CN1493361A - Lipid nanoparticles of behenic acid glyceride and preparation method thereof - Google Patents

Abstract

The invention discloses a preparation technology of fat-soluble drug lipid nanoparticles. ATO and soybean lecithin are used as mixed carrier materials, poloxamer188 is used as a suspending agent, and a method of combining solvent-melting method and high-pressure emulsion is adopted to make the drug package Loaded in lipid nanoparticles to form a uniform water dispersion, the nanoparticle size is 100-200nm. In the present invention, the fat-soluble drug can be embedded in the method, and the obtained finished product can be directly applied in the clinic, or can be prepared into tablets, pills, capsules, soft capsules and powders by methods known in the art, and has passive targeting After entering the circulatory system, it is usually quickly ingested by the mononuclear phagocyte system and cleared from the bloodstream, so that its drugs are enriched in the organs with rich distribution of the reticuloendothelial system, which greatly improves the lipid-soluble drugs after administration. The bioavailability and absorption stability can significantly improve the deficiencies of fat-soluble drugs after administration.

Description

Lipid nanoparticles of behenic acid glyceride and preparation method thereof

technical field

The invention relates to a drug carrier, in particular to a behenic acid glyceride lipid nanoparticle for fat-soluble drugs and a preparation method thereof.

Background technique

In the field of pharmaceutical formulations, fat-soluble drugs often have disadvantages such as low bioavailability and unstable absorption after administration, which greatly limits the clinical application of such drugs. The rapid development of nanotechnology and its application in pharmacy have obviously improved the deficiencies of fat-soluble drugs after administration.

Generally, the size of nanoparticles in pharmacy is defined between 1 and 1000 nanometers, mainly including nanocarriers and nanomedicines. Nano-carrier system refers to encapsulating drugs in nanoparticles of different matrix materials by means of mosaic or adsorption, such as nanoliposomes, polymer nanocapsules, nanospheres, polymer micelles, etc.; Drug-processed nanoparticles.

Lipid nanoparticle is one of the nanocarriers that emerged in the early 1990s. It uses a lipid material that is solid at room temperature with good physiological compatibility as a carrier, and it has polymer nanoparticles such as polylactic acid ( PLA) nanoparticles have the advantages of controlling drug release, avoiding drug leakage, etc., and at the same time, the preparation method is simple (such as using a high-pressure homogenizer), suitable for industrial production, and mainly suitable for fat-soluble drugs. Lipid nanoparticles can be administered intravenously or orally to achieve the purpose of improving bioavailability or targeting.

Since lipid nanoparticles are a drug carrier that can improve the bioavailability and absorption of fat-soluble drugs after administration, research and development of new lipid nanoparticles has become a hot spot in the field of pharmacy Very much expected.

Contents of the invention

The technical problem to be solved in the present invention is to disclose a lipid nanoparticle of behenic acid glyceride, which can obviously improve the absorption of fat-soluble drugs, and has passive targeting, so as to meet the needs of relevant departments;

Another technical problem to be solved in the present invention is to provide a preparation method of the above-mentioned lipid nanoparticles of behenic acid glyceride, so as to facilitate industrial production.

The lipid nanoparticle of behenic acid glyceride of the present invention is a kind of composition, and its component and weight percent content comprise:

Glyceryl behenate 50～60%

Soy lecithin 20～30%

Poloxamer 188 20～30%

The particle size is between 100 and 200nm.

The so-called glyceryl behenic acid, its English trade name is compritol 888 ATO, referred to as ATO, and its chemical name is glyceryl behenic acid.

Commercially available products can be used as the main carrier material;

Said soybean phospholipid is a kind of lecithin extracted from soybean, which can adopt commercially available products, and its main function is to increase the affinity of drug lipid melt, which is the stabilizing agent of the present invention;

The said poloxamer 188 is a mixed suspending agent, and the commercially available product name is poloxamer 188, and its standardized chemical name is polyoxyethylene polyoxypropylene ether, that is, α-hydrogen-ω-hydroxyl poly(oxyethylene) a- Poly(oxypropylene) b-poly(oxyethylene) a block copolymer can adopt the model Pluronic F68 produced by Shanghai Puli Membrane Preparation and Accessory Technology Co., Ltd., and its molecular formula is: HO(C ₂ H ₄ O) _a ( C ₃ H ₆ O) _b (C ₂ H ₄ O) _a H.

The lipid nanoparticle of behenic acid glyceride of the present invention, preferred component and weight percentage content comprise:

Glyceryl behenate 30～50%

Soy lecithin 20～40%

poloxamer188 20～40%

The present invention also relates to a water dispersion system containing the above composition, wherein the content of the composition is 30-70 mg/ml, preferably 50 mg/ml.

The preparation method of the lipid nanoparticle of behenic acid glyceride of the present invention comprises the steps:

(1) Dissolve said ATO and soybean lecithin in a hot organic solvent at 60-90°C, preferably at 85°C, continue heating, evaporate the organic solvent, and freeze at -10-0°C for 1-5 hours;

Said organic solvent includes absolute ethanol.

