JPH04217926A - Percutaneous absorption composition of narcotic and non-narcotic analgesic agent composition - Google Patents
Percutaneous absorption composition of narcotic and non-narcotic analgesic agent compositionInfo
- Publication number
- JPH04217926A JPH04217926A JP8739491A JP8739491A JPH04217926A JP H04217926 A JPH04217926 A JP H04217926A JP 8739491 A JP8739491 A JP 8739491A JP 8739491 A JP8739491 A JP 8739491A JP H04217926 A JPH04217926 A JP H04217926A
- Authority
- JP
- Japan
- Prior art keywords
- narcotic
- transdermal absorption
- hydrochloride
- percutaneous absorption
- composition
- 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.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 33
- 238000010521 absorption reaction Methods 0.000 title claims abstract description 32
- 230000003533 narcotic effect Effects 0.000 title claims abstract description 10
- 239000000730 antalgic agent Substances 0.000 title claims description 14
- 239000004084 narcotic analgesic agent Substances 0.000 title 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000000341 volatile oil Substances 0.000 claims abstract description 5
- 150000003505 terpenes Chemical class 0.000 claims abstract description 3
- 235000007586 terpenes Nutrition 0.000 claims abstract description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract 4
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims abstract 2
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical group CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 claims description 11
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 11
- 229960005195 morphine hydrochloride Drugs 0.000 claims description 11
- 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 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 239000003623 enhancer Substances 0.000 claims description 10
- 229930003658 monoterpene Natural products 0.000 claims description 9
- 235000002577 monoterpenes Nutrition 0.000 claims description 9
- 230000001737 promoting effect Effects 0.000 claims description 7
- 229940035676 analgesics Drugs 0.000 claims description 6
- 150000002773 monoterpene derivatives Chemical class 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 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 claims description 4
- 239000001525 mentha piperita l. herb oil Substances 0.000 claims description 4
- 235000019477 peppermint oil Nutrition 0.000 claims description 4
- WUOACPNHFRMFPN-UHFFFAOYSA-N alpha-terpineol Chemical compound CC1=CCC(C(C)(C)O)CC1 WUOACPNHFRMFPN-UHFFFAOYSA-N 0.000 claims description 3
- 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 3
- 229960003771 cocaine hydrochloride Drugs 0.000 claims description 3
- SQIFACVGCPWBQZ-UHFFFAOYSA-N delta-terpineol Natural products CC(C)(O)C1CCC(=C)CC1 SQIFACVGCPWBQZ-UHFFFAOYSA-N 0.000 claims description 3
- 229960004207 fentanyl citrate Drugs 0.000 claims description 3
- 229940116411 terpineol Drugs 0.000 claims description 3
- ZPPBASOODYCKDP-YZZSNFJZSA-N (4r,4ar,7s,7ar,12bs)-9-ethoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;hydrochloride Chemical compound Cl.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OCC ZPPBASOODYCKDP-YZZSNFJZSA-N 0.000 claims description 2
- DKSZLDSPXIWGFO-BLOJGBSASA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;phosphoric acid;hydrate Chemical compound O.OP(O)(O)=O.OP(O)(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC DKSZLDSPXIWGFO-BLOJGBSASA-N 0.000 claims description 2
- NBUHTTJGQKIBMR-UHFFFAOYSA-N 4,6-dimethylpyrimidin-5-amine Chemical compound CC1=NC=NC(C)=C1N NBUHTTJGQKIBMR-UHFFFAOYSA-N 0.000 claims description 2
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 claims description 2
- 229960001889 buprenorphine hydrochloride Drugs 0.000 claims description 2
- UAIXRPCCYXNJMQ-RZIPZOSSSA-N buprenorphine hydrochlorie Chemical compound [Cl-].C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)C[NH+]2CC1CC1 UAIXRPCCYXNJMQ-RZIPZOSSSA-N 0.000 claims description 2
- GMTYREVWZXJPLF-AFHUBHILSA-N butorphanol D-tartrate Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O.N1([C@@H]2CC3=CC=C(C=C3[C@@]3([C@]2(CCCC3)O)CC1)O)CC1CCC1 GMTYREVWZXJPLF-AFHUBHILSA-N 0.000 claims description 2
- 229960001590 butorphanol tartrate Drugs 0.000 claims description 2
- 229960004415 codeine phosphate Drugs 0.000 claims description 2
- 229960000920 dihydrocodeine Drugs 0.000 claims description 2
- 229940051129 meperidine hydrochloride Drugs 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
- 229960000482 pethidine Drugs 0.000 claims description 2
