CN101773473A - Preparation method of supercritical antisolvent of nano-insulin powder - Google Patents
Preparation method of supercritical antisolvent of nano-insulin powder Download PDFInfo
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- CN101773473A CN101773473A CN201010105952A CN201010105952A CN101773473A CN 101773473 A CN101773473 A CN 101773473A CN 201010105952 A CN201010105952 A CN 201010105952A CN 201010105952 A CN201010105952 A CN 201010105952A CN 101773473 A CN101773473 A CN 101773473A
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Abstract
The invention relates to a preparation method of a supercritical antisolvent of a nano-insulin powder, which is characterized by comprising the following steps of: starting a CO2 high-pressure pump, injecting CO2 into a high-pressure crystallization kettle at the flow speed of 10-25L/h, and enabling the temperature of the high-pressure crystallization kettle to be stabilized at 35-45 DEG C and the pressure to be stabilized at 10-25MPa to achieve a supercritical state; spraying a DMSO or DMF solution with the insulin concentration of 1-8mg/ml into the high-pressure crystallization kettle at the speed of 1-20ml/min through a nozzle with the aperture of 100-300 microns, separating out the nano-insulin powder with the mean grain size of lower than 400 nanometers, and continuously running for at least half an hour in the high-pressure crystallization kettle to dry the formed nano-insulin powder by the CO2; and separating a solvent DMSO or DMF and the CO2 in a separation kettle under the pressure of 5-6.5MPa and at the temperature of 25-50 DEG C, reclaiming and then recycling the DMSO or the DMF, and directly recycling to use the CO2 gas. The nano-insulin powder obtained by the method has smooth surface, uniform grain size distribution, good water solubility, no solvent residue, no pollution of a production process, low cost, high yield and easy industrialization.
Description
Technical field
The present invention relates to a kind of method of medicament nano powder preparing, particularly a kind of preparation method for supercritical anti-solvent of Remedies for diabetes insulin.
Technical background
Insulin is the excretory a kind of protein hormone of pancreatic beta cell, has hypoglycemic effect, since nineteen twenty-three begins to be applied to treat diabetes, and the history in existing more than 70 year.Insulin is formed (Fig. 1) by two peptide chains of A, B, and wherein the A chain has 11 kinds of 21 aminoacid, and the B chain has 15 kinds of 30 aminoacid, is made up of 26 kinds of 51 aminoacid altogether, and molecular weight is about 6000.It is the hormone of unique blood sugar lowering in the body, also is unique hormone that promotes glycogen, fat, protein synthesis simultaneously, and the mechanism of action belongs to receptor tyrosine kinase mechanism.The isoelectric point, IP of insulin is 5.35-5.45, and is almost insoluble in water, ethanol, chloroform or ether.Divide according to route of administration, insulin preparation can be divided into injection, pulmonary's inhalation preparation, implant, oral or oral mucosa absorption drug-delivery preparation, preparation capable of permeating skin etc., and wherein using at present the most extensively is intramuscular dose (comprising the Needleless injection agent).And intramuscular dose is generally the suspension of white or off-white color, leaves standstill the back layering, and jolting postprecipitation homodisperse has used relatively large additive suspending in the preparation, and bioavailability is lower in the medicine body.
Conventional medicine nano powder preparation method generally is ball-milling method and comminution by gas stream, though can reach the granularity of medicine, energy consumption is big, and efficient is low, and distribution of particles is wide, easily pollutes, and is dangerous, easily degrades and destroys shortcoming such as medicines structure, is difficult to pharmacy.And supercritical CO
2Anti-solvent method can overcome above-mentioned shortcoming, especially is fit to the nanorize of easily degraded and destruction medicine.Supercritical CO
2The operation principle of the anti-solvent method of fluid is that the solid solute that will make superfine powder is dissolved in a kind of organic solvent wiring solution-forming, selects supercritical CO
2Fluid is as anti-solvent, the solute in generally can not solvent soln, but can dissolve each other with solvent, when anti-solvent contacted with solution, anti-solvent diffused to this solution rapidly, and its volume is expanded rapidly, solute dissolubility moment in solvent drops to degree of supersaturation, impels the solute crystallization to separate out.This process moment finishes, and forms purity height, the uniform superfine powder of particle size distribution.By selecting operating conditions such as suitable pressure, temperature, nozzle bore and flow velocity, can control the particle diameter and the shape of the nanorize powder body of separating out, have pollution-freely, cost is low, yield height, the easily advantage of industrialization.
