CN1274605A - Oral insulin granule and its preparation - Google Patents
Oral insulin granule and its preparation Download PDFInfo
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- CN1274605A CN1274605A CN 99112935 CN99112935A CN1274605A CN 1274605 A CN1274605 A CN 1274605A CN 99112935 CN99112935 CN 99112935 CN 99112935 A CN99112935 A CN 99112935A CN 1274605 A CN1274605 A CN 1274605A
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Abstract
The oral insulin granule is orally taken to reduce blood sugar content and is prepared into enteric coated capsule of granule comprising insulin-gelatine composition and liposome precursor and with an insulin coating rate over 90%. During its preparation, insulin and gelatine are first compounded into composition which is then prepared into liposome dispersed system, mixed with proper amount of supporting agent and freezing dried, and the mixture is finally ground and sieved after being added with some silica gel powder. The present invention is suitable for being taken by diabetics and has no side effect, such as atrophy of subcutaneous fat.
Description
The present invention relates to a kind of oral insulin granule and preparation method thereof.It is the novel form of hypoglycemic drug insulin.For the biochemical drug oral administration is explored a new road.
Insulin is a protein and peptide class medicine, can be by gastrointestinal Proteolytic enzyme enzymatic degradation, and be not absorbed, oral invalid, generally be drug administration by injection.Diabetics needs long term injections, and is very inconvenient and produce lipoatrophy etc.Both at home and abroad all in the oral non-injection administration dosage form that waits of research, oral administered dosage form is mainly concentrated following several respects: 1) make enteric coated preparation: British patent is adsorbed on insulin on cellulose and the glucose gel granule, enteric coated confession is oral, and (GB 1987,2180746), Saffran adorns enteric coated capsule (Science after with the insulin microparticles coating, 1987,233:1081).2) add enzyme inhibitor or protective agent: Zir etc. and developed insulin tablet (J Pharm Sic, 1994,83 (6): 792) of containing soybean trypsin inhibitor; Japan Patent is introduced mucin and can be protected insulin to make enteric coated capsule (JP 1979,54028807 (A)).3) add absorption enhancer: usefulness cetomacrogols such as Touitou 1000 and insulin make mixture preparation (J Pharm Pharmacol1980,32:108).4) insulin microcapsule and millimicro ball: Fallouh etc. make insulin nanocapsule (IntJ Pharm, 1986,28 (2): 125), preparation Polyalkylcyanoacrylanano insulin millimicro balls such as domestic Zhang Qiang all can have certain hypoglycemic activity (Acta Pharmaceutica Sinica, 1998,32 (2): 152).5) insulin liposome: Canadian Patent is made oral formulations (CA, 1994,1328401) with the liposome insulin.6) insulin Emulsion: Smithkline Beecham company system development has been developed insulin Emulsion (WO, 1994,9408603; US, 1993,5179079; WO, 1994,9408604); Domestic Wu Qiong pearls etc. are made multilamellar breast (W/O/W) with insulin and give mouse stomach, and dosage is that 70U/kg has hypoglycemic activity (Chinese Journal of Pharmaceuticals, 1990,21 (10): 445).In sum, though research report, patent have a lot, so far not in clinical practice, subject matter is that oral administration dosage is higher, and bioavailability is lower, so is difficult to actual clinically applying.
The objective of the invention is to utilize the gelatin-compounded thing of insulin to combine to make oral insulin granule to pack enteric coated capsule into for orally using with the liposome preparation technology.
The objective of the invention is to be achieved by the following scheme: oral insulin granule consists of gelatin-compounded thing of insulin and liposome precursor microgranule, to the encapsulation ratio of insulin more than 90%.At first, insulin and gelatin are made complex.The consumption weight ratio 1: 1～5 of insulin and gelatin, the solution concentration insulin is 5～10%, and gelatin is 1～6%, and pH value should be controlled at 5～6, and combination rate is 85%; Secondly, complex is made liposome microparticulate system, phospholipid mixed surfactant preparation: fabaceous lecithin 1.2～2.0, cholesterol 0～0.5, poloxamer 0.2～1.0, chlorobutanol 0.1～0.2 adds dissolve with ethanol, decompression, reclaim ethanol, make the phospholipid mixed surfactant, gelatin-compounded thing of insulin and mixed surfactant amount ratio are 1: 5～10; Then, make the gelatin-compounded composite lipidosome disperse system of insulin, add an amount of proppant microcrystalline Cellulose, micropowder silica gel etc. and carry out lyophilization again, with micropowder silica gel for well.With above-mentioned composite-18 ℃ freezing 24 hours, lyophilization again, dry particles caking adds an amount of micropowder silica gel through pulverizing and ground 32 mesh sieves.
