WO2003013589A1 - Spray buccal contenant de l'insuline et procede de preparation correspondant - Google Patents

Spray buccal contenant de l'insuline et procede de preparation correspondant Download PDF

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Publication number
WO2003013589A1
WO2003013589A1 PCT/CN2002/000342 CN0200342W WO03013589A1 WO 2003013589 A1 WO2003013589 A1 WO 2003013589A1 CN 0200342 W CN0200342 W CN 0200342W WO 03013589 A1 WO03013589 A1 WO 03013589A1
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WIPO (PCT)
Prior art keywords
insulin
microemulsion
phosphate buffer
preparation
oral spray
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PCT/CN2002/000342
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English (en)
French (fr)
Inventor
Huibi Xu
Kaixun Huang
Qiuhua Gao
Zhonghong Gao
Jilin Yang
Original Assignee
Huazhong University Of Science & Technology
Hubei Huagong Biochemistry Eng. Co., Ltd.
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Application filed by Huazhong University Of Science & Technology, Hubei Huagong Biochemistry Eng. Co., Ltd. filed Critical Huazhong University Of Science & Technology
Priority to DE60229647T priority Critical patent/DE60229647D1/de
Priority to US10/486,461 priority patent/US20040258623A1/en
Priority to EP02729761A priority patent/EP1424077B1/en
Publication of WO2003013589A1 publication Critical patent/WO2003013589A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • the invention relates to an insulin preparation and a method for producing the same, and particularly to an insulin oral spray for absorption into the oral mucosa of a human body and a preparation method thereof.
  • Insulin in the gastrointestinal tract is easily degraded by gastric acid and a variety of digestive enzymes. It cannot be taken orally, but can only be administered by injection. It must be injected half an hour before a meal to control blood sugar, and it must be administered for life, which makes patients feel inconvenient. Therefore, research is safe, convenient and effective, especially for non-injection preparations, which will greatly facilitate patients with disease.
  • the non-injective route of insulin administration has become a hot topic in the pharmaceutical industry at home and abroad in the 1970s, and great progress has been made since the 1990s.
  • There are several options for insulin administration For example, the method of embedding an insulin pump in the peritoneum has proven to be safe and effective.
  • Insulin is embedded in liposomes or polymers, and then used as an oral agent. Insulin is absorbed into the blood from the small intestinal mucosal cells to reduce blood sugar, but the bioavailability of the agent is low and the agent is easily cleared from the site of administration. Dropping is an important obstacle to the success of oral insulin. A large amount of research work is currently focused on the route of absorption and administration through the mucosa of the nose, eyes, lungs, and mouth.
  • the invention provides an insulin oral spray and a preparation process thereof.
  • the problem to be solved is to further improve the bioavailability of insulin through the human oral mucosa, while enhancing the stability of the preparation.
  • the inventors further optimized the distribution ratio of each group, and adopted ultrasonic treatment for each component instead of stirring to prepare a microemulsion formulation with an average particle size of less than 200 nm.
  • the insulin oral spray of the present invention is a microemulsion formulation with an average particle size of less than 200 nm.
  • Each 1000 ml of the microemulsion of the present invention contains 1000u-70000u insulin, 5-50g of soy lecithin as a promoter, and 25-80g as a helper.
  • the average particle diameter of the microemulsion is preferably 100-180 nm.
  • the preparation method of the insulin oral spray of the present invention comprises the following steps: taking soybean lecithin according to the formula, adding a corresponding amount of propylene glycol and stirring uniformly, and then adding a total amount of 25-60% by volume of a phosphate buffer solution to form a compound.
  • Forming agent ultrasonically treating the excipient for 0.5-2 hours to obtain a microemulsion oil phase; dissolve insulin in a formula proportion in a phosphate buffer solution of 40-75% by volume, and then gradually add it
  • the microemulsion oil phase is further sonicated for 2-10 minutes.
