CN1188642A - High-polymer encapsulated insulin microsome and its preparation method and use - Google Patents
High-polymer encapsulated insulin microsome and its preparation method and use Download PDFInfo
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- CN1188642A CN1188642A CN98100577A CN98100577A CN1188642A CN 1188642 A CN1188642 A CN 1188642A CN 98100577 A CN98100577 A CN 98100577A CN 98100577 A CN98100577 A CN 98100577A CN 1188642 A CN1188642 A CN 1188642A
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Abstract
A insulin microsome wrapped by high-molecular material is prepared from polylactones (90-99%) and insulin (1-10%) by double-emulsion technique, and features that the polylactones as wrapping material is easily absorbed by human body and biodegradable. It can be used for oral application or burying it in body.
Description
The present invention relates to a kind of high-polymer encapsulated insulin microsome and its production and use.
Diabetes are a kind of worldwide diseases, are a kind of diseases of the carbohydrate metabolism disturbance that is caused by the metabolism endocrine disturbance.At present, the sickness rate of diabetes increases year by year, and becomes the third-largest fatal disease that is only second to cardiovascular disease and cancer.Normal people is by usually regulating carbohydrate, lipid, amino acid whose metabolism by the islets of langerhans that beta Cell of islet produced in the pancreas, quicken the transportation of glucose, aminoacid and potassium, and control enzyme effect and other are active.And diabetics completely loses owing to the β cell rareness even the function that produce insulin, and hypoinsulinism causes e﹠M disorder, causes death when serious.Therefore insulin is the main medicine that is used to regulate carbohydrate metabolism, blood sugar lowering at present.But insulin is a class polypeptide class biologically active drug, and it is easily destroyed by protease in vivo, and the half-life is short, so also can't realize oralization of insulin so far.Can only adopt at present the method supplementation with insulin in tremulous pulse and intramuscular injection and intravenous drip before the meal clinically, one day several times, causes great misery and inconvenience to the patient.Because injection also can cause local response and anaphylaxis, therefore use also to be restricted.In recent years, trial research about the route of administration of insulin is arranged much: for example nasal cavity, eye, subcutaneous, insulin implantable pump, rectum and oral.In these route of administration, oral is most convenient and be easy to accept, however the key issue that will solve be how to prevent insulin in the gastro-intestinal digestion road not by the destructive difficult problem of enzyme.The preparation method of the relevant oral insulin of report has at present: (1) protease inhibitor method: add aprotinin, bacitracin, soybean trypsin in the buffer solution of insulin.(M.Kidron, H.Bar-On et al., Life Sci., 31,2837 (1982)) (2) two emulsion methods: be about to the aqueous phase that insulin is fixed on internal layer.(3) liposome is as the insulin medicament support methods: insulin liposome is made by two kinds of methods.Solvent evaporation evaporation and solvent balling-up evaporation.(T.Kimura, K.Higaki et al., Pharm.Res., 5,221 (1984)) (4) absorption enhancer method: because the molecular weight of insulin is bigger, the absorption difficulty in intestinal adds some absorption enhancers such as NaGC, Capric acid sodium salt, Na
2EDTA is used for strengthening the absorption of insulin in intestinal.(5) the insulin substituent of chemical modification: the chemical modification of insulin and fatty acid can strengthen its lipotropy, improves the absorption at large intestine.Above method is also very imperfect, has defective, only is among the research.In order to improve the toxic and side effects of curative effect of medication and reduction medicine, some new administering modes are development rapidly also.Particularly by the particle diameter of interface emulsion polymerization prepared poly-alkyl cyanide acrylate polymer microcyst insulin sustained release medicament (R.Marina, D.Christiane et al., Diabetes, 41,451 (1992)) less than 300 nanometers.Because it can be along with blood flow arrives each position of health, long term maintenance discharges to keep the constant of blood Chinese medicine concentration (blood drug level) controlled delivery of pharmaceutical agents in vivo, thereby reach the highest curative effect of medicine, institute may occur in the time of simultaneously also can avoiding taking common pharmaceutical preparation crosses the particular performances such as disadvantage that are of no curative effect when low because of the too high toxic and side effects that causes of local time's blood drug level or because of blood drug level, so become the focus of current research.But shortcoming is the catalyst toxicity introduced in polymerization process and lapping can not be absorbed in vivo and can cause the problem of gathering, in recent years, development along with Biodegradable high molecular research, particularly excellent biological compatibility that they had and biodegradable absorbability, make it obtain to use widely in medical field, aspect the medicine sustained release, as pharmaceutical carrier, just becoming a new research field with Biodegradable high molecular.The aliphatic poly lactone is the widely used Biodegradable high molecular of a class, because it has no side effect, can absorb in vivo, and final metabolism is water and carbon dioxide, is the synthesized polymer material that can use in human body therefore.
