CN101396364B - 扎来普隆口腔给药系统或组合物及其制备方法 - Google Patents
扎来普隆口腔给药系统或组合物及其制备方法 Download PDFInfo
- Publication number
- CN101396364B CN101396364B CN2007101752439A CN200710175243A CN101396364B CN 101396364 B CN101396364 B CN 101396364B CN 2007101752439 A CN2007101752439 A CN 2007101752439A CN 200710175243 A CN200710175243 A CN 200710175243A CN 101396364 B CN101396364 B CN 101396364B
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- China
- Prior art keywords
- zaleplon
- compounds
- cyclodextrin
- compound
- polyoxyethylene
- 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.)
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- HUNXMJYCHXQEGX-UHFFFAOYSA-N zaleplon Chemical compound CCN(C(C)=O)C1=CC=CC(C=2N3N=CC(=C3N=CC=2)C#N)=C1 HUNXMJYCHXQEGX-UHFFFAOYSA-N 0.000 title claims abstract description 80
- 229960004010 zaleplon Drugs 0.000 title claims abstract description 80
- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- 210000000214 mouth Anatomy 0.000 title claims description 11
- 239000000203 mixture Substances 0.000 title description 26
- 239000007921 spray Substances 0.000 claims abstract description 18
- -1 alcohol compound Chemical class 0.000 claims description 100
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical class CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 60
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 42
- 229920000858 Cyclodextrin Polymers 0.000 claims description 26
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical class OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 24
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical class CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 22
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims description 22
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 22
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 claims description 22
- 238000005507 spraying Methods 0.000 claims description 22
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical class CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 18
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 18
