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CN1163263C - Polypeptide medicine as oral spray - Google Patents

Polypeptide medicine as oral spray


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CN1163263C CN 00114318 CN00114318A CN1163263C CN 1163263 C CN1163263 C CN 1163263C CN 00114318 CN00114318 CN 00114318 CN 00114318 A CN00114318 A CN 00114318A CN 1163263 C CN1163263 C CN 1163263C
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polypeptide medicine
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CN 00114318
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CN1264596A (en )
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一种多肽类药物口腔粘膜吸收药剂的组方和配制方法。 Prescription and preparation method of the pharmaceutical oral mucosal absorption of peptide agent. 此种药剂由下列组分组成:多肽类药物、促进剂、助溶剂、矫味剂、抑菌剂及pH=6.8~7.8的磷酸盐缓冲溶液。 Such an agent consists of the following components: peptide drugs, enhancers, solubilizers, flavoring agents, antimicrobial agents and phosphate buffer solution pH = 6.8 to 7.8. 本发明的胰岛素口腔喷雾剂将给糖尿病人提供了一种安全简便的给药方式和药物。 Insulin buccal spray of the present invention will provide a safe diabetes convenient mode of administration and the drug.


一种多肽类药物口腔喷雾剂 Polypeptide pharmaceutical oral spray

本发明提供了制备多肽类药物如胰岛素口腔喷雾剂的组方和制备方法。 The present invention provides a preparation method of prescription and peptide drugs such as insulin buccal spray.

多肽类药物在胃肠道内极易被胃酸及多种消化酶所降解,不能直接口服,只能注射给药。 Acid peptide drugs can easily be in the gastrointestinal tract and degraded more digestive enzymes, it can be administered orally, by injection only. 如胰岛素须在餐前半小时注射,才能控制血糖,而且要终生给药,患者感到痛苦不便。 Such as insulin must be injected half an hour before meals to control blood sugar, but also life-long administration, the patient feels pain inconvenience. 因此研究安全、方便及有效的多肽类药物,尤其是胰岛素的非注射途径给药制剂,将极大方便疾病患者。 Thus study safe, convenient and effective peptide drugs, especially non-injection route of administration of insulin formulations, will greatly facilitate the patient's disease. 胰岛素非注射给药途径在本世纪七十年代就开始成为世界各国药学界竞相研究的热点课题,特别是九十年代以来取得了较大的进展。 Non-insulin-injection routes of administration in the seventies of this century began competing to become a hot topic in academic medicine research world, especially since the 1990s has made great progress.

目前可供选择的胰岛素给药途径有多种。 There are a variety of alternative routes of administration of insulin. 例如在腹膜内埋入胰岛素泵的途径,被证明是安全及代谢有效的,国外已用于临床,但价格昂贵,不是一般病人所能承受的。 For example in the way insulin pump buried intraperitoneal, proved to be safe and effective metabolic abroad has been used clinically, but the price is expensive, it is not an ordinary patient can bear. 也有结果表明通过支气管粘膜吸收胰岛素的方法有着诱人的应用前景,但这种方法还有一些难关要攻克。 The results also show that this method of insulin absorption through the bronchial mucosa has an attractive prospect, but this method there are some difficulties to be overcome. 通过脂质体或聚合物等包埋胰岛素,然后做成口服剂使用,胰岛素由小肠粘膜细胞吸收进入血液达到降低血糖的效果,但是药剂的生物利用度低及药剂容易从给药部位被快速清除掉是口服胰岛素成功的重要障碍。 By entrapping insulin, liposomes or polymers, then make an oral agent, the small intestinal cell insulin absorbed into the blood to reduce the effect of blood glucose, but low bioavailability and pharmaceutical agents are easily rapidly cleared from the site of administration out is a major obstacle to the success of oral insulin. 目前正进行的较大量的研究工作集中在通过鼻、眼、肺、口的粘膜吸收的给药途径上。 A relatively large amount of research work is currently being focused on the route of administration by the nasal mucous membranes, eyes, lungs, oral absorption. 这方面的工作经过十几年的探索取得一些进展,但这些途径的临床应用仍存在一些问题,主要是生物利用度低。 Work in this area after 10 years of exploration made some progress, but the clinical application of these pathways are still some problems, mainly low bioavailability.

由于多肽类药物分子量一般较大,口腔粘膜难以吸收,因此选择适当的低毒高效的吸收促进剂,以及增加吸收面积,是提高多肽类药物生物利用度的关键。 Since the generally higher molecular weight peptide drugs, oral mucosa is difficult to absorb, and therefore efficient absorption of selecting appropriate promoter low toxicity, as well as to increase the absorption area, is the key peptide bioavailability enhancing drugs.

