WO2013040784A1 - Poudre de liposomes renfermant de l'insuline lyophilisée, préparation complexe d'insuline à usage oral, procédé de préparation s'y rapportant et leur utilisation - Google Patents

Poudre de liposomes renfermant de l'insuline lyophilisée, préparation complexe d'insuline à usage oral, procédé de préparation s'y rapportant et leur utilisation Download PDF

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Publication number
WO2013040784A1
WO2013040784A1 PCT/CN2011/080069 CN2011080069W WO2013040784A1 WO 2013040784 A1 WO2013040784 A1 WO 2013040784A1 CN 2011080069 W CN2011080069 W CN 2011080069W WO 2013040784 A1 WO2013040784 A1 WO 2013040784A1
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insulin
concentration
mixture
preparation
servings
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PCT/CN2011/080069
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English (en)
Chinese (zh)
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范圣刚
王志萍
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Fan Shenggang
Wang Zhiping
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Priority to PCT/CN2011/080069 priority Critical patent/WO2013040784A1/fr
Publication of WO2013040784A1 publication Critical patent/WO2013040784A1/fr

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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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • 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

Definitions

  • Insulin liposome freeze-dried powder oral insulin composite preparation, preparation method and application thereof
  • the present invention relates to an insulin liposome lyophilized powder for treating type II diabetes, an oral insulin composite preparation, and a preparation method and application thereof.
  • insulin As a biochemical drug for lowering blood sugar, insulin has been used for the treatment of diabetes for nearly 100 years. It is still the drug of choice for patients with type 1 diabetes and is an indispensable drug for more and more patients with type 2 diabetes. At present, clinical treatment is more inclined to use insulin as early as possible for patients with type 2 diabetes, which can repair insulin cells and better reduce the incidence of diabetes. However, since insulin is a peptide drug, it is degraded by the proteolytic enzymes of the gastrointestinal tract without being absorbed, so the treatment of the oral route is almost ineffective. For this reason, insulin injections are commonly used in clinical practice.
  • the technical problem to be solved by the present invention is to provide an insulin liposome lyophilized powder with high embedding rate and an oral insulin compound preparation for treating type II diabetes containing the insulin liposome freeze-dried powder, the oral insulin compound
  • the preparation has good stability and is convenient for industrial production.
  • the concentrate is freeze-dried to obtain an insulin liposome lyophilized powder.
  • the insulin liposome lyophilized powder of the present invention is prepared according to the following steps:
  • the concentrate is freeze-dried to obtain an insulin liposome lyophilized powder.
  • An oral insulin combination preparation for treating type II diabetes comprising the following components by weight:
  • the above insulin liposome lyophilized powder 1 part;
  • Trichosanthin 9-29 servings
  • Ginseng 1-3 servings
  • Astragalus 3-9 servings
  • Oral insulin composite preparation for treating type II diabetes of the present invention is provided.
  • the insulin liposome lyophilized powder according to claim 1 or 2 1 part;
  • Trichosanthin 16 servings
  • Rehmannia 10 servings
  • Ginseng 2 servings
  • the invention relates to a method for preparing an oral insulin compound preparation for treating type II diabetes, comprising the following steps: weighing and mixing the components in the oral insulin compound preparation in proportion, pulverizing through a 80 mesh sieve, wet granulation, and wet granules 60 70 V drying, dry granules are sifted with a 20 mesh sieve and filled into capsules.
  • the above-mentioned insulin liposome lyophilized powder is used for preparing a medicament for treating type II diabetes.
  • the above oral insulin complex preparation is used for preparing a medicament for treating type II diabetes.
  • the invention adds pueraria, trichosanthin, rehmannia, ginseng, astragalus and yam Chinese herbal medicine as auxiliary materials, wherein: pueraria: sweet, spicy, cool; spleen and stomach. Function and Indications: Decompression of muscles, fluid, rash, sun and diarrhea.
  • "Compendium of Materia Medica” contains: Pueraria, cool, calm, sweet, with heat, fire, detoxification.
  • Trichosanthin Shengjin, thirst quenching, lowering fire, moistening dryness, draining pus, swelling. For fever, polydipsia, lung heat dry cough, internal heat and thirst, sore swollen poison.
  • "Materia Medica” Reduces fire and moisturizes, slips and quenches thirst, and ancients use diabetes to treat diabetes (ie diabetes). Passing through the water, stomach heat yellow, dry lips, swollen poison back, breast acne scars.
  • Medical Lin Shu Yao lungs, gas, fire, Ning Xin, and diarrhea liver stagnation, slow liver urgency, clear bladder heat, short urinary urination, except Yang Ming and damp heat.
  • Rehmannia nourishing yin, nourishing blood. Treatment of yin deficiency fever, thirst, vomiting blood, blood stasis, blood collapse, irregular menstruation, fetal movement, constipation.
