TWI451868B - 醫藥組成物之改良及相關之改良 - Google Patents
醫藥組成物之改良及相關之改良 Download PDFInfo
- Publication number
- TWI451868B TWI451868B TW097106779A TW97106779A TWI451868B TW I451868 B TWI451868 B TW I451868B TW 097106779 A TW097106779 A TW 097106779A TW 97106779 A TW97106779 A TW 97106779A TW I451868 B TWI451868 B TW I451868B
- Authority
- TW
- Taiwan
- Prior art keywords
- buprenorphine
- naloxone
- composition
- amount
- pain
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims description 37
- 229960001736 buprenorphine Drugs 0.000 claims description 54
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound 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)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 claims description 54
- 229960004127 naloxone Drugs 0.000 claims description 39
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 claims description 39
- SFNLWIKOKQVFPB-KZCPYJDTSA-N bunavail Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C.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)CN2CC1CC1 SFNLWIKOKQVFPB-KZCPYJDTSA-N 0.000 claims description 32
- 208000002193 Pain Diseases 0.000 claims description 20
- 230000036407 pain Effects 0.000 claims description 20
- 230000000202 analgesic effect Effects 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 16
- 230000037396 body weight Effects 0.000 claims description 11
- 239000002552 dosage form Substances 0.000 claims description 11
- 229940079593 drug Drugs 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 150000002576 ketones Chemical class 0.000 claims description 2
- 239000006211 transdermal dosage form Substances 0.000 claims 1
- 238000012360 testing method Methods 0.000 description 22
- 238000000034 method Methods 0.000 description 19
- 238000001802 infusion Methods 0.000 description 17
- 230000000694 effects Effects 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 210000004877 mucosa Anatomy 0.000 description 10
- 230000037325 pain tolerance Effects 0.000 description 8
- 229940005483 opioid analgesics Drugs 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000005557 antagonist Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 241000282412 Homo Species 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 230000003502 anti-nociceptive effect Effects 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 239000003708 ampul Substances 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000008121 dextrose Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000003887 narcotic antagonist Substances 0.000 description 3
- 230000003040 nociceptive effect Effects 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 230000035807 sensation Effects 0.000 description 3
