabolic steroids, preferably phenoxymesteron;
thyroid hormones, preferably levothyroxine;
folic acid analogue antimetabolites, preferably methotrexate;
purine-analogue antimetabolites, preferably azathoprine;
nitrofuran derivatives, preferably nitrofurantoin;
antineoplastic methylhydroxines, preferably pro-carbazine;
corticosteroids, preferably betamethasone;
sodium nitroprusside;
morphine derivatives, preferably morphine sulfate or papaverine hydrochloride;
catecholamines, preferably dopamine or isoprenaline;
estrogens, preferably hexosterol;
sulfadiazine;
alkaloids, preferably colchicine;
profen derivatives, preferably ketoprofen;
antibiotics, preferably mitomycin or bacitracin;
tricyclic antidepressants, preferably carbamazepine;
phenthiazines, preferably hibernal or trifluoperazine;
mustardnitrogens;
cocaine hydrochloride;
ethylenediamine derivatives, preferably tripelenamine;
or aminoquinoline derivatives, preferably chloroquine.
8. A process according to claim 7, w h i c h c o m p r i s e s using a dihydropyridine derivative, nitroglycerin or vitamin A as light-sensitive and optionally hardly water-soluble active ingredient.
9. A process according to claim 8, w h i c h c o m p r i s e s using nifedipine as light-sensitive and optionally hardly water-soluble active ingredient.
10. A process according to any of claims 4 to 9, w h i c h c o m p r i s e s preparing soft gelatin capsules, tablets, dragées or hard gelatin capsules as solid pharmaceutical composition.
11. A process according to claim 10, w h i c h c o m p r i s e s preparing soft gelatin capsules as solid pharmaceutical composition.
12. A process according to claim g or 11 for the preparation of soft gelatin capsules comprising nifedipine as active ingredient, w h i c h c o m p r i s e s incorporating into the filling and/or wall of the capsule a vegetable dye in an amount of 0.1 to 10 % by mass.
13. A process according to claim 12, w h i c h c o m p r i s e s using chlorophyll as vegetable dye.
14. A process according to any of claims 11 to 13, w h i c h c o m p r i s e s incorporating 1 to 10 % by mass, preferably 1 to 5 % by mass, particularly preferably 1.5 to 3.5 % by mass, of lipophilic chlorophyll into the filling of the soft gelatin capsule.
15. A process according to any of claims 11 to 13, w h i c h c o m p r i s e s incorporating 0.5 to 10 % by mass, preferably 1 to 7 % by mass, particularly preferably 1.5 to 5 % by mass, of hydrophilic chlorophyll into the filling of the soft gelatin capsule.
16. A process according to any of claims 11 to 15, w h i c h c o m p r i s e s using 1 to 7 % by mass, preferably 1.5 to 5 % by mass, of chlorophyll and conventional carriers and auxiliary agents, preferably vegetable and aromatic oils or non-ionic surfactants and flavouring agents, for the preparation of the filling of the soft gelatin capsules.
17. A process according to claim 12, w h i c h c o m p r i s e 5 incorporating 0.1 to 5 % by mass, preferably 0.2 to 3 % by mass, particularly preferably 0.3 to 1.5 % by mass of chlorophyll into the capsule wall.
