CN103040791B - Asiatic acid lipid nanoparticle capable of stimulating oral absorption and preparation method thereof - Google Patents

Abstract

The invention discloses asiatic acid lipid nanoparticles capable of promoting oral absorption and a preparation method thereof. The invention uses lipid material as a carrier, asiatic acid as a main agent, and is prepared by a solvent diffusion method. The particle size of the obtained lipid nanoparticles is less than 700nm, the encapsulation efficiency is 40-90%, and the drug loading capacity is 7-11%. The nanoparticles can increase intestinal drug absorption and improve oral bioavailability.

Description

A lipid nanoparticle of asiatic acid that can promote oral absorption and its preparation method

technical field

The invention relates to the technical field of pharmaceutical preparations, in particular to asiatic acid lipid nanoparticles capable of increasing intestinal drug absorption and oral bioavailability and a preparation method thereof.

Background technique

Centella asiatica (L.) Urban. is the dried or rooted whole plant of Centella asiatica (L.) Urban. It has the effects of clearing heat and dampness, detoxifying and reducing swelling (Zhang Leilei, et al. Chemical composition of Centella asiatica Research [J]. Chinese Herbal Medicine, 2005,36(12):1761-1763.). Asiatic Acid (Asiatic Acid) is one of the active ingredients of Centella asiatica, which belongs to pentacyclic triterpene acid. It has the effects of treating skin wounds and resisting liver and kidney fibrosis. It is often used in the treatment of scars related to beautifying the skin (Chen Jun, Etc. Research on the biological activity of Asiatic acid and its derivatives [J]. Chinese Herbal Medicine, 2006,37(3):458-460.). Asiatic acid has poor gastrointestinal absorption and low oral bioavailability. It has been reported in the literature that the peak blood concentration (Cmax) of rats orally administered asiatic acid (1.25mg) is far lower than that of intravenous injection (about 1/60), and that after oral administration of asiatic acid (12mg) by humans, the Cmax is only 0.098μg ·ml ^-1 , 0-12h area under the curve (AUC _0-12h ) is 0.61±0.25μg·h·mL ^-1 (Chasseaud L. F., et al.The metabolism of Asiatic Acid, Madecassic Acid and Asiaticoside in the Rat[J ]. Drug Res.,1971,21:1379-1384; Rush W. R., et al.The comparative steady-state bioavailability of the active ingredients of madecassol[J].Eur. J. Drug Metab. Pharmacokinet., 1993,18( 4): 323-326.).

Although asiatic acid has good biological activity, its solubility in water is extremely small and its intestinal absorption is poor, which brings certain difficulties to oral administration. People have been working on improving the intestinal absorption of asiatic acid. For example, Liu Ying et al. made water-soluble asiatic acid tromethamine salt through chemical structure modification of asiatic acid, and then made microemulsion, microemulsion soft capsule, Aerosol, hard capsule and tablet preparations, although the oral bioavailability of asiatic acid has increased (patent application number: CN 102755333 A; CN 102755328 A; CN 102755329 A; CN 102755331 A; CN 102755332 A), However, since the chemical structure of Asiatic acid has changed, whether the safety and efficacy have changed needs to be further confirmed.

Modern preparation technology can improve the oral absorption of drugs. Zhang Daping used self-emulsification technology to obtain Centella asiatica yogurt drops. After intragastric administration, the blood drug concentration was significantly higher than that of the raw material group (patent application number: CN 102784096 A), but the prescription A large amount of auxiliary materials such as emulsifiers, co-emulsifiers and antioxidants need to be added to the formula, which may have potential safety hazards, and the size of the emulsion formed by self-emulsification is easily affected by the gastrointestinal conditions, thereby affecting absorption.

Lipid nanoparticles are constructed with lipid materials as carriers through a certain preparation process, such as solid lipid nanoparticles (Solid Lipid Nanoparticles, SLN) and nanostructures made by changing the proportion of liquid lipids in lipid materials Lipid Carriers (Nanostructured Lipid Carriers, NLC). This type of lipid nanoparticle mainly has the following characteristics: 1) After oral administration, it can be absorbed into the systemic circulation through the lymphatic channel in the gastrointestinal tract, and this absorption bypass can avoid the first-pass effect of the liver and reduce drug loss (Hussain N., et al. al.Recent advances in the understanding of uptake of microparticulates across the gastrointestinal lymphatics[J].Adv.Drug Deliv.Rev.,2001,50:107-142.). 2) Due to the similarity between the structure of lipid nanoparticles and the structure of cell membrane, it has the ability to enhance cell membrane permeability. 3) Negatively charged nanoparticles with good bioadhesion properties (Jung T., et al. Biodegradable nanoparticles for oral delivery of peptides: is there a role for polymers to affect mucosal uptake? [J]. Eur. J . Pharm. Biopharm.,2000,50(1):147-160.), which can prolong the residence time of drug-loaded particles at the absorption site, increase absorption, and improve bioavailability.