The present invention has overcome prior art and has introduced catalyst toxicity and the unabsorbable defective of lapping and a kind of employing aliphatic poly lactone encapsulated insulin microsome is provided in polymerization process.Another object of the present invention has provided and has adopted two emulsion preparation technology to prepare the method for polylactone encapsulated insulin microsome.
The present invention utilizes special performances such as medicine sustained release that the microcapsule medicine has and flowable; and the protective effect of high-polymer encapsulated film; with biodegradable aliphatic poly lactone macromolecule is the medicine lapping, adopts two emulsion preparation technology and solvent extraction or solvent evaporation process to prepare biodegradable high-polymer encapsulated insulin microsome.
The composition of high-polymer encapsulated insulin microsome of the present invention (percetage by weight) is as follows:
Parcel macromolecular material 90-99
Insulin 1-10
High-polymer encapsulated insulin microsome of the present invention is prepared from the following order: (1) is with encapsulation absorbable biological degradability polylactone family macromolecule in the body, as poly-Acetic acid, hydroxy-, bimol. cyclic ester, polylactide, polycaprolactone, lactide-glycolide copolymer, caprolactone-lactide copolymer, polycaprolactone-copolyether, polylactide-copolyether, (molecular weight is 2000-150000 for aliphatic poly lactones such as polylactide-polycaprolactone-polyethers terpolymer and copolymer thereof, with 5000-100000 for better), use dichloromethane, chloroform, oiliness organic solvent dissolutions such as dichloroethanes, make the solution that concentration is the 5-200 mg/ml, with the 20-100 mg/ml for better; (2) with Iletin II (Lilly), all kinds of natural or insulin synthesis pH value such as bovine insulin or synthetic insulin are the acetic acid of 2-4.5, the solution of 40-1500 immunizing unit/milliliter is made in subacidity aqueous solutions such as hydrochloric acid dissolvings, with 100-1000 immunizing unit/milliliter for better; (3) be 40 by volume with above-mentioned two kinds of solution: 1-2: 1, with 20: 1-5: 1 for better, ultrasonic emulsification 30-120 second in the presence of micromolecule surfactants such as emulsifying agent department class 80, class of department 60, polysorbate60, Tween 80, be the better water-in-oil emulsion that makes second with 45-90; (4) in the presence of micromolecule surfactants such as class of emulsifying agent department 80, class of department 60, polysorbate60, Tween 80, be 1 with this water-in-oil emulsion by volume: 5-1: 50, with 1: 10-1: 30 for better, adding concentration is 0.5-10%, with 1-8% is better stabilizing agent gelatin, polyvinyl alcohol, stir in the aqueous solution of natural or synthetic polymer substance such as polyvinylpyrrolidone, mixing speed is 3000-20000 rev/min, with 5000-15000 rev/min for better, mixing time is 0.5-5 minute, with 1-3 minute for better.Make water-in-oil-in-water compositions; (5) water-in-oil-in-water compositions is continued to stir 2-10 hour, with 3-6 hour for better, mixing speed is 500-2000 rev/min, with 800-1500 rev/min for better, adopt centrifugal separation method to isolate insulin encapsulation microsome, the reuse distilled water washs, washing times is 1-5 time, with 2-4 time for better, the microsome that obtains is carried out lyophilization, finally obtain purpose product-high-polymer encapsulated insulin microsome of the present invention.
All operations among the present invention all carries out under 4-15 ℃ of temperature conditions.
The prepared microsome of the present invention is a hollow structure, and with the variation of preparation condition, particle diameter can be regulated between the 1-20 micron, and the microsome wall thickness can be regulated between the 100-6000 nanometer, and content of dispersion can reach 1-10%, and utilization ratio of drug can reach more than 80%.
Regulate by the kind, the four kinds of approach of wall thickness that change high molecular molecular weight, change MC particle diameter and change microcyst of macromolecular material that the insulin rate of release of the prepared high-polymer encapsulated insulin microsome of the present invention can be by changing encapsulation.By the choose reasonable of preparation condition, regulate the rate of release of insulin.
High-polymer encapsulated insulin microsome can be used as oral insulin or the in-vivo embed insulin uses by absorbing in the prepared body of the present invention.