  • the preparation method of the insulin oral spray of the present invention includes the following steps: taking phenol according to the formula ratio and adding it to the full amount of phosphate buffer solution; taking soybean lecithin according to the formula ratio Add the corresponding amount of propylene glycol, borneol-ethanol solution, stir and hook, and then add the total amount of 25-60% by volume of phenol-containing phosphate buffer solution to form an excipient, ultrasonically treat the excipient for 0.5-2 hours to obtain Oil phase of microemulsion; Dissolve insulin in group formula in 40-75% by volume of phenol-containing phosphate buffer solution, then gradually add it to the oil phase of the microemulsion, and continue ultrasonic treatment 2-10 minute.
  • the ultrasonic treatment has an ultrasonic frequency of 18.25 KHz and an ultrasonic condition duty cycle of 30-90%.
  • the temperature is controlled at 2-7 (TC) during the preparation.
  • Insulin is a polypeptide hormone, which has poor permeability when administered directly through the oral mucosa, in order to improve its bioavailability. It is necessary to select a suitable absorption enhancer.
  • the soybean lecithin used in the present invention is a non-toxic, safe and effective accelerator. Due to the poor water solubility of soybean lecithin, it is necessary to select a suitable co-solvent.
  • the present invention takes the hypoglycemic effect as an indicator The solubilizing effect of propylene glycol was studied.
  • any pharmaceutically acceptable excipient may be included as long as it does not damage the properties of the microemulsion and the effect of the medicine.
  • pharmaceutically acceptable excipients include, but are not limited to, various diluents, solvents, emulsifiers, preservatives, stabilizers, dissolution aids, flavoring agents, fragrances, and the like.
  • the insulin oral spray of the present invention is non-toxic.
  • the insulin oral spray prepared by sonication has significantly improved the efficacy and stability:
  • the present invention uses normal rabbits as a model and uses enzyme-linked immunoassay to determine the insulin content in the body.
  • the pharmacokinetics of insulin oral sprays are calculated and their pharmacokinetic parameters are calculated.
  • After oral mucosal administration (1.5u, kg- 1 body weight) in rabbits the serum insulin concentration increased rapidly, reaching a peak time of 55-70 minutes, and the peak concentration reached 145.2 ⁇ 5.8 ⁇ / ⁇ 1, gradually after 4 to 6 hours. Reduced to the basic level before medication, bioavailability reached 29.8%.
  • the serum insulin concentrations of the insulin oral mucosa administration group and the insulin subcutaneous injection control group were significantly different within 30 to 120 minutes ( ⁇ ⁇ 0.05).
  • the peak concentration and peak time of serum insulin were basically the same, and there was no significant difference ( ⁇ > 0.1).
  • the oral spray of the present invention can be administered in a single dose or in multiple doses, preferably 3 times (every morning, middle, before dinner) or 4 times (before meals and before bedtime) every white, and sprayed 60 minutes before meals medicine.
  • the dosage of the oral spray of the present invention is not particularly limited, and it is a conventional insulin dosage. The specific dose depends on the individual patient, bioavailability, and severity of the condition, and should be administered under the guidance of a doctor.
  • This medicine spray is a microemulsion, which has the characteristics of large contact area with the oral mucosa, fast absorption, good hypoglycemic effect, and safe use.
  • This preparation is packed in a packaging bottle with a metering pump. It can convert insulin like Sprayed into the cavity like a mist, insulin adheres to the mucous membrane of the oral cavity, through which the mucosa can quickly enter the blood circulation, improve the absorption rate, and avoid the acid and enzymatic hydrolysis of the intestine and stomach, and the first-pass effect of the liver.
  • the insulin oral spray of the present invention is a new non-injection administration method convenient for patients, which will bring convenience to the patients with diabetes, reduce the pain of injection administration, and has strong practicability. detailed description
  • the preparation of insulin oral spray according to this formula needs to be performed under strict aseptic conditions.