Advantage of the present invention is: can reduce the insulin inactivation, oral administration dosage is suitable, bioavailability is higher, through to model mice oral administration dosage 8U/kg the time, the blood sugar lowering percentage rate is 33%, and the Canis familiaris L. of hyperglycemia rabbit, euglycemia all had hypoglycemic activity, thereby has potential applicability in clinical practice widely.The side effect such as lipoatrophy that can avoid the administration of diabetics long term injections to produce.
Below in conjunction with embodiment the present invention is done further detailed description.
The step of preparation process of insulin granule is as follows:
1, the gelatin-compounded thing preparation of insulin:
1) insulin 1g adds hydrochloric acid solution (pH 1-2) 10ml dissolving, and the dissolving back is 4 with sodium hydroxide solution (10%-20%) adjust pH.
2) gelatin 1g-2g adding distilled water 50-100ml is dissolved into gelatin solution.
3) insulin solutions is under agitation added in the gelatin solution, mix homogeneously is transferred pH5-8 with 10%NaOH solution, and complex is separated out, and forms the gelatin-compounded thing suspension of insulin, with the stability of protection insulin.
2, the gelatin-compounded composite lipidosome preparation of insulin
1) adds the phospholipid mixed surfactant in the gelatin-compounded thing suspension of insulin, purpose is complex is wrapped in the liposome, disperse to form the composite liposome body in 3 minutes through bruisher 10000rpm, the stability that can further strengthen insulin absorbs with promotion.
2) preparation of phospholipid mixed surfactant: soybean phospholipid 12g adds 2g cholesterol, 2g-5g poloxamer, 0.5-1g chlorobutanol, add anhydrous alcohol solution again and become solution, ethanol is reclaimed in decompression down, drains preparation phospholipid mixed surfactant, and its consumption is 5-10 with the complex ratio: 1.
3, the preparation of insulin granule
1) the gelatin-compounded composite lipidosome of insulin adds the proppant microcrystalline Cellulose, micropowder silica gel is an amount of, and dispersed with stirring is even, and in refrigerator-freezer freezing 24 hours, lyophilization again.
2) dried cake is ground in mortar: and add micropowder silica gel in right amount to blot residual moisture content, cross 32 mesh sieves, the enteric coated capsule of packing into, sealing, refrigerator is frozen.
Embodiment 1:
1, insulin 0.1g adds pH2 hydrochloric acid solution 1.0ml dissolving, and the dissolving back transfers pH4 to make insulin solutions with 10%NaOH solution.
2, gelatin 0.1g adds water 5.0ml and is dissolved into solution, under agitation, insulin solutions added is mixed into solution, transfers pH5.8 with 10%NaOH solution, has precipitation to separate out, and is the gelatin-compounded thing of insulin, forms the muddy liquid of complex.
3, adding phospholipid mixed surfactant 1.7g in the gelatin-compounded thing suspension of insulin (forms: fabaceous lecithin 1.2g, cholesterol 0.2g, poloxamer 0.2g, chlorobutanol 0.1g adds dissolve with ethanol and mixes, decompression is reclaimed ethanol and is made the phospholipid mixed surfactant), disperseed 3 minutes through bruisher, add micropowder silica gel 1.0g again, the even liposome disperse system of dispersed with stirring.
4, gelatin-compounded thing of the insulin of making and liposome are disperseed to lie in refrigerator-freezer (18 ℃) freezing 24 hours, lyophilization again.
5, exsiccant solid grinds in mortar, and adding is blotted the agent micropowder silica gel and become microgranule, crosses 32 mesh sieves, promptly gets insulin granule, and mensuration is tired.Sealing, freezer storage.
Embodiment 2:
1, insulin 0.2g adds pH2 hydrochloric acid solution 1.0ml dissolving, and pH4 is transferred with 10%NaOH solution in the dissolving back, is made into insulin liquor.
2, gelatin 0.2g adds water 5.0ml heating for dissolving, puts to be chilled to 20 ℃ and under agitation to add the insulin solutions that is made into, and is uniformly mixed into solution, transfers pH5.8 with 10%NaOH solution, has precipitation to separate out, and forms the gelatin-compounded thing of insulin.