Embodiment 1:
The dichloromethane solution of 5mg Iletin II (Lilly) aqueous solution and 200mg polylactide (molecular weight is 5,000) ultrasonic emulsification 1 minute in the presence of department class 80, the formation water-in-oil emulsion, 15, under 000 rev/min of mixing speed, in the presence of Tween 80, inject the gelatin solution of 100ml 1%, emulsifying 1 minute.The gained water-in-oil-in-water compositions stirred the microcyst centrifugalize that obtains 5 hours at 1000 rev/mins.Clean four times with distilled water, be dispersed at last in the water, lyophilization obtains the polylactide encapsulated insulin microsome.Embodiment 2:
(molecular weight is 10 for 5mg synthetic insulin aqueous solution and 200mg lactide-glycolide copolymer, 000) dichloromethane solution ultrasonic emulsification 1 minute in the presence of department class 60, form water-in-oil emulsion. 15, under 000 rev/min of mixing speed, in the presence of polysorbate60, inject the gelatin solution of 100ml 3%, emulsifying 1 minute.300ml distilled water (dichloromethane is saturated) adds, and stirs the microcyst centrifugalize that obtains 30 minutes.Clean three times with distilled water, be dispersed at last in the water, lyophilization obtains the polylactide encapsulated insulin microsome.Embodiment 3:
(molecular weight is 100 for 3mg bovine insulin aqueous solution and 200mg polycaprolactone, 000) dichloromethane solution ultrasonic emulsification in the presence of class 60 of department formed water-in-oil emulsion in 90 seconds, under 5000 rev/mins of mixing speeds, inject the poly-vinyl alcohol solution of 100ml 5%, emulsifying 5 minutes.The gained water-in-oil-in-water compositions stirred the microcyst centrifugalize that obtains 3 hours at 1000 rev/mins.Clean three times with distilled water, be dispersed at last in the water, lyophilization obtains the polycaprolactone encapsulated insulin microsome.Embodiment 4:
The dichloromethane solution of 10mg Iletin II (Lilly) aqueous solution and 200mg polycaprolactone-copolyether (molecular weight is 60,000) ultrasonic emulsification 45 seconds in the presence of department class 80, the poly-vinyl alcohol solution of injection 100ml8% in the presence of polysorbate60, emulsifying 5 minutes.The gained water-in-oil-in-water compositions stirred the microcyst centrifugalize that obtains 3 hours at 1000 rev/mins.Clean four times with distilled water, be dispersed at last in the water, lyophilization obtains polycaprolactone-copolyether encapsulated insulin microsome.
The encapsulation result of the different microcysts of table 1
Embodiment 9:
| Embodiment | The parcel macromolecular material | The insulin kind | Packaging method | Mean diameter (micron) | Average packet cyst wall thick (nanometer) | In the pastille (%) | Utilization ratio of drug (%) |
| Embodiment 5 | Polylactide | Iletin II (Lilly) | With embodiment 1 | ????2 | ????400 | ??2.5 | ??82 |
| Embodiment 6 | Lactide-7 lactide copolymer | Insulin synthesis | With embodiment 2 | ????1.5 | ????350 | ??2.5 | ??93 |
| Embodiment 7 | Polycaprolactone | Bovine insulin | With embodiment 3 | ????12 | ????3500 | ??1.5 | ??80 |
| Embodiment 8 | Polycaprolactone-polyethers | Iletin II (Lilly) | With embodiment 4 | ????7 | ????2000 | ??5 | ??87 |
Press embodiment 1,2,3,4,5,6, the scanning electron microscopic observation of the insulin microcyst of 7,8 methods preparation shows, the microcyst smooth surface that obtains, particle size distribution is even, and its inside is hollow structure.
Claims (12)
1. high-polymer encapsulated insulin microsome is characterized in that described MC composition (percetage by weight) is as follows:
Parcel macromolecular material 90-99
Insulin 1-10
2. a kind of high-polymer encapsulated insulin microsome according to claim 1 is characterized in that described macromolecular material is a biological degradability polylactone family macromolecule.
3. a kind of high-polymer encapsulated insulin microsome according to claim 2 is characterized in that described polylactone family macromolecule is polylactide, polycaprolactone, lactide-glycolide copolymer or polylactide-copolyether.
4. a kind of high-polymer encapsulated insulin microsome according to claim 2, the molecular weight that it is characterized in that described polylactone family macromolecule is 2000-150000.
5. a kind of high-polymer encapsulated insulin microsome according to claim 1 is characterized in that described insulin is bovine insulin, Iletin II (Lilly) or synthetic insulin.