  • the prepared spray is stored in a refrigerator at 2-8 ° C.
  • the insulin oral spray prepared according to the formula has a better blood glucose lowering effect.
  • streptozotocin-induced diabetic rats received oral doses of 1, 3, 9u * kg- 1 , the hypoglycemic rates were 20.9%, 47.6%, and 58.8%, respectively.
  • the oral administration doses of dioxin-induced diabetic rabbits were 0.5, 1.5, and ⁇ Su. Kg- 1 , and the hypoglycemic rates were 24.9%, 52.6%, and 60.9%, respectively.
  • Example 2 1000mU Isulin microemulsion
  • the insulin oral spray prepared according to this formula was stored in a refrigerator at 2-8 ° C for one year, without precipitation.
  • the insulin oral spray prepared according to the formula has a better blood glucose lowering effect.
  • the oral administration dose of streptozotocin-induced diabetic rats was 1, 3, 9u * kg- 1 , and the hypoglycemic rates were 21.8%, 47.2%, and 56.2 respectively.
  • the oral dosage is 0.5, 1.5, and 4.5u 1
  • the hypoglycemic rate is 28.6%, 55.2%, and 60.7%, respectively.
  • Example 3 1000ml insulin microemulsion
  • the insulin oral spray prepared according to this formula was stored in a refrigerator at 2-8 ° C for one year, without precipitation.
  • the insulin oral spray prepared according to the formula has a better blood glucose lowering effect. Induced with streptozotocin When the oral doses of diabetic rats were 1, 3, and 9 u'kg- 1 , the hypoglycemic rates were 21.3%, 49.8%, and 60.2%, respectively. The oral administration doses of dioxin-induced diabetic rabbits were 0.5, 1.5, and 4.5u * kg- 1 , and the hypoglycemic rates were 29.6%, 55.4%, and 62.2%.
  • Example 4 1000ml insulin microemulsion
  • the insulin oral spray prepared according to this formula was stored in a refrigerator at 2-8 ° C for 1 year, without precipitation.
