胰岛素油溶液的制备及性质研究
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摘要
制备蛋白质等大分子物质的疏水性溶液的技术-Macrosol-为实现胰岛素等蛋白多肽药物的口服提供了一种新的载体形式。我们通过溶媒的选择和工艺的改进得到了一种制备工艺简单、稳定性好的胰岛素油溶液。
体外实验表明该油溶液在不同pH值的水中均可以发生自乳化,其中在pH=7.9的水相中,自乳化得到的乳液颗粒粒径在300nm左右,粒径分布窄,适合于在消化道中吸收。乳化后,制剂可以保护胰岛素抵抗各种蛋白消化酶的分解作用。
正常小鼠和糖尿病大鼠的降血糖实验表明该制剂在口服后有明显的降血糖作用,并且具有量效关系。比较口服经胃给药和肠道注入给药,发现胰岛素油溶液肠道注入后的降血糖效果更佳。故此我们制备了内容物为这种油溶液的肠溶胶丸,糖尿病犬的口服实验表明,一次口服2.5IU/Kg体重该胶丸有长达24小时的持续降血糖作用。以皮下注射中效胰岛素(NPH)为对照,该制剂的相对药效生物利用度为15.21%。
油溶液中胰岛素含量测定是本论文工作的一个重要部分,我们建立了一种适用于该制剂的回收率高,重复性好的毛细管电泳检测方法。
Macrasol, the technique which can make the macromolecule dissolve in oil phase, is a new drug carrier system for oral administration of protein or peptide. In this work, we screened out appropriate oil menstruum and technical conditions to get a satisfying insulin oil solution, which are prepared simply and show long term stability.
The studies in vitro show that this formulation can self emulsified in water. The Eff. Diam. of the emulsified particles was about 300nm with narrow distribution after the insulin oil solution was dispersed in water with pH of 7.9. After emulsification in water, insulin in the oil can be protected from digestive enzymes in vitro.
The biological effect of this formulation in normal mouse and diabetic rats after orally administrated was studied in this work. It showed a dosage dependent degrease of blood glucose level. The effect after intestinal administration is better than it after oral administration. There was a significant decrease of blood glucose level for about 24 hours after the Enteric-Coated Soft Capsules containing insulin oil formulation were orally administered to diabetic dogs (2.5IU/kg). The pharmacodynamic bioavailability of this capsule after oral administration related to NPH insulin after subcutaneous(SC) injection was 15.21%.
Determination of insulin in oil phase was one important part of this work. We founded a suitable capillary electrophoresis method with high recovery of insulin and good repetition.
体外实验表明该油溶液在不同pH值的水中均可以发生自乳化,其中在pH=7.9的水相中,自乳化得到的乳液颗粒粒径在300nm左右,粒径分布窄,适合于在消化道中吸收。乳化后,制剂可以保护胰岛素抵抗各种蛋白消化酶的分解作用。
正常小鼠和糖尿病大鼠的降血糖实验表明该制剂在口服后有明显的降血糖作用,并且具有量效关系。比较口服经胃给药和肠道注入给药,发现胰岛素油溶液肠道注入后的降血糖效果更佳。故此我们制备了内容物为这种油溶液的肠溶胶丸,糖尿病犬的口服实验表明,一次口服2.5IU/Kg体重该胶丸有长达24小时的持续降血糖作用。以皮下注射中效胰岛素(NPH)为对照,该制剂的相对药效生物利用度为15.21%。
油溶液中胰岛素含量测定是本论文工作的一个重要部分,我们建立了一种适用于该制剂的回收率高,重复性好的毛细管电泳检测方法。
Macrasol, the technique which can make the macromolecule dissolve in oil phase, is a new drug carrier system for oral administration of protein or peptide. In this work, we screened out appropriate oil menstruum and technical conditions to get a satisfying insulin oil solution, which are prepared simply and show long term stability.
The studies in vitro show that this formulation can self emulsified in water. The Eff. Diam. of the emulsified particles was about 300nm with narrow distribution after the insulin oil solution was dispersed in water with pH of 7.9. After emulsification in water, insulin in the oil can be protected from digestive enzymes in vitro.
