JPH0341020A - Drug composition - Google Patents
Drug compositionInfo
- Publication number
- JPH0341020A JPH0341020A JP17771589A JP17771589A JPH0341020A JP H0341020 A JPH0341020 A JP H0341020A JP 17771589 A JP17771589 A JP 17771589A JP 17771589 A JP17771589 A JP 17771589A JP H0341020 A JPH0341020 A JP H0341020A
- Authority
- JP
- Japan
- Prior art keywords
- pharmaceutical composition
- drug
- sustained
- release
- water
- 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.)
- Pending
Links
- 229940079593 drug Drugs 0.000 title claims abstract description 80
- 239000003814 drug Substances 0.000 title claims abstract description 80
- 239000000203 mixture Substances 0.000 title abstract description 27
- 229920002451 polyvinyl alcohol Polymers 0.000 claims abstract description 44
- 239000004372 Polyvinyl alcohol Substances 0.000 claims abstract description 42
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 35
- 239000000194 fatty acid Substances 0.000 claims abstract description 35
- 229930195729 fatty acid Natural products 0.000 claims abstract description 35
- 150000004665 fatty acids Chemical class 0.000 claims abstract description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000000839 emulsion Substances 0.000 claims abstract description 23
- 238000013268 sustained release Methods 0.000 claims abstract description 21
- 239000012730 sustained-release form Substances 0.000 claims abstract description 21
- 125000002091 cationic group Chemical group 0.000 claims abstract description 17
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 claims abstract description 10
- BTFJIXJJCSYFAL-UHFFFAOYSA-N arachidyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCO BTFJIXJJCSYFAL-UHFFFAOYSA-N 0.000 claims abstract description 10
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims abstract description 7
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 claims abstract description 6
- 229940055577 oleyl alcohol Drugs 0.000 claims abstract description 6
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 30
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 230000008014 freezing Effects 0.000 claims description 10
- 238000007710 freezing Methods 0.000 claims description 10
- 238000006116 polymerization reaction Methods 0.000 claims description 9
- 238000010257 thawing Methods 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 5
- 238000007127 saponification reaction Methods 0.000 claims description 4
- 238000011049 filling Methods 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 2
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 125000001302 tertiary amino group Chemical group 0.000 claims 1
- XDOFQFKRPWOURC-UHFFFAOYSA-N 16-methylheptadecanoic acid Chemical compound CC(C)CCCCCCCCCCCCCCC(O)=O XDOFQFKRPWOURC-UHFFFAOYSA-N 0.000 abstract description 10
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 abstract description 7
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 abstract description 7
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 abstract description 7
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 abstract description 7
- 239000005642 Oleic acid Substances 0.000 abstract description 7
- TVQZAMVBTVNYLA-UHFFFAOYSA-N Pranoprofen Chemical compound C1=CC=C2CC3=CC(C(C(O)=O)C)=CC=C3OC2=N1 TVQZAMVBTVNYLA-UHFFFAOYSA-N 0.000 abstract description 7
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 abstract description 7
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 abstract description 7
- 229960003101 pranoprofen Drugs 0.000 abstract description 7
- 235000021355 Stearic acid Nutrition 0.000 abstract description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 abstract description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 abstract description 3
- 239000008117 stearic acid Substances 0.000 abstract description 3
- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 abstract description 2
- 229960004207 fentanyl citrate Drugs 0.000 abstract description 2
- HTJXMOGUGMSZOG-UHFFFAOYSA-N tiaramide Chemical compound C1CN(CCO)CCN1C(=O)CN1C(=O)SC2=CC=C(Cl)C=C21 HTJXMOGUGMSZOG-UHFFFAOYSA-N 0.000 abstract description 2
- 229950010302 tiaramide Drugs 0.000 abstract description 2
- TWJNQYPJQDRXPH-UHFFFAOYSA-N 2-cyanobenzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1C#N TWJNQYPJQDRXPH-UHFFFAOYSA-N 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 abstract 1
- 235000021360 Myristic acid Nutrition 0.000 abstract 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 abstract 1
- 210000004877 mucosa Anatomy 0.000 abstract 1
- 235000021313 oleic acid Nutrition 0.000 abstract 1
- 238000007493 shaping process Methods 0.000 abstract 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 45
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 37
- 125000000914 phenoxymethylpenicillanyl group Chemical group CC1(S[C@H]2N([C@H]1C(=O)*)C([C@H]2NC(COC2=CC=CC=C2)=O)=O)C 0.000 description 35
- 235000019445 benzyl alcohol Nutrition 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- 239000012153 distilled water Substances 0.000 description 14
- 239000000017 hydrogel Substances 0.000 description 14
- 238000000034 method Methods 0.000 description 14
- 238000009472 formulation Methods 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 9
- 238000010828 elution Methods 0.000 description 9
- FEDJGPQLLNQAIY-UHFFFAOYSA-N 2-[(6-oxo-1h-pyridazin-3-yl)oxy]acetic acid Chemical compound OC(=O)COC=1C=CC(=O)NN=1 FEDJGPQLLNQAIY-UHFFFAOYSA-N 0.000 description 8
- 229960005316 diltiazem hydrochloride Drugs 0.000 description 8
- JJCQSGDBDPYCEO-XVZSLQNASA-N dibekacin Chemical compound O1[C@H](CN)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N JJCQSGDBDPYCEO-XVZSLQNASA-N 0.000 description 7
- 239000000499 gel Substances 0.000 description 7
- 229960002386 prazosin hydrochloride Drugs 0.000 description 7
- WFXFYZULCQKPIP-UHFFFAOYSA-N prazosin hydrochloride Chemical compound [H+].[Cl-].N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 WFXFYZULCQKPIP-UHFFFAOYSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 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 description 5
- 229960000991 ketoprofen Drugs 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 235000020778 linoleic acid Nutrition 0.000 description 4
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- -1 alkali metal salts Chemical class 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000003431 cross linking reagent Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000000774 hypoallergenic effect Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 210000004400 mucous membrane Anatomy 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 2
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- MEAPRSDUXBHXGD-UHFFFAOYSA-N 3-chloro-n-(4-propan-2-ylphenyl)propanamide Chemical compound CC(C)C1=CC=C(NC(=O)CCCl)C=C1 MEAPRSDUXBHXGD-UHFFFAOYSA-N 0.000 description 1
- WTJXVDPDEQKTCV-UHFFFAOYSA-N 4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydron;chloride Chemical compound Cl.C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2C1CC1C(N(C)C)C(=O)C(C(N)=O)=C(O)C1(O)C2=O WTJXVDPDEQKTCV-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical compound OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
- DMPRDSPPYMZQBT-CEAXSRTFSA-N Ifenprodil tartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1CC(CC=2C=CC=CC=2)CCN1C(C)C(O)C1=CC=C(O)C=C1.C1CC(CC=2C=CC=CC=2)CCN1C(C)C(O)C1=CC=C(O)C=C1 DMPRDSPPYMZQBT-CEAXSRTFSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000010669 acid-base reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002390 adhesive tape Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- WOLHOYHSEKDWQH-UHFFFAOYSA-N amantadine hydrochloride Chemical compound [Cl-].C1C(C2)CC3CC2CC1([NH3+])C3 WOLHOYHSEKDWQH-UHFFFAOYSA-N 0.000 description 1
- 229960001280 amantadine hydrochloride Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- KZOWNALBTMILAP-JBMRGDGGSA-N ancitabine hydrochloride Chemical compound Cl.N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 KZOWNALBTMILAP-JBMRGDGGSA-N 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 229940035678 anti-parkinson drug Drugs 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 230000009876 antimalignant effect Effects 0.000 description 1
- 229940124575 antispasmodic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000000168 bronchodilator agent Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003218 coronary vasodilator agent Substances 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- 229960000204 ifenprodil tartrate Drugs 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 229960003630 ketotifen fumarate Drugs 0.000 description 1
- YNQQEYBLVYAWNX-WLHGVMLRSA-N ketotifen fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 YNQQEYBLVYAWNX-WLHGVMLRSA-N 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960002421 minocycline hydrochloride Drugs 0.000 description 1
- 229960005195 morphine hydrochloride Drugs 0.000 description 1
- XELXKCKNPPSFNN-BJWPBXOKSA-N morphine hydrochloride trihydrate Chemical compound O.O.O.Cl.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O XELXKCKNPPSFNN-BJWPBXOKSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 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 description 1
- KJONHKAYOJNZEC-UHFFFAOYSA-N nitrazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1 KJONHKAYOJNZEC-UHFFFAOYSA-N 0.000 description 1
- 229960001454 nitrazepam Drugs 0.000 description 1
- 235000019645 odor Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000000810 peripheral vasodilating agent Substances 0.000 description 1
- 229960002116 peripheral vasodilator Drugs 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 229960001289 prazosin Drugs 0.000 description 1
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229960004604 propranolol hydrochloride Drugs 0.000 description 1
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol hydrochloride Natural products C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 150000003512 tertiary amines Chemical group 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000003021 water soluble solvent Substances 0.000 description 1
Abstract
Description
【発明の詳細な説明】
[産業上の利用分野1
本発明は、ポリビニルアルコール(以下、PVAと略記
する。)を主たる基剤原料とする医薬品組成物に係り、
その製剤のp目を非生理的範囲に設定することなく陽イ
オン性薬物の放出挙動を制御し得る、例えば型剤等の粘
膜適用型製剤に適切な医薬品組成物に関するものである
。Detailed Description of the Invention [Industrial Application Field 1] The present invention relates to a pharmaceutical composition containing polyvinyl alcohol (hereinafter abbreviated as PVA) as a main base material,
The present invention relates to a pharmaceutical composition suitable for mucosally applied preparations such as molds, which can control the release behavior of a cationic drug without setting the p value of the preparation to a non-physiological range.