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- 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 14
- 229930195725 Mannitol Natural products 0.000 claims description 14
- 239000000594 mannitol Substances 0.000 claims description 14
- 235000010355 mannitol Nutrition 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 12
- 229930195729 fatty acid Natural products 0.000 claims description 12
- 239000000194 fatty acid Substances 0.000 claims description 12
- NOOLISFMXDJSKH-UHFFFAOYSA-N p-menthan-3-ol Chemical compound CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 12
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical class CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical class CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 8
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical class OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 claims description 8
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic 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)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims description 8
- 239000002552 dosage form Substances 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical class CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 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 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 6
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 6
- 238000010521 absorption reaction Methods 0.000 claims description 6
- 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 6
- 238000012377 drug delivery Methods 0.000 claims description 6
- 239000008103 glucose Substances 0.000 claims description 6
- 229920000136 polysorbate Polymers 0.000 claims description 6
- 239000004094 surface-active agent Substances 0.000 claims description 6
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 claims description 4
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 claims description 4
- NZAQRZWBQUIBSF-UHFFFAOYSA-N 4-(4-sulfobutoxy)butane-1-sulfonic acid Chemical compound OS(=O)(=O)CCCCOCCCCS(O)(=O)=O NZAQRZWBQUIBSF-UHFFFAOYSA-N 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 241001597008 Nomeidae Species 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 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