- RBOXVHNMENFORY-DNJOTXNNSA-N dihydrocodeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC RBOXVHNMENFORY-DNJOTXNNSA-N 0.000 claims 1
- 229960002428 fentanyl Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 19
- 229940079593 drug Drugs 0.000 abstract description 17
- 229940124532 absorption promoter Drugs 0.000 abstract description 7
- 238000002347 injection Methods 0.000 abstract description 7
- 239000007924 injection Substances 0.000 abstract description 7
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- 238000009472 formulation Methods 0.000 description 24
- 210000003491 skin Anatomy 0.000 description 15
- 231100000245 skin permeability Toxicity 0.000 description 11
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound 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 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- -1 hydrocarbon monoterpenes Chemical class 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 229960005181 morphine Drugs 0.000 description 5
- 210000000434 stratum corneum Anatomy 0.000 description 5
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000004888 barrier function Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 230000035699 permeability Effects 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 230000002500 effect on skin Effects 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 description 1
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- ZGSZBVAEVPSPFM-FFHNEAJVSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,5,6,7,7a,13-octahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;2,3-dihydroxybutanedioic acid Chemical compound OC(=O)C(O)C(O)C(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC ZGSZBVAEVPSPFM-FFHNEAJVSA-N 0.000 description 1
- SJVGFKBLUYAEOK-SFHVURJKSA-N 6-[4-[(3S)-3-(3,5-difluorophenyl)-3,4-dihydropyrazole-2-carbonyl]piperidin-1-yl]pyrimidine-4-carbonitrile Chemical compound FC=1C=C(C=C(C=1)F)[C@@H]1CC=NN1C(=O)C1CCN(CC1)C1=CC(=NC=N1)C#N SJVGFKBLUYAEOK-SFHVURJKSA-N 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- WTEVQBCEXWBHNA-UHFFFAOYSA-N Citral Natural products CC(C)=CCCC(C)=CC=O WTEVQBCEXWBHNA-UHFFFAOYSA-N 0.000 description 1
- WEEGYLXZBRQIMU-UHFFFAOYSA-N Eucalyptol Chemical compound C1CC2CCC1(C)OC2(C)C WEEGYLXZBRQIMU-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- CKDOCTFBFTVPSN-UHFFFAOYSA-N borneol Natural products C1CC2(C)C(C)CC1C2(C)C CKDOCTFBFTVPSN-UHFFFAOYSA-N 0.000 description 1
- 229940116229 borneol Drugs 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229960005233 cineole Drugs 0.000 description 1
- RFFOTVCVTJUTAD-UHFFFAOYSA-N cineole Natural products C1CC2(C)CCC1(C(C)C)O2 RFFOTVCVTJUTAD-UHFFFAOYSA-N 0.000 description 1
- 229940043350 citral Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- DTGKSKDOIYIVQL-UHFFFAOYSA-N dl-isoborneol Natural products C1CC2(C)C(O)CC1C2(C)C DTGKSKDOIYIVQL-UHFFFAOYSA-N 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000010642 eucalyptus oil Substances 0.000 description 1
- 229940044949 eucalyptus oil Drugs 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- WTEVQBCEXWBHNA-JXMROGBWSA-N geranial Chemical compound CC(C)=CCC\C(C)=C\C=O WTEVQBCEXWBHNA-JXMROGBWSA-N 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 229930002839 ionone Natural products 0.000 description 1
- 150000002499 ionone derivatives Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 235000001510 limonene Nutrition 0.000 description 1
- 229940087305 limonene Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229960004739 sufentanil Drugs 0.000 description 1
- GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical compound C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】0001
【産業上の利用分野】本発明は、モルヒネ或はその塩類
又は塩基類に代表される鎮痛剤等の経皮吸収性製剤に関
するものである。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to transdermal absorbable preparations such as analgesics such as morphine or its salts or bases.
【０００２】0002
【従来技術】モルヒネ或はその塩類に代表される鎮痛剤
や非麻薬性鎮痛剤は、術後及び癌性とう痛の緩和を目的
として注射或は経口的に投与されている。BACKGROUND OF THE INVENTION Analgesics and non-narcotic analgesics such as morphine or its salts are administered by injection or orally for the purpose of alleviating postoperative and cancer pain.
【０００３】0003
【発明が解決しようとする課題】しかしながら、かかる
注射剤の場合は、一般に第三者による投与を必要とする
ために在宅療法が難しく、さらにモルヒネのように作用
時間の短い薬物では投与頻度が増加するので激痛時の投
与が難しいという欠点がある。[Problems to be Solved by the Invention] However, in the case of such injections, home therapy is difficult because they generally require administration by a third party, and furthermore, drugs such as morphine that have a short action time require frequent administration. Therefore, it has the disadvantage that it is difficult to administer when there is severe pain.