[従来の技術]
PVAのゲル化法は、従来数多く知られている。それら
を大別すると、
■いわゆる架橋化剤を添加し、化学反応を介して共有結
合もしくはイオン結合を形成させることによりゲル化さ
せる方法、
■特に添加物を加えず、放射線を照射するか、または凍
結・解凍操作を施すことによりゲル化させる方法、
の三者に分類される。[Prior Art] Many methods for gelling PVA are known. Broadly speaking, they are: 1) A method of gelling by adding a so-called crosslinking agent and forming covalent or ionic bonds through a chemical reaction, 2) A method of irradiating with radiation without adding any additives, or It is classified into three methods: 1. A method of gelling by freezing and thawing.
■の場合、用いられる架橋化剤の大部分は生体刺激性を
有し、さらに得られるゲルは機械的強度に劣るため、型
剤などの基剤としては不適当である。In the case of (2), most of the crosslinking agents used are bioirritating and the resulting gel has poor mechanical strength, making it unsuitable as a base material for molds and the like.
上記■の場合、PVAそれ自体は生体に対して低刺激性
であるため、医薬品基剤としての応用の可能性は高い。In the case of (2) above, since PVA itself is hypoallergenic to living organisms, it has a high possibility of application as a pharmaceutical base.
しかしながら、放剣線照割によるゲル化法(例えば、特
開昭50−55647号)を行なうには、放射線照射施
設を必要とし、その製造には比較的大きな経費と労力を
要するため、好ましくない。However, in order to carry out the gelation method using Houken-ray Teruwari (for example, Japanese Patent Application Laid-Open No. 50-55647), a radiation irradiation facility is required, and its production requires relatively large costs and labor, which is not desirable. .
一方、凍結・解凍操作による低温結晶化法(特開昭60
−177066号〉、凍結・部分真空乾燥法(特開昭5
7−130543号)等により得られるPVAヒドロゲ
ルは、医薬品基剤として充分な成域的強度を有し、生体
に対して低刺激性であり、ざらに安価にかつ簡便に製造
できるという優れた特性を有する。On the other hand, a low-temperature crystallization method using freezing and thawing operations (Unexamined Japanese Patent Publication No. 1983
-177066>, freezing/partial vacuum drying method (Unexamined Japanese Patent Publication No. 5
PVA hydrogel obtained by methods such as No. 7-130543) has sufficient structural strength as a pharmaceutical base, is hypoallergenic to living organisms, and has excellent properties such as being able to be produced easily and at a relatively low cost. has.
かかるPVAヒドロゲルを基剤としていわゆる型剤を調
製した場合、当該型剤からの薬物溶出挙動は、一般にそ
の薬物の水溶性と高い相関があり、水溶性が低いほど溶
出速度が小さくなる。When a so-called mold is prepared using such a PVA hydrogel as a base, the elution behavior of a drug from the mold generally has a high correlation with the water solubility of the drug, and the lower the water solubility, the lower the elution rate.
従って、難水溶性薬物であっても塩形成等により水溶性
となり得るものは、製剤のp口を変えることによりその
溶出速度をある程度調節でき(例えば、岩本洋子、他、
日本薬学会第107年会講演要旨集(198γ>、89
4頁)、水発明者も別途これを確認している。Therefore, for poorly water-soluble drugs that can become water-soluble due to salt formation, etc., the dissolution rate can be adjusted to some extent by changing the p-portion of the formulation (for example, Yoko Iwamoto et al.
Abstracts of the 107th Annual Meeting of the Pharmaceutical Society of Japan (198γ>, 89
(p. 4), and the inventor of the water has also separately confirmed this.
しかしながら、例えばpKaが7より大きい陽イオン性
薬物の溶出挙動をPVAヒドロゲルにより制御する場合
には、これら薬物を含有する製剤の0日が7を越えてし
まうことが多い。このような塩基性条件(すなわち、非
生理的条件〉にある製剤を生体、特に粘膜等に適用した
場合には、これらに対し少なからず損傷を与えるから実
質的には適用不可能である。また、たとえ製剤のpl−
1を変えて薬物の溶出速度を調節し得たとしても、かか
る難水溶性薬物はその非水溶性ゆえに、これを均一に含
有せしめることが困難なうえ、薬物が経時的に製剤表面
等に析出することが多く、これをそのまま医療現場に供
給することは困難である。However, for example, when the elution behavior of cationic drugs with a pKa greater than 7 is controlled by PVA hydrogel, the day 0 of formulations containing these drugs often exceeds 7. When a preparation under such basic conditions (i.e., non-physiological conditions) is applied to living organisms, especially mucous membranes, etc., it is practically impossible to apply because it causes considerable damage to these organs. , even if the formulation pl-
Even if it is possible to adjust the elution rate of the drug by changing 1, it is difficult to uniformly contain such poorly water-soluble drugs due to their water insolubility, and the drug may precipitate on the surface of the preparation over time. It is difficult to supply this directly to the medical field.
一方、水溶性有機溶媒を添加して、上記と類似のPVA
ヒドロゲルを得る方法(例えば、特開昭59−6794
6号、または特開昭61−252261号等)も知られ
ている。On the other hand, PVA similar to the above was prepared by adding a water-soluble organic solvent.
Methods for obtaining hydrogels (e.g., JP-A-59-6794)
No. 6, or JP-A No. 61-252261, etc.) are also known.