  • the insulin oral spray prepared according to the formula has a better blood glucose lowering effect.
  • streptozotocin-induced diabetic rats received oral doses of 1, 3, 9u * kg- 1 , the hypoglycemic rates were 18.3%, 35.2%, and 44.2%, respectively.
  • the oral doses of dioxin-induced diabetic rabbits were 0.5, 1.5, and 4.5u * kg- 1 , the hypoglycemic rates were 20.1%, 45.4%, and 52.2%, respectively.

Description

胰岛素口腔喷剂及其制备工艺 技术领域
本发明涉及胰岛素制剂及其生产方法， 特别涉及用于人体口腔粘膜吸收的胰岛 素口腔喷剂及其制备方法。 背景技术
胰岛素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。 它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。 因此研究安全、 方便及有效， 尤其是非注射途径给药制剂， 将极大地方便疾病 患者。 胰岛素非注射给药途径在本世纪七十年代就开始成为国内外药学界竟相研究 的热点课题， 特别是九十年代来取得了较大的进展。 目前可供选择的胰岛素给药途 径有多种。 例如在腹膜内埋入胰岛素泵的途径， 被证明是安全有效的， 国外已用于 临床， 但价格昂贵， 不是一般病人所能承受的。 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。 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。 目前正进行的较大量的研究工作集中在通过鼻、 眼、 肺、 口的粘膜吸收给药途径上， 这方面的工作经过十几年的探索取得一些进展， 但由于胰岛素分子量较大， 粘膜难以吸收， 这些途径的临床应用仍存在生物利用度 低的问题。 因此选择适当的低毒高效的吸收促进剂以增加吸收， 是提高胰岛素生物 利用率的关键。 发明内容
本发明提供一种胰岛素口腔喷剂及其制备工艺， 要解决的问题是进一步提高胰 岛素通过人类口腔粘膜吸收的生物利用度， 同时增强制剂的稳定性。
本发明者在 00114318.2专利申请的基础上， 进一步优化各组分配比， 并对各组 分采取超声处理以代替搅拌配制， 制成平均粒径小于 200nm的微乳剂型。
1
替换页（细则第 26条） 本发明的胰岛素口腔喷剂， 为平均粒径小于 200nm的微乳剂型， 其中每 1000ml 本发明的微乳中含有 lOOOOu— 70000u胰岛素， 5— 50g作为促进剂的大豆卵磷脂， 25 一 80g作为助溶剂的丙二醇， 余量为 pH==6.8— 7.8的磷酸盐缓冲溶液。
按照本发明的胰岛素口腔喷剂， 所述微乳的平均粒径优选在 100-180 nm。
本发明的胰岛素口腔喷剂， 可以以进一步含有冰片一乙醇溶液作为矫味剂， 苯 酚作为抑菌剂。 即每 1000ml本发明的微乳中含有 15000u—60000u胰岛素， 20— 50g 作为促进剂的大豆卵磷脂， 40— 80g作为助溶剂的丙二醇， 1.2— 10g冰片溶解于 1一 15ml无水乙醇得到的作为矫味剂的冰片一乙醇溶液， 2g-5g作为抑菌剂的苯酚， 余 量为 pH=6.8— 7.8的磷酸盐缓冲溶液。
本发明的胰岛素口腔喷剂的制备方法， 包括以下步骤： 按组方比例取大豆卵磷 月旨， 加入对应量的丙二醇搅拌均匀， 再加入全部用量 25-60体积％的磷酸盐缓冲溶液 构成赋形剂， 对赋形剂进行超声处理 0.5— 2小时， 获得微乳的油相； 将组方比例的 胰岛素溶解在占全部用量 40-75体积％的磷酸盐缓冲溶液中， 再逐渐将其加入所述微 乳的油相， 继续超声处理 2— 10分钟。