【０００４】また経口投与剤は、投与や使用の簡便かを
目的に開発され、注射剤の欠点をいくつか克服している
が、作用時間に関しては注射剤に比較してあまり改善さ
れておらず、徐放化のために製剤的工夫を凝らしても消
化器内の製剤の移行性、滞留性の制御が難しく、持続性
には限界がある。さらに癌末期患者の中には抗癌剤の副
作用である嘔吐や吐き気のために鎮痛剤が経口投与でき
ない者もいる。[0004] Orally administered drugs were developed for ease of administration and use, and have overcome some of the drawbacks of injections, but their duration of action has not been much improved compared to injections. However, even if formulation efforts are made to achieve sustained release, it is difficult to control the transfer and retention of the formulation in the gastrointestinal tract, and its sustainability is limited. Furthermore, some terminally ill cancer patients cannot receive oral painkillers due to vomiting and nausea, which are side effects of anticancer drugs.
【０００５】一方経皮適用製剤は、１回の投与で２４時
間〜１週間程度の薬効の持続性が期待できると共に、経
口投与が不可能な患者にも適用できる。 一般に薬物
の経皮吸収性は低く、モルヒネやその塩類を始めとする
鎮痛剤も例外ではない。On the other hand, transdermal preparations can be expected to maintain efficacy for about 24 hours to one week after a single administration, and can also be applied to patients who are unable to administer the drug orally. Transdermal absorption of drugs is generally low, and analgesics such as morphine and its salts are no exception.
【０００６】薬物の経皮吸収の主なバリアーは角質層に
あり、角質層の脂質等に対して促進剤が経皮吸収性を高
めるものとして種々促進剤が開発されてきたが、角質層
に作用する単純な吸収促進剤やその組合せだけでは角質
層以外の表皮の薬物透化性がバリアーとなることからあ
まり優れたものは開発されていない。The main barrier to transdermal absorption of drugs is the stratum corneum, and various accelerators have been developed for lipids in the stratum corneum to enhance transdermal absorption. Only simple absorption enhancers or combinations thereof have not been developed that are particularly effective because the drug permeability of the epidermis, other than the stratum corneum, acts as a barrier.
【０００７】そこで本発明者達は、かかる従来技術の欠
点に鑑み、従来注射剤又は経口剤としてしか利用されな
かったモルヒネ等の鎮痛剤を軟膏、クリーム、テープ剤
、プラスター剤、パッチ剤、パップ剤等の外用剤への利
用を鋭意検討した結果本発明を見いだし完成させたもの
である。[0007] In view of the drawbacks of the prior art, the present inventors developed an analgesic agent such as morphine, which was conventionally available only as an injection or an oral agent, into ointments, creams, tapes, plasters, patches, and poultices. The present invention was discovered and completed as a result of intensive study on its use in external preparations such as preparations.
【０００８】[0008]
【課題を解決するための手段】すなわち本発明は、テル
ペン類及び／又は精油からなる経皮吸収促進剤と、炭素
数が１〜５の低級アルコールからなる経皮吸収促進助剤
とを含有する麻薬性及び皮麻薬性鎮痛剤の経皮吸収組成
物により本目的を達成する。[Means for Solving the Problems] That is, the present invention contains a transdermal absorption promoter comprising a terpene and/or an essential oil, and a transdermal absorption promoter comprising a lower alcohol having 1 to 5 carbon atoms. This object is achieved by transdermal compositions of narcotic and narcotic analgesics.
【０００９】本発明に使用する麻薬性の沈痛剤としては
、塩酸モルヒネ、塩酸エチルモルヒネ、硫酸モルヒネ、
塩酸コカイン、塩酸ペチジン、リン酸コデイン、リン酸
ジヒドロコデイン、クエン酸フェンタニール、スフェン
タニール、塩酸メペリジン、等を用い、非麻薬性の鎮痛
剤としては塩酸ブプレノルフィン、酒石酸ブトルファノ
ールもしくはその他の塩類等の非麻薬性鎮痛剤を用いる
。尚、これらの製剤は塩基性のもので構成してもよい。[0009] Narcotic analgesics used in the present invention include morphine hydrochloride, ethylmorphine hydrochloride, morphine sulfate,
Cocaine hydrochloride, pethidine hydrochloride, codeine phosphate, dihydrocodeine phosphate, fentanyl citrate, sufentanil, meperidine hydrochloride, etc. are used, and non-narcotic analgesics such as buprenorphine hydrochloride, butorphanol tartrate or other salts are used. Use painkillers. Incidentally, these preparations may be made of basic ones.