  • 1 The Classic: The main folds and stagnation, wounds, bloody sputum, bone marrow, long muscles, soup for cold and heat accumulation, in addition to sputum. The living is especially good.
  • 2 "Do not record”: The main man has five labors and seven injuries, the woman is injured, the blood leaks from the blood, breaks the blood, sputum blood, and the large and small intestines, goes to the stomach to eat, fills the five internal organs, lacks internal injuries, passes blood, and benefits , Li and Ear.
  • Ginseng A big qi, a solid, free, and soothing.
  • “Medical Enlightenment” Record: Ginseng treatment of spleen and stomach yang deficiency and lung shortness of breath, short gas, less gas, Buzhongzhongzhong, diarrhea, spleen and stomach in the fire evil.
  • “Indications” Record: ginseng supplement vitality, diarrhea, Shengjin liquid.
  • “Minnan Materia Medica” records: ginseng treatment of yin and yang deficiency, lung weakness. Invigorating the qi and solidifying the table, diuretic toxic, drainage, and sore muscles. For qi deficiency and fatigue, eating less stool, qi sag, prolonged diarrhea, rectal prolapse, blood in the stool, sweating, qi deficiency and edema
  • Astragalus It is difficult to collapse, long-term ulceration, blood deficiency, yellowing, internal heat and thirst; chronic nephritis proteinuria, diabetes.
  • Yam Replenishing the spleen and nourishing the stomach, Shengjin Yifei, and tonifying the kidney.
  • the insulin liposome lyophilized powder provided by the invention has a high embedding rate and an insulin embedding rate of more than 90%; the oral insulin compound preparation containing the insulin liposome lyophilized powder has good stability and is preserved for 24 months. After that, the insulin content in the oral insulin combination still remained above 99%, while the entrapment rate of insulin liposomes was only reduced by 2% compared with 0 months. Left and right, it indicates that the leakage of insulin embedded in the liposome is not significant; the oral insulin composite preparation is convenient for industrial production due to high embedding rate and good stability.
  • anhydrous ethanol was used as solvent in the process of coating. Compared with ether and chloroform as solvents, the toxic side effect was small, and the binding of capsule to insulin solution was strong.
  • the insulin liposome lyophilized powder obtained in Example 1 was used as 1 part by weight, and then 4 parts of pueraria root, 9 parts of trichosanthin, 5 parts of rehmannia, 1 part of ginseng, 3 parts of astragalus, 3 parts of yam were uniformly mixed and pulverized. After 80 mesh sieve, wet granulation, the wet granules were dried at 60 ° C, and the dry granules were granulated with a 20 mesh sieve and filled into capsules.
  • Example 3 Preparation of insulin liposome lyophilized powder
  • the insulin liposome lyophilized powder obtained in Example 3 was used as 1 part by weight, and then 13 parts of pueraria root, 29 parts of trichosanthin, 15 parts of rehmannia, 3 parts of ginseng, 9 parts of scutellaria, and 10 parts of yam were uniformly mixed and pulverized. After 80 mesh sieve, wet granulation, the wet granules were dried at 70 ° C, and the dry granules were granulated with a 20 mesh sieve and filled into capsules.
  • Example 5 Preparation of insulin liposome lyophilized powder
  • the insulin liposome lyophilized powder obtained in Example 5 was used as 1 part by weight, and 8 parts of pueraria root, 16 parts of trichosanthin, 10 parts of rehmannia, 2 parts of ginseng, 6 parts of jaundice, and 6 parts of yam were uniformly mixed and pulverized. After 80 mesh sieve, wet granulation, the wet granules were dried at 65 °C, and the dry granules were sifted with 20 mesh sieves and filled into capsules.
  • Example 7 Preparation of insulin liposome lyophilized powder
  • the insulin liposome lyophilized powder obtained in Example 7 was used as 1 part by weight, and 8 parts of pueraria root, 16 parts of trichosanthin, 10 parts of rehmannia, 2 parts of ginseng, 6 parts of astragalus, and 6 parts of yam were uniformly mixed and pulverized. After 80 mesh sieve, wet granulation, the wet granules were dried at 65 °C, and the dry granules were sifted with 20 mesh sieves and filled into capsules.
  • Example 9 Detection of insulin embedding rate of insulin liposome freeze-dried powder
  • the contents of the capsules obtained in Examples 2, 4, 6 and P 8 were accurately weighed to 2.5 g each, and 10 ml of three distilled waters were separately added to uniformly disperse the contents and dissolve the lyophilized powder at 4 ° C in a low temperature centrifuge.
  • the Chinese medicine powder was removed by centrifugation at 12000 rpm for 10 min, and the supernatant was taken for ultrafiltration with a filter membrane having a molecular weight cut off of 12,000.
  • the free insulin solution was passed through a filter membrane to measure the volume of each free insulin solution, respectively, according to the Pharmacopoeia of the People's Republic of China 2010 edition 2
  • the insulin test method measures the free insulin concentration by HPLC, and the chromatographic conditions are as follows.
  • Embedding rate (1-free insulin concentration X free insulin solution volume / total insulin mass) X 100%, where total insulin mass refers to the embedding system when embedding in Examples 1, 3, 5, and 7 The total insulin quality.
  • the results of the embedding rate test are shown in Table 1.