本发明的目的是提出一种新型的多肽类药物口腔粘膜吸收喷雾剂。 Object of the present invention is to provide a novel peptide drugs absorption of oral mucosal spray.

以胰岛素为例,本发明的技术方案如下:多肽类药物口腔喷雾剂的组分为:作为多肽类药物的是胰岛素;作为促进剂的是大豆卵磷脂;作为助溶剂的是丙二醇和乙醇;作为矫味剂的是冰片;作为抑菌剂的是苯酚;作为缓冲溶液的是pH=6.8~7.8的磷酸盐缓冲溶液。 Insulin, for example, the technical solution of the present invention are as follows: oral spray of peptide drugs component: As the peptide drugs insulin; as a promoter soya lecithin; as co-solvents are propylene glycol and ethanol; as flavoring agents are norbornene; as a bacteriostatic agent are phenol; as a buffer solution is a phosphate buffer solution pH = 6.8 to 7.8.

其组方为(每1000毫升):胰岛素 5 000U-80 000U大豆卵磷脂 5-45g丙二醇 5-45g冰片 0-10g乙醇 0-15ml苯酚 0-8g磷酸盐缓冲溶液(pH=6.8~7.8) 稀释至1000ml胰岛素口腔喷雾剂的配制:按组方取大豆卵磷脂,加入丙二醇及冰片的乙醇溶液,缓慢搅拌至大豆卵磷脂完全溶解;胰岛素溶解在约为总量2/3,pH=6.8~7.8的含苯酚的磷酸盐缓冲液中。 Is a set of square (per 1000 ml): Insulin 5 000U-80 soy lecithin 5-45g 5-45g glycol isobornyl phenol 0-8g 0-10g ethanol 0-15ml phosphate buffer solution (pH = 6.8 ~ 7.8) was diluted 000U to 1000ml insulin buccal spray formulation: by taking prescription soybean lecithin, propylene glycol and borneol were added in ethanol, soy lecithin was slowly stirred until completely dissolved; the total amount of insulin was dissolved in about 2/3, pH = 6.8 ~ 7.8 the phenol-containing phosphate buffer. 在不断搅拌(400±100转/分钟)下,将胰岛素的磷酸盐缓冲溶液缓慢加入到大豆卵磷脂的丙二醇溶液中,加完后继续搅拌约10~30分钟,再加磷酸盐缓冲液至全量。 Under continuous stirring (400 ± 100 revolutions / min), the phosphate buffer solution was slowly added to the insulin, soybean lecithin in propylene glycol solution, after stirring was continued for about 10 to 30 minutes, plus phosphate buffer to the total amount .

这种药物喷雾剂是一种乳剂,含水和油,但无需另加表面活性剂。 This drug is a spray emulsion, oil and water, but without the addition of a surfactant. 作为本发明药物粘膜促进剂的大豆卵磷脂(油)同时还在此药剂中作为表面活性剂。 Soy lecithin as a pharmaceutical agent of the present invention, promoting mucosal (oil) as a surfactant while still in this medicament.

将这种制剂装入一种带有定量喷雾泵的包装瓶中,它可以将胰岛素像薄雾一样喷入口腔,胰岛素附着在口腔和咽喉的粘膜上,通过粘膜可以迅速进入血液循环,这是一种增大药剂吸收面积,提高吸收速度,方便患者的新型非注射给药方式。 This formulation was charged with one kind of quantitative spray pump bottle packaging, it can be sprayed as a mist into the insulin-like mouth, insulin adhering to the mucosa of the mouth and throat can quickly through mucosa into the blood circulation, which is method of increasing the agent absorption area, absorption rate, non-parenteral administration conveniently new patient. 目前国内外还未见有类似的胰岛素喷雾剂的报道。 At home and abroad has not been a similar insulin spray coverage.

在胰岛素口腔喷雾剂中,胰岛素是主药,但其经口腔粘膜给药的通透性差,为提高其降糖率必须选用合适的吸收促进剂。 Insulin buccal spray, the insulin is the main drug, but the poor permeability of the oral transmucosal administration, to improve the hypoglycemic rate must choose a suitable absorption enhancers. 本发明使用大豆卵磷脂是作为一种无毒、安全、有效的促进剂。 The present invention is the use of soya lecithin as a non-toxic, safe, effective accelerators. 由于大豆卵磷脂的水溶性差,需选择合适的助溶剂。 Since poorly water-soluble soybean lecithin, you need to choose a suitable co-solvent. 本发明以降糖作用为指标,研究了丙二醇的助溶效果。 Hypoglycemic effect in the present invention as an index, the effect studied the solubilization of the propylene glycol. 实验结果表明,丙二醇能增加大豆卵磷脂促进口腔粘膜对胰岛素的吸收作用,通过正交实验确定了它们的最佳配比。 The results show that propylene glycol can increase the absorption promoting effect of soy lecithin on the oral mucosa insulin, determined by the optimum ratio thereof orthogonal.

