CN101036651A - Naloxone hydrochloride spraying agent for mouth and nose - Google Patents
Naloxone hydrochloride spraying agent for mouth and nose Download PDFInfo
- Publication number
- CN101036651A CN101036651A CN 200610013316 CN200610013316A CN101036651A CN 101036651 A CN101036651 A CN 101036651A CN 200610013316 CN200610013316 CN 200610013316 CN 200610013316 A CN200610013316 A CN 200610013316A CN 101036651 A CN101036651 A CN 101036651A
- Authority
- CN
- China
- Prior art keywords
- naloxone hydrochloride
- acid
- oral cavity
- nasal mist
- naloxone
- 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
- RGPDIGOSVORSAK-STHHAXOLSA-N naloxone hydrochloride Chemical compound Cl.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C RGPDIGOSVORSAK-STHHAXOLSA-N 0.000 title claims abstract description 41
- 229960005250 naloxone hydrochloride Drugs 0.000 title claims abstract description 39
- 238000005507 spraying Methods 0.000 title abstract 4
- 210000000214 mouth Anatomy 0.000 claims abstract description 22
- 238000010521 absorption reaction Methods 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- 239000007922 nasal spray Substances 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 150000002576 ketones Chemical class 0.000 claims description 8
- 239000007921 spray Substances 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- -1 polyoxyethylene Polymers 0.000 claims description 6
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 claims description 4
- 241000283690 Bos taurus Species 0.000 claims description 4
- OCTANWXFBPBMPD-UHFFFAOYSA-N CCCCCCCCCCCC[N] Chemical compound CCCCCCCCCCCC[N] OCTANWXFBPBMPD-UHFFFAOYSA-N 0.000 claims description 4
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 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 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 229920002125 Sokalan® Polymers 0.000 claims description 4
- 230000002421 anti-septic effect Effects 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 4
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 4
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims description 4
- 229940099352 cholate Drugs 0.000 claims description 4
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims description 4
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 4
- 229940009976 deoxycholate Drugs 0.000 claims description 4
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 claims description 4
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims description 4
- 239000003623 enhancer Substances 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 4
- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 claims description 4
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims description 4
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 4
- 239000008103 glucose Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 claims description 4
- 230000003204 osmotic effect Effects 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 4
- 229920000053 polysorbate 80 Polymers 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 235000010199 sorbic acid Nutrition 0.000 claims description 4
- 239000004334 sorbic acid Substances 0.000 claims description 4
- 229940075582 sorbic acid Drugs 0.000 claims description 4
- 239000004094 surface-active agent Substances 0.000 claims description 4
- 239000002562 thickening agent Substances 0.000 claims description 4
- 238000005516 engineering process Methods 0.000 claims description 3
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 claims description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 2
- CJPDBKNETSCHCH-UHFFFAOYSA-N 1-methylsulfinyldodecane Chemical compound CCCCCCCCCCCCS(C)=O CJPDBKNETSCHCH-UHFFFAOYSA-N 0.000 claims description 2
- TWJNQYPJQDRXPH-UHFFFAOYSA-N 2-cyanobenzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1C#N TWJNQYPJQDRXPH-UHFFFAOYSA-N 0.000 claims description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 claims description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 229920002307 Dextran Polymers 0.000 claims description 2
- 241000196324 Embryophyta Species 0.000 claims description 2
- 108010007979 Glycocholic Acid Proteins 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- 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 claims description 2
- 239000005639 Lauric acid Substances 0.000 claims description 2
- 235000017858 Laurus nobilis Nutrition 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 claims description 2
- 235000021360 Myristic acid Nutrition 0.000 claims description 2
- 239000005642 Oleic acid Substances 0.000 claims description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- 239000004698 Polyethylene Substances 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 2
- 235000005212 Terminalia tomentosa Nutrition 0.000 claims description 2
- 244000125380 Terminalia tomentosa Species 0.000 claims description 2
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2r)-2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims 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 claims description 2
- 229960002152 chlorhexidine acetate Drugs 0.000 claims description 2
- 229960004926 chlorobutanol Drugs 0.000 claims description 2
- 229960004106 citric acid Drugs 0.000 claims description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 2
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 claims description 2
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 claims description 2
- 229940116333 ethyl lactate Drugs 0.000 claims description 2
