CN1305474C - 盐酸纳美芬鼻腔给药制剂 - Google Patents
盐酸纳美芬鼻腔给药制剂 Download PDFInfo
- Publication number
- CN1305474C CN1305474C CNB2004100836132A CN200410083613A CN1305474C CN 1305474 C CN1305474 C CN 1305474C CN B2004100836132 A CNB2004100836132 A CN B2004100836132A CN 200410083613 A CN200410083613 A CN 200410083613A CN 1305474 C CN1305474 C CN 1305474C
- Authority
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- China
- Prior art keywords
- nalmefene
- preparation
- nasal
- present
- drug
- 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.)
- Expired - Lifetime
Links
- 229960005297 nalmefene Drugs 0.000 title claims abstract description 35
- WJBLNOPPDWQMCH-MBPVOVBZSA-N Nalmefene Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=C)O)CC1)O)CC1CC1 WJBLNOPPDWQMCH-MBPVOVBZSA-N 0.000 title abstract description 30
- 239000000203 mixture Substances 0.000 title description 6
- 238000009472 formulation Methods 0.000 title description 5
- GYWMRGWFQPSQLK-OPHZJPRHSA-N (4r,4as,7as,12bs)-3-(cyclopropylmethyl)-7-methylidene-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,9-diol;hydron;chloride Chemical compound Cl.N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=C)O)CC1)O)CC1CC1 GYWMRGWFQPSQLK-OPHZJPRHSA-N 0.000 claims abstract description 32
- 229960000677 nalmefene hydrochloride Drugs 0.000 claims abstract description 32
- 238000002360 preparation method Methods 0.000 claims abstract description 26
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- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims description 12
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 12
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 claims description 12
- -1 nalmefene hydrochlorides Chemical class 0.000 claims description 9
- 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 8
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 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
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