しかしながら、これらの方法で用いているジメチルスル
ホキシド等の非プロトン性有機溶媒は、薬物の溶解能は
一般に大きいものの、それゆえに皮膚や粘膜等に損傷を
与えることが報告されており、これらを含有するPVA
ヒドロゲルを医薬品製剤として応用することは好ましく
ない。また、多価アルコールの溶解能は一般に小さいた
め、難水溶性薬物を可溶化する目的でこれを添加するの
は不適当である。However, although the aprotic organic solvents used in these methods, such as dimethyl sulfoxide, generally have a high ability to dissolve drugs, they have been reported to damage the skin and mucous membranes, etc. PVA
Application of hydrogels as pharmaceutical formulations is not preferred. Furthermore, since the solubility of polyhydric alcohols is generally low, it is inappropriate to add them for the purpose of solubilizing poorly water-soluble drugs.
[発明が解決しようとする課題]
従って、本発明の課題は、上述の如く徐放化が困難であ
る分子内にアミン基または含窒素芳香環を有する陽イオ
ン性薬物製剤を調製するに際して、製剤のpHを非生理
的条件に設定する等の手段によらずに、製剤からの薬物
の析出防止と徐放化の両方を同時に満足させた医薬品製
剤処方を提案することにある。[Problems to be Solved by the Invention] Therefore, the problem to be solved by the present invention is to solve the following problems when preparing a cationic drug preparation having an amine group or a nitrogen-containing aromatic ring in the molecule, which is difficult to achieve sustained release as described above. The object of the present invention is to propose a pharmaceutical formulation that simultaneously satisfies both the prevention of precipitation of the drug and the sustained release of the drug from the formulation, without resorting to measures such as setting the pH of the drug to a non-physiological condition.
[課題を解決するための手段]
本発明者は鋭意検討の結果、徐放化のためには製剤のp
ト1を非生理的な塩基性に傾けねばならなかった陽イオ
ン性薬物に対して、親和性もしくは相互作用を有する油
状物質をPVA水溶液に加えてエマルジョンを形成させ
、これをヒドロゲル化することにより当該薬物の徐放化
を図る一方、結晶化等による製剤からの薬物析出を起す
ことのないPVAヒドロゲル製剤を設置↑することに成
功した。[Means for Solving the Problems] As a result of extensive studies, the present inventor found that for sustained release,
For cationic drugs, which had to be made non-physiologically basic, an oily substance with affinity or interaction was added to the PVA aqueous solution to form an emulsion, which was then turned into a hydrogel. While aiming for sustained release of the drug, we succeeded in installing a PVA hydrogel formulation that does not cause drug precipitation from the formulation due to crystallization.
すなわち、本発明は、脂肪酸、または脂肪酸とベンジル
アルコール、オクチルドデカノールおよびオレイルアル
コールの中より選ばれる1種または2種以上からなる組
合せとを、エマルジョンの分散質の成分としてPVAヒ
ドロゲルの組成に組み込んだ徐放性粘膜適用型医薬品組
成物に関するものである。That is, the present invention incorporates fatty acids or a combination of fatty acids and one or more selected from benzyl alcohol, octyldodecanol, and oleyl alcohol into the composition of PVA hydrogel as a component of the dispersoid of the emulsion. The present invention relates to a sustained release mucosally applicable pharmaceutical composition.
より詳しくは、炭素数10〜20の脂肪酸、またはかか
る脂肪酸と、ベンジルアルコール、オクチルドデカノー
ルもしくはオレイルアルコールの中より選ばれる1種ま
たはそれ以上からなる組合せ、ポリビニルアルコール、
陽イオン性薬物および水からなる均一な粘性エマルジョ
ンを成形用鋳型に充填し、凍結・解凍操作を施すことに
よりゲル化させてなることを特徴とする徐放性粘膜適用
型医薬品組成物である。More specifically, fatty acids having 10 to 20 carbon atoms, or a combination of such fatty acids and one or more selected from benzyl alcohol, octyldodecanol, or oleyl alcohol, polyvinyl alcohol,
This is a sustained-release mucosal-applicable pharmaceutical composition characterized by filling a uniform viscous emulsion consisting of a cationic drug and water into a mold and gelling it by subjecting it to freezing and thawing operations.
本発明に用いる脂肪酸は炭素数10〜20の脂肪酸であ
り、常温で液体であるものも、固体であるものも用いる
ことができる。The fatty acid used in the present invention is a fatty acid having 10 to 20 carbon atoms, and can be either liquid or solid at room temperature.
常温で液体である炭素数10〜20の脂肪酸としては、
イソステアリン酸やオレイン酸等を好適に使用すること
ができ、また常温で固体である炭素数10〜20の脂肪
酸としては、ミリスチン酸やステアリン酸等が好ましい
。Fatty acids with 10 to 20 carbon atoms that are liquid at room temperature include:
Isostearic acid, oleic acid, etc. can be suitably used, and as the fatty acid having 10 to 20 carbon atoms that is solid at room temperature, myristic acid, stearic acid, etc. are preferable.
常温で液体である炭素数10〜20の脂肪酸は、それ単
独でPVA水溶液と適宜混合することにより安定なエマ
ルジョンを形成させることができ、また薬物の溶解性向
上等、必要に応じてベンジルアルコール、オクチルドデ
カノールもしくはオレイルアルコールの中より選ばれる
1種またはそれ以上からなる組合せと混合することによ
っても同様のエマルジョンを形成させることができる。A fatty acid having 10 to 20 carbon atoms, which is liquid at room temperature, can form a stable emulsion by mixing it alone with an aqueous PVA solution, and it can also be mixed with benzyl alcohol, A similar emulsion can also be formed by mixing with a combination of one or more selected from octyldodecanol or oleyl alcohol.
しかしながら、常温で固体である炭素数10〜20の脂
肪酸は、それ単独でPVA水溶液と混合しても、固体と
して分散するいわゆる懸濁状態を呈するのみで、安定な
エマルジョンを形成させることはできない。従って、本
発明の課題を解決するためには、エマルジョンの分散質
として上記アルコール類が必須であり、これに溶解し得
る量の脂肪酸が用いられる。However, even if a fatty acid having 10 to 20 carbon atoms, which is solid at room temperature, is mixed alone with an aqueous PVA solution, it only exhibits a so-called suspended state in which it is dispersed as a solid, and a stable emulsion cannot be formed. Therefore, in order to solve the problems of the present invention, the above-mentioned alcohol is essential as a dispersoid of the emulsion, and an amount of fatty acid that can be dissolved in this is used.
かかる脂肪酸類は、アルカリ金属塩またはアンモニアを
含む有機アンモニウム塩とすることにより、界面活性を
有するようになる。従って、これらの塩を加えるか、も
しくは適宜このような塩を形成させることによって界面
活性を付与することにより、ざらに−層のエマルジョン
の安定化を図ることかできる。Such fatty acids come to have surface activity by forming them into alkali metal salts or organic ammonium salts containing ammonia. Therefore, by imparting surface activity by adding these salts or forming such salts as appropriate, it is possible to stabilize the emulsion of the rough layer.
炭素数が10未満の脂肪酸については、その大部分が不
快な臭いを発し、またあるものは水溶性であるためエマ
ルジョンを形成せず、それゆえ製剤の0口の著しい低下
が認められるため好ましくない。Fatty acids with less than 10 carbon atoms are undesirable because most of them emit unpleasant odors, and some are water-soluble and therefore do not form emulsions, resulting in a significant decrease in the 0-mouth ratio of the formulation. .
一方、炭素数が20を越える脂肪酸については、安価で
かつ入手か容易な常温で液体であるものがなく、また常
温で固体であるものは上記アルコール類に対する溶解性
が乏しいため、本発明組成物には不適当である。On the other hand, regarding fatty acids having more than 20 carbon atoms, there are no cheap and easily available ones that are liquid at room temperature, and fatty acids that are solid at room temperature have poor solubility in the above alcohols. It is inappropriate for
本発明では、エマルジョンの分散質として上記脂肪酸も
しくは脂肪酸およびアルコール類をその重量百分率で2
〜20%用いるのが好ましい。In the present invention, the above fatty acids or fatty acids and alcohols are used as dispersoids in the emulsion in a weight percentage of 2.