(2) Disperse poloxamer188 in water to form a uniform water phase for later use, with a preferred concentration of 1-100 mg/ml;

(3) Mix and grind the solid prepared in step (1) and the aqueous phase obtained in step (2) at 0-10°C, preferably 3-5°C, until the particle size is below 100 μm, to form a uniform particle water dispersion system;

(4) Homogenize the aqueous dispersion obtained in step (3) under high pressure under a pressure of 700-1800 bar, and rapidly cool to room temperature to obtain an aqueous dispersion containing lipid nanoparticles of 100-200 nm.

(5) freeze-drying the aqueous dispersion obtained in step (4) at -25 to -30°C to obtain lipid nanoparticles.

The lipid nanoparticle of behenic acid glyceride of the present invention can entrap fat-soluble drugs in a mosaic method, and the obtained finished product can be directly applied clinically, or prepared into tablets, pills, capsules, etc. by methods recognized in the art. Take soft capsules and powders. The present invention is a fat-soluble drug carrier of 100-200nm nanoparticles. After the drug is loaded, it has passive targeting. Drugs are enriched in organs rich in reticuloendothelial system, such as liver and spleen. In addition, by controlling the particle size of nanoparticles or changing the surface properties of nanoparticles, drugs can be enriched in organs such as the lungs and brain, which greatly improves the bioavailability and absorption stability of fat-soluble drugs after administration. Improve deficiencies after administration of fat-soluble drugs.

Description of drawings

Fig. 1 is the electron micrograph of the lipid nanoparticle of behenic acid glyceride of the present invention.

Figure 2 is a particle size distribution diagram.

Detailed ways

Example 1

(1) Take 2.0g ATO and 1.8g soybean lecithin, heat it in a water bath at 85°C, dissolve it in 15ml absolute ethanol, continue heating, evaporate the organic solvent, and freeze it at 0°C for 2 hours. spare;

(2) Disperse 1.5g of poloxamer188 in 100ml of water at 4°C to form a uniform aqueous phase for later use;

(3) Mix and grind (mortar, homogenizer) the solid obtained from (1) and the water phase obtained from (2) at 4°C until the particle size is below 100 μm (through a 180-mesh sieve) to form uniform particles water dispersion system;

(4) the water dispersion of (3) gained is at room temperature, the pressure of 700bar (adopting the Niro Soavi high-pressure homogenizer produced by GEA company) high-pressure homogenization cycle 5 times (3 minutes), and the water dispersion is cooled to After 10°C, recirculate rapidly 5 times (3 minutes), and rapidly cool to room temperature to prepare 100ml of a water dispersion system of lipid nanoparticles with a particle size of 100-200nm;

(5) Freeze-dry the water dispersion system in step (4) by a conventional method to obtain lipid nanoparticles. Its electron micrograph is shown in Figure 1, and its particle size distribution is shown in Figure 2.

Example 2

Prepared by the same method as in Example 1, the amount of ATO added was 1.0 g, soybean lecithin was 2.5 g, and poloxamer188 was 1.5 g.

Example 3

Prepared by the same method as in Example 1, the amount of ATO added was 3.0 g, soybean lecithin was 0.5 g, and poloxamer188 was 1.5 g.

Example 4

The same method as in Example 1 was used for preparation, the amount of ATO added was 2.0 g, soybean lecithin was 1.0 g, and poloxamer188 was 2.0 g.

Example 5

Using the same method as in Example 1, 120 mg of schisandrin was added in step (1) to obtain lipid nanoparticles of behenic acid glyceride loaded with fat-soluble drugs.

Claims (9)

1. a lipid nanoparticle of behenic acid glyceride, it is characterized in that, component and weight percentage content comprise: Glyceryl behenate 20～60% Soy lecithin 20～30% Poloxamer188 20-30%. 2. the lipid nanoparticle of behenic acid glyceride according to claim 1, is characterized in that, preferred component and weight percent content comprise: Glyceryl behenate 20～60% Soy lecithin 20～30% Poloxamer188 20-30%. 3. a kind of aqueous dispersion system containing the lipid nanoparticle of behenic acid glyceride described in claim 1 or 2. 4 . The aqueous dispersion system of lipid nanoparticles of glyceryl behenate according to claim 3 , wherein the content of lipid nanoparticles of glyceryl behenate is 30-70 mg/ml. 5. the aqueous dispersion system preparation method of the lipid nanoparticle of behenic acid glyceride according to claim 3, is characterized in that, comprises the steps: (1) said glyceryl behenate and soybean lecithin are dissolved in an organic solvent, heated to evaporate the organic solvent, and frozen; (2) Disperse poloxamer188 in water to form a uniform water phase for later use, with a preferred concentration of 1-100 mg/ml; (3) mixing and grinding the solid prepared in step (1) and the aqueous phase obtained in step (2) to form a uniform particle water dispersion system; (4) Homogenize the aqueous dispersion obtained in step (3) under a pressure of 700-1800 bar, and cool to room temperature to obtain an aqueous dispersion containing lipid nanoparticles of 100-200 nm. 6. The method according to claim 5, characterized in that said glyceryl behenate and soybean lecithin are dissolved in an organic solvent, heated to evaporate the organic solvent, and then frozen at -10 to 0°C. 7. The method according to claim 5, wherein said organic solvent comprises absolute ethanol. 8. The method according to claim 5, characterized in that poloxamer188 is dispersed in water to form a uniform water phase with a concentration of 1-100 mg/ml. 9. The method according to claim 5, characterized in that, after the water dispersion obtained in step (3) is homogenized, it is rapidly cooled to room temperature.