奥氮平口溶膜的制备和体内外评价
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摘要
首先测定了参比制剂市售奥氮平片和口崩片在4种不同pH介质中的溶出曲线,观察到市售口崩片在不同介质中的溶出均快于普通片,其中以水为溶出介质时区分力最强。随后考察了奥氮平原料药在水中的溶出特性,结果显示药物溶出缓慢,但与高分子材料混合后,溶出速率明显加快。以药物在水中的溶出速率和口溶膜的溶化时间为评价指标,进行处方筛选,制备了奥氮平口溶膜,并进行体内外评价。结果表明,当普鲁兰多糖、玉米淀粉和Tween-80用量分别为39.4%、40%和0.6%时,制备的厚度约为80μm的奥氮平口溶膜可在30 s内快速溶化,在4种不同pH介质中的溶出行为均与市售口崩片相似。差示扫描量热(DSC)和X射线衍射(XRD)分析结果显示,奥氮平以其原有晶型分散于膜剂中。Beagle犬体内药动学试验结果表明,自制口溶膜与市售口崩片相比,相对生物利用度为(108.14±22.23)%。
The dissolution profiles of the commercial olanzapine tablets and orodispersible tablets in four dissolution media with different pH values were measured.The results showed that the marketed orodispersible tablet,produced by freeze drying process,dissolved more quickly than the marketed tablets,and water was considered as the most discriminative media.Subsequently,the dissolution behaviors of olanzapine with different diameters and its mixture with different polymers in water were investigated.It was found that pure olanzapine dissolved slowly,but when mixed with polymers,its dissolution rate was significantly accelerated.Then the formulation factors of olanzapine orodispersible films were optimized with disintegration time and drug dissolution rate as the evaluation parameters.The results showed that the optimal films composed of 39.4% pullulan,40% com starch and 0.6% Tween-80 with a thickness of about 80μm could disintegrate within 30 s.The dissolution behaviors of olanzapine orodispersible films in various pH media were similar to the marketed orodispersible tablets.Differential scanning calorimetry(DSC)and X-ray diffraction(XRD)demonstrated that olanzapine was dispersed in the carrier materials with its original crystal form.The results of pharmacokinetics in Beagle dogs indicated that the relative bioavailability of the optimized films was(108.14±22.23)%,compared with the marketed orodispersible tablets.
The dissolution profiles of the commercial olanzapine tablets and orodispersible tablets in four dissolution media with different pH values were measured.The results showed that the marketed orodispersible tablet,produced by freeze drying process,dissolved more quickly than the marketed tablets,and water was considered as the most discriminative media.Subsequently,the dissolution behaviors of olanzapine with different diameters and its mixture with different polymers in water were investigated.It was found that pure olanzapine dissolved slowly,but when mixed with polymers,its dissolution rate was significantly accelerated.Then the formulation factors of olanzapine orodispersible films were optimized with disintegration time and drug dissolution rate as the evaluation parameters.The results showed that the optimal films composed of 39.4% pullulan,40% com starch and 0.6% Tween-80 with a thickness of about 80μm could disintegrate within 30 s.The dissolution behaviors of olanzapine orodispersible films in various pH media were similar to the marketed orodispersible tablets.Differential scanning calorimetry(DSC)and X-ray diffraction(XRD)demonstrated that olanzapine was dispersed in the carrier materials with its original crystal form.The results of pharmacokinetics in Beagle dogs indicated that the relative bioavailability of the optimized films was(108.14±22.23)%,compared with the marketed orodispersible tablets.
引文
[1]龚坚,宋伟明.奥氮平治疗精神分裂症血药浓度、剂量与临床疗效、不良反应的相关性分析[J].海峡药学,2010,22(1):161-163.
[2]BORGES A F,SILVA C,COELHO J F J,et al.Oral films:Current status and future perspectivesⅡ—Intellectual property,technologies and market needs[J].J Controlled Release,2015,206:108-121.
[3]张桦,王栋海,王兵,等.利培酮口溶膜的制备及体内外评价[J].中国医药工业杂志.2017.48(3):406-412.
[4]陈芳,夏怡然,张惠平,等.流延法制备口溶膜剂及其质量评价[J].中国医药工业杂志,2013,44(9):938-942.
[5]陈芳,杨柳榴,周臻,等.马来酸阿塞那平舌下膜的制备及体内外评价[J].中国医药工业杂志,2015,46(8):843-849.
[6]PRAJAPATI V D,CHAUDHARI A M,GANDHI A K,et al.Pullulan based oral thin film formulation of zolmitriptan:Development and optimization using factorial design[J].Int J Biol Macromol 2018,107(Pt B):2075-2085.