After searching, there is currently no patent application or literature report on the improvement of intestinal absorption by asiatic acid lipid nanoparticles. the

Contents of the invention

The object of the present invention is to provide a lipid nanoparticle of asiatic acid and a preparation method thereof for the deficiencies of the prior art.

In order to achieve the above object, the present invention adopts the following technical scheme: a lipid nanoparticle of asiatic acid that can promote oral absorption, the medicine wrapped in the nanoparticle is asiatic acid, and the carrier is a lipid material, and the lipid material Including solid lipids and liquid lipids, the mass ratio of solid lipids and liquid lipids is 80-100:0-20; solid lipids are selected from glycerol monostearate or stearic acid, and liquid lipids are selected from oleic acid or triolein; the diameter of the obtained lipid nanoparticles is less than 700nm, the encapsulation efficiency is 40-90%, and the drug loading is 7-11%.

Described asiatic acid lipid nanoparticles are prepared through the following process:

(1) Using absolute ethanol as a solvent, add lipid materials and asiatic acid with a chromatographic purity greater than 90%, heat and dissolve in a water bath at (70±2)°C, and use it as an organic phase, in which the mass of asiatic acid and lipid materials The ratio is 1:7~11, and the solution concentration of lipid material is 7~11mg/mL;

(2) With water as the dispersed phase, heat to (70±2)°C;

(3) Under 400r/min mechanical stirring, inject the organic phase into the dispersed phase, the volume ratio of absolute ethanol to water is 1:10; continue stirring for 5 minutes to obtain a cloudy liquid with opalescence. After the turbid solution was cooled to room temperature, the pH was adjusted to 1.2 with hydrochloric acid, centrifuged, the precipitate was washed with a small amount of deionized water, centrifuged again, and the upper liquid was discarded to obtain asiatic acid lipid nanoparticles. The nanoparticles can be dispersed in an aqueous solution of poloxamer 188 with a mass volume ratio of 0.001 g/mL to obtain a lipid nanoparticle dispersion of asiatic acid.

The beneficial effects of the present invention are: simple, easy to implement, safe and effective, which are the characteristics of the present invention. "Simple" means that the composition of the prescription is simple; "easy" means that the preparation process is very simple, just add the organic phase (absolute ethanol) to the water phase, without high-speed stirring or high-pressure treatment, and the process has good reproducibility; "safe and effective" : It means that the composition of the prescription is safe, no emulsifiers and toxic solvents are added, and the carrier of the nanoparticles is the same lipid component as the intestinal epithelial cells, so it is easy to be absorbed through the intestinal tract. The asiatic acid lipid nanoparticles obtained in the invention have a particle size of less than 700nm, an encapsulation rate of 40-90%, a drug loading capacity of 7-11%, and can effectively increase intestinal drug absorption and improve oral bioavailability. the

Description of drawings

Fig. 1 is the transmission electron micrograph of asiatic acid lipid nanoparticles in embodiment 2;

Fig. 2 is the transmission electron micrograph of asiatic acid lipid nanoparticles in embodiment 5;

Fig. 3 is the percentage curve of drug absorption of asiatic acid lipid nanoparticle rats in vivo intestinal perfusion model;

Fig. 4 is the excretion-time curve of bile Asiatic acid lipid nanoparticles after gavage to rats.

Detailed ways

The drug encapsulated by asiatic acid lipid nanoparticles that can promote oral absorption in the present invention is asiatic acid, the carrier is lipid material, the mass ratio of asiatic acid to lipid material is 1:7-11, and the lipid material includes Solid lipids and liquid lipids, the mass ratio of solid lipids and liquid lipids is 80-100:0-20; solid lipids are selected from glycerol monostearate or stearic acid, and liquid lipids are selected from oleic acid or Glyceryl trioleate; the diameter of the obtained lipid nanoparticles is less than 700nm, the encapsulation rate is 40-90%, and the drug loading is 7-11%.