It is preferable to use ~20%.
特に、脂肪酸の添加量は、本発明組成物の薬物溶出速度
を制御するに当り極めて重要な要素となるが、これは目
的とする薬物の種類およびその用法・用量に応じて、0
.1〜20重量%の範囲内で設定することが好ましい。In particular, the amount of fatty acid added is an extremely important factor in controlling the drug elution rate of the composition of the present invention, and this varies depending on the type of target drug and its usage/dose.
.. It is preferable to set it within the range of 1 to 20% by weight.
この含有率が0.1重量%未満の場合には、充分な徐放
化の効果が得られない場合が多いので好ましくない。ま
た、これが20重量%を越えると、ヒドロゲルを作製す
るための操作中、そのエマルジョン状態を安定かつ均一
に保持することが困難である場合が多く、ざらに得られ
たゲルを長期間保存している際に、当該ゲルにおいて一
部同相・液相分離を起こすため、好ましくない。If this content is less than 0.1% by weight, it is not preferable because a sufficient sustained release effect may not be obtained in many cases. Moreover, if this exceeds 20% by weight, it is often difficult to maintain the emulsion state stably and uniformly during the operation for producing a hydrogel, and the roughly obtained gel may not be stored for a long period of time. This is not preferable because some in-phase/liquid phase separation occurs in the gel when the gel is injected.
本発明に用いるPVAは、そのケン化度が95モル%以
上、好ましくは97モル%以上のものである。これより
低いケン化度、特に90モル%未満では、得られるゲル
の機械的強度が劣るため、好ましくない。The PVA used in the present invention has a degree of saponification of 95 mol% or more, preferably 97 mol% or more. A degree of saponification lower than this, particularly less than 90 mol %, is not preferred because the resulting gel has poor mechanical strength.
また、PVAの平均重合度は、1400以上であること
が好ましく、それ以下では充分な機械的強度を有するゲ
ル状態を呈ざない。ただし、平均重合度の異なるPVA
を2種類以上混合して本発明組成物を調製する場合には
、その一方の平均重合度が1800以上であれば、他方
に平均重合度500〜i oooのPVAを用いること
も可能である。Further, the average degree of polymerization of PVA is preferably 1400 or more, and if it is less than that, it will not exhibit a gel state with sufficient mechanical strength. However, PVA with different average degree of polymerization
When preparing the composition of the present invention by mixing two or more types of PVA, as long as one of them has an average degree of polymerization of 1800 or more, it is also possible to use PVA with an average degree of polymerization of 500 to i ooo as the other.
本発明では、これらのPVAを製剤の全体量に対して5
〜30重量%用いることが好ましい。この範囲外の濃度
では、PVAが完全に溶解しなかったり、また溶解して
も、例えばその粘度が著しく高くなってしまうため、後
述する操作上不都合が生ずる。特に平均重合度が140
0以上のPVAを用いる場合には、そのS度は10〜2
5重量%が好ましい。また、平均重合度が500〜1o
ooと平均重合度1800以上のPVAを混合して用い
る場合には、それらのS度をそれぞれ1〜25重量%お
よび5〜20重量%とするのが好ましい。In the present invention, these PVAs are added in an amount of 5% to the total amount of the formulation.
It is preferable to use up to 30% by weight. If the concentration is outside this range, the PVA may not be completely dissolved, or even if it is dissolved, its viscosity will be extremely high, resulting in operational inconveniences as described below. In particular, the average degree of polymerization is 140
When using PVA of 0 or more, its S degree is 10 to 2
5% by weight is preferred. In addition, the average degree of polymerization is 500 to 1o
When using a mixture of PVA having an average degree of polymerization of 1800 or more, it is preferable that the S degree thereof is 1 to 25% by weight and 5 to 20% by weight, respectively.
上記の組成、すなわち基剤に以下に述べる陽イオン性薬
物をその必要量加え、さらに水を加えて100%として
、これを溶解せしめ、均一な粘性エマルジョンを得る(
以下、これを薬物含有ゾルと称する。)。Add the required amount of the cationic drug described below to the above composition, that is, the base, and then add water to make it 100% and dissolve it to obtain a uniform viscous emulsion (
Hereinafter, this will be referred to as a drug-containing sol. ).
なお、目的とする薬物が高温下で不安定な場合には、上
記組成より薬物を除いた成分を予め加熱溶解させ、適度
な温度以下になった後、その薬物を適宜これに加えて混
合し、均一な薬物含有ゾルを得るとよい。In addition, if the target drug is unstable at high temperatures, heat and dissolve the components of the above composition excluding the drug in advance, and after the temperature drops to an appropriate temperature or below, add the drug as appropriate and mix. , it is preferable to obtain a uniform drug-containing sol.
この薬物含有ゾルを所望の成形用鋳型に注入し、凝固点
以下の温度、通常−10℃〜−20’Cにて凍結し、1
〜5°Cにて徐々に解凍する。この凍結・解凍操作を施
す回数は、多いほど得られるゲルの機械的強度が増加す
るが、通常1〜3回程度が好ましい。This drug-containing sol is injected into a desired mold and frozen at a temperature below the freezing point, usually -10°C to -20'C.
Thaw gradually at ~5°C. The greater the number of times this freezing/thawing operation is performed, the greater the mechanical strength of the resulting gel, but it is usually preferably about 1 to 3 times.
本発明の対象となる陽イオン性薬物は、その分子内に第
一級、第二級または第三級アミン基、第四級アンモニウ
ム基もしくは含窒素芳香環を有する薬物を意味する。ま
た、その含有率は、製剤中において0,01〜30重量
%の範囲が適当である。The cationic drug that is the subject of the present invention means a drug that has a primary, secondary or tertiary amine group, quaternary ammonium group, or nitrogen-containing aromatic ring in its molecule. Moreover, its content in the formulation is suitably in the range of 0.01 to 30% by weight.
含有率が0.01重量%に満だない場合には、薬物の必
要量を含有させ得ないか、もしくは、その薬効が充分に
発揮され得る程の薬物溶出速度がjqられないことがあ
るので好ましくない。また、30重量%を越えると、保
存中に製剤表面等に薬物が析出することがあるので好ま
しくない。If the content is less than 0.01% by weight, it may not be possible to contain the necessary amount of the drug, or the drug dissolution rate may not be high enough to fully demonstrate its medicinal efficacy. Undesirable. Moreover, if it exceeds 30% by weight, the drug may precipitate on the surface of the preparation during storage, which is not preferable.
ただし、薬物によってその物性はそれぞれ異aるため、
上記薬物の全てに関して、その必要量を含有せしめ得る
わけではないが、例えば、以下に掲げる薬物が、その製
剤学士許容し得る塩を含めて対象となり得る。However, since the physical properties differ depending on the drug,
Although it is not possible to contain all of the above-mentioned drugs in the necessary amounts, for example, the drugs listed below, including their pharmaceutically acceptable salts, may be included.