当增加矫味剂和抑菌剂时， 本发明的胰岛素口腔喷剂的制备方法， 包括以下步 骤： 按组方比例取苯酚加入到全量的磷酸盐缓冲溶液中； 按组方比例取大豆卵磷脂， 加入对应量的丙二醇、 冰片一乙醇溶液中， 搅拌均勾， 再加入全量 25-60体积％的含 苯酚磷酸盐缓冲溶液构成赋形剂， 对赋形剂进行超声处理 0.5— 2小时， 获得微乳的 油相； 将组方比例的胰岛素溶解在占全量 40-75体积％的含苯酚磷酸盐缓冲溶液中， 再逐渐将其加入所述微乳的油相中， 继续超声处理 2— 10分钟。
在本发明的胰岛素口腔喷剂的制备方法中， 其进一步的特征在于所述超声处理 超声频率为 18.25 KHz, 超声条件占空比为 30—90%。
在本发明的胰岛素口腔喷剂的制备方法中， 配制过程中温度控制在 2— 7(TC。 胰岛素是一种多肽类激素， 直接经口腔粘膜给药的通透性差， 为提高其生物利 用度， 必须选用合适的吸收促进剂。 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。 由于大豆卵磷脂的水溶性差， 需选择合适的助溶剂。 本发明以降糖 作用为指标， 研究了丙二醇的助溶效果。 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。 胰岛素 在大豆卵磷脂和丙二醇的系统中形成一种热力学稳定的微乳体系， 大豆卵磷脂同时 还在此药剂中作为表面活性剂和药物的载体， 水溶性的胰岛素嵌在大豆卵磷脂的脂 质双层的水溶液中。
在本发明的口腔喷剂中， 可以包括任何可药用的辅料， 只要其不破坏微乳的性 质和药物的效果。 这些可药用的辅料包括但不限于各种稀释剂、 溶剂、 乳化剂、 防 腐剂、 稳定剂、 溶解助剂、 调味剂、 芳香剂等。
本发明的胰岛素口腔喷剂无毒。 胰岛素口腔喷剂大鼠局部给药的长期毒性试验， 给药剂量为 4.5、 9.0、 18.0 u - kg"1, 以生理盐水和赋形剂作对照组。 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。
利用超声处理的方法制得的胰岛素口腔喷剂与其原来的方法比较， 在药效和稳 定性上有明显提高：
1. 稳定性： 由于超声处理制得的胰岛素口腔喷剂的微乳， 其颗粒的粒径明显变 小， 由原来平均粒度为 427.2nm 的颗粒变成了现在的纳米级粒子， 平均粒径小于 200nm, 粒度分布在 100— 160nm。 这种纳米微乳既有利于粘膜吸收， 而且提高了制 剂的稳定性。 从肉眼观察， 超声处理制备的胰岛素口腔喷剂呈半透明状态， 存放于 2 一 8°C冰箱中 1年， 未见有沉淀产生， 原来通过搅拌配制的胰岛素口腔喷剂呈不透明 状态， 存放于 2— 8°C冰箱中 1 年， 有少量沉淀产生， 可见超声处理的方法对制备微 乳极其重要。
2. 药效： 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剂的药代动力学并计算其药代动力学参数， 结果表明， 对正常 家兔口腔粘膜给药（1.5u，kg— 1体重）后， 其血清胰岛素浓度迅速升高， 达峰时间为 55-70分钟， 峰浓度达到 145.2±5.8μ / ηι1， 4一 6 小时后逐渐降低到用药前的基础 水平， 生物利用度达到 29.8 %。 与不含胰岛素的赋形剂组比较， 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 （ρ<0.05)。 在该剂量下， 与胰岛素皮下注射对照组 （0.5u，kg— 相比， 血 清胰岛素的峰浓度和达峰时间基本相同， 无显著性差别 （ρ>0.1 )。
本发明的口腔喷剂可以单剂量给药或多剂量给药， 优选每白给药 3次 (早、 中、 晚餐前)或 4次 (三餐前及睡前)， 于餐前 60分钟喷药。 本发明的口腔喷剂的剂量没有 特别的限定， 为常规胰岛素的剂量。 具体的剂量根据个体患者、 生物利用度和病情 严重程度而定， 应该在医生指导下用药。
这种药物喷剂是一种微乳， 具有与口粘膜接触面积大、 吸收快、 降糖作用较好、 使用安全的特点， 将这种制剂装入一种带有定量泵的包装瓶中， 它可以将胰岛素像 薄雾一样喷入口腔， 胰岛素附着在口腔的粘膜上， 通过粘膜可以迅速进入血液循环， 提高吸收速度， 而且， 避免了肠、 胃道的酸解和酶解以及肝脏的首过效应。 本发明 的胰岛素口腔喷剂是一种方便患者的新型非注射给药方式， 将给糖尿病患者带来用 药方便， 减轻注射给药的痛苦， 具有很强的实用性。 具体实施方式