- RFDAIACWWDREDC-FRVQLJSFSA-N glycocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 RFDAIACWWDREDC-FRVQLJSFSA-N 0.000 claims description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 2
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 229940070765 laurate Drugs 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 2
- 229940055577 oleyl alcohol Drugs 0.000 claims description 2
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 claims description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 2
- 239000004584 polyacrylic acid Substances 0.000 claims description 2
- 229920000573 polyethylene Polymers 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- MCSINKKTEDDPNK-UHFFFAOYSA-N propyl propionate Chemical compound CCCOC(=O)CC MCSINKKTEDDPNK-UHFFFAOYSA-N 0.000 claims description 2
- 150000003856 quaternary ammonium compounds Chemical class 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 2
- 235000011067 sorbitan monolaureate Nutrition 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- WBWWGRHZICKQGZ-HZAMXZRMSA-N taurocholic acid Chemical class C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@@H](O)C1 WBWWGRHZICKQGZ-HZAMXZRMSA-N 0.000 claims description 2
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 claims description 2
- 229940033663 thimerosal Drugs 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract 3
- 210000002200 mouth mucosa Anatomy 0.000 abstract 2
- 229960004127 naloxone Drugs 0.000 abstract 2
- 210000003928 nasal cavity Anatomy 0.000 abstract 2
- 210000002850 nasal mucosa Anatomy 0.000 abstract 2
- 239000004480 active ingredient Substances 0.000 abstract 1
- 230000004936 stimulating effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000008215 water for injection Substances 0.000 description 6
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical group CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 3
- 208000010513 Stupor Diseases 0.000 description 3
- 238000001467 acupuncture Methods 0.000 description 3
- 238000007689 inspection Methods 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 230000008485 antagonism Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000029058 respiratory gaseous exchange Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000004593 Epoxy Substances 0.000 description 1
- 102000003840 Opioid Receptors Human genes 0.000 description 1
- 108090000137 Opioid Receptors Proteins 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- ZLWULWWXACZTPR-UHFFFAOYSA-N [ClH]=O Chemical compound [ClH]=O ZLWULWWXACZTPR-UHFFFAOYSA-N 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000009084 cardiovascular function Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 102000051367 mu Opioid Receptors Human genes 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000003401 opiate antagonist Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a naloxone hydrochloride spraying agent for oral or nasal cavity, which is prepared by naloxone hydrochloride, naloxone free alkali or the other naloxone acceptable in medicine having a ratio by weight of 1:2.5~10 with pharmaceutic edjuvant based on general spraying agent preparation process. Active ingredient of the naloxone hydrochloride spraying agent for oral or nasal cavity in the invention can directly participate intracorporeal circulation after absorbed by capillary tube under oral or nasal mucosa of a patient, thus has advantages of fast absorption and high bioavailability, without stimulating to the oral or nasal mucosa. In particular, the drugs of the invention can be taken with no requirement of use situation, so that it is convenient for using which dosage is controllable and has little side effect.
Description
Technical field
The invention belongs to field of medicaments, particularly relate to a kind of naloxone hydrochloride oral cavity and nasal mist.
Background technology
The chemical name of naloxone hydrochloride is 17-pi-allyl-4,5 α-epoxy radicals-3, and 14-dihydroxy morphinan-6 keto hydrochloride does not have hydrate, monohydrate or dihydrate.It is a kind of opiate receptor antagonist, no intrinsic activity own, but each opioid receptor of energy competitive antagonism, the μ receptor had very strong affinity, having comes into force reaches characteristics such as antagonism is strong rapidly, be mainly used in treatment clinically because of taking symptoms such as excessive respiration inhibition that causes of narcosis analgesic and stupor, thereby cause patient's fever, so that its cardiovascular function is hyperfunction.At present the naloxone hydrochloride preparation that uses clinically is hydro-acupuncture preparation and the powder injection formulation through subcutaneous, muscle or intravenous injection administration.Though that these naloxone hydrochloride preparations have is rapid-action, bioavailability is high and be easy to dose titration and advantage such as control, but owing to contain phenolic hydroxyl structure in the molecular structure of naloxone hydrochloride, thereby unstable chemcial property, so in the process that it is prepared into hydro-acupuncture preparation, might decompose because of heat sterilization causes medicine.Although powder injection formulation can avoid this medicine rotten because of the decomposition that high-temperature heating causes, and storage period is longer relatively, but its same with hydro-acupuncture preparation all need be by injecting to the patient through the medical personnel of professional training, thereby the occasion of using is subjected to great restriction.