- 235000019437 butane-1,3-diol Nutrition 0.000 claims description 4
- 239000004359 castor oil Substances 0.000 claims description 4
- 235000019438 castor oil Nutrition 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
- 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
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 claims description 4
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 claims description 4
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 4
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-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
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 claims description 4
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 4
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 4
- 150000002334 glycols Chemical class 0.000 claims description 4
- MLFHJEHSLIIPHL-UHFFFAOYSA-N isoamyl acetate Chemical compound CC(C)CCOC(C)=O MLFHJEHSLIIPHL-UHFFFAOYSA-N 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 150000003951 lactams Chemical class 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000003921 oil Substances 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims description 4
- 229920002503 polyoxyethylene-polyoxypropylene Chemical class 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical class CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 125000004368 propenyl group Chemical class C(=CC)* 0.000 claims description 4
- 229920006395 saturated elastomer Chemical class 0.000 claims description 4
- 150000004671 saturated fatty acids Chemical class 0.000 claims description 4
- 239000000600 sorbitol Substances 0.000 claims description 4
- 150000004670 unsaturated fatty acids Chemical class 0.000 claims description 4
- 235000021122 unsaturated fatty acids Nutrition 0.000 claims description 4
- 230000002421 anti-septic effect Effects 0.000 claims description 3
- 239000006184 cosolvent Substances 0.000 claims description 3
- 239000003623 enhancer Substances 0.000 claims description 3
- 230000003204 osmotic effect Effects 0.000 claims description 3
