TW201524595A - Method of making lipid particles and method of making liposomes using same - Google Patents

Abstract

A method of making lipid particles according to the present invention includes the following steps: (a) preparing solution containing lipid composition and solvent; (b) preparing supercritical fluid; (c) inputting the solution containing lipid composition and solvent and the supercritical fluid into a high pressure tank; and (d) dissolving the solvent of the solution into the supercritical fluid, and the lipid composition of the solution is separated out and refined into lipid particles. With the method of making lipid particles of the present invention, the solution and the supercritical liquid are continuously fed into the tank to promote the productivity and lower the cost, which can industrialize the process and achieve better efficiency, and restrict residual of solvent. In addition, the lipid particles made by this invention have uniform and smaller particle diameters, which can reach the degree of nanometer or submicrometer and are hence suitable for making liposome for delivering drug.

Description

Method for producing lipid microparticles and method for preparing same

The present invention relates to a method for producing lipid microparticles and a method for producing the same.

The application field of drug delivery control is quite extensive. In addition to cosmetics, food, agricultural products and other industries, it is particularly valued by the pharmaceutical industry. Drug delivery control products are usually based on biocompatible or biodegradable polymer materials. The bioactive active ingredient is evenly coated so as to release the drug in an appropriate amount when used, providing a long-term and stable therapeutic effect. Liposome is an excellent drug delivery carrier. By the special structure of phospholipids, spherical vesicles with bilayer membranes can be formed in water. The core can coat hydrophilicity. The drug, a fat-soluble drug, can be coated in the lipid bilayer membrane. When the liposome is transported to the target area, it will fuse with the cell membrane and the like, and release the drug to achieve the purpose of drug delivery.

The liposome is a carrier having a single or multiple phospholipid bilayer structure, and the center of the carrier can be loaded with a hydrophilic drug, which can be as small as several tens of nanometers or as large as several micrometers. Most of the liposomes are not toxic and antigenic, but are biodegradable. When the liposome is used as a carrier for the drug, it has the following characteristics, including increasing the efficacy of the drug, reducing the toxicity of the drug, and prolonging the circulation time of the drug in the body.

The object of the present invention is to improve the above problems, and to provide a method for producing lipid microparticles, which can continuously feed a solution and a supercritical fluid to increase productivity and reduce cost, industrialize the process, and achieve better efficiency, and Limit solvent residue. And use The lipid microparticles produced by the manufacturing method of the invention have uniform particle size distribution and smaller particle size, can reach the level of nanometer or submicron, and can be applied to prepare drug-transferred microlipids.

The present invention relates to a method for producing a lipid microparticle, comprising the steps of: (a) preparing a solution containing a lipid component and a solvent; (b) preparing a supercritical fluid; and (c) inputting a solution containing a lipid component and a solvent with a supercritical fluid And (d) the solvent in the solution dissolves into the supercritical fluid, and the lipid component in the solution is precipitated and refined into lipid particles.

The present invention relates to a method for producing a liposome using a lipid microparticle, comprising the steps of: (a) a lipid microparticle produced by the above method for producing a lipid microparticle; and (b) a hydrated lipid microparticle and a solute containing a pharmaceutical component, To form a liposome.

By using the method for producing the lipid microparticles of the present invention, the solution and the supercritical fluid system are continuously fed to increase the productivity and reduce the cost, and the process can be industrialized, and the efficiency is achieved, and the residual of the solvent can be restricted. Further, the lipid microparticles produced by the production method of the present invention have a uniform particle size distribution and a smaller particle size, and can reach a level of nanometer or submicron, and are suitable for producing a drug-transferred liposome.

The method for producing the liposome of the present invention is carried out in a low temperature process without deteriorating the characteristics of the heat sensitive drug. The solute and solvent can be effectively separated to avoid toxic solvent residue to meet the drug specifications.

20‧‧‧Liquid Particle Manufacturing System

21‧‧‧ Container

22‧‧‧First high pressure pump

23‧‧‧First pressure regulating valve

24‧‧‧ pressure gauge

25‧‧‧ Temperature display device

31‧‧‧High pressure fluid storage tank

32‧‧‧Precooling device

33‧‧‧Second high pressure pump

34‧‧‧Preheater

35‧‧‧Second pressure regulating valve

41‧‧‧ high pressure tank

42‧‧‧ coaxial double casing

43‧‧‧Filter device

44‧‧‧ collection trough

45‧‧‧First thermostat

46‧‧‧Second thermostat

47‧‧‧ gas-liquid separation tank

421‧‧‧First casing

422‧‧‧second casing

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a schematic flow chart showing a method for producing a lipid microparticle of the present invention; and Fig. 2 is a view showing a system for producing a lipid microparticle of the present invention.