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- 230000000052 comparative effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- 229940009976 deoxycholate Drugs 0.000 description 2
- 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 description 2
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- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 description 2
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Abstract
本发明提供的经鼻腔给药的纳美芬制剂包括盐酸纳美芬、纳美芬游离碱或医药上可接受的纳美芬的其它药用盐和吸收促进剂。大量实验表明，根据本发明的鼻腔给药制剂通过鼻粘膜途径，将药物吸收，而进入血液循环发挥作用，具有性能稳定、质量可控、对鼻粘膜无刺激的优点。本发明提供的鼻腔给药制剂可用于抗休克、手术中的麻醉过量抢救、吗啡类药物中毒和毒品依赖者的诊断，急性酒精中毒，脑梗塞，新生儿窒息和药物中毒等应激性疾病的预防或治疗的经鼻给药制剂。
Description
发明领域
本发明涉及鼻腔给药制剂，具体讲涉及盐酸纳美芬鼻腔给药制剂。
背景技术
盐酸纳美芬(nalmefene hydrochloride)为阿片拮抗剂，由美国Ivax/Ohmeda公司创制，1995年在美国上市。是继纳络酮(NALOXONE)和纳曲酮(Naltrexone)之后合成的又一新的纯阿片受体拮抗剂。它与阿片受体μ、κ、δ均能结合，其中与μ受体结合作用最强。
盐酸纳美芬为纯阿片受体拮抗剂，是水溶性纳曲酮的衍生物，其6位亚甲基的化学结构，使它表现出生理活性更强，更易穿透生物膜的特性。它的血浆清除半衰期(t1/2)为8.2-8.9h，与同类化合物纳曲酮(F＝5％-20％，t1/2＝2-5h)和纳曲酮(F＝0％-5％，t1/2＝1.5h)相比，其药理作用时间长、作用强度大。毒副作用较低。虽在较大剂量时有轻微的头痛、倦怠、视力模糊等，但无明显不良反应，因此，越来越受到研究者的关注。1984年Katovich等人用纳美芬在大鼠模型上对吗啡所产生的依赖进行拮抗，结果表明，按每公斤0.001、0.005、0.01、0.02或0.1mg纳美芬用量下均有显著效果。1995年经美国FDA批准，纳美芬可用于手术后逆转阿片类药物引起的不良反应如呼吸抑制、血压降低等。
目前临床上，含盐酸纳美芬的制剂为口服给药的口服制剂及静脉和肌肉给药的注射剂。对1750例病人经注射给药，临床试验表明未发现其导致疾病或死亡(personal communication，S Fein，Anaquest，Inc，May 1991)；口服纳美芬 25、50、100mg时，不产生吗啡样作用(瞳孔缩小、欣快感等)，没有滥用潜能。实验表明，盐酸纳美芬和纳美芬具有作用时间长、生物利用度高、副作用少的特点，已用于拮抗麻醉性镇痛剂引起的呼吸抑制和用于心力衰竭、休克、酒精中毒、成瘾等的治疗。
实践还证明，临床上使用的盐酸纳美芬剂注射剂和口服制剂虽有一定治疗效果，但起效慢，给药后30分钟起效，tmax 1.5小时以上。而经静脉和肌肉注射给药，又必须有专业医护人员进行操作。对于要求在第一时间下及时方便给药的危重和昏迷的病人，以及在家发病的患者而言，提供一种除注射、口服外的给药途径，或者说多提供一种可供选择的给药途径无疑显得十分必要。
发明内容
虽然US 4,880,813号美国专利披露了一种含纳美芬的溶液经鼻腔给药，但其中披露的是用以治疗过敏性鼻烟，针对过敏性鼻炎的局部治疗。此外，没有记载进一步提高治疗效果的诸如渗透压调节剂、吸收促进剂、增稠剂一类助剂。或者说，由于未使用吸收促进剂，渗透压调节剂等，局部治疗，不能完全吸收到体内而全身发挥作用。
本发明的目的是克服已知盐酸纳美芬制剂的不足，开发新的盐酸纳美芬剂形，非注射途径和口服途径给药，而全身发挥作用，有利益医生，患者方便，用药快速。本发明人已通过广泛深入研究，现已发现将纳美芬或其药用盐与吸收促进剂，渗透压调节剂，增稠剂，防腐剂，或其它药用辅料配成经鼻腔给药，可有效地避免盐酸纳美芬口服生物利用度低，用药剂量大，同时又避免了注射给药的不顺应性。
