CN102961340B - Nanoscale insulin and preparation method thereof - Google Patents
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- 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
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
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- 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
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- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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Abstract
The invention discloses nanoscale insulin and a preparation method thereof, relating to specific medicine insulin for treating diabetes mellitus. In allusion to the defects that the insulin is low in bioavailability for oral administration and the existing insulin injections are severe in toxic and side effects and inconvenient in use, the invention firstly aims at providing a nanoscale insulin particle which can be prepared into an oral preparation; the nanoscale insulin particle is characterized by taking silicon dioxide aerogel as a carrier of the insulin; the invention secondly aims at providing a preparation method of the nanoscale insulin particle; and the preparation method is characterized by comprising the steps of: dissolving the insulin in a 0.01mol/L hydrochloric acid solution, adding the silicon dioxide aerogel, drying for later use after complete adsorption, dissolving PEG (Polyethylene Glycol) in absolute ethyl alcohol, adding the solid obtained via drying and sending into an emulsifying machine for emulsification, drying the obtained emulsified liquid in a constant-temperature drying box, grinding and sieving via a 200-mesh sieve to obtain the nanoscale insulin particle. The nanoscale insulin is especially suitable for oral administration.
Description
Technical field
The present invention relates to treat the specific drug insulin of diabetes, be specifically related to a kind of nanoscale insulin that can be oral and preparation method thereof.
Background technology
Diabetes are to be positioned at a large disease that threatens human health after cardiovascular disease and cancer.According to pointing out in 1998 ADA's annual reports, in world wide, diabetics is about 1.35 hundred million people at present, by 2025, estimates that diabetics will rise to 300,000,000 people, and wherein developed country is increased to 7,200 ten thousand by 5,100 ten thousand, increases by 42%; And developing country leaps to 2.28 hundred million people by 8,400 ten thousand, amplification reaches 170%.In developed country, U.S.'s diabetics approaches 1,600 ten thousand, accounts for 5.9% of U.S.'s total population, and the U.S. approximately spends 1,000 hundred million dollars of left and right every year in prevention and treatment diabetes for this reason.The patient of diabetes Prevalence of China also allows of no optimist.The statistics of 1998 shows, there are more than 2,000 ten thousand diabeticss in China, and in the crowd of 25 years old to 64 years old, sickness rate is 2.5%.Along with the live change of mode of the aging day by day of China's population and modern, prevention and treatment diabetes have caused widely to be paid close attention to.
First insulin found by the Banting of Canadian in nineteen twenty-one, and nineteen twenty-two starts for clinical, is one of the most effective medicine for the treatment of at present diabetes.For a long time, insulin is always taking drug administration by injection as main, and insulin is indispensable medicine during I type and middle severe type ii diabetes patient treat every day.Because insulin biological half-life is short, diabetics needs lifelong every day of subcutaneous injection insulin, frequently be administered to for a long time patient and bring very large misery and inconvenience, and insulin injection also may produce lipoatrophy, occur edema etc. for a long time, overdose administration also can cause the multiple untoward reaction such as hypoglycemia shock.Therefore, the insulin preparation of development non-injection administration is the focus of recent domestic research.
Oral administration is the optimal administering mode of insulin, and its main advantage is: (1) easily simulates the physiological patterns of human pancreas's nature excreting insulin; (2) through the metabolism of normal hepatocytes metabolic pathway, the generation that can lower diabetic complication; (3) taking convenience, good patient compliance.
But the regular insulin oral formulations bioavailability without special technical finesse only has 0.1%～0.2%, without clinical meaning.Its main cause have following some: (1) insulin is a kind of peptide hormone, its under the effect of gastric juice sour environment and the various protease of digestive tract, the inactivation of very easily degrading; (2) insulin molecule amount is 6000 left and right, and intermolecularly has very strong polymerization trend, thereby makes it be difficult to be absorbed by the epithelium layer of gastrointestinal wall by diffusion; (3) have liver first-pass effect, bioavailability is low; (4) the insulin conformation problem in preparation process.The oral administration of insulin is a global difficult problem always.
Nano medication is by medicine dissolution, seals or be adsorbed on carrier and insulin is made nano particle preparations by the microgranule of the nano-scale of making, and can greatly improve the absorption of insulin.At present about though the research report of this direction is many, but still fail fundamentally to solve the low problem of oral administration biaavailability of insulin, after oral, nanoparticle is not absorbed and directly excretes greatly, only has sub-fraction nanoparticle to be absorbed, if drug absorption is in low-level fluctuation, the percent error of its absorbed dose will be significant so, for a given dose, if the picked-up of microgranule has exceeded desired value, toxicity will produce so; And if the amount absorbing is less or make the dosage range of drug level lower than treatment, cause treating unsuccessfully.