The above-mentioned preparation method of asiatic acid lipid nanoparticles comprises the following process:

1. Using absolute ethanol as a solvent, add lipid materials and asiatic acid (chromatographic purity greater than 90%), heat and dissolve in a water bath at (70±2) ° C, as an organic phase, in which the mass of asiatic acid and lipid materials The ratio is 1:7-11, and the solution concentration of the lipid material is 7-11 mg/mL.

2. With water as the dispersed phase, heat to (70±2)°C.

3. Under 400r/min mechanical stirring, inject the organic phase into the dispersed phase, the volume ratio of absolute ethanol to water is 1:10; continue stirring for 5 minutes to obtain a cloudy liquid with opalescence. After the turbid solution was cooled to room temperature, the pH was adjusted to 1.2 with hydrochloric acid, centrifuged, the precipitate was washed with a small amount of deionized water, centrifuged again, and the upper liquid was discarded to obtain asiatic acid lipid nanoparticles. The nanoparticles can be dispersed in an aqueous solution of poloxamer 188 with a mass volume ratio of 0.001 g/mL to obtain a lipid nanoparticle dispersion of asiatic acid.

The purpose and effects of the present invention will become more apparent by describing the present invention in detail according to the accompanying drawings and embodiments.

Example 1: Preparation of asiatic acid glyceryl monostearate lipid nanoparticles (mass ratio of main drug to lipid material is 1:7)

Accurately weigh 5 mg of asiatic acid and 35 mg of glyceryl monostearate (commercially available, purity > 90%), dissolve in 5 mL of absolute ethanol under heating in a water bath at (70±2) °C, and use it as the organic phase, lipid material The concentration of the solution is 7mg/mL. With water as the dispersed phase, heat to (70±2)°C. Under mechanical stirring at 400 rpm, inject the organic phase into 50 mL of the dispersed phase, and continue stirring for 5 min to obtain a cloudy liquid with opalescence. After the turbid solution was allowed to cool to room temperature, the pH was adjusted to 1.2 with hydrochloric acid, centrifuged, the precipitate was washed with a small amount of deionized water, and the supernatant liquid was discarded by centrifugation to obtain asiatic acid lipid nanoparticles. The nanoparticles can be dispersed in an aqueous solution of poloxamer 188 with a mass volume ratio of 0.001 g/mL to obtain a lipid nanoparticle dispersion of asiatic acid.

The particle size of the lipid nanoparticles was determined to be 214±35nm (Malvern Zetaszier Nano-S900);

The drug encapsulation rate is 44.1±4.8% (encapsulation rate = drug amount in nanoparticles (mg)/administration amount (mg) × 100%);

The drug loading was 9.8±0.5% (drug loading = drug amount in nanoparticles (mg)/total weight of nanoparticles (lyophilized powder, mg) × 100%).

Example 2: Preparation of asiatic acid glyceryl monostearate lipid nanoparticles (mass ratio of main drug to lipid material is 1:9)

Accurately weigh 5 mg of asiatic acid and 45 mg of glyceryl monostearate (commercially available, purity> 90%), (70

±2) Dissolve in 5mL of absolute ethanol under heating in a water bath at ℃, and use as the organic phase, the solution concentration of the lipid material is 9mg/mL. Use water as the dispersed phase, heat to (70±2)°C, and under mechanical stirring at 400rpm, inject the organic phase into 50mL of the dispersed phase, and continue stirring for 5min to obtain a cloudy liquid with opalescence. After the turbid solution was cooled to room temperature, the pH was adjusted to 1.2 with hydrochloric acid, centrifuged, the precipitate was washed with a small amount of deionized water, centrifuged again, and the upper liquid was discarded to obtain asiatic acid lipid nanoparticles. The nanoparticles can be dispersed in an aqueous solution of poloxamer 188 with a mass volume ratio of 0.001 g/mL to obtain a lipid nanoparticle dispersion of asiatic acid.

After measurement, the particle size of the lipid nanoparticles is 208±24nm (Malvern Zetaszier Nano-S900);

The drug encapsulation rate is 67.6±5.5% (encapsulation rate=drug amount in nanoparticles (mg)/administration amount (mg)×100%);

The drug loading was 8.6±0.5% (drug loading=drug amount in nanoparticles (mg)/total weight of nanoparticles (lyophilized powder, mg)×100%).