- 210000000582 semen Anatomy 0.000 claims description 3
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 claims description 2
- AOFUBOWZWQFQJU-SNOJBQEQSA-N (2r,3s,4s,5r)-2,5-bis(hydroxymethyl)oxolane-2,3,4-triol;(2s,3r,4s,5s,6r)-6-(hydroxymethyl)oxane-2,3,4,5-tetrol Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O.OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O AOFUBOWZWQFQJU-SNOJBQEQSA-N 0.000 claims description 2
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- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
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Abstract
本发明涉及一种扎来普隆口腔给药制剂,属于药剂学领域。扎来普隆口腔给药制剂,由活性成分扎来普隆和药学可接受的辅料组成,每100ml制剂中含有扎来普隆1-10g。本发明的优点在于:优选了扎来普隆作为舌下给药系统中的活性成分,该系统或组合物通过喷雾形式给药,可避免消化道作用和肝脏首过效应、并且有起效快、生物利用度高、药效确切、使用方便、其剂量可根据需要进行调整、顺应性好,特别是适用于老年人和不便于吞咽的患者。且制备工艺简单可行,适合工业化生产等优点。
Description
技术领域
本发明涉及扎来普隆口腔给药系统或组合物及其制备方法,属医药领域。
背景技术
失眠在我国乃至整个世界都是一个很普遍的问题,流行病学调查表明,成人失眠症的发病率约为30~35%,特别是以妇女和老人居多。同时由于生活节奏的不断加快,生活压力的不断加大,许多年轻人也成为失眠症的受害者,失眠正呈现年轻化趋势。我国成人有7亿之多,老人达1.2亿,照此推算,我国应有上亿人患有失眠症。失眠处理不当,不仅是一个医疗问题,更是一个严重的社会和家庭问题。
药物治疗,特别是镇静、催眠药的应用,对治疗失眠症是十分有效的。目前治疗失眠的药物主要可分为两大类,即苯二氮卓类和非苯二氮卓类。苯二氮卓类催眠药主要通过抑制大脑边缘系统的功能而导致睡眠作用,大脑边缘系统是情绪活动伴同记忆有密切联系的部位,由于苯二氮卓类对该部位的ω受体均有一定亲和力,极易引起记忆力和情绪障碍,故此类药物的主要副作用(特别是在高剂量和长期用药时)是后遗作用、反跳性失眠、顺行性遗忘、耐受性及药物依赖性。另外,由于苯二氮卓类药物的呼吸抑制作用,它们尤其不适用于睡眠性呼吸暂停及慢性阻塞性肺病(COPD)患者。
扎来普隆是由Wyeth-Ayerst公司开发,85年获美国专利,专利号为US4626538,86年获日本专利,专利号为JP86260083;化学名N-乙基-N-3-[7-(3-氰基吡唑并[1,5a]嘧啶基)苯基]乙酰胺,结构为
其为白色或类白色结晶性粉末,无臭无味,属于非苯二氮卓类催眠药,也是第一个吡唑嘧啶类催眠药,临床应用疗效显著。本药通过GABA-苯二氮卓受体复合物产生中枢抑制作用,增加氯离子通道开放频率,引起神经细胞膜超极化,使兴奋性下降,对ω1受体选择性强,对ω2-受体的亲和力较弱,但不与其它神经递质结合。与传统的苯二氮卓类药物相比,其优点主要体现在以下几方面:
1、ω1-受体选择性
在大脑边缘系统有ω1,ω2-受体,其中ω1-受体与镇静、催眠作用有关,ω2-受体与记忆、情绪有关。受体结合试验表明,扎来普隆可选择性作用于大脑边缘系统的ω1-受体,,因此它对记忆和情绪的影响也相对较弱。
2、药动学性质
催眠药作用的时间取决于药物的消除半衰期和它们是否有活性代谢物。若药物半衰期长在使用时需小心监测,因为它们可产生持续的高血药浓度,导致白天的镇静作用过度。扎来普隆给药后吸收迅速,半衰期为0.9~1.1小时,其三种主要代谢物均没有药理活性,它能帮助患者很快入睡,然后随即很快被代谢,但病人接着能自然睡眠,这意味着本品可以“当需要时”服用,而不导致第二天的宿醉感。
3、安全性
传统的苯二氮卓类药物长期困扰患者的是其依赖性、后遗效应及反跳性失眠,后遗效应使患者白天精神恍惚,无法正常生活和工作;反跳性失眠使患者停药后的睡眠状况变得更加糟糕。与苯二氮卓类药物相比,扎来普隆的后遗作用(白天镇静作用、焦虑、瞌睡和损害识别记忆能力等)较小,长期或短期使用本品时,极少产生耐受性和依赖性,几乎不引起反弹性睡眠障碍。
扎来普隆在全球的注册资料包括超过3700名患者的安全数据以及已治疗至少6个月的300例患者的资料。本品除了缩短入睡时间,改善睡眠质量和时间外,并不改变睡眠时相,即使深夜入睡困难服用,也不引起醒来时的“残余宿睡”,4周后也未显示有反跳性失眠。