- 206010013654 Drug abuse Diseases 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
- 229940127450 Opioid Agonists Drugs 0.000 description 2
- 239000008896 Opium Substances 0.000 description 2
- 208000000114 Pain Threshold Diseases 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 2
- 206010038678 Respiratory depression Diseases 0.000 description 2
- 206010039897 Sedation Diseases 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 210000000245 forearm Anatomy 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- 229960001027 opium Drugs 0.000 description 2
- 230000037040 pain threshold Effects 0.000 description 2
- 239000006201 parenteral dosage form Substances 0.000 description 2
- 239000004031 partial agonist Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000036280 sedation Effects 0.000 description 2
- 208000011117 substance-related disease Diseases 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- TXMZWEASFRBVKY-IOQDSZRYSA-N (4r,4as,7ar,12bs)-4a,9-dihydroxy-3-prop-2-enyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one;dihydrate;hydrochloride Chemical compound O.O.Cl.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C TXMZWEASFRBVKY-IOQDSZRYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 239000000150 Sympathomimetic Substances 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 150000001557 benzodiazepines Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229930003827 cannabinoid Natural products 0.000 description 1
- 239000003557 cannabinoid Substances 0.000 description 1
- 229940065144 cannabinoids Drugs 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 230000035487 diastolic blood pressure Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000002050 international nonproprietary name Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 210000002850 nasal mucosa Anatomy 0.000 description 1
- 229940121367 non-opioid analgesics Drugs 0.000 description 1
- 239000003402 opiate agonist Substances 0.000 description 1
- 239000003401 opiate antagonist Substances 0.000 description 1
- 239000000014 opioid analgesic Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 1
- 229960004134 propofol Drugs 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000025488 response to cold Effects 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
Description
本發明係關於含丁丙諾非(buprenorphine)合併納洛酮(naloxone)之醫藥組成物;及其於製造此組成物與臨床實務之用途,如作為止痛劑。
雖然類鴉片(opioids)特別有效於處理中等至嚴重疼痛時,其使用被令人不舒服及潛在的危險副作用所限制,此等副作用可包括鎮靜、呼吸抑制、噁心及腸胃道問題,因此已致力於最小化副作用。
有很多類鴉片且某些產生較其他者更明顯的副作用,因此,小心地選擇類鴉片使用於止痛組成物可自我降低副作用之發生率及嚴重性。一特別合適之類鴉片為丁丙諾非,其已顯示具有激動劑(類嗎啡)及拮抗劑性質,而不會產生明顯的生理依賴性。