【００１０】経皮吸収促進剤は、リモネン等の炭化水素
系モノテルペン類、ｌーメントール、テルピネオール、
ボルネオール等のモノテルペンアルコール、シトラール
等のモノテルペンアルデヒド、ヨノン等のモノテルペン
ケトン、シネオール等のその他のモノテルペン類又はハ
ッカ油、ペパーミント油、ユーカリ油のようなモノテル
ペンを含む精油を用いる。また経皮吸収促進助剤は、エ
タノール、イソプロピルアルコールのような炭素数１〜
５の低級アルコールを用いる。[0010] Transdermal absorption enhancers include hydrocarbon monoterpenes such as limonene, l-menthol, terpineol,
Monoterpene alcohols such as borneol, monoterpene aldehydes such as citral, monoterpene ketones such as ionone, other monoterpenes such as cineole, or essential oils containing monoterpenes such as peppermint oil, peppermint oil, and eucalyptus oil are used. In addition, percutaneous absorption promoting aids include ethanol and isopropyl alcohol, which have 1 or more carbon atoms.
5 lower alcohol is used.
【００１１】又配合量としては、経皮吸収促進剤が２〜
２０重量％で、経皮吸収促進助剤が２０〜６０重量％で
あるのが好ましい。尚、その他の経皮吸収促進剤として
炭素数８〜２２個のアルコール、炭素数８〜２２個の脂
肪酸、炭素数が８〜２２個の脂肪酸メチル、エチル、ビ
ニル、ｎ−プロピル、イソプロピル、プロピレン、ｎ−
ブチル、イソブチル又はブチレンエステル、炭素数１〜
１６個のｎ−アルキルピロリドン類及び／又はこれらの
混合物を添加しても良い。[0011] The amount of percutaneous absorption enhancer is 2 to 2.
20% by weight, and preferably 20 to 60% by weight of the transdermal absorption promoting aid. In addition, other transdermal absorption enhancers include alcohols having 8 to 22 carbon atoms, fatty acids having 8 to 22 carbon atoms, fatty acids having 8 to 22 carbon atoms, methyl, ethyl, vinyl, n-propyl, isopropyl, propylene. , n-
Butyl, isobutyl or butylene ester, carbon number 1 -
16 n-alkylpyrrolidones and/or mixtures thereof may be added.
【００１２】さらにその他の経皮吸収促進助剤として、
水、グリセリン、プロピレングリコール等の炭素数が２
〜２０個の低級グリコール、炭素数が２〜５個の低級ケ
トンまたはアルデヒドを添加してもよい。[0012] Furthermore, as other percutaneous absorption promoting aids,
Water, glycerin, propylene glycol, etc. have 2 carbon atoms
~20 lower glycols, lower ketones having 2 to 5 carbon atoms, or aldehydes may be added.
【００１３】[0013]
【作用】組成物中の経皮吸収促進剤は、皮膚の角質層の
バリアー能を物理的に取り除き、皮膚の薬物透過性を高
める。経皮吸収促進助剤は、薬物の溶解度を高めると共
に薬物透過性を高めることから相乗効果として薬物の吸
収性が著しく向上する。[Action] The transdermal absorption enhancer in the composition physically removes the barrier ability of the stratum corneum of the skin and increases the drug permeability of the skin. Transdermal absorption promoting agents increase drug solubility and drug permeability, resulting in a synergistic effect that significantly improves drug absorption.
【００１４】[0014]
【実施例】以下に本発明を実施例に従って詳細に説明す
る。EXAMPLES The present invention will be explained in detail below according to examples.
【実施例−１】以下の表１に示すような製剤を作成し、
これらについて皮膚透過量の経時変化を以下に示す皮膚
透過試験方法にて確認した。
（皮膚透過試験方法）ヘアレスラット（オス、体重１５
０ｇ、埼玉実験動物株式会社より入手）の腹部摘出皮膚
を３７゜Ｃに保った２−チャンバー拡散セル（接触面積
１．０ｃｍ２）に挟み、角質層側に薬物溶液２．５ｍｌ
、真皮側に水２．５ｍｌを入れ、経時的に拡散セル１０
個の真皮溶液をサンプリングしながら、２、４、６、８
及び１０時間後における皮膚を透過した薬物量を測定す
る。結果は、表２及び図１に示す通りとなった。[Example-1] A preparation as shown in Table 1 below was prepared,
For these, changes over time in the amount of skin permeation were confirmed using the skin permeation test method shown below. (Skin permeation test method) Hairless rat (male, weight 15
0 g, obtained from Saitama Experimental Animal Co., Ltd.) was placed in a two-chamber diffusion cell (contact area 1.0 cm2) maintained at 37°C, and 2.5 ml of drug solution was placed on the stratum corneum side.
, put 2.5 ml of water on the dermis side, and spread the diffusion cell 10 over time.
2, 4, 6, 8 while sampling dermal solutions.
And the amount of drug that permeated through the skin 10 hours later is measured. The results were as shown in Table 2 and FIG. 1.
【００１５】[0015]
【表１】[Table 1]
【表２】[Table 2]
【００１６】この毛か吸収促進剤としてｌ−メントール
を選択し、吸収促進助剤としてエタノールを選択したも
のが経皮吸収性に優れることが判明した。[0016] It has been found that a product in which l-menthol is selected as the absorption promoter and ethanol is selected as the absorption promoter has excellent transdermal absorption.