Summary of the invention
In order to address the above problem, the object of the present invention is to provide a kind of convenient drug administration, absorption and rapid-action, to oral cavity and nasal membrane is non-stimulated and bioavailability is high naloxone hydrochloride oral cavity and nasal mist.
In order to achieve the above object, naloxone hydrochloride oral cavity provided by the invention and nasal mist are by making with 1: 2.5～10 the weight ratio spray preparation technology according to routine as other pharmaceutical salts of naloxone hydrochloride, Allylnoroxymorphone free alkali or the pharmaceutically acceptable Allylnoroxymorphone of active component and pharmaceutic adjuvant.
Described pharmaceutic adjuvant comprises absorption enhancer, osmotic pressure regulator, thickening agent, antiseptic and surfactant.
Described absorption enhancer is selected from methyl-beta-schardinger dextrin-; DM-; HP-; glycocholate; cholate; deoxycholate; cholyltaurine salt; the glucose cholate; CDC; the ursol deoxycholate; lauric acid; oleic acid; myristic acid; capric acid; laurate; monooctyl ester acid; the certain herbaceous plants with big flowers acid esters; cetylate; ethyl lactate; propylene glycol; isopropyl alcohol; hexadecanol; lauryl alcohol; oleyl alcohol; polyoxyethylene laurel ether; the polyoxyethylene octyl ether; dodecyl methyl sulfoxide; dimethyl sulfoxide; the tall and erect ketone of dodecyl nitrogen; hold together in the tall and erect ketone of cattle base nitrogen any.
Described osmotic pressure regulator is selected from sodium chloride, lactose, glucose, dextran, sorbitol, mannitol or its pharmaceutically acceptable inorganic salt.
Described thickening agent is selected from carboxymethyl cellulose, hydroxypropyl cellulose, Polyethylene Glycol, polyacrylic acid, acid polyethylene, polyvinylpyrrolidone, carbopol.
Described antiseptic is selected from ethyl hydroxybenzoate, p-Hydroxybenzoate, benzoic acid and pharmaceutically acceptable salt thereof, sorbic acid, citric acid, chlorobutanol, benzyl alcohol, thimerosal, chlorhexidine acetate and quaternary ammonium compound.
Described surfactant is selected from sodium lauryl sulphate, sad monoglyceride, Tween 80, span 20 or their mixture.
Effective ingredient in naloxone hydrochloride provided by the invention oral cavity and the nasal mist directly enters body-internal-circulation after can absorbing by the capillary tube under patient oral cavity or the nasal membrane, thereby it is rapid-action and bioavailability is high, and non-stimulated to oral cavity or nasal membrane.Medicine particularly of the present invention is not subjected to the restriction of use occasion, thereby easy to use, and dosage is controlled and toxic and side effects is little.
The specific embodiment
Describe naloxone hydrochloride provided by the invention oral cavity and nasal mist in detail below in conjunction with specific embodiment.
Embodiment 1: the naloxone hydrochloride spray
Prescription:
Naloxone hydrochloride 0.4g
Polyvinylpyrrolidone 0.6g
Hold together the tall and erect ketone 5ml of cattle base nitrogen
Sad monoglyceride 0.05g
Citric acid 0.3g
Ethyl hydroxybenzoate 0.1g
Water for injection is diluted to 1000ml
Method for making: with naloxone hydrochloride, the polyvinylpyrrolidone of above-mentioned recipe quantity, hold together tall and erect ketone, sad monoglyceride, citric acid, the abundant mixing of ethyl hydroxybenzoate of cattle base nitrogen and make whole dissolvings, mend at last and add to the full amount of water for injection, make clear solutions.After sampling inspection is qualified gained solution is sub-packed in atomizing pump or quantitatively drips in the pump.