大量实验表明，根据本发明的鼻腔给药制剂通过鼻粘膜途径，将药物吸收，而进入血液循环发挥作用，具有性能稳定、质量可控、对鼻粘膜无刺激的优点。
本发明具有吸收迅速，生物利用度高，疗效确切，使用方便的特点，每次用药剂量可根据需要在0.1mg-40mg范围内调整。
本发明提供的经鼻腔给药的纳美芬制剂包括盐酸纳美芬、纳美芬游离碱或医药上可接受的纳美芬的其它药用盐和吸收促进剂。
本发明提供的第二纳美芬制剂中包括渗透压调节剂。
本发明提供第三的鼻腔给药纳美芬制剂中包括防腐剂、表面活性剂和PH调节剂。
本发明提供第四的鼻腔给药纳美芬制剂中的所述吸收促进剂选自下述(1)——(8)中的任一种物质：
(1)α、β、γ-环糊精的环糊精类，及烷基取代的环糊精类，如甲基-β-环糊精、二甲基-β-环糊精、羟丙基-β-环糊精；
(2)胆酸盐类：如甘胆酸盐、胆酸盐、去氧胆酸盐、牛黄胆酸盐、葡萄糖胆酸盐、鹅去氧胆酸盐、乌索去氧胆酸盐；
(3)饱和和不饱和脂肪酸及其酯类：如月桂酸、油酸、肉豆蔻酸、癸酸、月桂酸酯、辛酯酸、葵酸酯、棕榈酸酯、乳酸乙酯：
(4)醇类：丙二醇、异丙醇、十六醇、月桂醇、油醇等；
(5)醚类：聚氧乙烯月桂醚、聚氧乙烯辛醚；
(6)亚砜类：如十二烷基甲基亚砜、二甲基亚砜；
(7)内酰胺类：如十二烷基氮卓酮、拢牛儿基氮卓酮；
(8)离子型非离子型面活性剂：如十二烷基硫酸钠、辛酸单甘油酯、
吐温80、司盘20或它们的两种或两种以上混合物；
选自乳糖、葡萄糖、右旋糖苷、山梨醇、甘露醇或其药学上可接受的无机盐的所述渗透压调节剂；
选自高分子化合物、羧甲基纤维素、羟丙基纤维素、聚乙二醇、聚丙烯酸、聚乙烯酸、卡波普所述增稠剂；
选自尼泊金乙酯、对羟基苯甲酸酯、苯甲酸及其药学上可接受的盐、山梨酸、三氯叔丁醇、苯甲醇、苯乙醇、硫柳汞、醋酸洗必泰及季銨化合物的阳离子表面活性剂所述防腐剂。
本发明提供第五的鼻腔给药纳美芬制剂，按百分重量计，所说制剂含0.2-80％的盐酸纳美芬、其游离碱或医药上可接受的纳美芬的其它盐。
本发明提供第六的鼻腔给药的100毫升所说制剂中含盐酸纳美芬80毫克，聚乙烯吡咯烷酮0.5克，月桂氮酮0.5毫升，丙二醇1.0克，尼泊金乙酯0.1克。
本发明提供第七的鼻腔给药纳美芬的100毫升所说制剂中包括盐酸纳美芬80毫克，羟丙基B-环糊精2.5克，尼泊金乙酯0.1克，甘露醇0.5克，聚乙二醇400 1.0毫升，纯化水至100毫升。
本发明提供第八的鼻腔给药纳美芬的100毫升所说制剂中包括盐酸纳美芬160毫克，甲基B-环糊精5克，尼泊金乙酯0.1克，聚乙烯醇0.5克，甘露醇2-4克，纯化水至100毫升。
本发明提供的鼻腔给药的给药纳美芬制剂为鼻腔喷雾剂或鼻腔滴鼻剂。
本发明提供的鼻腔给药制剂可用于抗休克、手术中的麻醉过量抢救、吗啡类药物中毒和毒品依赖者的诊断，急性酒精中毒，脑梗塞，新生儿窒息和药物中毒等应激性疾病的预防或治疗的经鼻给药制剂。
根据本发明，盐酸纳美芬或纳美芬其它药用盐在单位经鼻给药制剂中的含量为0.1-160％(重量％)，优选0.2-80％(重量％)。
下面通过实施例对本发明做进一步说明，但其不意味着对本发明的保护范围仅限于此。
实施例1：盐酸纳美芬喷雾剂
成份 量
盐酸纳美芬 80mg
聚乙稀吡咯烷酮 0.5g
月桂氮酮 0.5ml
丙二醇 1.0g
尼泊金乙酯 0.1g
蒸馏水 至100ml
制法：将上述量聚乙烯吡咯烷酮、盐酸纳美芬、丙二醇、月桂氮统计尼泊金乙酯充分搅匀使全部溶解，最后补加蒸馏水至100ml。所得溶液分装于喷雾泵或定量滴泵中。
实施例2：盐酸纳美芬喷雾剂
成份 量
盐酸纳美芬 80mg
羟丙基-β-环糊精 2.5g
尼泊金乙酯 0.1g
甘露醇 0.5g
聚乙二醇400 1.0ml
蒸馏水 至100ml
制法：将上述量盐酸纳美芬、羟丙基-β-环糊精、尼泊金乙酯、甘露醇加蒸馏水振摇使溶解后，加入上述聚乙二醇400，最后补加蒸馏水至100ml。
实施例3：盐酸纳美芬喷雾剂
成份 量
盐酸纳美芬 160mg
甲基-β-环糊精 5g
尼泊金乙酯 0.1g
聚乙烯醇 0.5g
甘露醇 2-4g
蒸馏水 至100ml
制法：将上述量盐酸纳美芬、甲基-β-环糊精、尼泊金乙酯、聚乙烯醇加蒸馏水，振摇使全部溶解后，最后补加蒸馏水至100ml。
药理学试验
实验1
实施利1 本发明提供的盐酸纳美芬鼻喷剂与盐酸纳美芬注射液给药后在比格狗体内的血药浓度比较试验，结果见表1、
表1：盐酸纳美芬喷雾剂鼻和注射剂在比格犬体内的血药浓度比较试验
| 时间(min) | 血药浓度ng.ml-1 | |
| 纳美芬注射液8mg/条 | 纳美芬鼻喷剂8mg/条 | |