扎来普隆在水中极难溶解,目前扎来普隆市售主要剂型为片剂和胶囊剂等口服制剂而没有液体制剂。口服剂型由于严重的肝脏首过作用,生物利用度较低,只有大约30%左右,且这些组合物在体内大多经过崩解和溶出的过程,起效相对较慢。而对于老年患者及不能或不愿吞咽的患者来说常会因产生卡在喉咙中的感觉而引起不适。目前已有扎来普隆速溶口服片的专利报道(专利号:00129669.8),其虽然在用药顺应性等方面有所改进,但主要还是经胃肠道吸收,不能有效避免肝脏首过效应,药物吸收速度及生物利用度均会受到影响。
发明内容
本发明的目的是提供一种生物利用度高、起效快、质量稳定、具有镇静催眠作用的扎来普隆口腔给药系统。
本发明的另一个目的是提供一种简单易行的扎来普隆口腔给药系统制备方法。
为实现上述目的,本发明采用以下技术方案:
一种扎来普隆口腔给药制剂,由活性成分扎来普隆和药学可接受的辅料组成,每100ml制剂中含有扎来普隆1-10g。
所述每100ml制剂中所含组分及其含量如下:
扎来普隆 1-10g
主要溶媒 30-70ml
增溶助溶剂 30-70ml
防腐剂 0.01-0.1g
矫味剂 0.1-2g
吸收促进剂 0.1-2g
渗透压调节剂 0.2-3g。
所述主要溶媒选自水、醇类化合物、酯及油脂类化合物、醚类化合物和羧酸类化合物中的一种或几种,其中醇类化合物包括乙醇、丙醇、丙二醇、丙三醇、异丙醇、丁醇、异丁醇、1,3-丁二醇、1,4-丁二醇、丙烯醇等;酯及油脂类化合物包括甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、乙酸丁酯、乙酸异丁酯、乙酸异戊酯、豆油、芝麻油、花生油、蓖麻油、杏仁油等;醚类化合物包括乙醚、三丁甲基乙醚、二乙二醇单乙醚、二乙二醇二甲醚等;羧酸类化合物包括甲酸、乙酸或丙酸。
所述增溶助溶剂选自醇类化合物、酰胺类化合物、脱水山梨醇脂肪酸酯类化合物、聚氧乙烯脱水山梨醇脂肪酸酯类化合物、聚氧乙烯脂肪酸酯类化合物、聚氧乙烯脂肪醇醚类化合物、聚氧乙烯-聚氧丙烯共聚物类化合物、环糊精类化合物或聚乙二醇类化合物中的一种或几种;其中醇类化合物包括乙醇、丙醇、丙二醇、丙三醇、异丙醇、丁醇、异丁醇、1,3-丁二醇、1,4-丁二醇、丙烯醇等;酰胺类化合物包括:二甲基甲酰胺、二甲基乙酰胺等;脱水山梨醇脂肪酸酯类(司盘类)化合物包括:司盘-20、司盘-40、司盘-60、司盘-80、司盘-85;聚氧乙烯脱水山梨醇脂肪酸酯类(吐温类)化合物包括:吐温-20、吐温-40、吐温-60、吐温-80、吐温-85;聚氧乙烯脂肪酸酯类(卖泽类)化合物包括:聚氧乙烯月桂酸酯类、聚氧乙烯单月桂酸酯类、聚氧乙烯硬脂酸酯类、聚氧乙烯氢化蓖麻油类、聚氧乙烯蓖麻油类、聚氧乙烯单油酸酯类等;聚氧乙烯脂肪醇醚类化合物包括:苄泽类、平平加-O、平平加-A等;聚氧乙烯-聚氧丙烯共聚物类(泊洛沙姆)化合物包括:泊洛沙姆124、泊洛沙姆188、泊洛沙姆237、泊洛沙姆338、泊洛沙姆407等;环糊精类化合物包括:α、β、γ-环糊精及其衍生物,如甲基环糊精、乙基环糊精、羟乙基环糊精、羟丙基环糊精、支链环糊精、磺甲基醚环糊精、磺丁基醚环糊精等;聚乙二醇类化合物包括:聚乙二醇-200、聚乙二醇-300、聚乙二醇-400、聚乙二醇-500或聚乙二醇-600。
所述吸收促进剂选自环糊精类化合物、胆酸盐类化合物、饱和或不饱和脂肪酸及其酯化合物、醇类化合物、醚类化合物、亚砜类化合物、内酰胺类化合物和表面活性剂化合物中的一种或几种;其中环糊精类化合物:包括α、β、γ-环糊精及其衍生物,如甲基环糊精、乙基环糊精、羟乙基环糊精、羟丙基环糊精、支链环糊精、磺丁基醚环糊精;胆酸盐类化合物:包括甘胆酸盐、胆酸盐、去氧胆酸盐、牛磺胆酸盐、葡萄糖胆酸盐、鹅去氧胆酸盐、鸟索去氧胆酸盐等;饱和或不饱和脂肪酸及其酯化合物:包括油酸、肉豆蔻酸、月桂酸及其酯、癸酸及其酯、辛酸酯、棕榈酸酯、乳酸乙酯;醇类化合物:包括丙二醇、丙三醇、异丙醇、十六醇、月桂醇、油醇等;醚类化合物:包括聚氧乙烯月桂醚、聚氧乙烯辛醚等;亚砜类化合物:包括十二烷基甲基亚砜、二甲基亚砜等;内酰胺类化合物:包括十二烷基氮卓酮、拢牛儿基氮卓酮等;表面活性剂化合物:包括十二烷基硫酸钠、辛酸单甘油酯、吐温及司盘类。
所述防腐剂选自:苯甲酸及其盐、对羟基苯甲酸酯类、山梨酸、三氯叔丁醇、尼泊金乙酯、苯甲醇、苯乙醇、硫柳汞、醋酸洗必泰和季铵化合物类阳离子表面活性剂中的一中或几种。
所述矫味剂主要选自:蔗糖、转化糖、葡萄糖、果糖、葡聚糖、甘露醇、木糖醇、甘草酸二钠、甘草酸三钠、甜菊糖苷、糖精钠、薄荷油、薄荷脑、橙皮酊、柠檬酸、酒石酸或乳酸中的一种或几种。
所述渗透压调节剂选自:葡萄糖、乳糖、右旋糖苷、山梨醇、甘露醇及其无机盐中的一种或几种。
所述扎来普隆口腔给药系统为舌下给药的剂型。
根据本发明,舌下给药的剂型有滴剂、气雾剂、喷雾剂、粉雾剂、凝胶剂、微球及乳剂等。考虑到用药的方便性、工业化生产的可行性和上述剂型的特点,本发明优选舌下喷雾剂。