Embodiment 2: the naloxone hydrochloride spray
Prescription:
Naloxone hydrochloride 0.4g
HP-0.8g
The tall and erect ketone 3ml of dodecyl nitrogen
Macrogol 4000 1.0g
Tween 80 1.0g
Sorbic acid 0.1g
Water for injection is diluted to 1000ml
Method for making: with the naloxone hydrochloride of above-mentioned recipe quantity, HP-, dodecyl nitrogen tall and erect ketone, Macrogol 4000, Tween 80, the abundant mixing of sorbic acid and make whole dissolvings, mend at last and add to the full amount of water for injection, make clear solutions.After sampling inspection is qualified gained solution is sub-packed in atomizing pump or quantitatively drips in the pump.
Embodiment 3: the naloxone hydrochloride spray
Prescription:
Naloxone hydrochloride 0.4g
Carboxymethyl cellulose 1.0g
Citric acid 0.3g
Water for injection is diluted to 1000ml
Method for making: with the abundant mixing of naloxone hydrochloride, carboxymethyl cellulose, citric acid of above-mentioned recipe quantity and make whole dissolvings, mend at last and add to the full amount of water for injection, make clear solutions.After sampling inspection is qualified gained solution is sub-packed in atomizing pump or quantitatively drips in the pump.
Naloxone hydrochloride provided by the invention oral cavity and nasal mist are colourless or the off-white color transparency liquid, and each dosage is in the scope of 1～4ml.
For verifying the drug effect of naloxone hydrochloride provided by the invention oral cavity and nasal mist, the inventor has carried out the nasal absorption test with rabbit as experimental animal: rabbit is put in the rabbit box, insert the about 12mm of rabbit intranasal with aerosol apparatus with 60 °, about 30～50 μ l of each nostril administration, get the about 1min of dorsal position, from ear edge vein exploitating blood; Measure blood drug level, estimate the nasal absorption situation of naloxone hydrochloride spray.The result shows that the biological relatively average utilization factor of naloxone hydrochloride oral cavity and nasal mist is greater than 98%.
In addition symptoms such as treatment respiration inhibition and stupor have been carried out clinical verification.Going into to organize case in this test is 20 examples, every day 3 times, each 1ml (being equivalent to naloxone hydrochloride 0.4mg), the statistical result of its therapeutic evaluation is: the cure-remarkable-effectiveness rate of naloxone hydrochloride provided by the invention oral cavity and nasal mist is 96.7%, does not find any untoward reaction simultaneously.
Claims (7)
1, a kind of naloxone hydrochloride oral cavity and nasal mist is characterized in that: described naloxone hydrochloride spray is by making with 1: 2.5～10 the weight ratio spray preparation technology according to routine as other pharmaceutical salts of naloxone hydrochloride, Allylnoroxymorphone free alkali or the pharmaceutically acceptable Allylnoroxymorphone of active component and pharmaceutic adjuvant.
2, naloxone hydrochloride oral cavity according to claim 1 and nasal mist, it is characterized in that: described pharmaceutic adjuvant comprises absorption enhancer, osmotic pressure regulator, thickening agent, antiseptic and surfactant etc.
3; naloxone hydrochloride according to claim 2 oral cavity and nasal mist is characterized in that: described absorption enhancer is selected from methyl-beta-schardinger dextrin-; DM-; HP-; glycocholate; cholate; deoxycholate; cholyltaurine salt; the glucose cholate; CDC; the ursol deoxycholate; lauric acid; oleic acid; myristic acid; capric acid; laurate; monooctyl ester acid; the certain herbaceous plants with big flowers acid esters; cetylate; ethyl lactate; propylene glycol; isopropyl alcohol; hexadecanol; lauryl alcohol; oleyl alcohol; polyoxyethylene laurel ether; the polyoxyethylene octyl ether; dodecyl methyl sulfoxide; dimethyl sulfoxide; the tall and erect ketone of dodecyl nitrogen; hold together in the tall and erect ketone of cattle base nitrogen any.
