CN101773473A - Preparation method of supercritical antisolvent of nano-insulin powder - Google Patents

Abstract

A supercritical anti-solvent preparation method for nano-sized insulin powder, characterized in that: start the _CO2 high-pressure pump, inject _CO2 into the high-pressure crystallization kettle at a flow rate of 10-25L/h, and stabilize the temperature of the high-pressure crystallization kettle at 35 ℃～45℃, the pressure is stable at 10～25MPa, reaching the supercritical state; the DMSO or DMF solution with the insulin concentration of 1～8mg/ml is sprayed at the flow rate of 1～20ml/min through the nozzle with the aperture of 100～300um In the high-pressure crystallization kettle, the nano-sized insulin powder with an average particle size of less than 400nm is precipitated, and CO ₂ continues to run in the high-pressure crystallization kettle for at least half an hour to dry the formed nano-sized insulin powder; the solvent DMSO or DMF and CO ₂ under pressure 5~6.5MPa and temperature of 25~50℃ in the separation tank for separation, DMSO or DMF is recycled for reuse, and CO ₂ gas is directly recycled. The nanometerized insulin powder obtained by the method has a smooth surface, uniform particle size distribution, good water solubility, no solvent residue, no pollution in the production process, low cost, high yield and easy industrialization.

Description

A kind of supercritical anti-solvent preparation method of nano-sized insulin powder

technical field

The invention relates to a method for preparing drug nano-powder, in particular to a method for preparing a supercritical anti-solvent of insulin, a medicine for treating diabetes.

technical background

Insulin is a protein hormone secreted by pancreatic β cells, which has the effect of lowering blood sugar. It has been used in the treatment of diabetes since 1923 and has a history of more than 70 years. Insulin is composed of two peptide chains, A and B (Figure 1), of which the A chain has 11 kinds of 21 amino acids, and the B chain has 15 kinds of 30 amino acids, consisting of 26 kinds of 51 amino acids, with a molecular weight of about 6000. It is the only hormone that lowers blood sugar in the body, and it is also the only hormone that simultaneously promotes the synthesis of glycogen, fat, and protein. The mechanism of action belongs to the receptor tyrosine kinase mechanism. Insulin has an isoelectric point of 5.35-5.45 and is almost insoluble in water, ethanol, chloroform or ether. According to the route of administration, insulin preparations can be divided into injections, pulmonary inhalation preparations, implants, oral or oral mucosal absorption preparations, transdermal preparations, etc. Among them, intramuscular injections (including needle-free preparations) are the most widely used at present. injection). In addition, intramuscular injections are generally white or off-white suspensions, which are layered after standing, and the precipitate is uniformly dispersed after shaking. A large amount of additives are used in the preparation to suspend, and the bioavailability of the drug in vivo is low.

Conventional drug nanopowder preparation methods are generally ball milling and jet milling. Although the particle size of the drug can be achieved, it has the disadvantages of high energy consumption, low efficiency, wide particle distribution, easy pollution, unsafe, easy to degrade and destroy the structure of the drug, etc. Difficult to drug. The supercritical _CO2 anti-solvent method can overcome the above-mentioned shortcomings, and is especially suitable for the nanometerization of easily degraded and destroyed drugs. The working principle of the supercritical _CO2 fluid anti-solvent method is to dissolve the solid solute to be made into an ultrafine powder into an organic solvent to form a solution. The supercritical _CO2 fluid is selected as the anti-solvent, which generally cannot dissolve the solute in the solution. However, it can be miscible with the solvent. When the anti-solvent is in contact with the solution, the anti-solvent rapidly diffuses into the solution, causing its volume to expand rapidly, and the solubility of the solute in the solvent instantly drops to supersaturation, prompting the crystallization of the solute. The process is completed in an instant, forming an ultrafine powder with high purity and uniform particle size distribution. By selecting appropriate operating conditions such as pressure, temperature, nozzle aperture, and flow rate, the particle size and shape of the precipitated nanopowder can be controlled, which has the advantages of no pollution, low cost, high yield, and easy industrialization.

Contents of the invention

The purpose of the present invention is to provide a method for preparing drug nano-powder, in particular to a method for preparing a supercritical anti-solvent of diabetes drug insulin.

