扎来普隆舌下喷雾剂的研制
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摘要
扎来普隆(Zaleplon)为非苯二氮卓类镇静催眠药。该药在临床上主要用于治疗失眠症,其可显著缩短失眠患者的入睡时间,疗效确切,副作用小。目前国内外临床上所用扎来普隆的剂型主要为片剂和胶囊剂等口服制剂。这些口服剂型不仅吸收较慢,而且由于肝脏首过效应严重,生物利用度只有大约30%。本研究根据扎来普隆的理化性质和舌下给药的特点,研制了扎来普隆舌下喷雾剂,旨在提高该药的用药水平和病人使用的顺应性,增加该药的新剂型。
本研究首先进行了扎来普隆舌下喷雾剂的制剂学研究,该部分工作是本研究的关键。分别通过规格确定、溶剂的选择、矫味剂的选择及给药装置的选择确定处方,确定了制备工艺,并制备出一系列样品供质量标准研究和稳定性研究。结果表明该剂型的处方合理、工艺简单、重现性和稳定性好。
为控制扎来普隆舌下喷雾剂的质量,建立了HPLC含量测定方法及稳定性分析方法,该方法准确、灵敏,辅料及降解产物不干扰主药测定。进而对扎来普隆舌下喷雾剂稳定性进行了考察。影响因素试验、加速试验、长期试验的结果显示该制剂外观、pH、药物含量、有关物质等指标在试验过程中没有明显变化,证明该制剂稳定性良好,为其包装选择和质量标准制订提供了依据。并在此基础上制定了扎来普隆舌下喷雾剂的质量标准草案,其能较好地控制该制剂的质量。
扎来普隆舌下喷雾剂在6条比格犬体内的药代动力学和生物利用度研究表明:其体内药代动力学过程均符合一房室模型,扎来普隆舌下喷雾剂吸收速度比片剂约快1倍,Cmax比片剂约高1倍,对片剂的相对生物利用度为157.6%,经统计学检验具有生物等效性。
关于扎来普隆舌下喷雾剂笔者未见国内外文献的相关报道,具有一定的新颖性和临床应用价值。本研究基本完成了国家二类新药的临床前资料,并已申报国家发明专利,专利申请号:200710175243.9
Zaleplon is a kind of non-benzodiazepine sedative hypnotic drugs. It is used clinically for the treatment of insomnia. It can markedly shorten the time of falling asleep with good curative effect and few side effect. The dosage forms of Zaleplon mainly used on domestic and aboard clinical practice is tablet and capsule. Because of a serious liver first-pass effect, the absolute bioavailability of the oral administration was only 30%. At the same time , oral administration takes on action slowly. In order to provide an alternative administration of Zaleplon for systemic drug delivery to increase its absorption and improve patient compliance, considering the physiochemical properties of Zaleplon and the characteristics of sublingual administration, we planed to study on the sublingual spray of Zaleplon.
The optimization of the formulation was the key work in our study. After selection of dosage, solvent, correctant and administration instrument, the formulation of the dosage form was detemined. A series of samples were prepared for quality criterion study, stability study. The result showed that the formulation of the dosage form was reasonable, simple and convenient to prepare, with good reproductivity.
In order to control the quality of the preparation, a reliable HPLC method of determination of Zaleplon and its relative substances was established. Under the condition of test, the pharmaceutical aids and the decomposition products could be well separated from Zaleplon. The stability study on Zaleplon sublingual spray indicated that it was stable, nearly without any changes during the stability study. On base of formulation study and stability study, quality criterion studies were put forward. It was proved that the draft of quality criterion for the dosage form could well control the quality of products.
The pharmacokinetics and bioavailability study of the sublingual spray of Zaleplon was carried out on 6 Beagle dogs in a randomized crossover manner. The result indicated that the concentration- time curves conformed to 1–compartment model with first-order absorption. The new dosage form took on action faster than oral administration. It was absorbed about 1 times faster than tablet, Tmax was 37.5min and Cmax was 415.5ng/mL, about 1 times higher than tablet. The bioavailability of it was 157.6% and it was bioequivalent to tablet.