4, naloxone hydrochloride oral cavity according to claim 2 and nasal mist is characterized in that: described osmotic pressure regulator is selected from sodium chloride, lactose, glucose, dextran, sorbitol, mannitol or its pharmaceutically acceptable inorganic salt.
5, naloxone hydrochloride oral cavity according to claim 2 and nasal mist, it is characterized in that: described thickening agent is selected from carboxymethyl cellulose, hydroxypropyl cellulose, Polyethylene Glycol, polyacrylic acid, acid polyethylene, polyvinylpyrrolidone, carbopol.
6, naloxone hydrochloride oral cavity according to claim 2 and nasal mist, it is characterized in that: described antiseptic is selected from ethyl hydroxybenzoate, p-Hydroxybenzoate, benzoic acid and pharmaceutically acceptable salt thereof, sorbic acid, citric acid, chlorobutanol, benzyl alcohol, thimerosal, chlorhexidine acetate and quaternary ammonium compound.
7, naloxone hydrochloride oral cavity according to claim 2 and nasal mist is characterized in that: described surfactant is selected from sodium lauryl sulphate, sad monoglyceride, Tween 80, span 20 or their mixture.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610013316 CN101036651A (en) | 2006-03-16 | 2006-03-16 | Naloxone hydrochloride spraying agent for mouth and nose |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610013316 CN101036651A (en) | 2006-03-16 | 2006-03-16 | Naloxone hydrochloride spraying agent for mouth and nose |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101036651A true CN101036651A (en) | 2007-09-19 |
Family
ID=38887957
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200610013316 Pending CN101036651A (en) | 2006-03-16 | 2006-03-16 | Naloxone hydrochloride spraying agent for mouth and nose |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101036651A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015095644A1 (en) * | 2013-12-20 | 2015-06-25 | AntiOP, Inc. | Intranasal naloxone compositions and methods of making and using same |
| RU2572217C2 (en) * | 2013-10-21 | 2015-12-27 | Российская Федерация, от имени которой выступает Федеральное государственное казенное учреждение "Войсковая часть 68240" | Pharmaceutical composition in form of naloxone hydrochloride-based nasal spray and method of obtaining thereof |
| JP2017519803A (en) * | 2014-07-08 | 2017-07-20 | インシス・ファーマ・インコーポレーテッド | Sublingual naloxone spray |
| US20230181500A1 (en) * | 2020-05-04 | 2023-06-15 | Amphastar Pharmaceuticals, Inc. | Naloxone Pharmaceutical Formulations for Intranasal (IN) Delivery |
-
2006
- 2006-03-16 CN CN 200610013316 patent/CN101036651A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2572217C2 (en) * | 2013-10-21 | 2015-12-27 | Российская Федерация, от имени которой выступает Федеральное государственное казенное учреждение "Войсковая часть 68240" | Pharmaceutical composition in form of naloxone hydrochloride-based nasal spray and method of obtaining thereof |
| WO2015095644A1 (en) * | 2013-12-20 | 2015-06-25 | AntiOP, Inc. | Intranasal naloxone compositions and methods of making and using same |
| US9192570B2 (en) | 2013-12-20 | 2015-11-24 | AntiOP, Inc. | Intranasal naloxone compositions and methods of making and using same |
| US9289425B2 (en) | 2013-12-20 | 2016-03-22 | AntiOP, Inc. | Intranasal naloxone compositions and methods of making and using same |
| JP2017519803A (en) * | 2014-07-08 | 2017-07-20 | インシス・ファーマ・インコーポレーテッド | Sublingual naloxone spray |
| EP3177146A4 (en) * | 2014-07-08 | 2018-01-03 | Insys Pharma, Inc. | Sublingual naloxone spray |
| US20230181500A1 (en) * | 2020-05-04 | 2023-06-15 | Amphastar Pharmaceuticals, Inc. | Naloxone Pharmaceutical Formulations for Intranasal (IN) Delivery |
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