Fig. 1 is a schematic flow chart showing a method of producing the lipid microparticles of the present invention. Fig. 2 is a schematic view showing a manufacturing system of the lipid microparticles of the present invention. The method for producing the lipid microparticles of the present invention can be carried out using the manufacturing system 20 of the lipid microparticles of the present invention. Referring to FIG. 1 and FIG. 2, first, referring to step S11, a solution containing a lipid component and a solvent is prepared. Formulating an organic solvent containing a phospholipid component, cholesterol, or the like and dissolving the lipid to form a solution required in the present embodiment, and juxtaposing Into a container 21. In this embodiment, the concentration of the solution is from 0.5% to 2.0%.

Lipids may be phospholipids, including but not limited to phospholipidylcholine, phosphatidylserine, phosphatidic acid, phosphatidylethanolamine, guanidine phosphate ( Phosphatidylglycerol) and its derivatives, phospholipid PEG derivatives.

The solvent may be: alkanols (e.g. methanol, ethanol, isopropanol), acetate, THF, DMSO, DMF, NMP, dichloromethane, chloroform, ethyl acetate, and the like.

If it is necessary to prepare a lipid containing other substances, the solute may be further formulated into a solution, and the solute may be a drug, such as polyenes, taxaens, antifungal triazole derivatives, and antifungal triazole derivatives. , onhracyclines, camptothecin, etc.

The solution can be pressurized by a first high pressure pump 22 and passed through a first pressure regulating valve 23 to adjust the pressure of the solution.

Referring to step S12, a supercritical fluid is prepared. In this embodiment, the supercritical fluid may be liquid carbon dioxide, and the liquid carbon dioxide is stored in a high pressure fluid storage tank 31. Cooling is performed using a pre-cooling unit 32 to ensure that the liquid carbon dioxide is in the liquid phase. The second high-pressure pump 33 is used to pressurize the liquid carbon dioxide, and the function and efficiency of the second high-pressure pump 33 are affected to avoid the occurrence of idling, and then the liquid carbon dioxide reaches a critical temperature (about 31.1 ° C) via a preheater 34. )the above. A second pressure regulating valve 35 is utilized to adjust the pressure of the liquid carbon dioxide.

Referring to step S13, the solution containing the lipid component and the solvent and the supercritical fluid are introduced into a high pressure tank 41. In this embodiment, a nozzle, a coaxial double sleeve 42 or a capillary tube can be used to input a solution containing a lipid component and a solvent with a supercritical fluid, and atomize the solution. The coaxial double sleeve 42 has a first sleeve 421 and a second sleeve 422, respectively input a solution containing a lipid component and a solvent and a supercritical fluid, and the first sleeve 421 is disposed on the second sleeve 422. The inner diameter of the first sleeve 421 is smaller than the second sleeve 422. The solution may be input by the first sleeve 421; and the supercritical fluid is input by the second sleeve 422. Alternatively, the solution may be input by the second sleeve 422; and the supercritical fluid is input by the first sleeve 421. The coaxial double sleeve has an inner diameter of 128 μm to 256 μm. Also, the ratio of the input supercritical fluid to the solution to the high pressure tank 41 is between 8:1 and 10:1.

Referring to step S14, the solvent in the solution is dissolved in the supercritical fluid, and the lipid component in the solution is precipitated and refined into lipid particles. In this embodiment, the high pressure tank 41 can be a crystallization reactor. The high pressure tank 41 has an operating pressure of from 250 bar to 300 bar and a temperature of from 50 ° C to 60 ° C. The solution and the supercritical fluid are input to the high pressure tank 41, and since the ratio of the supercritical fluid to the solution is between 8:1 and 10:1, most of the high pressure tank 41 is a supercritical fluid. Since the solubility of the organic solvent component in the solution is different in the supercritical fluid, and the solution dissolves the solvent in the solution into the supercritical fluid due to atomization through the nozzle, capillary or coaxial double sleeve, the lipid component in the solution is caused by The solubility is lowered, and the lipid component is precipitated and simultaneously miniaturized to form lipid microparticles. The particle size of the lipid particles may be between 30 nm and 1 μm.