18. A process according to claim 11 for the preparation of soft gelatin capsules comprising nifedipine as active ingredient, w h i c h c o m p r i s e s filling a composition containing 2 to 5 % by mass of nifedipine, a vegetable dye or a non-ionic surfactant and 0.5 to 10 % by mass, preferably 1 to 7 % by mass, particularly preferably 1.5 to 5 % by mass, of chlorophyll into a capsule having a wall enclosing a plasticizer of gelatin base, preferably glycerol or sorbitol, and optionally a conserver and optionally 0.1 to 5 % by mass, preferably 0.2 to 3 % by mass, particularly preferably 0.3 to 1.5 % by mass of chlorophyll
19. A process according to claim 18, w h i c h c o m p r i s e s filling a composition containing 2 to 5 % by mass of nifedipine, an oil selected from the group consisting of sunflower oil, calabash oil, olive oil and lemon oil, a poly(ethylene oxide)--sorbitan fatty acid ester, preferably poly(ethylene oxide)-sorbitan monooleate, or polyethylene glycol and 1.5 to 3.5 % by mass of chlorophyll into a capsule having a wall of gelatin base comprising glycerol and optionally 0.3 to 1.5 % by mass of chlorophyll.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU904564A HUT59592A (en) | 1990-07-20 | 1990-07-20 | Process for the preparation of solid medical products |
HU4564/90 | 1990-07-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2047482A1 true CA2047482A1 (en) | 1992-01-21 |
Family
ID=10968329
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002047482A Abandoned CA2047482A1 (en) | 1990-07-20 | 1991-07-19 | Solid pharmaceutical composition |
Country Status (22)
Country | Link |
---|---|
JP (1) | JPH04253924A (en) |
KR (1) | KR920002162A (en) |
BE (1) | BE1006829A3 (en) |
CA (1) | CA2047482A1 (en) |
CH (1) | CH681960A5 (en) |
CY (1) | CY1840A (en) |
CZ (1) | CZ280064B6 (en) |
DE (1) | DE4124081A1 (en) |
DK (1) | DK137591A (en) |
ES (1) | ES2039177B1 (en) |
FI (1) | FI913493L (en) |
FR (1) | FR2664814B1 (en) |
GB (1) | GB2246072B (en) |
GR (1) | GR1002175B (en) |
HU (1) | HUT59592A (en) |
IL (1) | IL98894A0 (en) |
IT (1) | IT1250681B (en) |
NL (1) | NL9101268A (en) |
SE (1) | SE9102160L (en) |
TW (1) | TW203012B (en) |
YU (1) | YU47573B (en) |
ZA (1) | ZA915677B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9072791B2 (en) | 2008-09-30 | 2015-07-07 | Denki Kagaku Kogyo Kabushiki Kaisha | Photostabilized pharmaceutical compositions |
US10543202B2 (en) | 2017-05-30 | 2020-01-28 | University Of Sasktachewan | Topical nifedipine formulations and uses thereof |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9411115D0 (en) * | 1994-06-03 | 1994-07-27 | Secr Defence | Stabilisation of photosensitive material |
RU2109510C1 (en) * | 1995-04-24 | 1998-04-27 | Пфайзер Инк. | Method of inhibition, tablet and capsule |
DE19912623A1 (en) * | 1999-03-20 | 2000-09-28 | Lohmann Therapie Syst Lts | Process for increasing the stability when storing and / or using light-sensitive therapeutic systems or their components |
JP3549522B1 (en) * | 2003-10-24 | 2004-08-04 | 日清ファルマ株式会社 | Coenzyme Q10-containing capsule |
KR200489660Y1 (en) * | 2018-02-09 | 2019-07-19 | 김순희 | Putting Exerciser |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS55127448A (en) * | 1979-03-23 | 1980-10-02 | Chugai Pharmaceut Co Ltd | Gelatin coating |
JPS6043046B2 (en) * | 1979-04-24 | 1985-09-26 | パ−ク・デ−ビス・エンド・コンパニ− | gelatin capsules |
JPS55161863A (en) * | 1979-06-06 | 1980-12-16 | Paaku Deebisu Kk | Colored gelatin capsule |
EP0143857B1 (en) * | 1983-11-30 | 1988-04-06 | Siegfried Aktiengesellschaft | Therapeutic coronary composition in the form of soft gelatine capsules |
JPS61225109A (en) * | 1985-03-29 | 1986-10-06 | Shiseido Co Ltd | Caramel-containing composition |