No report about Zaleplon sublingual spray was found. This study has its innovation and appli- cation value in clinics. The preclinical study of it as 2nd category new drug of China have been finished basically. Patent of it has been applied in process, filed No.was 200710175243.9
本研究首先进行了扎来普隆舌下喷雾剂的制剂学研究,该部分工作是本研究的关键。分别通过规格确定、溶剂的选择、矫味剂的选择及给药装置的选择确定处方,确定了制备工艺,并制备出一系列样品供质量标准研究和稳定性研究。结果表明该剂型的处方合理、工艺简单、重现性和稳定性好。
为控制扎来普隆舌下喷雾剂的质量,建立了HPLC含量测定方法及稳定性分析方法,该方法准确、灵敏,辅料及降解产物不干扰主药测定。进而对扎来普隆舌下喷雾剂稳定性进行了考察。影响因素试验、加速试验、长期试验的结果显示该制剂外观、pH、药物含量、有关物质等指标在试验过程中没有明显变化,证明该制剂稳定性良好,为其包装选择和质量标准制订提供了依据。并在此基础上制定了扎来普隆舌下喷雾剂的质量标准草案,其能较好地控制该制剂的质量。
扎来普隆舌下喷雾剂在6条比格犬体内的药代动力学和生物利用度研究表明:其体内药代动力学过程均符合一房室模型,扎来普隆舌下喷雾剂吸收速度比片剂约快1倍,Cmax比片剂约高1倍,对片剂的相对生物利用度为157.6%,经统计学检验具有生物等效性。
关于扎来普隆舌下喷雾剂笔者未见国内外文献的相关报道,具有一定的新颖性和临床应用价值。本研究基本完成了国家二类新药的临床前资料,并已申报国家发明专利,专利申请号:200710175243.9
Zaleplon is a kind of non-benzodiazepine sedative hypnotic drugs. It is used clinically for the treatment of insomnia. It can markedly shorten the time of falling asleep with good curative effect and few side effect. The dosage forms of Zaleplon mainly used on domestic and aboard clinical practice is tablet and capsule. Because of a serious liver first-pass effect, the absolute bioavailability of the oral administration was only 30%. At the same time , oral administration takes on action slowly. In order to provide an alternative administration of Zaleplon for systemic drug delivery to increase its absorption and improve patient compliance, considering the physiochemical properties of Zaleplon and the characteristics of sublingual administration, we planed to study on the sublingual spray of Zaleplon.
The optimization of the formulation was the key work in our study. After selection of dosage, solvent, correctant and administration instrument, the formulation of the dosage form was detemined. A series of samples were prepared for quality criterion study, stability study. The result showed that the formulation of the dosage form was reasonable, simple and convenient to prepare, with good reproductivity.
In order to control the quality of the preparation, a reliable HPLC method of determination of Zaleplon and its relative substances was established. Under the condition of test, the pharmaceutical aids and the decomposition products could be well separated from Zaleplon. The stability study on Zaleplon sublingual spray indicated that it was stable, nearly without any changes during the stability study. On base of formulation study and stability study, quality criterion studies were put forward. It was proved that the draft of quality criterion for the dosage form could well control the quality of products.
The pharmacokinetics and bioavailability study of the sublingual spray of Zaleplon was carried out on 6 Beagle dogs in a randomized crossover manner. The result indicated that the concentration- time curves conformed to 1–compartment model with first-order absorption. The new dosage form took on action faster than oral administration. It was absorbed about 1 times faster than tablet, Tmax was 37.5min and Cmax was 415.5ng/mL, about 1 times higher than tablet. The bioavailability of it was 157.6% and it was bioequivalent to tablet.