The lipid microparticles can be reused by a filtration device 43 and filtered and buffered into a collection tank 44. Lipid microparticles can be collected in the collection tank 44.

To ensure the temperature of the high pressure tank 41, a first thermostat 45 can be disposed on the outer wall of the high pressure tank 41 to maintain the temperature of the high pressure tank 41 at 50 ° C - 60 ° C. And a second thermostat 46 can be disposed on the outer wall of the collecting tank 44 to maintain the temperature of the collecting tank 44.

In order to effectively atomize the solution and contact with the supercritical fluid, the pressure of the solution containing the lipid component and the solvent and the supercritical fluid is higher than the operating pressure of the high pressure tank by 20 bar to 50 bar before being introduced into the high pressure tank. A pressure gauge 24 can be utilized to monitor the pressure before the solution and supercritical fluid are input to the high pressure tank 41. A temperature display device 25 can also be utilized to monitor the temperature before the solution and supercritical fluid are input to the high pressure tank 41.

The method of producing the lipid microparticles of the present invention further includes a separation step to separate the solvent from the supercritical fluid. As described above, the solvent is dissolved in the supercritical fluid, and in order to recover the supercritical fluid, in the present embodiment, the solvent and the supercritical fluid are separated by a gas-liquid separation tank 47. The separated supercritical fluid can be recycled to the high pressure fluid storage tank 31 for use.

By using the method for producing the lipid microparticles of the present invention, the solution and the supercritical fluid system are continuously fed to increase the productivity and reduce the cost, and the process can be industrialized, and the efficiency is achieved, and the residual of the solvent can be restricted. Further, the lipid microparticles produced by the production method of the present invention have a uniform particle size distribution and a smaller particle size, and can reach a level of nanometer or submicron, and are suitable for producing a drug-transferred liposome.

The present invention further provides a method for producing a liposome using a lipid microparticle, which is a lipid microparticle produced by the above-described method for producing a lipid microparticle of the present invention, and hydrates the lipid microparticle and a solute containing a pharmaceutical component to form a liposome.

The method for producing the liposome of the present invention is carried out in a low temperature process without deteriorating the characteristics of the heat sensitive drug. The solute and solvent can be effectively separated to avoid toxic solvent residue to meet the drug specifications.

However, the above embodiments are merely illustrative of the principles and effects of the invention and are not intended to limit the invention. Therefore, those skilled in the art can make modifications and changes to the above embodiments without departing from the spirit of the invention. The scope of the invention should be as set forth in the appended claims.

Claims (10)

A method for producing a lipid microparticle, comprising the steps of: (a) preparing a solution containing a lipid component and a solvent; (b) preparing a supercritical fluid; (c) inputting a solution containing a lipid component and a solvent and a supercritical fluid to a high pressure tank And (d) the solvent in the solution is dissolved in the supercritical fluid, and the lipid component in the solution is precipitated and refined into lipid particles. The method of claim 1, wherein the step (a) further comprises formulating the solute into the solution. The manufacturing method of claim 1, wherein in the step (c), a solution containing a lipid component and a solvent and a supercritical fluid are input by using a nozzle or a capillary, and the solution is atomized. The manufacturing method of claim 1, wherein in step (c), a coaxial double sleeve is used, the coaxial double sleeve having a first sleeve and a second sleeve, respectively inputting a solution containing a lipid component and a solvent And the supercritical fluid, and the atomization solution, the coaxial double sleeve has an inner diameter of 128 μm to 256 μm. The manufacturing method of claim 1, wherein the high pressure tank has an operating pressure of from 250 bar to 300 bar and a temperature of from 50 ° C to 60 ° C. The manufacturing method of claim 5, wherein the pressure of the solution containing the lipid component and the solvent and the supercritical fluid is higher than the operating pressure of the high pressure tank by 20 bar to 50 bar before the high pressure tank is input. The manufacturing method of claim 1, The ratio of the input supercritical fluid to the solution to the high pressure tank is between 8:1 and 10:1. The method of claim 1, wherein the concentration of the solution is from 0.5% to 2.0%. The manufacturing method of claim 1, further comprising a separating step to separate the solvent from the supercritical fluid. A method for producing a liposome using a lipid particle, comprising the steps of: (a) using the lipid particle produced by the manufacturing method of claim 1; and (b) hydrating the lipid particle and the solute containing the drug component to form a lipid body.