| 60120180240300360420480540600660 | 367.12307.12289.23254.34209.12176.54120.3486.5447.9823.1612.57 | 306.34278.98240.78209.34198.35140.87103.5667.9838.9819.679.98 |
实验2 盐酸纳美芬在比格狗体内绝对生物利用度表3
表2：盐酸纳美芬在比格犬体内的绝对生物利用度
| No | 绝对生物利用度(％) | ( X±SD)％ |
| 123456 | 89.0996.9890.8588.0391.5888.94 | 91.05±5.97 |
实验1和实验2结果说明盐酸纳美芬鼻喷剂在体内代谢过程与盐酸纳美芬注射液在体内代谢过程一样。
实验3 本发明的盐酸纳美芬鼻喷剂对阿片类药物中毒的解毒作用试验表3盐酸纳美芬鼻喷剂对盐酸双氢埃托啡中毒(50ug/kg)的解毒作用试验
| 分组 | N | 剂量 | 解毒时间(min) | 结果 |
| 对照组注射机组鼻喷剂组 | 91010 | 00.80.8 | 4-74-204-27 | 死亡恢复正常恢复正常 |
以上结果说明将盐酸纳美芬鼻喷剂，通过鼻粘膜的吸收而发挥全身作用，起效快，药效好，对阿片类药物中毒有良好救治效果。
技术人员阅读本专利申请说明书后可以进行种种变更和修改，但这些变更和修改均在申请待批的权利要求保护范围之内。
Claims (2)
1.一种用于抗休克、手术中的麻醉过量抢救的经鼻腔给药的盐酸纳美芬制剂，其特征在于，100ml所说制剂中包括
盐酸纳美芬80毫克，
羟丙基-β-环糊精2.5克，
尼泊金乙酯0.1克，
甘露醇0.5克，
聚乙二醇400 1.0毫升，
纯化水至100毫升。
2.一种用于抗休克、手术中的麻醉过量抢救的经鼻腔给药的盐酸纳美芬制剂，其特征在于，100ml所说制剂中包括
盐酸纳美芬160毫克，
甲基-β-环糊精5克，
尼泊金乙酯0.1克，
甘露醇2-4克，
聚乙烯醇0.5克，
纯化水至100毫升。
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| US10653690B1 (en) * | 2019-07-09 | 2020-05-19 | Orexo Ab | Pharmaceutical composition for nasal delivery |
| CN115804754A (zh) * | 2022-12-16 | 2023-03-17 | 广州新济药业科技有限公司 | 吗啡鼻喷剂及其制备方法 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4880813A (en) * | 1988-07-22 | 1989-11-14 | Baker Cummins Pharmaceuticals, Inc. | Method of treatment for allergic rhinitis |
-
2004
- 2004-10-13 CN CNB2004100836132A patent/CN1305474C/zh not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4880813A (en) * | 1988-07-22 | 1989-11-14 | Baker Cummins Pharmaceuticals, Inc. | Method of treatment for allergic rhinitis |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11458091B2 (en) | 2016-11-18 | 2022-10-04 | Opiant Pharmaceuticals, Inc. | Compositions and methods for the treatment of opioid overdose |
| EP3793558A4 (en) * | 2018-05-17 | 2022-04-20 | Aegis Therapeutics, LLC | FORMULATIONS AND METHODS TO PREVENT OPIOID OVERDOSE |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1634062A (zh) | 2005-07-06 |
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