No report about Zaleplon sublingual spray was found. This study has its innovation and appli- cation value in clinics. The preclinical study of it as 2nd category new drug of China have been finished basically. Patent of it has been applied in process, filed No.was 200710175243.9
引文
[1] CarLos H.,Mark W, Roberl L.失眠的评估和处理[J ].美国医学会杂志中文版,2004,23 (4):208-211.
[2] Ashton H. Guidelines for the rational use of benzodiazepines when and what to use[J]. Drugs,1994,48(1):25-40.
[3] Mellingsaeter T. C.,Bramness J. G.,Slordal L. Are z-hypnotics better and safer sleeping pills than benzodia- zepines? [J]. Tidsskr Nor Laegeforen,2006,22(126):2954-2956.
[4] Bharathi Ch,Prabahar K. J,Prasad Ch,S. Impurity profile study of Zaleplon [J]. Pharm Biomed Anal,2007,44(1):101-109.
[5] Mangano RM. Efficacy and safety of Zaleplon at peak plasma levels [J]. Int J Clin Pract,2001,116(Suppl):S9-S13.
[6] Ringdahl EN,Pereira SL,Delzell JE Jr. Treatment of primary insomnia[J]. J Am Board Fam Pract,2004,17(3):212-219.
[7] Hedner J,Yaeche R. Zaleplon shortens subjective sleep latency and improves subjective sleep quality in eld- erly patients with insomnia[J]. Int J Geriatr Psychiatry,2000,15(8):704-708.
[8] Ttoy SM,Lucki J,Unrch MA,etal. Comparison of the effects of zaleplon,zolpidem,and triazolam on memory,learning ,and psychomotor performance[J]. J Clin Psychopharmacol,2000,20(3):328-334.
[9]周秀梅,范佥.紫外分光光度法测定扎来普隆胶囊含量.山西医科大学学报,2004,35(4):377-378.
[10]倪楠,高永良.液体制剂中难溶性药物的增溶.中国新药杂志,2005 ,14(11):1276-1279.
[11] Sweetana S,Akers JM.Solubility principles and practices for parenteral drug dosage form development [J].PDA J Pharm SciTechnol ,1996 ,50 (5):130– 142.
[12] Li P,Zhao L,Yalkowsky SH.Combined effect of cosolvent and cyclodextrin on solubilization of nonpolar drugs [J].J Pharm Sci,1999,88 (11):1107– 1111.
[13] Millard JW,Yalkowsky SH.Solubilzation by cosolvents–establishing useful constants for the log–linear model [J]. Int J Pharm,2002,245(3) :153– 166.
[14] R.C.罗,P.J.舍斯基,P.J.韦勒.药用辅料手册[M].第四版
[15] Li P.Solubilization of flurbiprofen in pH–surfactant solutions [J ] . J Pharm Sci,2003,92(5):951 - 956.
[16]黎洪珊,王培玉.β-环糊精衍生物的研究进展及在药剂学上的应用.中国药学杂志,1999,34(4):220-223.
[17]罗昕,徐月红,陈宝等.羟丙基-β-环糊精对隐丹参酮的增溶作用及其包合物的制备.中国中药杂志,2005,30(17):1328-1331.
[18]化学药物制剂研究基本技术指导原则
[19]化学药物稳定性研究技术指导原则
[20]中国药典[M]. 2005版二部附录IL:附录11-附录12.
[21]中国药典[M].2005版二部附录ⅩⅨC:附录176-附录179.
[22]李琳,郭瑞芳,陆直.高效液相色谱法测定扎来普隆片剂含量.中国新药杂志,2005,14(5):590-592.
[23]中国药典[M].2005版二部附录VD:附录28-附录30.
[24]中国药典[M].2005版二部附录ⅠB、ⅠG、ⅠL:附录6-附录13.
[25]化学药物质量标准建立的规范化过程技术指导原则
[26]邓鸣,刘建芳,刘会臣.扎来普隆分散片的人体相对生物利用度[J].中国医院药学杂志,2004,24(7):402-404.