3, adding phospholipid mixed surfactant 3.4g in the gelatin-compounded thing suspension of insulin (forms: fabaceous lecithin 2.4g, cholesterol 0.4g, poloxamer 0.4g, chlorobutanol 0.2g), after bruisher 10000rpm disperses 3 minutes, add microcrystalline Cellulose 1g again, dispersed with stirring becomes even liposome disperse system, and envelop rate is low.
4, homodisperse was lain in refrigerator-freezer (18 ℃) freezing 24 hours, lyophilization again.
5, the gelatin-compounded thing microgranule of exsiccant insulin caking grinds in mortar and adds an amount of micropowder silica gel and absorbs remaining moisture content and become microgranule, crosses 32 mesh sieves, makes insulin granule, and mensuration is tired, and marks sealing, freezer storage.
Embodiment 3:
1, insulin 1g adds pH2 hydrochloric acid solution 5ml dissolving, and pH4.5 is transferred with concentrated NaOH solution in the dissolving back, is made into insulin solutions.
2, gelatin 1g adds water 50ml and is dissolved into solution, under agitation insulin solutions is added dropwise to wherein, and mix homogeneously is transferred pH5.8 with concentrated NaOH solution, and precipitation is separated out, and is the gelatin-compounded thing of insulin, forms the muddy liquid of complex.
3, adding phospholipid mixed surfactant 17g in the muddy liquid of insulin gelatin (forms: fabaceous lecithin 12g, cholesterol 2g, poloxamer 2g, chlorobutanol 1g adds dissolve with ethanol and mixes, and reclaims ethanol, makes the phospholipid mixed surfactant), disperseed 3 minutes through bruisher 10000rpm, add micropowder silica gel 10g again, the dispersed with stirring mixing forms insulin gelatin corpuscle disperse system.
4, microparticulate is lain in the refrigerator-freezer (18 ℃), freezing 24 hours, lyophilization.
5, exsiccant disperse particles caking grinds in mortar, and adds an amount of micropowder silica gel and absorb remaining moisture content and become microgranule, crosses 32 mesh sieves, makes insulin granule, and measuring tires marks, sealing, freezer storage.
Claims (3)
1, oral insulin granule and preparation method thereof is characterized in that: oral insulin granule consists of gelatin-compounded thing of insulin and liposome precursor microgranule, and the encapsulation ratio of insulin more than 90%, is enteric coated capsule.
2, oral insulin granule according to claim 1 and preparation method thereof is characterized in that:
1) insulin and gelatin are made complex.The consumption weight ratio 1: 1～5 of insulin and gelatin, the solution concentration insulin is 5～10%, and gelatin is 1～6%, and pH value should be controlled at 5～6, and combination rate is 85%;
2) complex is made liposome microparticulate system,
Phospholipid mixed surfactant preparation: fabaceous lecithin 1.2～2.0, cholesterol 0～0.5, poloxamer 0.2～1.0, chlorobutanol 0.1～0.2 adds dissolve with ethanol, decompression, reclaim ethanol, make the phospholipid mixed surfactant, gelatin-compounded thing of insulin and mixed surfactant amount ratio are 1: 5～10;
3) the gelatin-compounded composite lipidosome disperse system of insulin adds an amount of proppant microcrystalline Cellulose, micropowder silica gel etc. and carries out lyophilization again.