  • the chromatographic conditions using octadecylsilane bonded silica as a filler; 0. 2mol / L sulfate buffer (take anhydrous sodium sulfate 28.4g, dissolved in water, add phosphoric acid 2. 7ml, water 800ml, with The ethanolamine was adjusted to a pH of 2.3, and water was added to 1000 ml) - acetonitrile (volume ratio 74: 26)) as a mobile phase at a flow rate of 1.0 ml/min; the column temperature was 40 ° C; and the detection wavelength was 214 nm.
  • the oral insulin complex preparations obtained in Examples 2, 4, 6 and 8 were stored at a temperature of 25 ⁇ 2 ° C and a humidity of 60% ⁇ 10% at 0, 3, 6, 9, 12, 18, 24 Sampled separately in months.
  • the contents of the capsules obtained in Examples 2, 4, 6 and P 8 were accurately weighed to 2.5 g each, and 10 ml of an aqueous solution of 0.1 mol/L hydrochloric acid was added to uniformly disperse the contents and the lyophilized powder was dissolved, and allowed to stand overnight.
  • the liposome was ruptured, and the Chinese medicinal powder was removed by centrifugation at 10 ° C and 12000 rpm for 10 min in a low temperature centrifuge. The supernatant was taken and the volume of each supernatant was measured.
  • the 2010 edition of the second insulin test method was HPLC.
  • the method measures the insulin concentration in the supernatant.
  • Percentage of retained insulin insulin concentration in supernatant X supernatant volume / total insulin mass X 100%, where total insulin mass refers to embedding when embedded in Examples 1, 3, 5, and 7
  • the total insulin quality in the system The specific test results are shown in Table 2.
  • the oral insulin complex preparations obtained in Examples 2, 4, 6 and 8 were stored at a temperature of 25 ⁇ 2 ° C and a humidity of 60% ⁇ 10% at 0, 3, 6, 9, 12, 18, 24 Sampled separately in months.
  • the insulin embedding rate test was carried out according to the method of Example 9, that is, the stability of the oral insulin complex preparation and the stability of the liposome in the oral insulin complex preparation were examined to see if there was liposome instability in the oral insulin complex preparation. , resulting in the leakage of the embedded insulin into free insulin, the results are shown in Table 3.
  • Example 2 91.7% 91.7% 91.0% 91.1% 90.9% 90.3% 90.1%
  • Example 4 91.2% 91.2% 90.7% 90.5% 90.5% 90.4% 90.0%
  • Example 6 92.0% 92.0% 91.0% 91.0% 90.8% 90.6% 90.2 %
  • Example 8 91.5% 91.5% 91.0% 91.1% 90.9% 90.3% 90.1%
  • the results showed that after 24 months of storage of the oral insulin complex, the insulin embedding rate was only about 2% lower than that at 0 months. It shows that the stability of liposome is good and the stability of oral insulin compound preparation is good.
  • Example 12 Hypoglycemic experiment of oral insulin complex preparation on type 2 diabetic SD rat model
  • Test drug Oral insulin composite preparation prepared in Example 8; Positive control: Jiangtangning capsule, specification: 0.4 g/granule.
  • mice Male SPF Wistar rats, 150, 180-200g, provided by Shandong University Experimental Animal Center, certificate number: SCXK (Lu) 2003004, NO.0006088.
  • Rats were fed for 3 days after purchase, and 10 rats were randomly selected to measure normal blood glucose level. After fasting for 24 hours, intraperitoneal injection of streptozotocin 50 mg/kg (dissolved in a concentration of 0.01 g/ml) Aqueous citric acid). The fasting blood glucose was measured once at 72 h after injection, and the rats with unsuccessful modeling were excluded.
  • Dosage Jiangtangning Capsule, the clinical equivalent of the rat is 0.648g/kg, and it is configured to be 0.0648g/ml before administration, and it is administered at 10ml/kg.
  • One dose The day after grouping, 2 hours after fasting, the blood glucose levels were measured at 1 h, 2 h, 4 h, and 8 h after administration.
  • Administration for several consecutive days After one administration, the administration was continued for 4 days, and after 2 hours of fasting per day, it was administered once a day. On the sixth day, the blood glucose level after fasting for 2 hours was measured.
  • Measurement index The blood glucose level at different time points after one administration and the blood glucose level after continuous administration for several days.
  • Statistical Methods All data were expressed as X ⁇ s, and t-tests were used between groups.
  • the tail-breaking method was used to measure the blood glucose levels of lh, 2h, 4h and 8h after one dose.
  • the results showed that the high, medium and low dose groups significantly reduced the blood glucose level in rats at l-4h, compared with the model control group. There are significant differences.
  • the hypoglycemic control group also had a significant effect on lowering blood glucose, and its intensity of action was similar to that of the low dose group. The results are shown in Table 5.
  • the insulin liposome lyophilized powder provided by the invention has a high embedding rate and an insulin embedding rate of more than 90%; the oral insulin compound preparation containing the insulin liposome lyophilized powder has good stability and is preserved for 24 months. After that, the insulin content in the oral insulin compound preparation remained above 99%, and the embedding rate of insulin liposome was only reduced by about 2% compared with 0 months, indicating that it was embedded in the liposome. The situation of insulin leakage is not significant; the oral insulin complex preparation is convenient for industrial production due to high embedding rate and good stability.
  • anhydrous ethanol was used as the solvent. Compared with diethyl ether and chloroform, the toxic side effect was small, and the binding of the envelope to the insulin solution was strong.