本发明的胰岛素口腔喷雾剂安全、无毒。 Insulin buccal spray of the present invention is safe, non-toxic. 胰岛素口腔喷雾剂大鼠局部给药的长期毒性试验,给药剂量组为4.5、9.0、18.0U·kg-1,以及生理盐水对照组和赋形剂对照组。 Long-term toxicity test insulin buccal spray for topical administration in rats, dose group 4.5,9.0,18.0U · kg-1, and the control group and the vehicle control group. 进行6个月后,各给药组动物的局部和整体情况与生理盐水对照组比较,均未发现明显异常。 After six months, local and comparing drug-treated animals where a whole with the control group, no significant findings.

本发明的胰岛素口腔喷雾剂具有较高的生物利用度。 Insulin buccal spray of the present invention has high bioavailability. 本发明以正常家兔为模型,采用酶联免疫法测定其体内胰岛素含量,研究了胰岛素口腔喷雾剂的药代动力学并计算其药代动力学参数。 The present invention in normal rabbits as a model, in vivo insulin content was determined by enzyme-linked immunosorbent assay, pharmacokinetics study insulin buccal spray and calculate the pharmacokinetic parameters. 结果表明,对正常家兔口腔粘膜给药(1.5U/kg体重)后,其血清胰岛素浓度迅速升高,达峰时间为64分钟,峰浓度为141.6±6.4μU/ml,4小时后逐渐降低到用药前基础水平。 The results showed that, after normal oral mucosal administration in rabbits (1.5U / kg of body weight), serum insulin concentration increased rapidly, peak time was 64 minutes, the peak concentration was 141.6 ± 6.4μU / ml, decreased after 4 hours before basic level medication. 与赋形剂组比较,胰岛素口腔粘膜给药组和胰岛素皮下注射对照组家兔的血清胰岛素浓度在30~120分钟内均具有显著性差异(P<0.05)。 Compared with the vehicle group, the serum insulin concentrations and insulin buccal mucosa administration group, subcutaneous injection of insulin in the control group of rabbits showed significant difference (P <0.05) within 30 to 120 minutes. 在该剂量下,与胰岛素皮下注射对照组(0.5U·kg-1)相比,血清胰岛素的峰浓度和达峰时间基本相同,无显著性差异(P>0.1),胰岛素口腔喷雾剂的平均生物利用度为29.2%。 At this dose, compared with the control group, subcutaneous injection of insulin (0.5U · kg-1), and peak serum insulin concentration peak substantially the same time, no significant difference (P> 0.1), the average insulin buccal spray bioavailability was 29.2%.

胰岛素口腔喷雾剂具有与口腔粘膜接触面积大、吸收快、降糖率较高、使用安全的特点,因此胰岛素口腔喷雾剂的发明将给糖尿病患者带来用药方便,减轻注射给药的痛苦,从而此项发明具有较大的社会效益与经济利益。 Insulin buccal spray having a large area contact with the oral mucosa, faster absorption, higher hypoglycemic rate, safety features, and therefore insulin buccal spray of the present invention will bring convenient administration, administration by injection to alleviate the pain of diabetic patients, whereby this invention has great social and economic benefits.