The technical solution adopted in the present invention is: start the _CO2 high-pressure pump, inject _CO2 into the high-pressure crystallization kettle at a flow rate of 10-25L/h, stabilize the temperature of the high-pressure crystallization kettle at 35°C-45°C, and stabilize the pressure at 10-25L/h. 25MPa, reaching the supercritical state; spray DMSO or DMF solution with an insulin concentration of 1-8mg/ml into the high-pressure crystallization kettle at a flow rate of 1-20ml/min through a nozzle with an aperture of 100-300um, and the average particle size of the precipitate is low For the nano-sized insulin powder at 400nm, CO ₂ continues to run in the high-pressure crystallizer for at least half an hour to dry the formed nano-sized insulin powder; the solvent DMSO or DMF and CO ₂ are mixed at a pressure of 5-6.5MPa and a temperature of 25- Separation in a separation tank at 50°C, DMSO or DMF is recovered for reuse, and CO ₂ gas is directly recycled.

Advantages of the present invention:

1. The process of the present invention is simple, easy to operate, good in reproducibility, and easy for industrialized production.

2. The nanometerized insulin powder obtained in the present invention has a small average particle size, narrow particle size distribution, controllable particle size and shape, no solvent residue, smooth surface, good fluidity, and high powder quality.

3. The _CO2 of the present invention can be directly recycled, and can be recycled after the solvent is recovered. The production cost is low, the yield is high, and there is no pollution to the environment.

Description of drawings

Accompanying drawing 1 is the schematic flow chart of the preparation process of the supercritical anti-solvent of nano-sized insulin powder.

specific implementation plan

The embodiments of the present invention are described in further detail below: start the _CO2 high-pressure pump, inject _CO2 into the high-pressure crystallizer at a constant flow rate, stabilize the temperature and pressure of the high-pressure crystallizer above the supercritical state, and use a high-pressure plunger pump The DMSO or DMF solution of insulin is sprayed into the high-pressure crystallization kettle through a nozzle with a hole diameter of 100-300 μm at a flow rate of 1-20ml/min, and nano-sized insulin powder with an average particle size of less than 400nm is precipitated, and _CO2 is crystallized under high pressure. The kettle continues to run for at least half an hour to dry the formed nano-insulin powder; the solvent DMSO or DMF is separated from CO ₂ in the separation kettle, DMSO or DMF is recovered and reused, and CO ₂ gas is directly recycled.

The flow rate of the CO _injected into the autoclave is 10-25 L/h.

The temperature of the high-pressure crystallization kettle is 35°C-45°C, and the pressure is 10-25MPa.

The concentration of the DMSO or DMF solution of the insulin is 1-8 mg/ml.

The hole diameter of the nozzle is 100-300um.

The flow rate of the DMSO or DMF solution of insulin sprayed into the crystallization kettle is 1-20ml/min.

The separation kettle is 5-6.5MPa, and the temperature is 25-50°C.

Example 1:

Accurately weigh 0.1 g of insulin, dissolve it in 100 ml DMSO, and inject it into the solution cylinder 13 . Open the _CO2 valve 5, start the high-pressure _CO2 pump 3, pressurize the high-pressure crystallization kettle 6 to 25Mpa, raise the temperature to 45°C, open the separation valve 7 and the solution valve 11, start the high-pressure liquid pump 12, and pass through the nozzle 9 with an aperture of 200um. The DMSO solution of insulin is sprayed into the autoclave 6 . Continue to feed _CO2 to run for 50 minutes, close the _CO2 valve 5 and the separation valve 7, open the pressure relief valve 10 to release the pressure, and obtain nano-sized insulin powder with an average particle size of 200nm.

Example 2:

Accurately weigh 0.8 g of insulin, dissolve it in 100 ml of DMSO, and inject it into the solution cylinder 13 . Open the _CO2 valve 5, start the high-pressure _CO2 pump 3, pressurize the high-pressure crystallization kettle 6 to 15Mpa, raise the temperature to 40°C, open the separation valve 7 and the solution valve 11, start the high-pressure liquid pump 12, and pass through the nozzle 9 with an aperture of 150um. The DMF solution of insulin is sprayed into the autoclave 6 . Continue to feed _CO2 to run for 70 minutes, close the _CO2 valve 5 and the separation valve 7, open the pressure relief valve 10 to release the pressure, and obtain nano-sized insulin powder with an average particle size 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 ℃.

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