【００１７】[0017]
【実施例−２】塩酸モルヒネの皮膚透過性に及ぼす濃度
との関係を調べるために以下の表３に示す製剤を作成し
、皮膚透過性試験に基づき検討した。その結果は図２及
び表４に示す通り塩酸モルヒネの濃度に対応して経皮吸
収されることが判明した。[Example 2] In order to investigate the relationship between concentration and skin permeability of morphine hydrochloride, formulations shown in Table 3 below were prepared and examined based on a skin permeability test. As shown in FIG. 2 and Table 4, it was found that morphine hydrochloride was absorbed transdermally in proportion to its concentration.
【００１８】[0018]
【表３】[Table 3]
【表４】[Table 4]
【００１９】[0019]
【実施例−３】表５に示すように経皮吸収促進剤の種類
を変えた製剤を作成し、塩酸モルヒネの経皮吸収性につ
いて比較検討した。 その結果は、図３及び表６に示
すようにいずれの経皮吸収促進剤の場合も塩酸モルヒネ
の経皮吸収性に対して優れていたが、特にテルピネオー
ルが一番良かった。[Example 3] As shown in Table 5, preparations were prepared using different types of transdermal absorption enhancers, and the transdermal absorption of morphine hydrochloride was compared and studied. As shown in FIG. 3 and Table 6, all of the transdermal absorption enhancers were superior to the transdermal absorption of morphine hydrochloride, but terpineol was particularly good.
【００２０】[0020]
【表５】[Table 5]
【表６】[Table 6]
【００２１】[0021]
【実施例−４】ｌ−メントール・エタノール・水系から
の塩酸モルヒネの皮膚透過性に影響を及ぼすｌ−メント
ールの濃度の影響を調べるべく、以下の表７に示すよう
な製剤を作成し、これらの経皮吸収性を検討した。その
結果図４及び表８に示すようにメントールの濃度が２．
５ｗ％以上の時に皮膚透過性に優れることが判明した。[Example 4] In order to investigate the influence of the concentration of l-menthol on the skin permeability of morphine hydrochloride from an l-menthol/ethanol/water system, formulations as shown in Table 7 below were prepared, and these The transdermal absorbability of the compound was investigated. As a result, as shown in Figure 4 and Table 8, the concentration of menthol was 2.
It was found that skin permeability is excellent when the amount is 5w% or more.
【００２２】[0022]
【表７】[Table 7]
【表８】[Table 8]
【００２３】[0023]
【実施例−５】ｌ−メントール・エタノール・水系から
塩酸モルヒネの皮膚透過性に及ぼす経皮吸収促進助剤で
あるエタノールの濃度の影響を調べるべく、以下の表９
に示す製剤を作成し、これらの経皮吸収性を検討した。
その結果図５及び表１０に示すようにエタノールの濃度
が２０ｗ％以上、６０ｗ％以下の時に皮膚透過性に優れ
ることが判明した。[Example 5] In order to investigate the influence of the concentration of ethanol, which is a transdermal absorption promoting agent, on the skin permeability of morphine hydrochloride from l-menthol/ethanol/water system, Table 9 below is shown.
The following formulations were prepared and their percutaneous absorption properties were investigated. As a result, as shown in FIG. 5 and Table 10, it was found that skin permeability was excellent when the concentration of ethanol was 20 w% or more and 60 w% or less.
【００２４】[0024]
【表９】[Table 9]
【表１０】[Table 10]
【００２５】[0025]
【実施例−６】ｌ−メントール・アルコール・水系から
の塩酸モルヒネの皮膚透過性に及ぼすエタノールの代わ
りにイソプロピルアルコール（ＩＰＡと呼ぶ）を採用し
、この濃度の影響を調べるべく以下の表１１に示す製剤
を作成し、これらの経皮吸収性を検討した。その結果図
６及び表１２に示すようにエタノールと同じようにイソ
プロピルアルコールの場合も濃度が２０ｗ％以上で、６
０ｗ％以下の時に皮膚透過性に優れるが、濃度が濃すぎ
るとかえって吸収性が悪くなった。[Example 6] In order to investigate the effect of isopropyl alcohol (referred to as IPA) instead of ethanol on the skin permeability of morphine hydrochloride from l-menthol/alcohol/water system, Table 11 below is shown. The following formulations were prepared and their percutaneous absorption properties were investigated. As a result, as shown in Figure 6 and Table 12, in the case of isopropyl alcohol as well as ethanol, when the concentration is 20 w% or more, 6
When the concentration was 0 w% or less, the skin permeability was excellent, but when the concentration was too high, the absorbency worsened.