根据上述技术方案制成的胰岛素口腔喷雾剂具有很好的降糖效果。 According to the above aspect of the insulin buccal spray prepared having good hypoglycemic effect. 例如,采用化学试剂诱发的高血糖动物和正常动物(大鼠和家兔)等模型,以胰岛素口腔喷雾剂的降糖率为主要指标,对胰岛素口腔喷雾剂的主要药效学进行研究。 For example, use of a chemical agent-induced hyperglycemic animals and normal animals (rats and rabbits), and other models to hypoglycemic insulin buccal spray rate of the main indicators of the main pharmacodynamic study insulin buccal spray. 在动物实验中,动物用戊巴比妥钠麻醉,结扎食道至给药后10分钟:口腔粘膜给药后,每隔30分钟用电子感应血糖仪和电子感应试纸条测定动物血糖,持续测定4~6小时。 In animal experiments, the animal anesthetized with sodium pentobarbital, 10 minutes after ligation of the esophagus to the administration: oral mucosa after administration, the animals blood glucose measured every 30 minutes with a blood glucose meter and electronic sensing electronics sense examination strip for measuring 4 to 6 hours. 同时设胰岛素皮下注射(阳性对照)组和生理盐水(阴性对照)组。 Meanwhile provided subcutaneous insulin (positive control) and saline (negative control) group. 结果表明:①用链脲佐霉素诱发的糖尿病大鼠的口腔给药剂量为1、3、9U·kg-1,降糖率分别为21.6%、46.3%、54 4%。 The results showed that: ① oral dosing with streptozotocin-induced diabetic rats was 1,3,9U · kg-1, hypoglycemic rates were 21.6%, 46.3%, 544%. ②用四氧嘧啶诱发的糖尿病家兔的口腔给药剂量为0.5、1.5、4.5U·kg-1,降糖率分别为:26.2%、50.8%、55.8%。 ② oral dose alloxan-induced diabetic rabbits is 0.5,1.5,4.5U · kg-1, hypoglycemic rates were: 26.2%, 50.8%, 55.8%. ③正常大鼠口腔给药剂量分别为1、3、9 U·kg-1时,降糖率分别为30.7%、51.6%、58 4%。 Oral dosage ③ normal rats were 1,3,9 U · kg-1, the hypoglycemic rates were 30.7%, 51.6%, 584%. ④正常家兔的口腔给药剂量为0.5、1.5、4.5U·kg-1,降糖率分别为31.2%、54.8%、59.1%。 ④ normal oral dosage for rabbits 0.5,1.5,4.5U · kg-1, hypoglycemic rates were 31.2%, 54.8%, 59.1%. ⑤正常大鼠糖耐量试验,按3U/kg剂量给药,降糖率为48.3%。 ⑤ tolerance test in normal rats, in kg dose 3U /, hypoglycemic rate was 48.3%.

Claims (2)

1.一种多肽类药物口腔粘膜喷雾剂,由多肽类药物、促进剂、助溶剂、矫味剂、抑菌剂及缓冲溶液配制而成,其特征在于药剂的组方为每1000ml内作为多肽类药物的胰岛素是5,000U-80,000U,作为促进剂的是大豆卵磷脂5-45g,作为助溶剂的是丙二醇5-45克,乙醇0-15ml,作为矫味剂的是冰片0-10g,作为抑菌剂的是苯酚0-8g,作为缓冲溶液的是pH=6.8~7.8的磷酸盐缓冲溶液。 A peptide pharmaceutical oral mucosal spray, a peptide drugs, enhancers, solubilizers, flavoring agents, buffer solution, bacteriostatic agents formulated, wherein the drug prescription to a polypeptide per 1000ml insulin drug is 5,000U-80,000U, as a promoter soya lecithin 5-45g, propylene glycol as the co-solvent is 5-45 g, ethanol 0-15ml, as flavoring agents is 0 - 10 g borneol, as bacteriostatic agents are phenol 0-8g, a buffer solution is a phosphate buffer solution pH = 6.8 to 7.8.
2.权利要求1的多肽类药物口腔粘膜喷雾剂的配制方法:由多肽类药物、促进剂、助陶剂、矫味剂、抑菌剂及缓冲溶液配制而成,按组方取大豆卵磷脂,加入丙二醇及冰片的乙醇溶液,缓慢搅拌至大豆卵磷脂完全溶解;胰岛素溶解在为总量2/3,pH=6.8~7.8含苯酚的磷酸盐缓冲溶液中;在不断搅拌(400±100转/分钟)下,将胰岛素的磷酸盐缓冲溶液缓慢加入到大豆卵磷脂的丙二醇溶液中,加完后继续搅拌10~30分钟,再加磷酸盐缓冲液至全量。 The method of formulating a pharmaceutical oral mucosal spray polypeptide according to claim 1: a peptide drugs, accelerators, co-Tao agents, flavoring agents, antimicrobial agents and buffer preparation, by taking prescription soy lecithin , propylene glycol and borneol in ethanol, soy lecithin was slowly stirred until completely dissolved; the total amount of insulin was dissolved in 2/3, pH = 6.8 ~ 7.8 phenol-containing phosphate buffer solution; continuous stirring (400 ± 100 rpm in / min), a phosphate buffer solution of insulin was slowly added to the solution of soy lecithin propylene glycol. after the addition stirring was continued for 10 to 30 minutes, plus phosphate buffer to the total amount.
CN 00114318 2000-01-07 2000-01-07 Polypeptide medicine as oral spray CN1163263C (en)

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CN1335182A (en) * 2001-08-08 2002-02-13 华中科技大学 Insulin spray for oral cavity and its prepn process
US20060051413A1 (en) * 2004-09-08 2006-03-09 Chow Sing S M Method of enhancing absorptions of transmucosal administration formulations
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