3, oral insulin granule according to claim 2 and preparation method thereof is characterized in that: composite-18 ℃ freezing 24 hours, lyophilization again, dry particles caking adds an amount of micropowder silica gel through pulverizing and ground 32 mesh sieves.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 99112935 CN1221283C (en) | 1999-05-19 | 1999-05-19 | Oral insulin granule and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 99112935 CN1221283C (en) | 1999-05-19 | 1999-05-19 | Oral insulin granule and its preparation |
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| Publication Number | Publication Date |
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| CN1274605A true CN1274605A (en) | 2000-11-29 |
| CN1221283C CN1221283C (en) | 2005-10-05 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN 99112935 Expired - Fee Related CN1221283C (en) | 1999-05-19 | 1999-05-19 | Oral insulin granule and its preparation |
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1296098C (en) * | 2004-09-29 | 2007-01-24 | 薛南荣 | Oral insulin protecting agent |
| CN100522141C (en) * | 2004-05-19 | 2009-08-05 | 新疆维吾尔自治区包虫病临床研究所 | Prosoma liposome preparation, its production method and using method |
| CN1635872B (en) * | 2001-04-25 | 2010-05-26 | 西部健康大学,药学院,西部药物开发中心 | Proliposomal drug delivery system |
| CN101259115B (en) * | 2008-04-18 | 2010-11-24 | 范圣刚 | Orally-administered insulin soft capsule for treating diabetes and preparation thereof |
| CN102188364A (en) * | 2010-03-18 | 2011-09-21 | 鲁翠涛 | Preparation method of drug-carrying lipoid particles |
| US8658202B2 (en) | 2001-04-25 | 2014-02-25 | Western University Of Health Sciences | Coated drug delivery formulations |
| CN103720656A (en) * | 2012-10-15 | 2014-04-16 | 北京大学 | Oral and injection dual-effect protein or polypeptide drug controlled-release vesicle and preparation method thereof |
| CN104666246A (en) * | 2007-09-28 | 2015-06-03 | Sdg公司 | Orally Bioavailable Lipid-based Constructs |
| CN106581646A (en) * | 2016-11-03 | 2017-04-26 | 广州凯耀资产管理有限公司 | Oral insulin composition |
| US10751418B2 (en) | 2007-09-28 | 2020-08-25 | Sdg, Inc. | Orally bioavailable lipid-based constructs |
| US11071715B2 (en) | 2017-03-13 | 2021-07-27 | Sdg, Inc. | Lipid-based nanoparticles and methods using same |
| US11077173B2 (en) | 2017-03-13 | 2021-08-03 | Sdg, Inc. | Lipid-based nanoparticles and methods using same |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN117956984A (en) * | 2021-09-09 | 2024-04-30 | 巴斯夫欧洲公司 | Novel microparticles containing active substances |
-
1999
- 1999-05-19 CN CN 99112935 patent/CN1221283C/en not_active Expired - Fee Related
Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8658202B2 (en) | 2001-04-25 | 2014-02-25 | Western University Of Health Sciences | Coated drug delivery formulations |
| CN1635872B (en) * | 2001-04-25 | 2010-05-26 | 西部健康大学,药学院,西部药物开发中心 | Proliposomal drug delivery system |
| US8889180B2 (en) | 2001-04-25 | 2014-11-18 | Western University Of Health Sciences | Coated drug delivery formulations |
| CN100522141C (en) * | 2004-05-19 | 2009-08-05 | 新疆维吾尔自治区包虫病临床研究所 | Prosoma liposome preparation, its production method and using method |
| CN1296098C (en) * | 2004-09-29 | 2007-01-24 | 薛南荣 | Oral insulin protecting agent |
| US10751418B2 (en) | 2007-09-28 | 2020-08-25 | Sdg, Inc. | Orally bioavailable lipid-based constructs |
| CN104666246A (en) * | 2007-09-28 | 2015-06-03 | Sdg公司 | Orally Bioavailable Lipid-based Constructs |
| US10568835B2 (en) | 2007-09-28 | 2020-02-25 | Sdg, Inc. | Orally bioavailable lipid-based constructs |
| US11517529B2 (en) | 2007-09-28 | 2022-12-06 | Sdg, Inc. | Orally bioavailable lipid-based constructs |
| CN101259115B (en) * | 2008-04-18 | 2010-11-24 | 范圣刚 | Orally-administered insulin soft capsule for treating diabetes and preparation thereof |
| CN102188364A (en) * | 2010-03-18 | 2011-09-21 | 鲁翠涛 | Preparation method of drug-carrying lipoid particles |
| CN102188364B (en) * | 2010-03-18 | 2016-01-20 | 浙江海正药业股份有限公司 | The preparation method of medicament-carrying lipoid particulates |
| CN103720656A (en) * | 2012-10-15 | 2014-04-16 | 北京大学 | Oral and injection dual-effect protein or polypeptide drug controlled-release vesicle and preparation method thereof |
| CN106581646A (en) * | 2016-11-03 | 2017-04-26 | 广州凯耀资产管理有限公司 | Oral insulin composition |
| US11071715B2 (en) | 2017-03-13 | 2021-07-27 | Sdg, Inc. | Lipid-based nanoparticles and methods using same |
| US11077173B2 (en) | 2017-03-13 | 2021-08-03 | Sdg, Inc. | Lipid-based nanoparticles and methods using same |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1221283C (en) | 2005-10-05 |
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