本发明的优点是:本发明优选扎来普隆作为舌下给药系统中的活性成分,成功解决了扎来普隆极难溶解的问题,该系统或组合物通过喷雾形式给药,可避免消化道作用和肝脏首过效应、并且有起效快、生物利用度高、药效确切、使用方便、其剂量可根据需要进行调整、顺应性好,特别适合老年人和不便于吞咽的患者。且制备工艺简单可行,适合工业化生产等优点。
下面结合具体实施方式对本发明作进一步说明,并非对本发明的限定,依照本领域公知的现有技术,本发明的实施方式并不限于此,因此凡依照本发明公开内容所作出的本领域的等同替换,均属于本发明的保护范围。
具体实施方式
实施例1 扎来普隆喷雾剂
处方成分 用量
扎来普隆 2.5g
丙二醇 50ml
尼泊金乙酯 0.05g
薄荷脑 0.1g
甘露醇 0.5g
蒸馏水 至100ml
制备方法:准确称取上述量的扎来普隆、尼泊金乙酯、薄荷脑、甘露醇,混合均匀,加入上述量的丙二醇,再加水至100ml,于40℃超声或振荡至溶解,过0.45um微孔滤膜即得扎来普隆舌下喷雾剂药液,再分装于喷雾装置中。
实施例2 扎来普隆喷雾剂
处方成分 用量
扎来普隆 2.5g
丙三醇 50ml
尼泊金乙酯 0.05g
薄荷脑 0.1g
甘露醇 0.5g
蒸馏水 至100ml
制备方法:准确称取上述量的扎来普隆、尼泊金乙酯、薄荷脑、甘露醇,混合均匀,加入上述量的丙三醇,再加水至100ml,于40℃超声或振荡至溶解,过0.45um微孔滤膜即得扎来普隆舌下喷雾剂药液,再分装于喷雾装置中。
实施例3 扎来普隆喷雾剂
处方成分 用量
扎来普隆 2.5g
聚乙二醇400 50ml
尼泊金乙酯 0.05g
薄荷脑 0.1g
山梨醇 0.5g
蒸馏水 至100ml
制备方法:准确称取上述量的扎来普隆、尼泊金乙酯、薄荷脑、山梨醇,混合均匀,加入上述量的聚乙二醇400,再加水至100ml,于40℃超声或振荡至溶解,过0.45um微孔滤膜即得扎来普隆舌下喷雾剂药液,再分装于喷雾装置中。
实施例4 扎来普隆喷雾剂
处方成分 用量
扎来普隆 5g
乙醇 30ml
聚乙二醇-400 40ml
羟丙基-β-环糊精 5g
尼泊金乙酯 0.05g
薄荷脑 0.1g
蒸馏水 至100ml
制备方法:准确称取上述量的扎来普隆、羟丙基-β-环糊精、尼泊金乙酯、薄荷脑,混合均匀,加入上述量的聚乙二醇-400、乙醇及水至100ml,于40℃超声或振荡至溶解,过0.45um微孔滤膜即得扎来普隆舌下喷雾剂药液,再分装于喷雾装置中。
实施例5 扎来普隆喷雾剂
处方成分 用量
扎来普隆 2.5g
乙醇 40ml
聚乙二醇400 60ml
薄荷脑 0.1g
制备方法:准确称取上述量的扎来普隆和薄荷脑,加入上述量的聚乙二醇400、乙醇至100ml,于40℃超声或振荡至溶解,过0.45um微孔滤膜即得扎来普隆舌下喷雾剂药液,再分装于喷雾装置中。
实施例6 扎来普隆喷雾剂
处方成分 用量
扎来普隆 2.5g
乙醇 40ml
二乙二醇单乙醚 20ml
尼泊金乙酯 0.05g
柠檬酸 0.5g
甘露醇 0.5g
蒸馏水 至100ml
制备方法:准确称取上述量的扎来普隆、尼泊金乙酯、柠檬酸、甘露醇,混合均匀,加入上述量的二乙二醇单乙醚、乙醇及水至100ml,于40℃超声或振荡至溶解,过0.45um微孔滤膜即得扎来普隆舌下喷雾剂药液,再分装于喷雾装置中。
实施例7 扎来普隆喷雾剂
处方成分 用量
扎来普隆 5g
乙醇 40ml
二甲基亚砜 10ml
尼泊金乙酯 0.05g
柠檬酸 0.5g
甘露醇 0.5g
蒸馏水 至100ml
制备方法:准确称取上述量的扎来普隆、尼泊金乙酯、柠檬酸、甘露醇,混合均匀,加入上述量的二甲基亚砜、乙醇及水至100ml,于40℃超声或振荡至溶解,过0.45um微孔滤膜即得扎来普隆舌下喷雾剂药液,再分装于喷雾装置中。
实施例8 扎来普隆喷雾剂
处方成分 用量
扎来普隆 5g
乙醇 40ml
聚氧乙烯蓖麻油 10ml
尼泊金乙酯 0.05g
柠檬酸 0.5g
甘露醇 0.5g
蒸馏水 至100ml
制备方法:准确称取上述量的扎来普隆、尼泊金乙酯、柠檬酸、甘露醇,混合均匀,加入上述量的聚氧乙烯蓖麻油、乙醇及水至100ml,于40℃超声或振荡至溶解,过0.45um微孔滤膜即得扎来普隆舌下喷雾剂药液,再分装于喷雾装置中。
实施例9 扎来普隆喷雾剂
处方成分 用量
扎来普隆 5g
乙醇 40ml
羟丙基-β-环糊精 15g
尼泊金乙酯 0.05g
柠檬酸 0.5g
蒸馏水 至100ml
制备方法:准确称取上述量的扎来普隆、羟丙基-β-环糊精,混合均匀,加入上述量的乙醇及水至100ml,于50℃振荡48h,再加入上述量的尼泊金乙酯、柠檬酸,振荡至溶解,过0.45um微孔滤膜即得扎来普隆舌下喷雾剂药液,再分装于喷雾装置中。
实施例10 扎来普隆喷雾剂
处方成分 用量
扎来普隆 2.5g
乙醇 40ml
磺丁基醚-β-环糊精 15g
尼泊金乙酯 0.05g
柠檬酸 0.5g
蒸馏水 至100ml
制备方法:准确称取上述量的扎来普隆、磺丁基醚-β-环糊精,混合均匀,加入上述量的乙醇及水至100ml,于50℃振荡48h,再加入上述量的尼泊金乙酯、柠檬酸,震荡至溶解,过0.45um微孔滤膜即得扎来普隆舌下喷雾剂药液,再分装于喷雾装置中。