【００２６】[0026]
【表１１】[Table 11]
【表１２】[Table 12]
【００２７】[0027]
【実施例−７】ｌ−メントール・エタノール・水系から
の塩酸モルヒネの皮膚透過性に及ぼす経皮吸収性促進助
剤のエタノールの補助として添加した水の代わりに表１
３に示すようにグリセリンを混合した場合の経皮吸収性
を比較検討した。その結果図７及び表１４に示すように
水と同じようにグリセリンを用いても経皮吸収性が維持
されることが判明した。[Example 7] Effect on skin permeability of morphine hydrochloride from l-menthol/ethanol/water system Table 1
As shown in 3, the transdermal absorbability when glycerin was mixed was compared and studied. As a result, as shown in FIG. 7 and Table 14, it was found that transdermal absorbability was maintained even when glycerin was used in the same way as water.
【００２８】[0028]
【表１３】[Table 13]
【表１４】[Table 14]
【００２９】[0029]
【実施例−８】ｌ−メントール・エタノール・水系に対
する他の薬物の皮膚透過性について調査するべく、表１
５に示すようなクエン酸フェンタニール（ＦＴＣと呼ぶ
）、塩酸コカイン（ＣＣＨと呼ぶ）、塩酸モルヒネを用
いた製剤を作成し、これらの経皮吸収性について検討し
た。その結果図８及び表１６に示すようにｌ−メントー
ル・エタノール・水系の場合はいずれも薬剤の場合つい
ても、皮膚透過性に優れることが判明した。[Example 8] In order to investigate the skin permeability of other drugs to l-menthol/ethanol/water system, Table 1
Formulations using fentanyl citrate (referred to as FTC), cocaine hydrochloride (referred to as CCH), and morphine hydrochloride as shown in No. 5 were prepared, and their transdermal absorbability was examined. As a result, as shown in FIG. 8 and Table 16, it was found that all l-menthol/ethanol/water systems had excellent skin permeability even when using drugs.
【００３０】[0030]
【表１５】[Table 15]
【表１６】[Table 16]
【００３１】[0031]
【効果】以上述べたように本発明にかかる経皮吸収促進
性の製剤は、いままで香料としてしか利用されていなか
ったモノテルペン類を経皮吸収促進剤として採用すると
共に経皮吸収促進助剤として炭素数１〜５個の低級アル
コールを採用してこれらを組み合わせることにより従来
のものでは不可能であった薬剤に関して皮膚ぁらの投与
が可能となった。注射剤、経口剤に比べ処方が簡単であ
るため、在宅療法に向いていると共に、持続性に優れる
。[Effects] As described above, the transdermal absorption-promoting formulation according to the present invention employs monoterpenes, which have hitherto been used only as fragrances, as a transdermal absorption promoter, and also as a transdermal absorption-promoting aid. By employing lower alcohols having 1 to 5 carbon atoms and combining them, it has become possible to administer drugs to skin ailments, which was impossible with conventional drugs. Because it is easier to prescribe than injections and oral medications, it is suitable for home therapy and has excellent sustainability.
【図１】実施例−１にかかる製剤と比較例の製剤に関す
る皮膚への透過量の掲示変化を示したグラフである。FIG. 1 is a graph showing changes in the amount of skin permeation for the formulation of Example-1 and the formulation of Comparative Example.
【図２】実施例−２にかかる製剤と比較例の製剤に関す
る皮膚への透過量の掲示変化を示したグラフである。FIG. 2 is a graph showing changes in the amount of skin permeation for the formulation of Example-2 and the formulation of Comparative Example.
【図３】実施例−３にかかる製剤と比較例の製剤に関す
る皮膚への透過量の掲示変化を示したグラフである。FIG. 3 is a graph showing changes in the amount of skin permeation for the formulation according to Example 3 and the formulation of Comparative Example.
【図４】実施例−４にかかる製剤と比較例の製剤に関す
る皮膚への透過量の掲示変化を示したグラフである。FIG. 4 is a graph showing changes in the amount of skin permeation for the formulation of Example-4 and the formulation of Comparative Example.
【図５】実施例−５にかかる製剤と比較例の製剤に関す
る皮膚への透過量の掲示変化を示したグラフである。FIG. 5 is a graph showing changes in the amount of skin permeation for the formulation of Example-5 and the formulation of Comparative Example.
【図６】実施例−６にかかる製剤と比較例の製剤に関す
る皮膚への透過量の掲示変化を示したグラフである。FIG. 6 is a graph showing changes in the amount of skin permeation for the formulation of Example-6 and the formulation of Comparative Example.
【図７】実施例−７にかかる製剤と比較例の製剤に関す
る皮膚への透過量の掲示変化を示したグラフである。FIG. 7 is a graph showing changes in the amount of skin permeation for the formulation of Example 7 and the formulation of Comparative Example.