對於其他鴉片類止痛劑而言,丁丙諾非(國際非私屬名稱(International Non-proprietary Name)為N-環丙基甲基-7[α]-[1-(S)-羥基-1,2,2-三甲基-丙基]6,14-內乙基橋-6,7,8.14-四氫降奧列巴因(nororipavine))為一種強效鴉片類部分激動劑止痛劑,不會引起精神異常效果。然而,即使因為部分激動劑性質的直接結果,其在呼吸抑制之作用有限度,丁丙諾非具有典型鴉片類激動劑之副作用,例如在一些病患中會噁心及嘔吐、便秘及呼吸抑制。
經由合併類鴉片治療與其他醫藥,亦已嘗試增加類鴉片
之止痛效果同時最小化副作用之發生率及嚴重性。
一種方法係添加非類鴉片止痛劑至類鴉片治療,此理論依據為較低程度之類鴉片應是達到抗傷害性感受(antinociception)所需,因此可降低副作用。
另一方法為與類鴉片激動劑共同投與低劑量之類鴉片拮抗劑。
給予與類鴉片拮抗劑投與有關之類鴉片結合的強力封鎖,此等劑之使用可提供無改良疼痛緩解且與其合併透過激動劑之部份封鎖可想像會增加疼痛為典型被預期者。然而,已發現於某些情形抗傷害性感受可經拮抗劑之共同投與而被強化。
一此種拮抗劑為納洛酮(國際非私屬名稱為1-N-烯丙基-14-羥基降氫-嗎啡酮(morphinone)),其為一種麻醉劑拮抗劑(narcotic antagonist)。
於GB 2150832A揭示一種非腸胃道或舌下型式之止痛組成物,包含活性劑量之丁丙諾非及一定量之納洛酮證實經非腸胃道投與足以排拒麻醉劑成癮但不足以危害丁丙諾非之止痛作用。此非腸胃道劑量型式可包含丁丙諾非及納洛酮,以3:1至1:1之重量比且舌下型式可包含丁丙諾非及納洛酮以1:2至2:1之比例。於GB-A-2150832之試驗係於大鼠。
於EP 1242087A中,其揭示以低劑量納洛酮加強及改良丁丙諾非之非腸胃道及舌下劑量型式。基於在大鼠之試驗,宣稱以丁丙諾非對納洛酮為12.5:1至27.5:1之重量比為一
適合的比例,較佳為15:1至20:1。
現已進行人類研究且已產生以作為類鴉片激動劑之丁丙諾非及以作為類鴉片拮抗劑之納洛酮之組合使用的新發現。此等新發現擴大吾人了解可於人類中給予有效止痛之治療劑量。
依據本發明之第一態樣,其提供一種止痛組成物,為非腸胃道單位劑型或適合經由黏膜或皮膚遞送之單位劑型,此含丁丙諾非及納洛酮含量之組成物為被遞送或到達病患血漿之丁丙諾非對納洛酮重量比範圍為7.5:1至12.4:1之比例。
咸信丁丙諾非之止痛作用經由相對少量之納洛酮而被加強。
應了解本文使用之丁丙諾非及納洛酮一詞意圖涵蓋相關之單體、醫藥化合物,諸如酯類、鹼類及鹽類,例如酸加成鹽。特佳鹽類為氫氯酸鹽。然而本文所指比例及重量係指丁丙諾非及納洛酮本身,而非鹽類、鹼類或酯類。
非腸胃道一詞意圖包涵經由任何非透過消化道路徑之方式投與此組成物。
黏膜一詞意圖包涵任何黏膜,包括口腔黏膜、直腸黏膜、陰道黏膜及鼻腔黏膜。皮膚一詞代表非黏膜皮膚。
端示其性質,投與可經數分鐘,較佳為經至少1分鐘期間,較佳至少2分鐘,更佳至少3分鐘。較佳其經多至10分鐘,更佳多至7分鐘,較佳多至5分鐘。
經皮投與可涵括任何通過皮膚之投與模式。經黏膜投與可涵括任何通過黏膜之投與模式,且投與位置可包括例如陰道及直腸黏膜,且較佳為口腔-鼻腔黏膜,例如鼻、咽喉、頰及舌下位置。鼻及舌下投與為特佳。
較佳於投與完成後60分鐘間達到丁丙諾非對納洛酮之界定比例,即,較佳於投與完成之60分鐘間之某時間,達成於血漿中經界定的醫藥比。
此組成物可包含丁丙諾非及納洛酮以被遞送至或到達病患血漿的丁丙諾非對納洛酮之重量比為至少X:1(X對1),其中X為8.0,較佳為9.0,較佳為9.5,較佳為10.0,較佳為10.5,較佳為11.0。
此組成物可包含丁丙諾非及納洛酮以被遞送至或到達病患血漿的丁丙諾非對納洛酮之重量比為不大於Y:1(Y對1),其中Y為12.3,較佳為12.2,較佳為12.0,較佳為11.5。
另人驚訝地,已發現儘管本發明中納洛酮對丁丙諾非之相對量較高於EP 1242087B,但納洛酮之拮抗劑作用不會“勝出”且納洛酮實際上促進丁丙諾非之激動劑作用。
此組成物可包含非腸胃道單位劑型且丁丙諾非對納洛酮之比例於非腸胃道組成物中可為實質上相同於應用時於病患血漿中所產生者。如此,此非腸胃道劑型可包含丁丙諾非及納洛酮以7.5:1至12.4:1之重量比,此比例之較佳上限及下限如上述於血漿中之丁丙諾非及納洛酮之比。
於人類,如EP 1242087B所述,於缺乏加強作用下為獲得滿意的疼痛緩解要求每公斤體重約40μg丁丙諾非之劑量
為適當的。如此於50至80 kg之典型體重,丁丙諾非劑量可為每日2mg至3.2mg之丁丙諾非。此可以4單位劑被方便投與。
於本發明組成物中為有效所需之丁丙諾非之量係少於無納洛酮加強效果作用所需之量。
重要地,當比較有或無納洛酮之加強效果之相等劑量的丁丙諾非時,前者組成物(即,亦含納洛酮)達到的止痛之強度及期間被顯著地增加。因此當與納洛酮組合時相同的止痛劑效能可以較低的丁丙諾非劑量而達成。已提議於此治療範圍間或超過此治療範圍可達到增加的止痛效果及/或可使用降低濃度之丁丙諾非。
適當地,本發明之組成物(含納洛酮)之單位劑量含丁丙諾非之量低於不含納洛酮之丁丙諾非的單位劑量中獲得相等疼痛緩解所需劑量。
適當地,本發明之組成物每單位劑量包含至少10μg丁丙諾非,較佳至少15μg,較佳至少20μg,更佳至少30μg且最佳至少40μg。此等數值反應出本發明於低劑量達成止痛之優點。
適當地,本發明之組成物可含有任何量之丁丙諾非,多至習用臨床實務之上端。適當地,其每單位劑量可含多至32mg丁丙諾非,較佳地多至16mg,較佳多至8mg,較佳多至4mg,較佳多至2mg,較佳多至1mg,較佳多至600μg,較佳多至400μg,較佳多至200μg,較佳多至160μg,較佳多至100μg。
適當地,依據本發明,每24小時投與病患每公斤體重至少0.25μg之丁丙諾非。此量較佳為至少0.5μg,較佳為至少1μg,較佳為至少1.5μg且最佳為至少2μg。
適當地,依據本發明,每24小時投與病患每公斤(體重)多至640μg之丁丙諾非。此量較佳為多至320μg,較佳多至160μg,較佳多至80μg,較佳多至40μg,較佳多至20μg,較佳多至16μg,較佳多至12μg。最佳此量為不大於8μg。