[27]张萌,陈大为,马莉.扎来普隆口腔速溶片的制备及其犬体内生物利用度.中国药剂学杂志,2007,5(1):7-11.
[2] Ashton H. Guidelines for the rational use of benzodiazepines when and what to use[J]. Drugs,1994,48(1):25-40.
[3] Mellingsaeter T. C.,Bramness J. G.,Slordal L. Are z-hypnotics better and safer sleeping pills than benzodia- zepines? [J]. Tidsskr Nor Laegeforen,2006,22(126):2954-2956.
[4] Bharathi Ch,Prabahar K. J,Prasad Ch,S. Impurity profile study of Zaleplon [J]. Pharm Biomed Anal,2007,44(1):101-109.
[5] Mangano RM. Efficacy and safety of Zaleplon at peak plasma levels [J]. Int J Clin Pract,2001,116(Suppl):S9-S13.
[6] Ringdahl EN,Pereira SL,Delzell JE Jr. Treatment of primary insomnia[J]. J Am Board Fam Pract,2004,17(3):212-219.
[7] Hedner J,Yaeche R. Zaleplon shortens subjective sleep latency and improves subjective sleep quality in eld- erly patients with insomnia[J]. Int J Geriatr Psychiatry,2000,15(8):704-708.
[8] Ttoy SM,Lucki J,Unrch MA,etal. Comparison of the effects of zaleplon,zolpidem,and triazolam on memory,learning ,and psychomotor performance[J]. J Clin Psychopharmacol,2000,20(3):328-334.
[9]周秀梅,范佥.紫外分光光度法测定扎来普隆胶囊含量.山西医科大学学报,2004,35(4):377-378.
[10]倪楠,高永良.液体制剂中难溶性药物的增溶.中国新药杂志,2005 ,14(11):1276-1279.
[11] Sweetana S,Akers JM.Solubility principles and practices for parenteral drug dosage form development [J].PDA J Pharm SciTechnol ,1996 ,50 (5):130– 142.
[12] Li P,Zhao L,Yalkowsky SH.Combined effect of cosolvent and cyclodextrin on solubilization of nonpolar drugs [J].J Pharm Sci,1999,88 (11):1107– 1111.
[13] Millard JW,Yalkowsky SH.Solubilzation by cosolvents–establishing useful constants for the log–linear model [J]. Int J Pharm,2002,245(3) :153– 166.
[14] R.C.罗,P.J.舍斯基,P.J.韦勒.药用辅料手册[M].第四版
[15] Li P.Solubilization of flurbiprofen in pH–surfactant solutions [J ] . J Pharm Sci,2003,92(5):951 - 956.
[16]黎洪珊,王培玉.β-环糊精衍生物的研究进展及在药剂学上的应用.中国药学杂志,1999,34(4):220-223.
[17]罗昕,徐月红,陈宝等.羟丙基-β-环糊精对隐丹参酮的增溶作用及其包合物的制备.中国中药杂志,2005,30(17):1328-1331.
[18]化学药物制剂研究基本技术指导原则
[19]化学药物稳定性研究技术指导原则
[20]中国药典[M]. 2005版二部附录IL:附录11-附录12.
[21]中国药典[M].2005版二部附录ⅩⅨC:附录176-附录179.
[22]李琳,郭瑞芳,陆直.高效液相色谱法测定扎来普隆片剂含量.中国新药杂志,2005,14(5):590-592.
[23]中国药典[M].2005版二部附录VD:附录28-附录30.
[24]中国药典[M].2005版二部附录ⅠB、ⅠG、ⅠL:附录6-附录13.
[25]化学药物质量标准建立的规范化过程技术指导原则
[26]邓鸣,刘建芳,刘会臣.扎来普隆分散片的人体相对生物利用度[J].中国医院药学杂志,2004,24(7):402-404.
[27]张萌,陈大为,马莉.扎来普隆口腔速溶片的制备及其犬体内生物利用度.中国药剂学杂志,2007,5(1):7-11.