すなわち、ニトラゼパム等の抗てんかん薬、プラノプロ
フェン、塩酸チアラミド等の抗炎症薬、クエン酸フエン
タニール、塩酸モルヒネ等の鎮痛薬、硫酸ジベカシン、
塩酸ミノサイクリン等の抗生物質、臭化チメピジウム等
の鎮痙薬、塩酸アマンタジン等の抗パーキンソン薬、硫
!ナルブタモール等の気管支拡張薬、フマル酸ケトチフ
エン等の抗アレルギー薬、塩酸プラ′ゾシン等の降圧薬
、ニフェジピン等の冠血管拡張薬、酒石酸イフエンプロ
ジル等の末梢血管拡張薬、塩酸プロプラノロール等のβ
−受容体遮断薬、塩酸アンシタビン等の抗悪性腫瘍薬等
である。Namely, antiepileptic drugs such as nitrazepam, anti-inflammatory drugs such as pranoprofen and tiaramide hydrochloride, analgesics such as fentanyl citrate and morphine hydrochloride, dibekacin sulfate,
Antibiotics such as minocycline hydrochloride, antispasmodics such as thimepidium bromide, antiparkinsonian drugs such as amantadine hydrochloride, sulfur! Bronchodilators such as nalbutamol, antiallergic drugs such as ketotifen fumarate, antihypertensive drugs such as prazosin hydrochloride, coronary vasodilators such as nifedipine, peripheral vasodilators such as ifenprodil tartrate, β-based drugs such as propranolol hydrochloride, etc.
- Receptor blockers, ancitabine hydrochloride, and other anti-malignant tumor drugs.
[作用]
本発明により得られるヒドロゲル製剤は、その組成中に
脂肪酸、または脂肪酸と、ベンジルアルコール
ルアルコールの中より選ばれる1種またはそれ以上から
なる組合せを含有している。これらの油状物質は、脂溶
性薬物に対して優れた溶解能を有するものの、水との相
溶性は極めて低い。[Function] The hydrogel preparation obtained by the present invention contains in its composition a fatty acid or a combination of a fatty acid and one or more selected from benzyl alcohol. Although these oily substances have excellent ability to dissolve fat-soluble drugs, their compatibility with water is extremely low.
この相互に混じり合わない水−油状物質両相をPVAに
て安定かつ均一なエマルジョンとし、ざらにこれに凍結
・解凍操作を施すことにより、そのエマルジョン状態を
保持したままヒドロゲル化することができた。By forming these mutually immiscible water and oil phases into a stable and uniform emulsion using PVA and roughly freezing and thawing this, we were able to form a hydrogel while maintaining the emulsion state. .
この方法により、従来困難であった難水溶性薬物をPV
Aヒドロゲル中に安定かつ均一に含有せしめることがで
きた。これは、多価アルコールやジメチルスルホキシド
等の非プロトン性極性有機溶媒等、水に可溶な溶媒をP
VAヒドロゲル中に添加した場合とは本質的に異なり、
水に溶けない油状物質を用いたことによって初めて得ら
れた、いわばエマルジョン型PVAヒドロゲルにより達
成された新知見である。With this method, poorly water-soluble drugs, which were previously difficult to use, can be treated with PV.
A: It was possible to stably and uniformly contain it in the hydrogel. This allows water-soluble solvents such as polyhydric alcohols and aprotic polar organic solvents such as dimethyl sulfoxide to be
Essentially different from when added into VA hydrogel,
This is a new finding achieved for the first time by using an oily substance that is insoluble in water, so to speak, with an emulsion-type PVA hydrogel.
さらに、上記陽イオン性薬物と上記脂肪酸との間で形成
される酸・塩基反応等に基づく相互作用もしくは親和性
により、製剤のpトlを非生理的範囲に設定することな
く同薬物の製剤からの放出挙動を制御することができた
。この技術は、陽イオン性薬物についてのみ適用され得
るものであるが、その薬物が水溶性であるか否かは重要
ではない。Furthermore, due to the interaction or affinity based on the acid-base reaction formed between the cationic drug and the fatty acid, it is possible to formulate the same drug without setting the PTL of the drug to a non-physiological range. We were able to control the release behavior from Although this technique can only be applied to cationic drugs, it does not matter whether the drug is water soluble or not.
[実施例]
次に実施例をあげて本発明の医薬品組成物について説明
するが、本発明はかかる実施例のみに限定されるもので
はない。なお、下記文中に用いられる単位%は、特にこ
とわりのある場合を除き、すべて重量百分率を意味する
。[Examples] Next, the pharmaceutical composition of the present invention will be explained with reference to Examples, but the present invention is not limited to these Examples. In addition, the unit % used in the following text means a weight percentage unless otherwise specified.
実施例1
塩酸プラゾシン106mff、オレイン酸1.6 g、
オクチルドデカノール6.4g、蒸溜水57.5 gお
よびPVA [日本合成化学工業■製、ゴーセノールN
ロー26(商品名)、ケン化度99.4モル%以上、平
均重合度2600] 14.4gを200m1入りガラ
ス製ビーカーに入れ、オートクレーブ(110℃、1.
2気圧)中にて40分間hD熱した。Example 1 Prazosin hydrochloride 106 mff, oleic acid 1.6 g,
Octyldodecanol 6.4 g, distilled water 57.5 g and PVA [manufactured by Nippon Gosei Kagaku Kogyo ■, Gohsenol N
Rho 26 (trade name), degree of saponification 99.4 mol% or more, average degree of polymerization 2600] 14.4 g was placed in a 200 ml glass beaker, and autoclaved (110°C, 1.
2 atm) for 40 minutes.
内圧が常圧と等しくなった後、熱時殴拌して均一な薬物
含有ゾルを得た。これを市販の型剤形成用鋳型((11
カナエ製、ポリ塩化ビニル製、1.59用鋳型〉に1,
59ずつ分注した。After the internal pressure became equal to normal pressure, the mixture was stirred while hot to obtain a uniform drug-containing sol. This was used as a commercially available mold agent forming mold ((11
Made by Kanae, made of polyvinyl chloride, mold for 1.59〉1,
59 portions were dispensed.
次いで、鋳型の開口部を粘着テープにて簡易に密封し、
−10℃にて10時間放置することにより上記ゾルを凍
結後、4℃にて14時間放置することによりこれを解凍
した。Next, the opening of the mold was simply sealed with adhesive tape.
The above sol was frozen by standing at -10°C for 10 hours, and then thawed by standing at 4°C for 14 hours.
この凍結・解凍操作をざらに1工程繰り返すことにより
、1剤中、塩酸プラゾシン2.0mgおよびオレイン酸
2%をそれぞれ含有する医薬品組成物A@得た。By roughly repeating this freezing/thawing operation for one step, a pharmaceutical composition A@ containing 2.0 mg of prazosin hydrochloride and 2% of oleic acid, respectively, was obtained.
実施例2
実施例1と同様の操作により、塩酸プラゾシン106m
g、ステアリン11.6 g、オクチルドデカノール6
.4g、蒸溜水57.5gおよびPVA14.4gより
、1剤1.50g中、塩酸プラゾシン2、Q mgおよ
びステアリン酸2%をそれぞれ含有する医薬品組成物B
を得た。Example 2 Prazosin hydrochloride 106m was prepared in the same manner as in Example 1.
g, stearin 11.6 g, octyldodecanol 6
.. Pharmaceutical composition B containing 2 mg of prazosin hydrochloride, 2 mg of Q, and 2% of stearic acid in 1.50 g of one drug from 4 g of distilled water, 57.5 g of distilled water, and 14.4 g of PVA.
I got it.
実施例3
リノール酸1.69、ベンジルアルコール6.49、蒸
溜水55.0gおよびPVA14.IJを200d入り
ガラス製ビーカーに入れ、オートクレーブ(110℃、
1,2気圧〉中にて40分間加熱した。Example 3 Linoleic acid 1.69, benzyl alcohol 6.49, distilled water 55.0 g and PVA 14. Place IJ in a 200d glass beaker and autoclave (110℃,
The mixture was heated for 40 minutes in a pressure of 1.2 atm.