適當地使用本發明之組成物,為達到緩解疼痛之目的投與丁丙諾非於病患之量為每24小時至少40μg,較佳至少60μg,較佳至少80μg,較佳至少120μg,最佳至少160μg。
適當地使用本發明之組成物,為達到緩解疼痛之目的投與丁丙諾非至病患之量為多至32mg,較佳多至16mg,較佳多至8mg,較佳多至4mg,較佳多至2mg,較佳多至1mg,較佳多至800μg,較佳多至600μg,較佳多至400μg,較佳多至200μg,較佳多至160μg,較佳多至100μg。
適當地,此組成物每單位劑量包含至少1μg之納洛酮較佳至少1.5μg,較佳至少2μg,最佳為至少4μg。
適當地,此組成物每單位劑量包含多至4mg之納洛酮較佳多至2mg,較佳多至1mg,較佳多至500μg,較佳多至300μg,較佳多至200μg,較佳多至100μg,較佳多至80μg,最佳多至50μg。
適當地,投與納洛酮至病患之量為每24小時每公斤體重至少0.025μg。較佳地,此量為至少0.05μg,較佳為至少0.1μg,較佳為至少0.15μg,較佳為至少0.2μg,較佳為至少
0.25μg,較佳為至少0.4μg。
適當地,投與納洛酮之量為每24小時每公斤體重多至320μg之納洛酮。較佳此量為多至160μg,較佳為多至80μg,較佳為多至40μg,較佳為多至20μg,較佳為多至10μg,較佳為多至8μg,較佳為多至6μg。較佳此量為每24小時每公斤體重不大於4μg。
適當地,投與納洛酮每24小時之量為至少5μg,較佳為至少8μg,較佳為至少10μg,較佳為至少15μg,最佳為至少20μg。
適當地,投與納洛酮每24小時之量為多至16mg,較佳為多至8mg,較佳為多至4mg,較佳為多至2mg,較佳為多至1mg,較佳為多至500μg,較佳為多至400μg,較佳為多至300μg,最佳為多至200μg。
上列論及可被投與至病患之化合物的量為指成人病患有關的量。
不管投與之丁丙諾非及納洛酮的絕對量為何,必須滿足本文所述之丁丙諾非對納洛酮之比例之定義。
其較佳為調配此組成物為單位劑型,即,物理學上分離的單位,含適當量之丁丙諾非及納洛酮,與醫藥上可接受的稀釋劑及/或載劑一起。此等非腸胃道投與用單位劑型適合為安瓿型式。經皮或經黏膜投與用單位劑型可例如為錠劑、薄膜、噴霧劑、貼片、擦劑組成物或菱形錠。將進一步描述於第二態樣之投與,可包含遞送含丁丙諾非及納洛酮之藥劑,較佳以此種之一形式。
本發明之組成物可含有緩衝系統,例如有機酸及其鹽,諸如檸檬酸及檸檬酸鈉。
為舌下劑型之組成物適當地含有選自諸如乳糖、木糖醇、右旋糖、蔗糖或其混合物之可溶性賦形劑。其亦可適當地含有顆粒化及崩解劑,選自諸如澱粉之材料,結合劑諸如普維酮(povidone)或羥基丙基甲基纖維素,及潤滑劑諸如硬脂酸鎂。
意圖用於非腸胃道投與之組成物可包含丁丙諾非及納洛酮於無菌水之等張溶液。經由使用右旋糖可方便地將此溶液作成等張,且經由高壓鍋滅菌或經由通過膜過濾器滅菌。此組成物可經肌肉內、皮內、腹腔內、靜脈內、動脈內、皮下或經硬膜外路徑投與。
非腸胃道投與用組成物,或經由黏膜遞送,諸如舌下投與,如上列詳細說明者,可經由彼等熟習此項技藝者已知之製造技術而製備。
依據本發明第二態樣,其提供一種治療人類病患疼痛之方法,此方法包含經由非腸胃道或皮膚或黏膜路徑投與人類病患,以丁丙諾非對納洛酮被遞送至或到達病患血漿之重量比為7.5:1至12.4:1之範圍投與丁丙諾非及納洛酮。
丁丙諾非對納洛酮被遞送至或到達病患血漿之較佳比例如上列定義於第一態樣者。
適當地,此方法包含經由黏膜遞送。此方法可包含以舌下單位劑型遞送。
適當地,於加強丁丙諾非之止痛作用的目的上此方法包
含投與丁丙諾非及及某量之納洛酮,特別是理想化丁丙諾非之止痛作用與納洛酮呈現之抗濫用之間的平衡。應明瞭此平衡係極為重要的。此藥劑必須為一強效止痛劑以達到其所欲功能。同時於現今,打斷鴉片藥劑被成癮者濫用為極重要的。咸信本發明於此等方面為極有效的。
此方法並未排除分開投與丁丙諾非及納洛酮。然而,適當地,此方法包含投與含丁丙諾非及納洛酮之組成物至人類。適當地,此方法運用依據第一態樣之組成物。運用上列所給與第一態樣有關定義於第二態樣,然而注意到丁丙諾非及納洛酮原則上於第二態樣中可被分開投與。
適當地,此方法包含每日投與人類或動物每公斤體重0.25μg至20μg之丁丙諾非。
若單獨投與時,此方法可包含投與一劑可產生最小化或無抗傷害性感受之丁丙諾非。此方法可包含投與人類如上述與本發明第一態樣有關之丁丙諾非及納洛酮之量。
此方法可包含如描述於第一態樣之任何特徵。
依據本發明之第三態樣,其提供丁丙諾非及納洛酮於製造治療疼痛之醫藥之用途,其中使用丁丙諾非及納洛酮之量為遞送此醫藥至病患或到達病患血漿之量為7.5:1至12.4:1之重量比。
適當地此用途包含丁丙諾非及納洛酮之用途,用於製造治療疼痛之醫藥,其中丁丙諾非係用於其止痛效果,但其量低於缺乏納洛酮時對抗所給病患之疼痛的止痛效果所需之量。如此納洛酮係加強丁丙諾非之止痛效果。又,其使此醫
藥較不吸引醫藥成癮者(且較佳為完全不吸引)。
依據第三態樣,丁丙諾非及納洛酮於製造醫藥之用途可包含如第一或第二態樣所述之任何特徵。
適當地,丁丙諾非及納洛酮於製造醫藥之用途包含製造含如第一態樣之組成物之醫藥。然而,並未排除丁丙諾非及納洛酮於製造具2個劑量單位(分別含丁丙諾非及納洛酮)之醫藥之用途。
現將以實施例參照附隨之圖式的方式說明本發明,其中:第1圖為丁丙諾非與納洛酮組合之疼痛耐性結果之圖;第2圖為僅丁丙諾非之疼痛耐性結果之圖;第3圖為一比較圖。
使用冷加壓試驗(cold pressor (CP) test)評價丁丙諾非、丁丙諾非及納洛酮組合之抗傷害性感受。化合物形式為丁丙諾非HCl及納洛酮HCl二水和物。CP試驗利用2個塑膠圓柱形容器,其一者填充溫水,另一者填充水及碎冰之組合使成為“雪泥狀”稠度。受試者將非主要使用的前臂及手浸入溫水恰好2分鐘。於1分45秒,於浸潤的手臂充氣血壓袖套至低於舒張血壓之20mmHg的壓力,於測定對冷的反應,血壓袖套將血流作用減低到最小。於恰好2分鐘時,將前臂由溫水移至冷水浴,於整個程序中覆蓋受試者眼睛以最
小化分心及時間的提示。於浸潤肢體於冷水浴時,要求受試者指出當其第一次經歷疼痛(痛覺閾,CPTHR),然後要求其手臂留置不動浸潤直到其無法再忍受疼痛(痛覺耐性,CPTOL)。以秒記錄由浸潤於冰水中痛覺閾及痛覺耐性時間。強給180秒未揭開的切斷,於由於凍僵而無法再精確評價痛覺耐性時間。痛覺耐性(CPTOL)為目前研究中報告的疼痛反應參數。