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Abstract

L'invention porte sur une poudre de liposomes renfermant de l'insuline lyophilisée et sur une préparation complexe d'insuline à usage oral pour le traitement du diabète de type II et sur un procédé de préparation s'y rapportant. La poudre de liposomes renfermant de l'insuline lyophilisée selon la présente invention est préparée au moyen des étapes suivantes : l'ajout d'insuline à une solution aqueuse d'HCl et ensuite l'ajout d'une solution tampon phosphate et d'une solution de cholate de sodium pour donner un mélange aqueux; la dissolution simultanée de cholestérol et de lécithine dans de l'alcool éthylique absolu, l'ajout de solution aqueuse de mannitol et de solution de cholate de sodium et l'homogénéisation pendant 10-30 minutes, pour donner un mélange huileux; le mélange uniforme du mélange aqueux avec le mélange huileux et le placement du mélange dans un bain d'eau à 2-6°C et sa distillation sous pression réduite, pour donner un concentré; et la lyophilisation du concentré.
PCT/CN2011/080069 2011-09-23 2011-09-23 Poudre de liposomes renfermant de l'insuline lyophilisée, préparation complexe d'insuline à usage oral, procédé de préparation s'y rapportant et leur utilisation WO2013040784A1 (fr)

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PCT/CN2011/080069 WO2013040784A1 (fr) 2011-09-23 2011-09-23 Poudre de liposomes renfermant de l'insuline lyophilisée, préparation complexe d'insuline à usage oral, procédé de préparation s'y rapportant et leur utilisation

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PCT/CN2011/080069 WO2013040784A1 (fr) 2011-09-23 2011-09-23 Poudre de liposomes renfermant de l'insuline lyophilisée, préparation complexe d'insuline à usage oral, procédé de préparation s'y rapportant et leur utilisation

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101259115A (zh) * 2008-04-18 2008-09-10 范圣刚 一种治疗糖尿病的口服胰岛素软胶囊及其制备方法
CN101406454A (zh) * 2008-11-14 2009-04-15 沈阳药科大学 低分子量壳聚糖修饰的脂质体及其制备方法
WO2009108554A2 (fr) * 2008-02-27 2009-09-03 Ramot At Tel Aviv University Ltd. Système d’administration de protéine sous forme de fibrilles ou d’agrégats insolubles
CN102144968A (zh) * 2010-02-08 2011-08-10 刘树森 脂质体包裹胰岛素冻干制剂口服悬液及其制备工艺

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009108554A2 (fr) * 2008-02-27 2009-09-03 Ramot At Tel Aviv University Ltd. Système d’administration de protéine sous forme de fibrilles ou d’agrégats insolubles
CN101259115A (zh) * 2008-04-18 2008-09-10 范圣刚 一种治疗糖尿病的口服胰岛素软胶囊及其制备方法
CN101406454A (zh) * 2008-11-14 2009-04-15 沈阳药科大学 低分子量壳聚糖修饰的脂质体及其制备方法
CN102144968A (zh) * 2010-02-08 2011-08-10 刘树森 脂质体包裹胰岛素冻干制剂口服悬液及其制备工艺

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PARK S. ET AL.: "hncapsulation enhancement and stabilization ot insulin in cationic liposomes", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 415, 27 May 2011 (2011-05-27), pages 267 - 272 *

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