实施例11 扎来普隆喷雾剂
处方成分 用量
扎来普隆 2.5g
乙醇 40ml
二甲基-β-环糊精 15g
尼泊金乙酯 0.05g
柠檬酸 0.5g
蒸馏水 至100ml
制备方法:准确称取上述量的扎来普隆、二甲基-β-环糊精,混合均匀,加入上述量的乙醇及水至100ml,于50℃振荡48h,再加入上述量的尼泊金乙酯、柠檬酸,震荡至溶解,过0.45um微孔滤膜即得扎来普隆舌下喷雾剂药液,再分装于喷雾装置中。
实施例12 比格犬舌下喷雾(实施例4)制剂给药药代动力学和相对生物利用度
6条比格犬,雄性,体重10~12kg,采用双周期交叉自身对照实验设计,比较实施例4制剂舌下喷雾给药10mg/条及口服市售片剂给药10mg/条的药代动力学,计算相对生物利用度。两种途径给药后分别于给药前(0min)和给药后10、20、30、45、60、75、90、120、150、180、240、360、480min时间点,于静脉取血2ml,3000×g离心分离血浆,β-萘酚为内标,采用Agilent 1100 HPLC荧光检测器测定血药浓度,荧光检测波长:激发波长为345nm,发射波长为460nm。标曲线性范围在5ng/ml~1000ng/ml,最低定量检测下线为5ng/ml,回收率为94.3%~101.5%,测定的日内日间精密度均在10%以内。具体测定结果见表1。
表1 比格犬扎来普隆舌下喷雾给药(10mg/条)及片剂口服给药(10mg/条)
后不同时间点血药浓度(ng/ml)
时间(min) | 舌下喷雾给药 | 口服片剂给药 | ||||||||||
1 | 2 | 3 | 4 | 5 | 6 | 1 | 2 | 3 | 4 | 5 | 6 | |
102030456075901201501805240360480 | 123.3250.2415.3372.5320.3267.4210.7163.6101.274.147.723.814.7 | 110.6234.8387.9410.4341.5287.6220.4172.1110.582.350.622.512.3 | 98.7243.4396.5374.3310.6259.4209.8165.598.270.744.421.914.2 | 120.6270.3433.4383.1331.2277.5220.6154.599.668.939.520.711.7 | 107.5226.7365.8425.7357.8289.2232.5160.4103.271.341.323.113.2 | 93.8196.5357.3411.6342.1277.9226.4157.8100.677.240.719.611.2 | 30.647.4100.7156.8220.6234.5183.6121.895.466.135.418.28.3 | 23.435.289.8130.2180.3190.8167.7116.288.665.541.217.59.7 | 40.551.6110.6166.5246.3230.2166.5131.698.563.241.320.510.1 | 33.445.790.2140180.9174.7155.1116.781.958.733.217.16.5 | 43.667.2122.5170.3236.2221.9176.8133.391.264.335.318.55.9 | 24.550.799.6145.7186.5232.7188.5136.793.263.636.718.57.2 |
计算以上血药浓度数据的主要药代动力学参数,并计算扎来普隆舌下喷雾给药的相对生物利用度,数据列于表2。
表2 比格犬扎来普隆舌下喷雾给药(10mg/条)及片剂口服给药(10mg/条)后
主要药代动力学参数及生物利用度
药代参数 | AUC(mg·min/L) | T1/2(min) | Cmax(ng/mL) | Tmax(min) | ||||
舌喷 | 片剂 | 舌喷 | 片剂 | 舌喷 | 片剂 | 舌喷 | 片剂 | |
1234 | 47.249.345.746.4 | 30.628.332.326.8 | 85.482.582.877.4 | 85.387.591.583.6 | 415.3410.4396.5433.4 | 234.5190.8246.3180.9 | 30453030 | 75756060 |
结果表明:比格犬扎来普隆舌下喷雾给药(10mg/条)及静脉给药(10mg/条)后,其体内药代动力学过程均符合一房室模型,消除相半衰期很接近,分别为81.0.7±3.1min和84.8±4.4min。舌下喷雾给药吸收很快,10min即能达到较高的血药浓度,平均37.5min血药浓度能达峰,较口服片剂平均血药浓度达峰时间提前30min。舌下喷雾给药制剂对口服片剂的相对生物利用度平均为157.6%,较口服片剂生物利用度提高了接近60%。
实施例13 实施例4制剂对增强戊巴比妥作用试验