於相同環境進行本試驗傷害性感受試驗,以最小化背景雜訊,可聽見的聲音及無可聽見滴嗒聲的鐘。週遭室溫及光照一致。沒有一次實驗者與受試者(他/她)討論試驗性能,或回答任何與平均痛覺耐性時間或任何先前結果有關的問題。
基於如先前醫學條件及醫藥濫用之此等因子,依據包涵及排除標準篩選測試前受試者。
依據下列步驟測試適合的經篩選受試者。於到達試驗日,受試者提供尿液樣本,測試有無醫藥濫用(類鴉片、類毒麻脂(cannabinoids)、苯并二氮呯(benzodiazepines)及擬交感神經胺類),於女性受試者,測試有無懷孕。於每一手臂(高於非主要使用的手臂之CP浸潤線)上插入22口徑留置性靜脈導管於最可取得之前臂靜脈。公螺旋式接口(luer lock)承接管注射位被附著於每一導管,使用一導管於試驗日全日血液抽樣,另一者用於輸液。然後將參加者連接監視
器,其於試驗期間被設定為連續監視生理參數。
於每一試驗日,受試者接受30分鐘未盲目的鹽水靜脈輸液,隨後一次或以上30分鐘的醫藥(或安慰劑)輸液。最初鹽水輸液之目的有2者:為了建立是否於輸液過程本身的反應可發生疼痛或生理參數之任何改變;及為確保經由導管進入靜脈無阻礙且輸液泵正確運作。
使用注射泵投與輸液,將醫藥及鹽水製備於30ml BD Plastipak注射器。輸液以每小時20ml的速率進行30分鐘。每一注射器附著於最小化體積延伸組(150cm管,母螺旋式接口,公螺旋式接口,0.5mL/30cm)。公螺旋式接口附著於桿栓套管。延伸組以醫藥/鹽水啟動,插入注射位。於丁丙諾非:拮抗劑比例研究,同時投與BUP及拮抗劑。於同時輸液此兩醫藥(經由一套管),附著具2注射位之Y型套管延伸組於此導管,並插入桿栓套管(經由最少量體積延伸組連接每一注射器)於每一注射位。
於每一試驗日之多數時刻上進行一段試驗期,每一段試驗以下列所列順序測量:記錄噁心及鎮靜,取血液樣品,記錄生理學參數(脈搏、氧飽和及血壓),完成傷害性感受試驗(如上列之細節),及記錄呼吸(於CP之溫水組份期間記數完整一分鐘之每分鐘呼吸次數)。
於每次試驗全日之所定間期上進行試驗期,此等如下:1.輸液開始前;2. 30分鐘鹽水輸液開始後20分鐘;3. 30分鐘醫藥輸液開始後20分鐘,及此(持續)醫藥輸液終止後每小時。此係稱為沖洗期。進行每次30分鐘輸液開始後
試驗期20分鐘之目的係使試驗完成的時間於開始隨後輸液之前。
各條件間之基線值不同,CPTOL資料表示為由基線之變化百分比以比較與不同醫藥組合有關之效果。於每一條件每一時間點之各參與者之反應表示為依據下列方程式由基線反應之變化百分比。數據表示為於每一條件之後醫藥期上此等值之平均(±SEM)。
此提供CPTOL改變百分比之值。
編入8位健康高加索人自願者(4位男性,4位女性)於此研究,由於在僅BUP試驗日之類鴉片陽性尿,自數據排除1位37歲男性作分析。然後最終樣本(n=7)包含3位男性及4位女性,平均年齡25.14(±1.02,21至37歲之範圍),於篩選之平均CPTOL為43.0秒(±6.73,29至80秒之範圍)。男性與女性間於年齡(p=0.265)或於篩選之CPTOL(p=0.764)無明顯差異。
以IV輸液10:1之比例投與丁丙諾非及納洛酮於受試者,投與之丁丙諾非為0.5μg/kg體重之劑量。沖洗監測進行10小時期間。CPTOL結果呈示於第1圖。未注意到引起擔心的副作用。
作為比較例,於分隔日,以IV輸液投與丁丙諾非及鹽水(稱為隨後為“僅BUP”)於實施例1之相同受試者,以0.5μg/kg體重之劑量再次投與丁丙諾非且沖洗監測進行超過10小時。CPTOL結果呈示於第2圖。
由實施例1及2計算由基線之CPTOL百分比改變,結果示於第3圖,其可見丁丙諾非及納洛酮組合相較於僅丁丙諾非之優點。
依序攪拌溶解右旋糖、丁丙諾非氫氯酸鹽及納洛酮氫氯酸鹽於約95%分批量之注射用水。經添加0.1M氫氯酸調整此溶液之酸度至pH 4.0,並製作溶液至注射用水之體積。將此溶液通過過濾膜並轉移至含經滅菌2ml玻璃安瓿而含2ml此溶液。密封此安瓿並經高壓鍋滅菌此產物。
除了硬脂酸鎂係通過750μm篩外,篩選所有材料並將其一起攙混而製備。然後將此混合粉末歷經水性顆粒化製程並於50℃乾燥。強迫此生成顆粒通過750μm篩並與硬脂酸鎂攙混(通過500μm篩之預過篩)。壓製此錠劑顆粒以獲得5.56mm直徑及重60mg之錠劑。
第1圖為丁丙諾非與納洛酮組合之疼痛耐性結果之圖;第2圖為僅丁丙諾非之疼痛耐性結果之圖;第3圖為一比較圖。
Claims (5)
- 一種止痛組成物,此組成物包含丁丙諾非(buprenorphine)及納洛酮(naloxone),其中丁丙諾比上與納洛酮之重量比(丁丙諾非:納洛酮)為7.5:1至9.5:1之範圍,一定量之丁丙諾非及納洛酮係合適提供止痛作用,該組成物為經黏膜或經皮膚劑型,其中單位劑型之丁丙諾非的量為10μg至1mg。
- 如申請專利範圍第1項之組成物,其中丁丙諾非比上納洛酮之重量比為8.0或9.0:1。
- 如申請專利範圍第1項之組成物,其中於單位劑型中丁丙諾非之量為10μg至8mg。
- 一種納洛酮及丁丙諾非於製造治療疼痛用醫藥之用途,其中使用納洛酮及丁丙諾非之量為此醫藥被遞送至病患或到達病患血漿之丁丙諾非對納洛酮重量比為7.5:1至9.5:1之範圍。
- 如申請專利範圍第4項之用途,其中丁丙諾非之投與為每24小時每公斤體重0.25至640μg之範圍。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0703968A GB2447016A (en) | 2007-03-01 | 2007-03-01 | Buprenorphine/naloxone compositions |
Publications (2)
Publication Number | Publication Date |
---|---|
TW200843773A TW200843773A (en) | 2008-11-16 |
TWI451868B true TWI451868B (zh) | 2014-09-11 |
Family
ID=37965735