Summary of the invention
Low for oral insulin bioavailability, and serious, the awkward defect of existing injection of insulin agent toxic and side effects, first object of the present invention is to provide a kind of nanoscale insulin granule that can be made into oral formulations.
For achieving the above object, the invention provides a kind of nanoscale insulin granule, it is characterized in that: the carrier using aerosil as insulin.
Further, the mass ratio of described insulin and described aerosil is 1:0.5～20.
In order further to improve the slow releasing function of this nanoscale insulin granule, preferably in granule, add PEG.
Further, the molecular weight of described PEG is 400～20000.
Further, the mass ratio of described PEG and described insulin is 1:05～20.
Above-mentioned nanoscale insulin granule can be made into pharmaceutically acceptable oral formulations.
Further, described oral formulations is tablet, pill, powder, capsule, granule or suspensoid.
Above-mentioned nanoscale insulin granule can be made into pharmaceutically acceptable injection or suppository.
Another object of the present invention is to provide the preparation method of above-mentioned nanoscale insulin granule, it is characterized in that, said method comprising the steps of:
(1) insulin is dissolved in the hydrochloric acid solution of 0.01mol/L;
(2) in above-mentioned hydrochloric acid solution, add aerosil;
(3) after insulin and aerosil absorption completely, after absorption completely, be dried;
(4) PEG is dissolved in dehydrated alcohol;
(5) solid of the dry gained of step (3) is added in the alcoholic solution of step (4);
(6) alcoholic solution of step (5) is sent into emulsifying in mulser;
(7) step (6) gained emulsion is dry in thermostatic drying chamber;
(8) solid of the dry gained of grinding steps (7), and cross 200 mesh sieves, obtain nanoscale insulin granule.
In the time that the aerosil described in step (2) has hydrophobicity, before adding hydrochloric acid solution, need first its surperficial alkyl is disappeared and there is hydrophilic through 300～1000 DEG C of heat treatments.
Further, being dried as natural drying or lyophilization described in step (3).
Aerosil used in the present invention preferably has the aerosil of following characteristic: porosity is 95～99%, aperture is that 10～50nm, specific surface area are 200～1000m
2/ g, density are 3～300kg/m
3, network consisting colloidal particle diameter be 1～50nm.
Beneficial effect:
1, the present invention has successfully prepared nanoscale insulin taking aerosil as carrier first, different from existing nanoscale insulin, the diameter of this nanoscale insulin, below 100nm, has reached the Nano grade of materialogy category, is nanoscale insulin truly.Although diameter is less than the particle of 1 μ m and is all called as nanoparticle, but people tend to develop the particle that particle diameter is less than 100nm, because these particles can show some unique physical propertys, and therefore demonstrate potential different and useful biological characteristics.As, limit by the microcirculation of body blood capillary and barrier cell, can enter blood circulation and then the optimum grain-diameter of the drug particle that absorbed by body is 10～100nm.Therefore, nanoscale insulin of the present invention has had qualitative leap aspect bioavailability.
2, the drug loading of nanoscale insulin granule of the present invention can reach more than 90%, that existing liposome nano granule, polymer nanoparticle etc. are too far behind to catch up, its drug loading can compare favourably with nanometer crystal formation pharmaceutical suspension, but manufacture method is simpler, and cost is cheaper.
3, in nanoscale insulin granule of the present invention, insulin is loaded in the countless nanoscale hole of aerosil, form the independence " Nanodispersion " that can not reunite, structure is extremely stable, and directly having cracked in micro-nano drug research can not patent medicine because reuniting, insoluble medicine is difficult to improve the galenic pharmacy international headaches such as bioavailability.
4, oral insulin is regarded as the most significant end technology of pharmaceutical field always, and many decades is attacked and is unable to for a long time.Nanoscale insulin provided by the invention, realize the brand-new oral mechanism taking nanometer picked-up as main absorption pattern, with the brand new of " nano-solid dispersion ", the drug effect of insulin is increased greatly again, be able to oral absorption, broken through the international forbidden zone that oral insulin cannot absorb.Directly realized first the bioavailability of oral replacement injection in material aspect.The appearance that oral insulin dosage form replaces injection type brings the revolutionary advancement for the treatment of diabetes medicament.Peroral dosage form has overcome that injection type complicate fabrication process, workshop appliance and packing instructions are high, the high defect of production cost simultaneously.