[7]ZHANG G,TERRY A V JR,BARTLETT M G.Liquid chromatography/tandem mass spectrometry method for the simultaneous determination of olanzapine,risperidone,9-hydroxyrisperidone,clozapine,haloperidol and ziprasidone in rat plasma[J].Rapid Commun Mass Spectrom,2007,21(6):920-928.
[8]MAHER E M,ALI A M,SALEM H F,et al.In vitro/in vivo evaluation of an optimized fast dissolving oral film containing olanzapine co-amorphous dispersion with selected carboxylic acids[J].Drug Deliv,2016,23(8):3088-3100.
[9]KRISHNAMOORTHY V,SUCHANDRASEN,PRASAD V P.Olanzapine-PEG 6000 binary systems:in vitro dissolution behavior,physicochemical characterization and mathematical modeling[J].Acta Pol Pharm,2015,72(5):999-1013.
[10]RUDRANGI S R,TRIVEDI V,MITCHELL J C,et al.Preparation of olanzapine and methyl-β-cyclodextrin complexes using a single-step,organic solvent-free supercritical fluid process:An approach to enhance the solubility and dissolution properties[J].Int J Pharm,2015,494(1):408-416.
[11]刘艳,冯印,王丽.普鲁兰多糖应用进展[J].北京农业,2014,(30):19.
[12]TIAN Y,VISSER J C,KLEVER J S,et al.Orodispersible films based on blends of trehalose and pullulan for protein delivery[J].Eur JPharm Biopharm,2018,133:1 04-111.
[13]VUDDANDA P R,MONTENEGRO-NICOLINI M,MORALES J O,et al.Effect of plasticizers on the physicomechanical properties of pullulan based pharmaceutical oral films[J].EurJ Pharm Sci,2017,96:290-298.
[14]小林化工株式会社,Loratadine OD Film[EB/OL].[2012-06-01].http://database.japic.or.jp/pdf/newPINS/00060383.pdf.
[2]BORGES A F,SILVA C,COELHO J F J,et al.Oral films:Current status and future perspectivesⅡ—Intellectual property,technologies and market needs[J].J Controlled Release,2015,206:108-121.
[3]张桦,王栋海,王兵,等.利培酮口溶膜的制备及体内外评价[J].中国医药工业杂志.2017.48(3):406-412.
[4]陈芳,夏怡然,张惠平,等.流延法制备口溶膜剂及其质量评价[J].中国医药工业杂志,2013,44(9):938-942.
[5]陈芳,杨柳榴,周臻,等.马来酸阿塞那平舌下膜的制备及体内外评价[J].中国医药工业杂志,2015,46(8):843-849.
[6]PRAJAPATI V D,CHAUDHARI A M,GANDHI A K,et al.Pullulan based oral thin film formulation of zolmitriptan:Development and optimization using factorial design[J].Int J Biol Macromol 2018,107(Pt B):2075-2085.
[7]ZHANG G,TERRY A V JR,BARTLETT M G.Liquid chromatography/tandem mass spectrometry method for the simultaneous determination of olanzapine,risperidone,9-hydroxyrisperidone,clozapine,haloperidol and ziprasidone in rat plasma[J].Rapid Commun Mass Spectrom,2007,21(6):920-928.
[8]MAHER E M,ALI A M,SALEM H F,et al.In vitro/in vivo evaluation of an optimized fast dissolving oral film containing olanzapine co-amorphous dispersion with selected carboxylic acids[J].Drug Deliv,2016,23(8):3088-3100.
[9]KRISHNAMOORTHY V,SUCHANDRASEN,PRASAD V P.Olanzapine-PEG 6000 binary systems:in vitro dissolution behavior,physicochemical characterization and mathematical modeling[J].Acta Pol Pharm,2015,72(5):999-1013.
[10]RUDRANGI S R,TRIVEDI V,MITCHELL J C,et al.Preparation of olanzapine and methyl-β-cyclodextrin complexes using a single-step,organic solvent-free supercritical fluid process:An approach to enhance the solubility and dissolution properties[J].Int J Pharm,2015,494(1):408-416.
[11]刘艳,冯印,王丽.普鲁兰多糖应用进展[J].北京农业,2014,(30):19.
[12]TIAN Y,VISSER J C,KLEVER J S,et al.Orodispersible films based on blends of trehalose and pullulan for protein delivery[J].Eur JPharm Biopharm,2018,133:1 04-111.
[13]VUDDANDA P R,MONTENEGRO-NICOLINI M,MORALES J O,et al.Effect of plasticizers on the physicomechanical properties of pullulan based pharmaceutical oral films[J].EurJ Pharm Sci,2017,96:290-298.
[14]小林化工株式会社,Loratadine OD Film[EB/OL].[2012-06-01].http://database.japic.or.jp/pdf/newPINS/00060383.pdf.
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