The biological effect of this formulation in normal mouse and diabetic rats after orally administrated was studied in this work. It showed a dosage dependent degrease of blood glucose level. The effect after intestinal administration is better than it after oral administration. There was a significant decrease of blood glucose level for about 24 hours after the Enteric-Coated Soft Capsules containing insulin oil formulation were orally administered to diabetic dogs (2.5IU/kg). The pharmacodynamic bioavailability of this capsule after oral administration related to NPH insulin after subcutaneous(SC) injection was 15.21%.
Determination of insulin in oil phase was one important part of this work. We founded a suitable capillary electrophoresis method with high recovery of insulin and good repetition.
引文
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[2]http://www.idf.org/home/index.cfm?node=264
[3]马学毅,潘国敏,陈戴蕤等 口服型胰岛素微囊研制的初步报告 中国糖尿病杂志 2000 Vol.8 No.4 p219-223
[4]Muramatsu K,Maitani Y,Takayama K,et a1.The relationship between the rigidity of the liposomal membrane and the absorption of insulin after nasal administration of lipsomes modified with aJl enhancer containing insulin in rabbits.Drug Dev Ind Pharm,1999;25(10):1099.
[5]王闻珠,邓英杰.脂质体肺部给药研究进展.沈阳药科大学学报,2000;17(5):226-9
[6]Mcgurk J G,Ross AR,Gilroy GC.A novel method for the in-situ preparation of liposomes using an aerosol delivery system.J Pharm Pharm,1986;38:20
[7]Taylor KMG,Taylor G,Kellaway IW.The stability of liposomes to nebulisation.Int J Pharm,1990,58(1):57-61
[8]江志强,吕剑.胰岛素脂质体混悬液的肺部给药.药学学报,2002;37(5):378-382
[9]Barnett AH.Exubera inhaled insulin:a review[J].Int J Clin Pract,2004,58(4):394-401.
[10]SelamJL.Inhaled insulin for the treatment of diabetes:projects and devices[J].Expert Opin Pharmacother,2003,4(8):1373-1377.
[11]Hermansen K,Ronnemaa T,Petersen AH,et al.Intensive therapy with inhaled insulin via the AERx insulin diabetes management system:a 12-weekproof-of-concept trial in patients with type 2 diabetes[J].Diabetes Care,2004,27(1):162-167.
[12]Dunbar C,Scheuch G,Sommerer K,et al.In vitro and invivo dose delivery characteristics of large porous particles for inhalation[J].Int J Pharm,2002,245(1/2):179-189.
[13]Perera AD,Kapitza C,Nosek L,et al.Absorption and metabolic effect of inhaled insulin:intrapatient variability after inhalation via the Aerodose insulin inhaler in patients with type 2 diabetes[J].Diabetes Care,2002,25(12):2276-2281.
[14]Ahn BN,Kim SK,Shim CK.Proliposomes as an intranasal dosage form for the sustained delivery of propranolol.J Control Release,1995;34:203
[15]Maitaini Y,Asano S,Takahashi S,et al.Permeability of insulin entrapped inliposome through the nasalmucosa of rabbits.Chem Pharm B ull Tokyo,1992;40(6):1569
[16]Kupila A,Sipila J,Simell T,et al.Effects of intranasal insulin in healthy subjects.Presented at the American Diabetes Association 58th Scientific Sessions,Chicago,Illinois,June 1998
[17]郭建新,平其能,张磊.胰岛素柔性脂质体经小鼠皮肤给药的降血糖作用.中国药学杂志,2002;36(1)35-7
[18]Muramatsu K,Maitani Y,Nagai T.Dipalmitoylphosphatidylcholine liposomes with soybean derived sterols and cholesterol as a carrier for the oral administration of insulin in rats.Biol Pharm B ull,1996;199(8):1055-8
[19]Asada H,Douen T,Mizokoshi Y,et al.Stability of acylderivatives of insulin in the small intestine:relative importance of insulin association characteristic in aqueous solution.Pharm Res,1994;11(8):1115-1120
[20]张口,齐宪荣,张强.胰岛素与脂质体的相互作用.药学学报,2002;37(5):370-3
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