内圧が常圧と等しくなった後、塩酸ジルチアゼム2.6
9を熱時加えて攪拌し、均一な薬物含有ゾルを得た。こ
れを実施例1にて記載した如く、1.99用坐剤成形用
鋳型に1.90gずつ分注し、凍結・解凍操作を2回施
すことにより、1剤中、塩酸ジルチアゼム60mF!お
よびリノール酸2%をそれぞれ含有する医薬品組成物C
を得た。After the internal pressure becomes equal to normal pressure, diltiazem hydrochloride 2.6
9 was added while hot and stirred to obtain a uniform drug-containing sol. As described in Example 1, by dispensing 1.90 g each into a mold for forming a 1.99 suppository and performing freezing and thawing twice, diltiazem hydrochloride 60 mF! and pharmaceutical composition C containing 2% of linoleic acid, respectively.
I got it.
実施例4
実施例3と同様の操作により、リノール酸4,09、ベ
ンジルアルコール4.09.蒸溜水55.09、PVA
14.4gおよび塩酸ジルチアゼム2.6gより、1剤
1.909中、塩酸ジルチアゼム60mgおよびリノー
ル酸5%をそれぞれ含有する医薬品組成物りを得た。Example 4 By the same operation as in Example 3, linoleic acid 4.09, benzyl alcohol 4.09. Distilled water 55.09, PVA
From 14.4 g of diltiazem hydrochloride and 2.6 g of diltiazem hydrochloride, a pharmaceutical composition containing 60 mg of diltiazem hydrochloride and 5% of linoleic acid in 1.909 mg of linoleic acid was obtained.
実施例5
実施例3と同様の操作により、イソステアリン13.2
9、ベンジルアルコール4,89、蒸溜水55.59、
PVA14.47および硫酸ジベカシン2.13より、
1剤1.90g中、5AWジベ力シン50mgおよびイ
ソステアリン酸4%をそれぞれ含有する医薬品組成物E
を得た。Example 5 By the same operation as in Example 3, isostearin 13.2
9, benzyl alcohol 4.89, distilled water 55.59,
From PVA14.47 and dibekacin sulfate 2.13,
Pharmaceutical composition E containing 50 mg of 5AW gibberycin and 4% isostearic acid in 1.90 g of one drug
I got it.
実施例6
実施例3と同様の操作により、イソステアリン酸6.4
g、ベンジルアルコール1.6g、蒸溜水55.5g、
PVA14.4g#よび硫酸シヘカシン2.13より、
1剤1.90g中、硫酸ジベカシン50mgおよびイソ
ステアリン酸8%をそれぞれ含有する医薬品組成物「を
得た。Example 6 By the same operation as in Example 3, isostearic acid 6.4
g, benzyl alcohol 1.6g, distilled water 55.5g,
From PVA 14.4g# and cyhekacin sulfate 2.13,
A pharmaceutical composition containing 50 mg of dibekacin sulfate and 8% of isostearic acid in 1.90 g of each drug was obtained.
実施例7
実施例1と同様の操作により、プラノプロフェン5.0
g、ベンジルアルコール4.og、オレイン98.0
(j、蒸溜水48.6g#cにヒPVA14.4gヨ
リ、1剤1.909中、プラノプロフェン120#Ig
およびオレイン酸10%をそれぞれ含有する医薬品組成
物Gを得た。Example 7 Pranoprofen 5.0 was prepared in the same manner as in Example 1.
g, benzyl alcohol 4. og, olein 98.0
(j, 14.4 g of human PVA in 48.6 g of distilled water #c, 1 drug of 1.909, 120 #Ig of pranoprofen
A pharmaceutical composition G containing 10% of oleic acid and 10% of oleic acid was obtained.
比較例1
実施例1と同様の操作により、塩酸プラゾシン106m
LiI、オクチルドデカノール8.0g、蒸溜水57.
5gお、に[PVA14.4gヨリ、1剤1.50g中
、塩酸プラゾシン2.0mgおよびエマルジョンの分散
質としてベンジルアルコール10%をそれぞれ含有し、
脂肪酸を含まない医薬品組成物P8得た。Comparative Example 1 By the same operation as in Example 1, 106 m of prazosin hydrochloride was
LiI, octyldodecanol 8.0g, distilled water 57.
5 g of rice [14.4 g of PVA, 1.50 g of 1 drug, each containing 2.0 mg of prazosin hydrochloride and 10% benzyl alcohol as a dispersoid of the emulsion,
Pharmaceutical composition P8 containing no fatty acid was obtained.
里較拠2
実施例3と同様の操作により、ベンジルアルD−/L/
8.0 ’j、蒸l水55.09、PVA14.4gお
よび塩酸ジルチアゼム2.6gより、1剤1.90g中
、塩酸ジルチアゼム601Qおよびエマルジョンの分散
質としてベンジルアルコール10%をそれぞれ含有し、
脂肪酸を含まない医薬品組成物Qを得た。Base 2 By the same operation as in Example 3, benzylal D-/L/
8.0 'j, 55.09 g of steamed water, 14.4 g of PVA and 2.6 g of diltiazem hydrochloride, each containing 1.90 g of diltiazem hydrochloride 601Q and 10% benzyl alcohol as a dispersoid of the emulsion,
A pharmaceutical composition Q containing no fatty acid was obtained.
止較坐旦
実施例3と同様の操作により、蒸溜水63.5g、PV
A14.4 ’j i13 ヨ(j硫M’、、’ヘカシ
ン2.1 !?、にす、1剤1.909中、硫酸ジベカ
シン50m’jを含有し、エマルジョン構造を持たない
医薬品組成物Rを得た。By the same operation as in Example 3, 63.5 g of distilled water and PV
A14.4 'j i13 yo (j sulfur M',, 'Hekacin 2.1!?, Nisu, 1 drug 1.909, pharmaceutical composition R containing 50m'j of dibekacin sulfate and having no emulsion structure I got it.
比較例4
実施例3と同様の操作により、ベンジルアルコール8.
0g、蒸溜水55.5g、PVA14.4g#よび硫酸
ジベカシン2.1gより、1剤1.90g中、硫酸ジベ
カシン501119およびエマルジョンの分散質として
ベンジルアルコール10%をそれぞれ含有し、脂肪酸を
含まない医薬品組成物Sを得た。Comparative Example 4 Benzyl alcohol 8.
0 g, distilled water 55.5 g, PVA 14.4 g, and dibekacin sulfate 2.1 g, each drug contains 1.90 g of dibekacin sulfate 501119 and 10% benzyl alcohol as a dispersoid in the emulsion, and does not contain fatty acids. Composition S was obtained.
比較例5
実施例1と同様の操作により、プラノプロフェン5.0
(j、ベンジルアルコール12.0g、蒸溜水48.
69cnJIFPVA14.4gより、1剤1.90g
中、プラノプロフェン120myおよびエマルジョンの
分散質としてベンジルアルコール10%をそれぞれ含有
し、脂肪酸を含まない医薬品組成物下を得た。Comparative Example 5 By the same operation as in Example 1, pranoprofen 5.0
(j, benzyl alcohol 12.0g, distilled water 48.
From 69cnJIFPVA14.4g, 1 drug 1.90g
A pharmaceutical composition containing 120 ml of pranoprofen and 10% benzyl alcohol as a dispersoid of the emulsion and containing no fatty acid was obtained.
比較例6
実施例1と同様の操作により、ケトプロフェン2.1g
、ベンジルアルコール8,09、蒸溜水55.5g#J
l:ヒPVA14.4gヨリ、1剤1.90g中、ケト
プロフェン50/#Iおよびベンジルアルコール10%
をそれぞれ含有する医薬品組成物Uを得た。Comparative Example 6 2.1 g of ketoprofen was prepared in the same manner as in Example 1.