The precursor of the aerosil 5, using as carrier in nanoscale insulin of the present invention for cheap, be easy to get and extensive use in medicine and food, the silica-based medicine edible adjuvant for many years of use with country and international standard, it is also one of adjuvant of recording in " pharmaceutic adjuvant handbook ", therefore the safety of nanoscale insulin of the present invention is reliable.
Test to illustrate the therapeutic effect of nanoscale insulin of the present invention to diabetes below by the treatment of diabetic mice:
1 materials and methods
1.1 instruments and material
Insulin (27.8u/mg, Jiangsu Wan Bang Biomedics Inc.), aerosil, PEG 600, PEG 4000, PEG 6000, PEG10000, hydrochloric acid, dehydrated alcohol are AR level;
Mice, BALB/c, SPF level, male, body weight 16 ± 2g, Guangdong Medical Lab Animal Center provides, the quality certification number: SCXK(Guangdong) 2008-0002;
Freezer dryer, Beijing Bo Yikang experimental apparatus company limited; Constant Temp. Oven; Ultrasonic emulsification machine; Blood glucose meter, Roche Holding Ag; Blood sugar test paper, Roche Holding Ag; Semilente Insulin injection, Jiangsu Wan Bang Biomedics Inc.; Novolin 30R injection, Novo Nordisk Co.,Ltd of Denmark.
1.2 method
1.2.1 get 50 of mices, male, fasting 12h, precision takes STZ 200mg, with citric acid solution dissolving, respectively to mouse peritoneal injection, then normally raises mice 6 days with 200mg/kg dosage, mouse blood sugar is raise and form diabetes pathological model.
1.2.2 by 27 of the diabetic mices of above-mentioned injection STZ, fasting is divided into 9 groups at random after 8 hours, every group 3, A group is Normal group, B group is subcutaneous injection Semilente Insulin (3U/kg), C group is subcutaneous injection Novolin 30R (3U/kg), D group is subcutaneous injection Nanometer Insulin-PEG600(3U/kg), E group is oral administration nanometer insulin-PEG600(1000U/kg), F group is subcutaneous injection Nanometer Insulin-PEG4000(3U/kg), G group is oral administration nanometer insulin PEG-4000(1000U/g), H group is subcutaneous injection Nanometer Insulin-PEG6000(3U/kg), I group is oral administration nanometer insulin-6000(1000U/kg), respectively at before administration with administration after 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, mice is cut tail and gets blood, with the variation of blood glucose meter measuring blood.
2 experimental results
2.1 experimental result data adopt blood glucose value to represent, measurement result is in table 1.
The therapeutic effect of table 1 Nanometer Insulin to diabetic mice
2.2 taking administration time as abscissa, blood glucose value is shown in Fig. 4 and Fig. 5 as the data in table 1 are depicted as chart by vertical coordinate.
3 discussion of results
3.1 subcutaneous injection Nanometer Insulins are compared with two kinds of commodity insulin injections, nano injection Insulin 3 u/kg(PEG600, PEG4000, PEG6000) all there is obvious blood sugar decreasing effect, wherein PEG600 and two kinds of commodity insulins more all have goodish hypoglycemic effect;
3.2 oral administration nanometer insulins are compared with two kinds of commodity insulin injections, have obvious hypoglycemic effect, linear blood sugar lowering behavior in first 3 hours, but hypoglycemic effect is lower than injection commodity group.After 3 hours, hypoglycemic effect is better than two kinds of commodity insulin injections, and drug effect steadily maintains more than 5 hours, and having pointed out oral administration nanometer insulin of the present invention is the good long-acting hypoglycemic medicine of curative effect.
Brief description of the drawings
Fig. 1 is the Electronic Speculum picture of the present invention's aerosil;
Fig. 2 is the Electronic Speculum picture of insulin raw material medicine;
Fig. 3 is the Electronic Speculum picture of nanoscale insulin of the present invention;
Fig. 4 is the treatment contrast of nano injection insulin of the present invention and commodity injection;
Fig. 5 is the treatment contrast of nano oral insulin of the present invention and commodity injection.
Detailed description of the invention
Below in conjunction with accompanying drawing, the present invention is described in further detail, and following examples are explanation of the invention, and the present invention is not limited to following examples.