6. the preparation method of a kind of high-polymer encapsulated insulin microsome according to claim 1 is characterized in that step is carried out in the following order:
(1) biodegradation polylactone family macromolecule is dissolved with dichloromethane or chloroform, makes the solution that concentration is the 5-200 mg/ml,
(2) be acetic acid or the dissolving of hydrochloric acid subacidity aqueous solution of 2-4.5 with the insulin pH value, make the solution of 40-1500 immunizing unit/milliliter,
(3) be 40 by volume with above-mentioned two kinds of solution: 1-2: 1 in the presence of emulsifying agent ultrasonic emulsification 30-120 make water-in-oil emulsion second,
(4) aqueous solution with above-mentioned water-in-oil emulsion and stabilizing agent is 1 by volume: 5-1: 50 stir in the presence of emulsifying agent, and mixing speed is 3000-20000 rev/min, and mixing time is 0.5-5 minute, makes water-in-oil-in-water compositions,
(5) water-in-oil-in-water compositions is continued to stir 2-10 hour, adopt centrifugal separation method to isolate insulin encapsulation microsome, the reuse distilled water washs, and the microsome that obtains is carried out lyophilization.
7. the preparation method of a kind of high-polymer encapsulated insulin microsome according to claim 6 is characterized in that described concentration is the solution of 20-100 mg/ml.
8. the preparation method of a kind of high-polymer encapsulated insulin microsome according to claim 6 is characterized in that described two kinds of liquor capacity ratios are 20: 1-5: 1.
9. the preparation method of a kind of high-polymer encapsulated insulin microsome according to claim 6, the volume ratio that it is characterized in that the aqueous solution of described water-in-oil emulsion and stabilizing agent is 1: 10-1: 30.
10. the preparation method of a kind of high-polymer encapsulated insulin microsome according to claim 6 is characterized in that described emulsifying agent is class of department 80, class of department 60, polysorbate60, Tween 80.
11. the preparation method of a kind of high-polymer encapsulated insulin microsome according to claim 6, the aqueous solution that it is characterized in that described stabilizing agent are concentration is gelatin or the polyvinyl alcohol water solution of 1-8%.
12. the purposes of a kind of high-polymer encapsulated insulin microsome according to claim 1 is characterized in that can be used as oral insulin and in-vivo embed insulin and uses.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN98100577A CN1075945C (en) | 1998-02-26 | 1998-02-26 | High-polymer encapsulated insulin microsome and its preparation method and use |
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| Application Number | Priority Date | Filing Date | Title |
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| CN98100577A CN1075945C (en) | 1998-02-26 | 1998-02-26 | High-polymer encapsulated insulin microsome and its preparation method and use |
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| CN1188642A true CN1188642A (en) | 1998-07-29 |
| CN1075945C CN1075945C (en) | 2001-12-12 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002020037A1 (en) * | 2000-06-07 | 2002-03-14 | Zhang, Hao | Biologically active oral preparation that can be site-specific released in colon |
| EP1296660A4 (en) * | 2000-06-27 | 2005-04-13 | Mi Tech Company Ltd | The controlled release preparation of insulin and its method |
| CN101658736B (en) * | 2005-02-25 | 2013-05-29 | Cytec技术有限公司 | Water-in-oil-in water emulsions of hydroxamated polymers and methods for using the same |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1302807C (en) * | 2004-03-19 | 2007-03-07 | 中国科学院长春应用化学研究所 | Biological degradable macromolecule microspheres of carrying insulin and preparation method |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0817619A4 (en) * | 1996-01-24 | 1999-02-03 | Us Army | Novel "burst-free" sustained release poly-(lactide/glycolide) mi crospheres |
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1998
- 1998-02-26 CN CN98100577A patent/CN1075945C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002020037A1 (en) * | 2000-06-07 | 2002-03-14 | Zhang, Hao | Biologically active oral preparation that can be site-specific released in colon |
| US6949258B2 (en) | 2000-06-07 | 2005-09-27 | Hao Zhang | Biologically active oral preparation that can be site-specific released in colon |
| EP1296660A4 (en) * | 2000-06-27 | 2005-04-13 | Mi Tech Company Ltd | The controlled release preparation of insulin and its method |
| CN101658736B (en) * | 2005-02-25 | 2013-05-29 | Cytec技术有限公司 | Water-in-oil-in water emulsions of hydroxamated polymers and methods for using the same |
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| CN1075945C (en) | 2001-12-12 |
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