实施例 1 : 1000ml胰岛素微乳
胰岛素 40000U
大豆卵磷脂 25.0g
丙二醇 75.0g
磷酸盐缓冲液 （pH=7.4) 适量， 加至 1000ml
按组方取大豆卵磷脂， 加入丙二醇， 搅拌均匀成稀糊状， 然后加入 550ml， pH =7.4 的瞵酸盐缓冲液， 上述组分作为胰岛素口腔喷剂配方中的赋形剂， 进行超声处 理 1小时，超声条件是：占空比为 50% ,温度控制在 40°C— 60°C，超声频率为 20KHz。 将胰岛素溶解在 350ml的 pH=7.4的含苯酚的磷酸盐缓冲液中， 并缓慢加入到超声 处理的赋形剂溶液中， 继续超声处理 5 分钟。 通过激光粒度测试仪测定， 其平均粒 径为 160-180 nm。
按本配方制备胰岛素口腔喷剂， 其工艺需在严格无菌条件下进行， 制备的喷剂 存放于 2— 8°C冰箱中。
按本配方制得的胰岛素口腔喷剂具有较好的降血糖效果。 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一1时， 降糖率分别为 20.9%， 47.6% , 58.8 %。 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， ^Su . kg—1时， 降糖 率分别为 24.9%， 52.6% , 60.9%。 实施例 2: lOOOmU夷岛素微乳
胰岛素 20000U
大豆卵磷脂 30.0g
丙二醇 45.0g
冰片 1.2g
无水乙醇 3.0ml 苯酚 2.0g
磷酸盐缓冲液（pH=7.4) 适量， 加至 1000ml
按组方将苯酚溶于磷酸盐缓冲液中。 按组方取大豆卵磷脂， 加入丙二醇及冰片 的乙醇溶液， 搅拌均匀加入 555ml， pH=7.4的含苯酚的磷酸盐缓冲液， 上述组分作 为胰岛素口腔喷剂配方中的赋形剂， 进行超声处理 1.5小时， 超声条件是： 占空比为 60% , 温度控制在 50°C— 60°C， 超声频率为 18KHz。 将胰岛素溶解在 345ml的 pH =7.4 的含苯酚的磷酸盐缓冲液中， 并缓慢加入到超声处理的赋形剂溶液中， 继续超 声处理 4分钟。 通过激光粒度测试仪测定， 其平均粒径为 160-180 nm。
按本配方制得的胰岛素口腔喷剂存放于 2— 8°C冰箱中 1年， 无沉淀产生。
按本配方制得的胰岛素口腔喷剂具有较好的降血糖效果。 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时， 降糖率分别为 21.8%， 47.2% , 56.2 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 1时， 降糖 率分别为 28.6%， 55.2% , 60.7% 实施例 3: 1000ml胰岛素微乳
胰岛素
大豆卵磷脂 25.0g
丙二醇 75.0g
冰片 1.2g
无水乙醇 4.0ml
苯酚 2.0g
磷酸盐缓冲液（pH=7.0) 适量， 加至 1000ml
按组方取大豆卵磷脂， 加入丙二醇及冰片的乙醇溶液， 搅拌均匀加入 540ml， pH =7.0 的含苯酚的磷酸盐缓冲液， 上述组分作为胰岛素口腔喷剂配方中的赋形剂， 进 行超声处理 1小时， 超声条件是： 占空比为 50%， 温度控制在 40— 55°C， 超声频率 为 20KHz。 将胰岛素溶解在 360ml的 pH=7.0的含苯酚的磷酸盐缓冲液中， 并缓慢 加入到超声处理的赋形剂溶液中， 继续超声处理 5分钟。 通过激光粒度测试仪测定， 其平均粒径为 130-150 nm。
按本配方制得的胰岛素口腔喷剂存放于 2— 8°C冰箱中 1年， 无沉淀产生。
按本配方制得的胰岛素口腔喷剂具有较好的降血糖效果。 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时， 降糖率分别为 21.3%， 49.8%, 60.2 %。 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时， 降糖 率分别为 29.6%， 55.4%, 62.2% 实施例 4: 1000ml胰岛素微乳
胰岛素 60000U
大豆卵磷脂 35.5g
丙二醇 80.0g
冰片 1.4g
无水乙醇 4.0ml
苯酚 2.0g