40只昆明种小鼠,雌雄各半,体重20±2g,分为空白溶媒对照组和实施例4制剂给药组2组。对照组给以实施例4制剂空白溶媒后20min,ip给予小鼠最大阈下催眠剂量的戊巴比妥钠15mg/kg,使90-100%的小鼠翻正反射不消失。给药组给以实施例4制剂1mg/kg后20min,同样ip给予小鼠最大阈下催眠剂量的戊巴比妥钠15mg/kg,观察两组动物给药后30min内翻正反射消失达1min以上者为阳性反应,表明动物发生了睡眠,用X2值来测定对照组和给药组入睡动物之间的差异。
结果表明:空白溶媒对照组20只动物给药后30min内翻正反射消失达1min以上的动物有1只,阳性率为5%,而实施例4制剂给药后30min内翻正反射消失达1min以上的动物有16只,阳性率为80%,两组之间有统计学的显著差异,说明本发明制剂治疗失眠作用有吸收起效快、作用强,有确切的治疗作用等特点。具体数据见表3。
表3 实施例4制剂增强戊巴比妥作用试验小鼠翻正反射消失作用
组别 | 阳性例数 | 阴性例数 | 合计 | 阳性率(%) |
空白溶媒对照组实施例4制剂组合计 | 11617 | 19423 | 202040 | 58042.5 |
X2=23.02 X2 0.005,1=7.88,P<0.005
Claims (3)
1.一种扎来普隆口腔给药制剂,其特征在于:所述每100ml制剂中所含组分及其含量如下:
所述主要溶媒选自水、醇类化合物、酯及油脂类化合物、醚类化合物和羧酸类化合物中的一种或几种,其中醇类化合物包括乙醇、丙醇、丙二醇、丙三醇、异丙醇、丁醇、异丁醇、1,3-丁二醇、1,4-丁二醇、丙烯醇;酯及油脂类化合物包括甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、乙酸丁酯、乙酸异丁酯、乙酸异戊酯、豆油、芝麻油、花生油、蓖麻油、杏仁油;醚类化合物包括乙醚、三丁甲基乙醚、二乙二醇单乙醚、二乙二醇二甲醚;羧酸类化合物包括甲酸、乙酸或丙酸;
所述增溶助溶剂选自醇类化合物、酰胺类化合物、脱水山梨醇脂肪酸酯类化合物、聚氧乙烯脱水山梨醇脂肪酸酯类化合物、聚氧乙烯脂肪酸酯类化合物、聚氧乙烯脂肪醇醚类化合物、聚氧乙烯-聚氧丙烯共聚物类化合物、环糊精类化合物或聚乙二醇类化合物中的一种或几种;其中醇类化合物包括乙醇、丙醇、丙二醇、丙三醇、异丙醇、丁醇、异丁醇、1,3-丁二醇、1,4-丁二醇、丙烯醇;酰胺类化合物包括:二甲基甲酰胺、二甲基乙酰胺;脱水山梨醇脂肪酸酯类(司盘类)化合物包括:司盘-20、司盘-40、司盘-60、司盘-80、司盘-85;聚氧乙烯脱水山梨醇脂肪酸酯类(吐温类)化合物包括:吐温-20、吐温-40、吐温-60、吐温-80、吐温-85;聚氧乙烯脂肪酸酯类(卖泽类)化合物包括:聚氧乙烯月桂酸酯类、聚氧乙烯单月桂酸酯类、聚氧乙烯硬脂酸酯类、聚氧乙烯氢化蓖麻油类、聚氧乙烯蓖麻油类、聚氧乙烯单油酸酯类;聚氧乙烯脂肪醇醚类化合物包括:苄泽类、平平加-O、平平加-A;聚氧乙烯-聚氧丙烯共聚物类(泊洛沙姆)化合物包括:泊洛沙姆124、泊洛沙姆188、泊洛沙姆237、泊洛沙姆338、泊洛沙姆407;环糊精类化合物包括:α、β、γ-环糊精及其选自甲基环糊精、乙基环糊精、羟乙基环糊精、羟丙基环糊精、支链环糊精、磺甲基醚环糊精、磺丁基醚环糊精的衍生物;聚乙二醇类化合物包括:聚乙二醇-200、聚乙二醇-300、聚乙二醇-400、聚乙二醇-500或聚乙二醇-600;
所述吸收促进剂选自环糊精类化合物、胆酸盐类化合物、饱和或不饱和脂肪酸及其酯化合物、醇类化合物、醚类化合物、亚砜类化合物、内酰胺类化合物和表面活性剂化合物中的一种或几种;其中环糊精类化合物:包括α、β、γ-环糊精及其选自甲基环糊精、乙基环糊精、羟乙基环糊精、羟丙基环糊精、支链环糊精、磺丁基醚环糊精的衍生物;胆酸盐类化合物:包括甘胆酸盐、胆酸盐、去氧胆酸盐、牛磺胆酸盐、葡萄糖胆酸盐、鹅去氧胆酸盐、鸟索去氧胆酸盐;饱和或不饱和脂肪酸及其酯化合物:包括油酸、肉豆蔻酸、月桂酸及其酯、癸酸及其酯、辛酸酯、棕榈酸酯、乳酸乙酯;醇类化合物:包括丙二醇、丙三醇、异丙醇、十六醇、月桂醇、油醇;醚类化合物:包括聚氧乙烯月桂醚、聚氧乙烯辛醚;亚砜类化合物:包括十二烷基甲基亚砜、二甲基亚砜;内酰胺类化合物:包括十二烷基氮卓酮、拢牛儿基氮卓酮;表面活性剂化合物:包括十二烷基硫酸钠、辛酸单甘油酯、吐温及司盘类;
所述防腐剂选自:苯甲酸及其盐、对羟基苯甲酸酯类、山梨酸、三氯叔丁醇、尼泊金乙酯、苯甲醇、苯乙醇、硫柳汞、醋酸洗必泰和季铵化合物类阳离子表面活性剂中的一中或几种;
所述矫味剂主要选自:蔗糖、转化糖、葡萄糖、果糖、葡聚糖、甘露醇、木糖醇、甘草酸二钠、甘草酸三钠、甜菊糖苷、糖精钠、薄荷油、薄荷脑、橙皮酊、柠檬酸、酒石酸或乳酸中的一种或几种;
所述渗透压调节剂选自:葡萄糖、乳糖、右旋糖苷、山梨醇、甘露醇及其无机盐中的一种或几种。
2.根据权利要求1所述的扎来普隆口腔给药制剂,其特征在于:所述扎来普隆口腔给药制剂为舌下给药的剂型,舌下给药剂型包括滴剂、气雾剂、喷雾剂、粉雾剂、凝胶剂、微球和乳剂。
3.根据权利要求2所述的扎来普隆口腔给药制剂,其特征在于:所述剂型为舌下喷雾剂。
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