Embodiment 1
The nanoscale insulin of the present embodiment is prepared by the following method:
1, insulin raw material medicine (Jiangsu Wanbang Biological Pharmaceutical Co., Ltd.) 1g, adds the AR grade hydrochloric acid 50ml of 0.01mol/L to dissolve;
2, add 800 DEG C of aerosil 5g after heat treatment to adsorb;
3, after adsorbing completely, with the dry 4h of freezer dryer;
4, the PEG-600 that separately gets 5g adds in the dehydrated alcohol of 1000ml and dissolves;
5, the solid after step 3 lyophilizing is added in the alcoholic solution of above-mentioned PEG-600 to ultrasonic emulsification machine emulsifying 3min;
6, by the emulsion of step 5 dry 12h in 60 DEG C of Constant Temp. Ovens;
7, the dried solid of grinding steps 6, and cross 200 mesh sieves, obtain nanoscale insulin granule.
Embodiment 2
The nanoscale insulin of the present embodiment is prepared by the following method:
1, insulin raw material medicine (Jiangsu Wanbang Biological Pharmaceutical Co., Ltd.) 1g, adds the AR grade hydrochloric acid 100ml of 0.01mol/L to dissolve;
2, add 500 DEG C of aerosil 10g after heat treatment to adsorb;
3, after adsorbing completely, natural drying 24h;
4, the PEG-400 that separately gets 10g adds in the dehydrated alcohol of 2000ml and dissolves;
5, dried step 3 solid is added in the alcoholic solution of above-mentioned PEG-400 to ultrasonic emulsification machine emulsifying 3min;
6, by the emulsion of step 5 dry 12h in 60 DEG C of Constant Temp. Ovens;
7, the dried solid of grinding steps 6, and cross 200 mesh sieves, obtain nanoscale insulin granule.
Embodiment 3
The nanoscale insulin of the present embodiment is prepared by the following method:
1, insulin raw material medicine (Jiangsu Wanbang Biological Pharmaceutical Co., Ltd.) 1g, adds the AR grade hydrochloric acid 5ml of 0.01mol/L to dissolve;
2, add 1000 DEG C of aerosil 0.5g after heat treatment to adsorb;
3, after adsorbing completely, with the dry 3h of freezer dryer;
4, the PEG-6000 that separately gets 0.5g adds in the dehydrated alcohol of 800ml and dissolves;
5, dried step 3 solid is added in the alcoholic solution of above-mentioned PEG-6000 to ultrasonic emulsification machine emulsifying 3min;
6, by the emulsion of step 5 dry 12h in 60 DEG C of Constant Temp. Ovens;
7, the dried solid of grinding steps 6, and cross 200 mesh sieves, obtain nanoscale insulin granule.
Embodiment 4
The nanoscale insulin of the present embodiment is prepared by the following method:
1, insulin raw material medicine (Jiangsu Wanbang Biological Pharmaceutical Co., Ltd.) 1g, adds the AR grade hydrochloric acid 200ml of 0.01mol/L to dissolve;
2, add 300 DEG C of aerosil 20g after heat treatment to adsorb;
3, after adsorbing completely, natural drying 24h;
4, the PEG-10000 that separately gets 20g adds in the dehydrated alcohol of 1500ml and dissolves;
5, dried step 3 solid is added in the alcoholic solution of above-mentioned PEG-10000 to ultrasonic emulsification machine emulsifying 3min;
6, by the emulsion of step 5 dry 12h in 60 DEG C of Constant Temp. Ovens;
7, the dried solid of grinding steps 6, and cross 200 mesh sieves, obtain nanoscale insulin granule.
Embodiment 5
The nanoscale insulin of the present embodiment is prepared by the following method:
1, insulin raw material medicine (Jiangsu Wanbang Biological Pharmaceutical Co., Ltd.) 1g, adds the AR grade hydrochloric acid 150ml of 0.01mol/L to dissolve;
2, add 400 DEG C of aerosil 15g after heat treatment to adsorb;
3, after adsorbing completely, dry 10h in 60 DEG C of Constant Temp. Ovens;
4, the PEG-20000 that separately gets 15g adds in the dehydrated alcohol of 1500ml and dissolves;
5, dried step 3 solid is added in the alcoholic solution of above-mentioned PEG-10000 to ultrasonic emulsification machine emulsifying 3min;
6, by the emulsion of step 5 dry 12h in 60 DEG C of Constant Temp. Ovens;
7, the dried solid of grinding steps 6, and cross 200 mesh sieves, obtain nanoscale insulin granule.