磷酸盐缓冲液（pH=7.8) 适量， 加至 1000ml
按组方取大豆卵磷脂， 加入丙二醇及冰片的乙醇溶液， 搅拌均匀加入 545ml， pH =7.8 的含苯酚的磷酸盐缓冲液， 上述组分作为胰岛素口腔喷剂配方中的赋形剂， 进 行超声处理 2小时， 超声条件是： 占空比为 70%， 温度控制在 55°C— 70°C， 超声频 率为 25KHz。 将胰岛素溶解在 360ml的 pH=7.8的含苯酚的磷酸盐缓冲液中， 并缓 慢加入到超声处理的赋形剂溶液中， 继续超声处理 3分钟。 通过激光粒度测试仪测 定， 其平均粒径为 140-160 nm。
按本配方制得的胰岛素口腔喷剂存放于 2 - 8°C冰箱中 1年， 无沉淀产生。
按本配方制得的胰岛素口腔喷剂具有较好的降血糖效果。 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时， 降糖率分别为 18.3%, 35.2%, 44.2 %。 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时， 降糖 率分别为 20.1%， 45.4%, 52.2%。

Claims

权 利 要 求 书
1. 一种胰岛素口腔喷剂， 其为平均粒径小于 200nm的微乳， 其中每 1000ml所 述微乳中含有 lOOOOu— 70000U胰岛素， 5— 50g作为促进剂的大豆卵磷脂， 25— 80g 作为助溶剂的丙二醇， 余量为 pH=6.8— 7.8的磷酸盐缓冲溶液。
2. 如权利要求 1所述的胰岛素口腔喷剂， 其特征在于每 1000ml所述微乳中含 有 15000U— 60000u胰岛素， 20— 50g作为促进剂的大豆卵磷脂， 40— 80g作为助溶 剂的丙二醇， 余量为 pH=6.8— 7.8的磷酸盐缓冲溶液。
3. 如权利要求 1 所述的胰岛素口腔喷剂， 其特征在于所述微乳的平均粒径为 100-180nm。
4. 如权利要求 2所述的胰岛素口腔喷剂， 其特征在于所述微乳还含有作为矫味 剂的冰片一乙醇溶液， 其中每 1000ml所述微乳中冰片用量为 1.2— 10g， 无水乙醇用 量为 1一 15ml。
5. 如权利要求 2所述的胰岛素口腔喷剂， 其特征在于所述微乳还含有作为抑菌 剂的苯酚， 其中每 1000ml所述微乳中苯酚用量为 2g— 5g。
6. 如权利要求 1-5中任何一个所述的胰岛素口腔喷剂的制备方法， 包括以下步 骤：
将 5— 50g大豆卵磷脂加入到 25— 80g丙二醇中， 再加入全部用量 25— 60体积 %的磷酸盐缓冲溶液构成赋形剂， 对赋形剂进行超声处理 0.5— 2小时， 得到微乳的 油相； lOOOOu— 70000U胰岛素溶解在占全量 40-75体积％的磷酸盐缓冲溶液中， 再 逐渐将其加入所述微乳的油相中， 继续超声处理 2— 10分钟。
7. 如权利要求 6所述的制备方法， 包括以下步骤：
将 2g— 5g苯酚溶解到磷酸盐缓冲溶液中；
将 20—50g大豆卵磷脂加入到 40— 80g丙二醇、 冰片一乙醇溶液中， 再加入全 部用量 25— 60体积％的含苯酚磷酸盐缓冲溶液， 构成赋形剂， 对赋形剂进行超声处 理 0.5— 2小时， 获得微乳的油相；
将 15000u— 60000U胰岛素溶解到占全部用量 40-75体积％的含苯酚磷酸盐缓冲 溶液中， 再逐渐将其加入所述微乳的油相中， 继续超声处理 2— 10分钟。
8. 如权利要求 6所述的制备方法， 其特征在于所述超声处理超声频率为 18— 25KHz, 超声条件占空比为 30—90%。
9. 如权利要求 7所述的制备方法， 其特征在于所述超声处理超声频率为 18—KHz, 超声条件占空比为 30— 90%。
10. 如权利要求 6所述的制备方法， 其特征在于配制过程中温度控制在 2—°C。
11 . 如权利要求 7所述的制备方法， 其特征在于配制过程中温度控制在 2—Ό。
PCT/CN2002/000342 2001-08-08 2002-05-20 Spray buccal contenant de l'insuline et procede de preparation correspondant WO2003013589A1 (fr)

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