Summary of the invention
The object of the present invention is to provide a kind of method of medicament nano powder preparing, particularly a kind of preparation method for supercritical anti-solvent of Remedies for diabetes insulin.
The technical solution adopted in the present invention is: start CO
2High-pressure pump is with CO
2Flow velocity with 10～25L/h injects the high pressure crystal still, and the temperature stabilization that makes the high pressure crystal still is at 35 ℃～45 ℃, and pressure stability reaches supercriticality at 10～25MPa; With insulin concentration is DMSO or the DMF solution of 1～8mg/ml, is that the nozzle of 100～300um sprays in the high pressure crystal still with the flow velocity of 1～20ml/min by the aperture, separates out the nanorize insulin powder that mean diameter is lower than 400nm, CO
2In the high pressure crystal still, continue to move to not a half hour with the dry nanorize insulin powder that formed; Solvent DMSO or DMF and CO
2At pressure is 5～6.5MPa and separate in temperature is 25～50 ℃ separating still, utilizes CO again after DMSO or DMF reclaim
2Gas directly recycles.
Advantage of the present invention:
1 technological process of the present invention is simple, easy and simple to handle, and favorable reproducibility is easy to industrialization production.
2 gained nanorize insulin powder mean diameters of the present invention are little, narrow particle size distribution and particle diameter and controllable shapes, no solvent residue, smooth surface, good fluidity, powder body quality height.
3 CO of the present invention
2Can directly recycle, but recirculation uses after the solvent recovery, production cost is low, yield height, environmentally safe.
Description of drawings
Preparation technology's schematic flow sheet of the super-critical anti-solvent of accompanying drawing 1 nanorize insulin powder.
Specific embodiments
Below embodiments of the invention are described in further detail: start CO
2High-pressure pump is with CO
2Inject the high pressure crystal still with constant flow velocity, the temperature and pressure of high pressure crystal still is stabilized on the supercriticality, with DMSO or the DMF solution of high-pressure plunger pump with insulin, the nozzle that by the aperture is 100～300 μ m sprays in the high pressure crystal still with the flow velocity of 1～20ml/min, separate out mean diameter and be lower than the nanorize insulin powder of 400nm, CO
2In the high pressure crystal still, continue to move to not a half hour with the dry nanorize insulin powder that formed; Solvent DMSO or DMF and CO
2In separating still, separate, utilize CO again after DMSO or DMF reclaim
2Gas directly recycles.
Described CO
2The flow velocity that injects the high pressure crystal still is 10～25L/h.
The temperature of described high pressure crystal still is 35 ℃～45 ℃, and pressure is 10～25MPa.
The concentration of the DMSO of described insulin or DMF solution is 1～8mg/ml.
Described nozzle bore is 100～300um.
The flow velocity that the DMSO of described insulin or DMF solution spray into crystallization kettle is 1～20ml/min.
Described separating still 5～6.5MPa, temperature is 25～50 ℃.
Example 1:
Accurately take by weighing insulin 0.1g, be dissolved in 100ml DMSO, inject solution barrel 13.Open CO
2Valve 5 starts high pressure CO
2Pump 3 is forced into 25Mpa in the high pressure crystal still 6, is warming up to 45 ℃, opens and separates valve 7 and solution valve 11, starts pressure liquid pump 12, is 200um nozzle 9 by the aperture, and the DMSO solution of insulin is sprayed into high pressure crystal still 6.Continue to feed CO
2Move 50 minutes, close CO
2Valve 5 with separate valve 7, open pressure relief valve 10 releases, obtaining mean diameter is the nanorize insulin powder of 200nm.