, benzyl alcohol 8.09, distilled water 55.5g#J
l: 14.4g of human PVA, 1.90g of 1 drug, 50/#I of ketoprofen and 10% benzyl alcohol
A pharmaceutical composition U containing each of the following was obtained.
比較例7
実施例1と同様の操作により、ケトプロフェン2.1g
、オレイン16.4 g、ベンジルアルコール1.6g
、蒸溜水55.5gおJ[PVA14.4gJ:す、1
剤1.90g中、ケトプロフェン50/#Iよびオレイ
ン酸8%をそれぞれ含有する医薬品組成物Vを得た。Comparative Example 7 2.1 g of ketoprofen was prepared in the same manner as in Example 1.
, olein 16.4 g, benzyl alcohol 1.6 g
, Distilled water 55.5g J [PVA 14.4g J: Su, 1
A pharmaceutical composition V containing 50/#I of ketoprofen and 8% of oleic acid in 1.90 g of the drug was obtained.
越」4例」−: 製剤表面における結晶析出性実施例
1〜7および比較例1〜7で得た医薬品組成物A−G、
P−Vを調製直後、それぞれ1個ずつ(1群4例〉ガラ
ス製スクリュー管瓶[■井内盛栄堂製、ラボラン(商品
名)パック、10d用]に入れて密栓を施した後、それ
ぞれ4.20および40’Cの温度条件にて3カ月間保
存し、製剤表面における薬物結晶析出の有無を観察した
。何れの条件下で保存しても、各製剤の表面に薬物の結
晶析出は認められなかった。"Example 4"-: Crystal precipitation on the surface of the preparation Pharmaceutical compositions A-G obtained in Examples 1 to 7 and Comparative Examples 1 to 7,
Immediately after preparing P-V, one each (4 cases per group) was placed in a glass screw tube bottle [Iuchi Seieido, Labolan (trade name) pack, for 10d] and sealed tightly. The preparations were stored for 3 months at temperatures of 20 and 40°C, and the presence or absence of drug crystal precipitation on the surface of the preparations was observed.No matter which conditions the preparations were stored, no drug crystal precipitation was observed on the surface of each preparation. I couldn't.
試験例2: 製剤からの薬物溶出挙動
第11改正日本薬局方の溶出試験法に準拠して行なった
。Test Example 2: Drug dissolution behavior from the preparation This was conducted in accordance with the dissolution test method of the 11th edition of the Japanese Pharmacopoeia.
すなわち、溶出試験器(富山産業■製、NTR5S3)
を用いて、50mMリン酸力ルシウム緩衝液(0口7.
4 ) 10100O!中にA−G、P−Vをそれぞれ
1個ずつ加え、37℃、毎分50回転(パドル法)にて
攪拌した。That is, dissolution tester (manufactured by Toyama Sangyo ■, NTR5S3)
Using 50mM lucium phosphate buffer (0 mouths 7.
4) 10100O! One each of A-G and PV was added thereto, and the mixture was stirred at 37° C. and 50 revolutions per minute (paddle method).
これらの試験液を24時間にわたり経時的(1時間、5
時間、24時間)に採取した後、−旦製剤を取り出して
これを細かく裁断し、これを再びその試験器に移し入れ
、さらに20時間攪拌して試験液を採取した。These test solutions were applied over 24 hours (1 hour, 5 hours).
After sampling at 24 hours, the preparation was taken out, cut into pieces, transferred to the tester again, stirred for another 20 hours, and a test solution was collected.
この最終採取液の薬物濃度に対する、試験開始後24時
間の各採取液のそれを画分率で表わして薬物溶出率と1
ノだ。その1および5時間後の溶出率および対応する比
較例に対する溶出率の比を画分率で表わし、表−1にま
とめた。The drug concentration of each sample sampled for 24 hours after the start of the test is expressed as a fraction ratio with respect to the drug concentration of this final sample sample, and is calculated as the drug elution rate.
No. The elution rate after 1 and 5 hours and the ratio of the elution rate to the corresponding comparative example were expressed as fractions and summarized in Table 1.
各製剤の]および5時間における薬物溶出率(%〉と対
応する比較例との比(カッコ内%)1時間
12.9 (66,5)
11.5 (59,3)
19.4 (100)
16.3 (76,2)
11.2 (52,3)
21.4 (100)
33.9 (86,0)
31.0 (78,7)
39.9 (101,3)
39.4 (100)
10.4 (53,1)
19.6 (100)
24.6 (100)
23.4 (95,1)
5時間
36.8 (79,1)
32.0 (68,8)
46.5 (100)
28.8 71.8)
20.4 50.9)
40.1 100)
62.0 80.5)
58.4 75.8)
72.0 93.5)
77.0 100)
26.9 65.1)
41.3 100)
57.5 (100)
51.9 (90,3)
[発明の効果]
表−1に示した如く、難水溶性の陽イオン性薬物である
塩酸プラゾシン(A、BおよびP)、水溶性ながらその
p口によっては脂溶性となり得る陽イオン性薬物の塩酸
ジルチアゼム(C,DおよびQ)、p口の如何にかかわ
らず脂溶性となり得ない陽イオン性薬物の硫酸ジベカシ
ン(E、F、RおよびS)、および分子内にカルボキシ
ル基と含窒素芳香環の両方を有するプラノプロフェン(
GおよびT)は、何れも本発明の処方によりその製剤か
ら徐放的に放出された。例えば、5時間までの薬物溶出
率で、脂肪酸を添加した実施例とこれを添加していない
比較例との対比では、20.5〜49.1%の徐放化が
認められた。Ratio of drug dissolution rate (%) of each formulation and 5 hours to the corresponding comparative example (% in parentheses) 1 hour 12.9 (66,5) 11.5 (59,3) 19.4 (100 ) 16.3 (76,2) 11.2 (52,3) 21.4 (100) 33.9 (86,0) 31.0 (78,7) 39.9 (101,3) 39.4 (100) 10.4 (53,1) 19.6 (100) 24.6 (100) 23.4 (95,1) 5 hours 36.8 (79,1) 32.0 (68,8) 46 .5 (100) 28.8 71.8) 20.4 50.9) 40.1 100) 62.0 80.5) 58.4 75.8) 72.0 93.5) 77.0 100) 26.9 65.1) 41.3 100) 57.5 (100) 51.9 (90,3) [Effects of the invention] As shown in Table 1, hydrochloric acid, a poorly water-soluble cationic drug, Prazosin (A, B and P), a cationic drug diltiazem hydrochloride (C, D and Q) which is water-soluble but can be fat-soluble depending on its p-position; a cation that cannot be fat-soluble regardless of its p-portion; dibekacin sulfate (E, F, R, and S), which are sex drugs, and pranoprofen (which has both a carboxyl group and a nitrogen-containing aromatic ring in the molecule)
G and T) were both released in a sustained manner from the formulation according to the present invention. For example, in the drug elution rate up to 5 hours, a sustained release of 20.5 to 49.1% was observed between Examples in which fatty acids were added and Comparative Examples in which fatty acids were not added.
また、それらの徐放化の度合は、既述の脂1’J/[の
添加量依存的であり(例えば、C,DおよびQ、または
E、「およびR,S)、かかる脂肪酸が上記薬物の徐放
化に対して大きく寄与していることが示唆される。In addition, the degree of sustained release of these fatty acids depends on the amount of added fat 1'J/[ (for example, C, D and Q, or E, "and R, S"), and such fatty acids are It is suggested that it greatly contributes to the sustained release of drugs.
さらに、これらの薬物は、少なくとも3力月の保存期間
内にその製剤表面に結晶として析出するようなことはな
かった(試験例1)。Furthermore, these drugs did not precipitate as crystals on the surface of the preparation within a storage period of at least 3 months (Test Example 1).