【図８】実施例−８にかかる製剤と比較例の製剤に関す
る皮膚への透過量の掲示変化を示したグラフである。FIG. 8 is a graph showing changes in the amount of skin permeation for the formulation of Example 8 and the formulation of Comparative Example.
Claims (3)
皮吸収促進剤と、炭素数が１〜５の低級アルコールと、
水又は炭素数２〜５の低級グリコールとからなる経皮吸
収促進助剤と、塩酸モルヒネ、塩酸エチルモルヒネ、硫
酸モルヒネ、塩酸コカイン、塩酸ペチジン、リン酸コデ
イン、リン酸ジヒドロコデイン、クエン酸フェンタニー
ル、スフェンタニール、塩酸メペリジンの麻薬性鎮痛剤
及び塩酸ブプレノルフィン、酒石酸ブトルファノールも
しくはその他の塩類の非麻薬性鎮痛剤のうち少なくとも
１種を混合してなる麻薬性及び非麻薬性鎮痛剤の経皮吸
収組成物。[Claim 1] A transdermal absorption enhancer consisting of terpenes and/or essential oil, a lower alcohol having 1 to 5 carbon atoms,
A transdermal absorption promoting aid consisting of water or a lower glycol having 2 to 5 carbon atoms, morphine hydrochloride, ethylmorphine hydrochloride, morphine sulfate, cocaine hydrochloride, pethidine hydrochloride, codeine phosphate, dihydrocodeine phosphate, fentanyl citrate, A transdermal absorption composition of narcotic and non-narcotic analgesics, which is obtained by mixing at least one of narcotic analgesics such as fentanyl, meperidine hydrochloride, and non-narcotic analgesics such as buprenorphine hydrochloride, butorphanol tartrate, or other salts.
テルピネオールのようなモノテルペン類又はハッカ油、
ペパーミント油のようなモノテルペン類を含む精油であ
る請求項１記載の麻薬性及び非麻薬性鎮痛剤の経皮吸収
組成物。[Claim 2] The transdermal absorption enhancer is l-menthol,
monoterpenes such as terpineol or peppermint oil,
The transdermal absorption composition of narcotic and non-narcotic analgesics according to claim 1, which is an essential oil containing monoterpenes such as peppermint oil.
経皮吸収促進助剤が２０〜６０重量％である請求項１又
は２記載の麻薬性及び非麻薬性鎮痛剤の経皮吸収組成物
。3. The transdermal absorption enhancer is 2 to 20% by weight,
The transdermal absorption composition for narcotic and non-narcotic analgesics according to claim 1 or 2, wherein the transdermal absorption promoting aid is 20 to 60% by weight.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3087394A JP2669951B2 (en) | 1991-03-28 | 1991-03-28 | Transdermal composition containing narcotic analgesic |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3087394A JP2669951B2 (en) | 1991-03-28 | 1991-03-28 | Transdermal composition containing narcotic analgesic |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP02081180 Division | 1990-03-30 | 1990-03-30 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04217926A true JPH04217926A (en) | 1992-08-07 |
| JP2669951B2 JP2669951B2 (en) | 1997-10-29 |
Family
ID=13913667
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3087394A Expired - Lifetime JP2669951B2 (en) | 1991-03-28 | 1991-03-28 | Transdermal composition containing narcotic analgesic |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2669951B2 (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995024197A1 (en) * | 1994-03-11 | 1995-09-14 | Sekisui Chemical Co., Ltd. | Percutaneously absorbable plaster comprising acid-addition salt of morphine |
| EP0819438A2 (en) | 1996-07-19 | 1998-01-21 | Nitto Denko Corporation | Buprenorphine percutaneous absorption preparation |
| JP2001506640A (en) * | 1996-12-16 | 2001-05-22 | エルティエス ローマン テラピー−ズュステーメ アーゲー | Flat formulation for oral administration and release of buprenorphine or a pharmacologically equivalent substance in the oral cavity, and method for producing the same |
| US7056527B2 (en) | 2000-02-25 | 2006-06-06 | Teijin Limited | Patches containing buprenorphine hydrochloride |
| JP2006151927A (en) * | 2004-12-01 | 2006-06-15 | Toin Gakuen | Photodynamic therapy composition |
| JP2007500133A (en) * | 2003-07-25 | 2007-01-11 | ユーロ−セルティーク エス．エイ． | Preoperative treatment of postoperative pain |
| JP2007246546A (en) * | 1998-07-16 | 2007-09-27 | Memorial Sloan-Kettering Cancer Center | Topical composition including opioid analgesic and nmda antagonist |
| WO2011158964A1 (en) | 2010-06-16 | 2011-12-22 | Takasago International Corporation | Transdermal absorption promoter, and external skin formulation thereof |
| WO2020158831A1 (en) * | 2019-01-30 | 2020-08-06 | 国立大学法人九州大学 | Transdermal absorption composition with controlled release of water-soluble hydrochloride |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101621999B (en) | 2007-03-02 | 2012-09-26 | 帝化制药株式会社 | Medicinal composition for transdermal absorption, medicinal composition storing unit and transdermal absorption preparation using the same |
-
1991
- 1991-03-28 JP JP3087394A patent/JP2669951B2/en not_active Expired - Lifetime