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW097106779A TWI451868B (zh) | 2007-03-01 | 2008-02-27 | 醫藥組成物之改良及相關之改良 |
Country Status (17)
Country | Link |
---|---|
US (1) | US20110046172A1 (zh) |
EP (1) | EP2129380A1 (zh) |
JP (2) | JP2010520186A (zh) |
KR (1) | KR20090117891A (zh) |
CN (1) | CN101626766B (zh) |
AR (1) | AR065579A1 (zh) |
AU (1) | AU2008220574A1 (zh) |
BR (1) | BRPI0807908A2 (zh) |
CA (1) | CA2678582A1 (zh) |
CL (1) | CL2008000606A1 (zh) |
GB (1) | GB2447016A (zh) |
HK (1) | HK1139871A1 (zh) |
MX (1) | MX2009009131A (zh) |
PE (1) | PE20090168A1 (zh) |
TW (1) | TWI451868B (zh) |
WO (1) | WO2008104738A1 (zh) |
ZA (1) | ZA200905664B (zh) |
Families Citing this family (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5968547A (en) | 1997-02-24 | 1999-10-19 | Euro-Celtique, S.A. | Method of providing sustained analgesia with buprenorphine |
US20190328679A1 (en) | 2001-10-12 | 2019-10-31 | Aquestive Therapeutics, Inc. | Uniform films for rapid-dissolve dosage form incorporating anti-tacking compositions |
US8663687B2 (en) | 2001-10-12 | 2014-03-04 | Monosol Rx, Llc | Film compositions for delivery of actives |
US8900497B2 (en) | 2001-10-12 | 2014-12-02 | Monosol Rx, Llc | Process for making a film having a substantially uniform distribution of components |
US8603514B2 (en) | 2002-04-11 | 2013-12-10 | Monosol Rx, Llc | Uniform films for rapid dissolve dosage form incorporating taste-masking compositions |
US20110033542A1 (en) * | 2009-08-07 | 2011-02-10 | Monosol Rx, Llc | Sublingual and buccal film compositions |
US7357891B2 (en) | 2001-10-12 | 2008-04-15 | Monosol Rx, Llc | Process for making an ingestible film |
US8765167B2 (en) | 2001-10-12 | 2014-07-01 | Monosol Rx, Llc | Uniform films for rapid-dissolve dosage form incorporating anti-tacking compositions |
US10285910B2 (en) | 2001-10-12 | 2019-05-14 | Aquestive Therapeutics, Inc. | Sublingual and buccal film compositions |
US11207805B2 (en) | 2001-10-12 | 2021-12-28 | Aquestive Therapeutics, Inc. | Process for manufacturing a resulting pharmaceutical film |
US8900498B2 (en) | 2001-10-12 | 2014-12-02 | Monosol Rx, Llc | Process for manufacturing a resulting multi-layer pharmaceutical film |
US20070281003A1 (en) | 2001-10-12 | 2007-12-06 | Fuisz Richard C | Polymer-Based Films and Drug Delivery Systems Made Therefrom |
UA102128C2 (en) | 2008-12-05 | 2013-06-10 | Х. Луннбек А/С | Nalmefene hydrochloride dihydrate |
US8475832B2 (en) * | 2009-08-07 | 2013-07-02 | Rb Pharmaceuticals Limited | Sublingual and buccal film compositions |
WO2011112956A1 (en) * | 2010-03-12 | 2011-09-15 | Government Of The Usa, As Represented By The Sec., Dept. Of Health And Human Services | Agonist/antagonist compositions and methods of use |