一方、分子内にアミン基および含窒素芳香環の何れをも
有さない薬物であるケトプロフェン(UおよびV)は、
本発明により上記保存安定性を付与することができるも
のの、その製剤からの放出挙動に徐放性は認められなか
った。On the other hand, ketoprofen (U and V), which is a drug that does not have either an amine group or a nitrogen-containing aromatic ring in its molecule,
Although the above storage stability can be imparted by the present invention, sustained release was not observed in the release behavior from the formulation.
特g![出願人 昭和電工株式会社Special g! [Applicant: Showa Denko Co., Ltd.
Claims (1)
、オクチルドデカノールおよびオレイルアルコールの中
から選ばれる1種または2種以上の組合せと、ポリビニ
ルアルコールと、陽イオン性薬物と水とからなる均一な
粘性エマルジョンを成形用鋳型に充填し、凍結・解凍操
作を施すことによりゲル化させてなることを特徴とする
徐放性粘膜適用型医薬品組成物。 2)常温で液体である炭素数10〜20の脂肪酸と、ポ
リビニルアルコールと、陽イオン性薬物と水とからなる
均一な粘性エマルジョンを成形用鋳型に充填し、凍結・
解凍操作を施すことによりゲル化させてなることを特徴
とする徐放性粘膜適用型医薬品組成物。 3)炭素数10〜20の脂肪酸が0.1〜20重量%含
有される請求項1または2記載の徐放性粘膜適用型医薬
品組成物。 4)炭素数10〜20の脂肪酸と、ベンジルアルコール
、オクチルドデカノールおよびオレイルアルコールの中
より選ばれる1種または2種以上の組合せとの和が、そ
の重量百分率として2〜20%含有される請求項1記載
の徐放性粘膜適用型医薬品組成物。 5)ポリビニルアルコールが、ケン化度95モル%以上
で、平均重合度が500以上である請求項1または2記
載の徐放性粘膜適用型医薬品組成物。 6)ポリビニルアルコールが5〜30重量%含有される
請求項1または2記載の徐放性粘膜適用型医薬品組成物
。 7)陽イオン性薬物が、その分子内に第一級、第二級ま
たは第三級アミノ基、第四級アンモニウム基もしくは含
窒素芳香環を有する請求項1または2記載の徐放性粘膜
適用型医薬品組成物。 8)陽イオン性薬物が0.01〜30重量%含有される
請求項1または2記載の徐放性粘膜適用型医薬品組成物
。 9)水が25〜92重量%含有される請求項1または2
記載の徐放性粘膜適用型医薬品組成物。[Scope of Claims] 1) A fatty acid having 10 to 20 carbon atoms, one or a combination of two or more selected from benzyl alcohol, octyldodecanol, and oleyl alcohol, polyvinyl alcohol, and a cationic drug. 1. A sustained-release mucosal-applicable pharmaceutical composition characterized by filling a uniform viscous emulsion with water into a mold and gelling it by freezing and thawing. 2) Fill a mold with a homogeneous viscous emulsion consisting of a fatty acid with a carbon number of 10 to 20, polyvinyl alcohol, a cationic drug, and water, which is liquid at room temperature, and freeze it.
A sustained-release mucosal-applicable pharmaceutical composition characterized by being gelled by thawing. 3) The sustained-release mucosally applicable pharmaceutical composition according to claim 1 or 2, which contains 0.1 to 20% by weight of a fatty acid having 10 to 20 carbon atoms. 4) A claim in which the sum of a fatty acid having 10 to 20 carbon atoms and one or more combinations selected from benzyl alcohol, octyldodecanol, and oleyl alcohol is contained in a weight percentage of 2 to 20%. Item 2. The sustained-release mucosally applicable pharmaceutical composition according to item 1. 5) The sustained-release mucosally applicable pharmaceutical composition according to claim 1 or 2, wherein the polyvinyl alcohol has a degree of saponification of 95 mol% or more and an average degree of polymerization of 500 or more. 6) The sustained-release mucosally applicable pharmaceutical composition according to claim 1 or 2, containing 5 to 30% by weight of polyvinyl alcohol. 7) The sustained release mucosal application according to claim 1 or 2, wherein the cationic drug has a primary, secondary or tertiary amino group, quaternary ammonium group or nitrogen-containing aromatic ring in its molecule. type pharmaceutical composition. 8) The sustained-release mucosally applicable pharmaceutical composition according to claim 1 or 2, wherein the cationic drug is contained in an amount of 0.01 to 30% by weight. 9) Claim 1 or 2, wherein water is contained in an amount of 25 to 92% by weight.
The sustained release mucosally applicable pharmaceutical composition as described.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP17771589A JPH0341020A (en) | 1989-07-10 | 1989-07-10 | Drug composition |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP17771589A JPH0341020A (en) | 1989-07-10 | 1989-07-10 | Drug composition |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH0341020A true JPH0341020A (en) | 1991-02-21 |
Family
ID=16035845
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP17771589A Pending JPH0341020A (en) | 1989-07-10 | 1989-07-10 | Drug composition |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0341020A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH04257519A (en) * | 1991-02-08 | 1992-09-11 | Ss Pharmaceut Co Ltd | Sustained release pharmaceutical preparation of pranoprofen |
US5482973A (en) * | 1991-05-24 | 1996-01-09 | Dojin Iyaku-Kako Co., Ltd. | Suppository preparation |
-
1989
- 1989-07-10 JP JP17771589A patent/JPH0341020A/en active Pending
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH04257519A (en) * | 1991-02-08 | 1992-09-11 | Ss Pharmaceut Co Ltd | Sustained release pharmaceutical preparation of pranoprofen |
US5482973A (en) * | 1991-05-24 | 1996-01-09 | Dojin Iyaku-Kako Co., Ltd. | Suppository preparation |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5541926B2 (en) | Novel biomaterials for ophthalmic drug delivery and methods for their manufacture and use | |
Tae et al. | Sustained release of human growth hormone from in situ forming hydrogels using self-assembly of fluoroalkyl-ended poly (ethylene glycol) | |
JP4648632B2 (en) | New biomaterials, their manufacture and use | |
WO2020029432A1 (en) | Medical hydrogel | |
JPH0624582B2 (en) | Absorbable hemostatic composition | |
JP2003192597A (en) | Adhesion preventive agent | |
JPH03502704A (en) | Method for producing water-insoluble biocompatible gel | |
US4983386A (en) | Method for inhibiting the decrease in viscosity of gel ointment base and ointment | |
US20150232623A1 (en) | Method of preparing a composition based on hyaluronic acid | |
CN112225912B (en) | Degradable medical hydrogel | |
EP2511336B1 (en) | Thixotropic composition, especially for postoperative adhesion prophylaxis | |
US20200171166A1 (en) | Gel composition and method for producing gel composition | |
JPH0341020A (en) | Drug composition | |
JP5107584B2 (en) | Functional jelly composition and method for producing the same | |
US20070213406A1 (en) | Anti-Inflammatory Analgesic External Aqueus Liquid Preparation | |
KR0159145B1 (en) | Method of manufacturing emulsion network for transdermal dry delivery system | |
JPH01186823A (en) | Production of medicament-permeating substance | |
WO2016152186A1 (en) | Gel local anesthetic agent and gel local anesthetic preparation using same | |
CN107693842B (en) | Medical water-resistant gel and preparation method thereof | |
JPH07188059A (en) | Therapeutic agent for periodontosis | |
JPH0288519A (en) | Pharmaceutical composition | |
EP1541144B1 (en) | Indometacin external preparation | |
JPH01311015A (en) | Drug composition | |
RU2745998C1 (en) | Bioadhesive antibacterial composition, the method of its manufacture (options) | |
JP4202656B2 (en) | Topical sustained-release ointment |