DE3526546A1 (en) * | 1985-07-25 | 1987-01-29 | Scherer Gmbh R P | LIGHT-RESISTANT OPAKED GELATINE CAPSULES AND METHOD FOR THE PRODUCTION THEREOF |
DE3532129A1 (en) * | 1985-09-10 | 1987-03-12 | Bayer Ag | GELATINE CONTAINING SS CAROTINE |
US4689233A (en) * | 1986-01-06 | 1987-08-25 | Siegfried Aktiengesellschaft | Coronary therapeutic agent in the form of soft gelatin capsules |
EP0272336B1 (en) * | 1986-12-18 | 1991-10-23 | Kurt H. Prof. Dr. Bauer | Nifidipine concentrate stabilized against the influence of light, and method for its preparation |
JPS63215641A (en) * | 1987-03-05 | 1988-09-08 | Toyo Jozo Co Ltd | Gelatin film composition |
JPH01218573A (en) * | 1988-02-25 | 1989-08-31 | Yoshio Tanaka | Dunaliella algae-containing solid food and production thereof |
-
1990
- 1990-07-20 HU HU904564A patent/HUT59592A/en unknown
-
1991
- 1991-07-10 SE SE9102160A patent/SE9102160L/en not_active Application Discontinuation
- 1991-07-17 CZ CS912222A patent/CZ280064B6/en unknown
- 1991-07-17 CH CH2125/91A patent/CH681960A5/de not_active IP Right Cessation
- 1991-07-18 KR KR1019910012224A patent/KR920002162A/en not_active Withdrawn
- 1991-07-19 YU YU127191A patent/YU47573B/en unknown
- 1991-07-19 ZA ZA915677A patent/ZA915677B/en unknown
- 1991-07-19 FR FR9109183A patent/FR2664814B1/en not_active Expired - Fee Related
- 1991-07-19 NL NL9101268A patent/NL9101268A/en not_active Application Discontinuation
- 1991-07-19 IL IL98894A patent/IL98894A0/en unknown
- 1991-07-19 DK DK137591A patent/DK137591A/en not_active Application Discontinuation
- 1991-07-19 IT ITMI912002A patent/IT1250681B/en active IP Right Grant
- 1991-07-19 CA CA002047482A patent/CA2047482A1/en not_active Abandoned
- 1991-07-19 JP JP3203542A patent/JPH04253924A/en active Pending
- 1991-07-19 BE BE9100683A patent/BE1006829A3/en not_active IP Right Cessation
- 1991-07-19 TW TW080105605A patent/TW203012B/zh active
- 1991-07-19 FI FI913493A patent/FI913493L/en not_active Application Discontinuation
- 1991-07-19 GR GR910100319A patent/GR1002175B/en unknown
- 1991-07-19 ES ES9101701A patent/ES2039177B1/en not_active Expired - Fee Related
- 1991-07-19 DE DE4124081A patent/DE4124081A1/en not_active Withdrawn
- 1991-07-19 GB GB9115693A patent/GB2246072B/en not_active Expired - Fee Related
-
1996
- 1996-03-08 CY CY184096A patent/CY1840A/en unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9072791B2 (en) | 2008-09-30 | 2015-07-07 | Denki Kagaku Kogyo Kabushiki Kaisha | Photostabilized pharmaceutical compositions |
US10543202B2 (en) | 2017-05-30 | 2020-01-28 | University Of Sasktachewan | Topical nifedipine formulations and uses thereof |
Also Published As
Publication number | Publication date |
---|---|
SE9102160D0 (en) | 1991-07-10 |
IT1250681B (en) | 1995-04-21 |
TW203012B (en) | 1993-04-01 |
KR920002162A (en) | 1992-02-28 |
DK137591D0 (en) | 1991-07-19 |
CZ280064B6 (en) | 1995-10-18 |
GB9115693D0 (en) | 1991-09-04 |
YU127191A (en) | 1994-05-10 |
FI913493A0 (en) | 1991-07-19 |
GR1002175B (en) | 1996-03-07 |
GR910100319A (en) | 1992-08-26 |
FI913493A7 (en) | 1992-01-21 |
DK137591A (en) | 1992-01-21 |
YU47573B (en) | 1995-10-03 |
IL98894A0 (en) | 1992-07-15 |
ITMI912002A1 (en) | 1993-01-19 |
CH681960A5 (en) | 1993-06-30 |
FR2664814A1 (en) | 1992-01-24 |
NL9101268A (en) | 1992-02-17 |
ES2039177A1 (en) | 1993-09-01 |
CS222291A3 (en) | 1992-02-19 |
HU904564D0 (en) | 1990-12-28 |
GB2246072B (en) | 1994-06-15 |
BE1006829A3 (en) | 1995-01-03 |
FR2664814B1 (en) | 1995-05-24 |
CY1840A (en) | 1996-03-08 |
ITMI912002A0 (en) | 1991-07-19 |
SE9102160L (en) | 1992-01-21 |
ZA915677B (en) | 1993-03-31 |
DE4124081A1 (en) | 1992-01-23 |
JPH04253924A (en) | 1992-09-09 |
ES2039177B1 (en) | 1994-03-16 |
HUT59592A (en) | 1992-06-29 |
FI913493L (en) | 1992-01-21 |
GB2246072A (en) | 1992-01-22 |
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FZDE | Discontinued |