US8529914B2 (en) * | 2010-06-28 | 2013-09-10 | Richard C. Fuisz | Bioactive dose having containing a material for modulating pH of a bodily fluid to help or hinder absorption of a bioactive |
US9149959B2 (en) | 2010-10-22 | 2015-10-06 | Monosol Rx, Llc | Manufacturing of small film strips |
BR112014003651B1 (pt) * | 2011-08-18 | 2022-03-29 | Biodelivery Sciences International, Inc | Dispositivos mucoadesivos resistentes ao mau uso para a liberação de buprenorfina |
SI2915525T1 (sl) | 2011-09-19 | 2022-01-31 | Orexo Ab | Sublingvalne tablete, odporne proti zlorabi, ki vsebujejo buprenorfin in nalokson |
SG11201403075XA (en) * | 2011-12-21 | 2014-07-30 | Biodelivery Sciences Int Inc | Transmucosal drug delivery devices for use in chronic pain relief |
CN103690495B (zh) * | 2013-12-19 | 2015-04-08 | 贵州景峰注射剂有限公司 | 注射用盐酸纳洛酮的冷冻干燥方法 |
US9561177B2 (en) | 2014-03-14 | 2017-02-07 | Adapt Pharma Limited | Nasal drug products and methods of their use |
RU2020112530A (ru) | 2014-03-14 | 2021-07-21 | ОПИАНТ ФАРМАСЮТИКАЛС, Инк. | Назальные готовые лекарственные формы и способы их применения |
US9480644B2 (en) | 2014-03-14 | 2016-11-01 | Opiant Pharmaceuticals, Inc. | Nasal drug products and methods of their use |
US10085937B2 (en) | 2014-03-14 | 2018-10-02 | Adapt Pharma Limited | Nasal drug products and methods of their use |
WO2017192921A1 (en) | 2016-05-05 | 2017-11-09 | Monosol Rx, Llc | Enhanced delivery epinephrine compositions |
US11273131B2 (en) | 2016-05-05 | 2022-03-15 | Aquestive Therapeutics, Inc. | Pharmaceutical compositions with enhanced permeation |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060069113A1 (en) * | 1999-11-19 | 2006-03-30 | Reckitt Benckiser Healthcare (Uk) Limited, A United Kingdom Corporation | Analgesic compositions containing buprenorphine |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8332556D0 (en) * | 1983-12-06 | 1984-01-11 | Reckitt & Colmann Prod Ltd | Analgesic compositions |
JPH1036265A (ja) * | 1996-07-19 | 1998-02-10 | Nitto Denko Corp | ブプレノルフィン経皮吸収製剤 |
US20050191340A1 (en) * | 2002-08-09 | 2005-09-01 | Gruenenthal Gmbh | Opioid-receptor antagonists in transdermal systems having buprenorphine |
DE50307717D1 (de) * | 2002-08-09 | 2007-08-30 | Gruenenthal Gmbh | Opiod-rezeptor-antagonisten in transdermalen systemen mit buprenorphin |
-
2007
- 2007-03-01 GB GB0703968A patent/GB2447016A/en not_active Withdrawn
-
2008
- 2008-02-15 MX MX2009009131A patent/MX2009009131A/es not_active Application Discontinuation
- 2008-02-15 WO PCT/GB2008/000526 patent/WO2008104738A1/en active Application Filing
- 2008-02-15 KR KR1020097018305A patent/KR20090117891A/ko not_active Application Discontinuation