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995024197A1 (en) * | 1994-03-11 | 1995-09-14 | Sekisui Chemical Co., Ltd. | Percutaneously absorbable plaster comprising acid-addition salt of morphine |
| EP0819438A2 (en) | 1996-07-19 | 1998-01-21 | Nitto Denko Corporation | Buprenorphine percutaneous absorption preparation |
| US6090405A (en) * | 1996-07-19 | 2000-07-18 | Nitto Denko Corporation | Buprenorphine percutaneous absorption preparation |
| JP2001506640A (en) * | 1996-12-16 | 2001-05-22 | エルティエス ローマン テラピー−ズュステーメ アーゲー | Flat formulation for oral administration and release of buprenorphine or a pharmacologically equivalent substance in the oral cavity, and method for producing the same |
| JP2007246546A (en) * | 1998-07-16 | 2007-09-27 | Memorial Sloan-Kettering Cancer Center | Topical composition including opioid analgesic and nmda antagonist |
| US7056527B2 (en) | 2000-02-25 | 2006-06-06 | Teijin Limited | Patches containing buprenorphine hydrochloride |
| JP2007500133A (en) * | 2003-07-25 | 2007-01-11 | ユーロ−セルティーク エス．エイ． | Preoperative treatment of postoperative pain |
| JP2006151927A (en) * | 2004-12-01 | 2006-06-15 | Toin Gakuen | Photodynamic therapy composition |
| WO2011158964A1 (en) | 2010-06-16 | 2011-12-22 | Takasago International Corporation | Transdermal absorption promoter, and external skin formulation thereof |
| WO2020158831A1 (en) * | 2019-01-30 | 2020-08-06 | 国立大学法人九州大学 | Transdermal absorption composition with controlled release of water-soluble hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2669951B2 (en) | 1997-10-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5240932A (en) | Percutaneously absorbable compositions of morphine or analogous analgesics of morphine | |
| US5665378A (en) | Transdermal therapeutic formulation | |
| JP4825305B2 (en) | Transdermal absorption preparation | |
| JPH03193728A (en) | Antiphlogistic and analgesic patch | |
| US4910205A (en) | Transdermal delivery of loratadine | |
| WO1996029988A1 (en) | Topical formulation for local delivery of a pharmaceutically active agent | |
| JPH02191214A (en) | Composition for percutaneous delivery of drug active agent | |
| WO2005077364A1 (en) | Transdermal solifenacin preparation and method of improving transdermal permeability thereof | |
| JP3487633B2 (en) | Skin disease treatment emulsion | |
| TW200418487A (en) | Pharmaceutical composition for topical delivery of meloxicam comprising an amine or amine as penetration enhancer. | |
| CA2528360A1 (en) | Anesthetic composition for topical administration comprising lidocaine, prilocaine and tetracaine | |
| JPS60152413A (en) | Composition for local application with improved percutaneousdrug release by menthol | |
| JP4387639B2 (en) | Transdermal absorption preparation | |
| AU2002350272B1 (en) | Transdermal transport of compounds | |
| JP2009013171A (en) | Memantine-containing transdermally absorbable preparation | |
| JPH04217926A (en) | Percutaneous absorption composition of narcotic and non-narcotic analgesic agent composition | |
| JPH0244815B2 (en) | ||
| Walters et al. | Dermatological formulation and transdermal systems | |
| PT96155A (en) | PROCESS FOR THE PREPARATION OF AN ADHESIVE THOUGHT FOR TREATMENT OF COCAINE AND HEROIN DEPENDENCE BY TRANSDERMIC LIBERATION OF BUPRENORFIN | |
| WO2008012071A2 (en) | Pharmaceutical compositions of nicotine and methods of use thereof | |
| JPH0640947A (en) | Composition for percutaneous absorption preparation and percutaneous absorption preparation | |
| JPH0648962A (en) | Composition for percutaneous absorption pharmaceutical preparation | |
| JPS61268631A (en) | Dermal external drug having improved percutaneous absorbability | |
| JPH10231248A (en) | Percutaneous absorption type preparation containing dihydroetorphine | |
| WO2001043736A1 (en) | Drugs for relieving hemicrania |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 19970527 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20080704 Year of fee payment: 11 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20080704 Year of fee payment: 11 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20090704 Year of fee payment: 12 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20100704 Year of fee payment: 13 |
|
| EXPY | Cancellation because of completion of term | ||
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20100704 Year of fee payment: 13 |