Example 2:
Accurately take by weighing insulin 0.8g, be dissolved in 100ml DMSO, inject solution barrel 13.Open CO
2Valve 5 starts high pressure CO
2Pump 3 is forced into 15Mpa in the high pressure crystal still 6, is warming up to 40 ℃, opens and separates valve 7 and solution valve 11, starts pressure liquid pump 12, is 150um nozzle 9 by the aperture, and the DMF solution of insulin is sprayed into high pressure crystal still 6.Continue to feed CO
2Move 70 minutes, close CO
2Valve 5 with separate valve 7, open pressure relief valve 10 releases, obtaining mean diameter is the nanorize insulin powder of 110nm.
Claims (5)
1. the preparation method for supercritical anti-solvent of a nanorize insulin powder may further comprise the steps: start CO
2High-pressure pump is with CO
2Inject the high pressure crystal still with constant flow velocity, the temperature and pressure of high pressure crystal still is stabilized on the supercriticality, with DMSO or the DMF solution of high-pressure plunger pump with insulin, the nozzle that by the aperture is 100～300 μ m sprays in the high pressure crystal still with the flow velocity of 1～20ml/min, separate out mean diameter and be lower than the nanorize insulin powder of 400nm, CO
2In the high pressure crystal still, continue to move to not a half hour with the dry nanorize insulin powder that formed; Solvent DMSO or DMF and CO
2In separating still, separate, utilize CO again after DMSO or DMF reclaim
2Gas directly recycles.
2. according to the preparation method for supercritical anti-solvent of claim 1 described nanorize insulin powder, it is characterized in that CO
2The flow velocity that injects the high pressure crystal still is 10～25L/h.
3. according to the preparation method for supercritical anti-solvent of claim 1 described nanorize insulin powder, it is characterized in that the temperature of high pressure crystal still is 35 ℃～45 ℃, pressure is 10～25MPa.
4. according to the preparation method for supercritical anti-solvent of claim 1 described nanorize insulin powder, it is characterized in that the DMSO of insulin or the concentration of DMF are 1～8mg/ml.
5. according to the preparation method for supercritical anti-solvent of claim 1 described nanorize insulin powder, it is characterized in that separating still pressure is 5～6.5MPa, temperature is 25～50 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010105952A CN101773473A (en) | 2010-02-04 | 2010-02-04 | Preparation method of supercritical antisolvent of nano-insulin powder |
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| CN201010105952A CN101773473A (en) | 2010-02-04 | 2010-02-04 | Preparation method of supercritical antisolvent of nano-insulin powder |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102058539A (en) * | 2010-12-24 | 2011-05-18 | 国家纳米技术与工程研究院 | Process for preparing composite fine insulin particles by applying supercritical fluid crystallization technology |
| CN108409821A (en) * | 2018-03-19 | 2018-08-17 | 青岛国海生物制药有限公司 | A kind of preparation method and megestrol acetate of megestrol acetate nanocrystal |
| CN109718205A (en) * | 2019-03-11 | 2019-05-07 | 塔尔普(北京)制药技术有限公司 | A kind of preparation method and system of medicinal liposome |
-
2010
- 2010-02-04 CN CN201010105952A patent/CN101773473A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102058539A (en) * | 2010-12-24 | 2011-05-18 | 国家纳米技术与工程研究院 | Process for preparing composite fine insulin particles by applying supercritical fluid crystallization technology |
| CN108409821A (en) * | 2018-03-19 | 2018-08-17 | 青岛国海生物制药有限公司 | A kind of preparation method and megestrol acetate of megestrol acetate nanocrystal |
| CN109718205A (en) * | 2019-03-11 | 2019-05-07 | 塔尔普(北京)制药技术有限公司 | A kind of preparation method and system of medicinal liposome |
| CN109718205B (en) * | 2019-03-11 | 2021-04-06 | 塔尔普(北京)制药技术有限公司 | Preparation method and system of drug liposome |
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Application publication date: 20100714 |