- 2008-02-15 BR BRPI0807908-0A2A patent/BRPI0807908A2/pt not_active IP Right Cessation
- 2008-02-15 EP EP08709417A patent/EP2129380A1/en not_active Withdrawn
- 2008-02-15 JP JP2009551256A patent/JP2010520186A/ja active Pending
- 2008-02-15 US US12/529,171 patent/US20110046172A1/en not_active Abandoned
- 2008-02-15 AU AU2008220574A patent/AU2008220574A1/en not_active Abandoned
- 2008-02-15 CA CA002678582A patent/CA2678582A1/en not_active Abandoned
- 2008-02-15 CN CN2008800068666A patent/CN101626766B/zh not_active Expired - Fee Related
- 2008-02-27 TW TW097106779A patent/TWI451868B/zh not_active IP Right Cessation
- 2008-02-28 CL CL200800606A patent/CL2008000606A1/es unknown
- 2008-02-29 PE PE2008000413A patent/PE20090168A1/es not_active Application Discontinuation
- 2008-02-29 AR ARP080100880A patent/AR065579A1/es not_active Application Discontinuation
-
2009
- 2009-08-14 ZA ZA200905664A patent/ZA200905664B/xx unknown
-
2010
- 2010-07-06 HK HK10106544.6A patent/HK1139871A1/xx not_active IP Right Cessation
-
2014
- 2014-06-16 JP JP2014123827A patent/JP2014196325A/ja not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060069113A1 (en) * | 1999-11-19 | 2006-03-30 | Reckitt Benckiser Healthcare (Uk) Limited, A United Kingdom Corporation | Analgesic compositions containing buprenorphine |
Also Published As
Publication number | Publication date |
---|---|
ZA200905664B (en) | 2010-10-27 |
BRPI0807908A2 (pt) | 2014-06-17 |
CN101626766A (zh) | 2010-01-13 |
TW200843773A (en) | 2008-11-16 |
PE20090168A1 (es) | 2009-03-19 |
US20110046172A1 (en) | 2011-02-24 |
GB2447016A (en) | 2008-09-03 |
AU2008220574A1 (en) | 2008-09-04 |
MX2009009131A (es) | 2009-09-03 |
KR20090117891A (ko) | 2009-11-13 |
HK1139871A1 (en) | 2010-09-30 |
CL2008000606A1 (es) | 2008-10-03 |
EP2129380A1 (en) | 2009-12-09 |
GB0703968D0 (en) | 2007-04-11 |
CN101626766B (zh) | 2013-07-10 |
CA2678582A1 (en) | 2008-09-04 |
JP2014196325A (ja) | 2014-10-16 |
AR065579A1 (es) | 2009-06-17 |
WO2008104738A1 (en) | 2008-09-04 |
JP2010520186A (ja) | 2010-06-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI451868B (zh) | 醫藥組成物之改良及相關之改良 | |
CA2678481C (en) | Improved medicinal compositions comprising buprenorphine and naltrexone | |
TWI468163B (zh) | 醫藥組成物之改良或相關之改良 | |
TW200836738A (en) | Improvements in or relating to medicinal compositions | |
AU2014201777A1 (en) | Improvements in and relating to medicinal compositions | |
AU2014201782A1 (en) | Improved medicinal compositions comprising buprenorphine and naltrexone |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM4A | Annulment or lapse of patent due to non-payment of fees |