Embodiment 6
The nanoscale insulin of the present embodiment is prepared by the following method:
1, insulin raw material medicine (Jiangsu Wanbang Biological Pharmaceutical Co., Ltd.) 1g, adds the AR grade hydrochloric acid 50ml of 0.01mol/L to dissolve;
2, add hydrophilic aerosil 5g to adsorb;
3, after adsorbing completely, with the dry 4h of freezer dryer;
4, the PEG-4000 that separately gets 5g adds in the dehydrated alcohol of 1000ml and dissolves;
5, the solid after step 3 lyophilizing is added in the alcoholic solution of above-mentioned PEG-600 to ultrasonic emulsification machine emulsifying 3min;
6, by the emulsion of step 5 dry 12h in 60 DEG C of Constant Temp. Ovens;
7, the dried solid of grinding steps 6, and cross 200 mesh sieves, obtain nanoscale insulin granule.
Embodiment 7
The nanoscale insulin granule that embodiment 1 to 6 obtains is used tablet machine tabletting after mixing homogeneously with appropriate microcrystalline Cellulose, starch and magnesium stearate, obtains nanoscale insulin tablet of the present invention.
Embodiment 8
The nanoscale insulin granule that embodiment 1 to 6 is obtained is directly packed in hard capsule case, obtains nanoscale insulin capsule of the present invention.
Embodiment 9
The nanoscale insulin granule that embodiment 1 to 6 obtains adds in aqueous solution, stirs, and obtains nanoscale insulin suspension of the present invention.This suspension can be directly oral, also can make injection according to the preparation standard of injection.
Embodiment 10
The nanoscale insulin granule that embodiment 1 to 6 obtains and appropriate Witepsol, adopt hot melt to prepare nanoscale insulin suppository of the present invention.
Claims (7)
1. a nanoscale insulin granule, is characterized in that: the carrier using aerosil as insulin, the porosity of described aerosil is 95～99%, aperture is that 10～50nm, specific surface area are 200～1000m
2/ g, density are 3～300kg/m
3, network consisting colloidal particle diameter be 1～50nm, the diameter of described nanoscale insulin granule is below 100nm;
Described nanoscale insulin granule also comprises PEG;
The preparation method of described nanoscale insulin granule comprises the following steps:
(1) insulin is dissolved in the hydrochloric acid solution of 0.01mol/L;
(2) in above-mentioned hydrochloric acid solution, add aerosil;
(3) after insulin and aerosil absorption completely, dry;
(4) PEG is dissolved in dehydrated alcohol;
(5) solid of the dry gained of step (3) is added in the alcoholic solution of step (4);
(6) alcoholic solution of step (5) is sent into emulsifying in mulser;
(7) step (6) gained emulsion is dry in thermostatic drying chamber;
(8) solid of the dry gained of grinding steps (7), and cross 200 mesh sieves, obtain nanoscale insulin granule;
In the time that the aerosil described in step (2) has hydrophobicity, before adding hydrochloric acid solution, need first to make it have hydrophilic through 300～1000 DEG C of heat treatments.
2. nanoscale insulin granule according to claim 1, is characterized in that: the mass ratio of described insulin and described aerosil is 1:0.5～20.
3. nanoscale insulin granule according to claim 1, is characterized in that: the molecular weight of described PEG is 400～20000.
4. nanoscale insulin granule according to claim 3, is characterized in that: the mass ratio of described PEG and described insulin is 1:0.5～20.
5. the pharmaceutically acceptable oral formulations of making according to the nanoscale insulin granule described in claim 1 to 4 any one.
6. oral formulations according to claim 5, is characterized in that: described oral formulations is tablet, pill, powder, capsule, granule or suspensoid.
7. pharmaceutically acceptable injection or the suppository made according to the nanoscale insulin granule described in claim 1 to 4 any one.
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| CN201210537083.9A CN102961340B (en) | 2012-12-13 | 2012-12-13 | Nanoscale insulin and preparation method thereof |
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| CN102961750B (en) * | 2012-12-13 | 2015-01-07 | 清华大学深圳研究生院 | Application of silicon dioxide aerogel in pharmacy |
| WO2017075777A1 (en) * | 2015-11-05 | 2017-05-11 | 清华大学深圳研究生院 | Method for preparing nanoscale pesticide preparation by using silica aerogel |
| CN107375244A (en) * | 2017-09-12 | 2017-11-24 | 吉林大学珠海学院 | A kind of nanoscale docetaxel and preparation method thereof |
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| US9125872B2 (en) * | 2009-10-13 | 2015-09-08 | Yosry A. Attia | Polyethylene glycol aerogels for targeted delivery of pharmaceutical drubs |
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| CN101111225A (en) * | 2005-02-03 | 2008-01-23 | 金文申有限公司 | Drug delivery materials made by sol/gel technology |
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| CN102961340A (en) | 2013-03-13 |
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