Example 3: Preparation of asiatic acid glyceryl monostearate lipid nanoparticles (mass ratio of main drug to lipid material is 1:11)

Accurately weigh 5 mg of asiatic acid and 55 mg of glyceryl monostearate (commercially available, purity > 90%), dissolve in 5 mL of absolute ethanol under heating in a water bath at (70±2) °C, and use it as the organic phase, lipid material The concentration of the solution is 11mg/mL. With water as the dispersed phase, heat to (70±2)°C. Under mechanical stirring at 400 rpm, inject the organic phase into 50 mL of the dispersed phase, and continue stirring for 5 min to obtain a cloudy liquid with opalescence. After the turbid solution was cooled to room temperature, the pH was adjusted to 1.2 with hydrochloric acid, centrifuged, the precipitate was washed with a small amount of deionized water, centrifuged again, and the upper liquid was discarded to obtain asiatic acid lipid nanoparticles. The nanoparticles can be dispersed in an aqueous solution of poloxamer 188 with a mass volume ratio of 0.001 g/mL to obtain a lipid nanoparticle dispersion of asiatic acid.

After measurement, the particle size of the lipid nanoparticles is 217±26nm (Malvern Zetaszier Nano-S900);

The drug encapsulation rate is 53.1±3.9% (encapsulation rate = drug amount in nanoparticles (mg)/administration amount (mg) × 100%);

The drug loading amount was 7.1±0.9% (drug loading amount=drug amount in nanoparticles (mg)/total weight of nanoparticles (lyophilized powder, mg)×100%).

Example 4: Preparation of asiatic acid stearate lipid nanoparticles (mass ratio of main drug to lipid material is 1:9)

Accurately weigh 5 mg of asiatic acid and 45 mg of stearic acid (commercially available, purity > 90%), dissolve in 5 mL of absolute ethanol under heating in a water bath at (70±2) °C, and use it as the organic phase, the solution concentration of the lipid material 9mg/mL. With water as the dispersed phase, heat to (70±2)°C. Under mechanical stirring at 400 rpm, inject the organic phase into 50 mL of the dispersed phase, and continue stirring for 5 min to obtain a cloudy liquid with opalescence. After the turbid solution was cooled to room temperature, the pH was adjusted to 1.2 with hydrochloric acid, centrifuged, the precipitate was washed with a small amount of deionized water, centrifuged again, and the upper liquid was discarded to obtain asiatic acid lipid nanoparticles. The nanoparticles can be dispersed in an aqueous solution of poloxamer 188 with a mass volume ratio of 0.001 g/mL to obtain a lipid nanoparticle dispersion of asiatic acid.

After measurement, the particle size of the lipid nanoparticles is 624±29nm (Malvern Zetaszier Nano-S900);

The drug encapsulation rate is 53.6±7.9% (encapsulation rate = drug amount in nanoparticles (mg)/administration amount (mg) × 100%);

The drug loading amount was 7.5±0.5% (drug loading = drug amount in nanoparticles (mg)/total weight of nanoparticles (lyophilized powder, mg) × 100%).

Example 5: Preparation of asiatic acid glyceryl monostearate-oleic acid lipid nanoparticles (mass ratio of main drug to lipid material is 1:9)

Accurately weigh 5 mg of asiatic acid, 36 mg of glyceryl monostearate (commercially available, purity > 90%) and 9 mg of liquid lipid oleic acid (commercially available, purity > 95%; the mass ratio of oleic acid to the lipid material is 20%), (70±2) ℃ water bath heating to dissolve in 5mL absolute ethanol, and as the organic phase, the solution concentration of lipid material is 9mg/mL. With water as the dispersed phase, heat to (70±2)°C. Under mechanical stirring at 400 rpm, inject the organic phase into 50 mL of the dispersed phase, and continue stirring for 5 min to obtain a cloudy liquid with opalescence. After the turbid solution was cooled to room temperature, the pH was adjusted to 1.2 with hydrochloric acid, centrifuged, the precipitate was washed with a small amount of deionized water, centrifuged again, and the upper liquid was discarded to obtain asiatic acid lipid nanoparticles. The nanoparticles can be dispersed in an aqueous solution of poloxamer 188 with a mass volume ratio of 0.001 g/mL to obtain a lipid nanoparticle dispersion of asiatic acid.

After measurement, the particle size of the lipid nanoparticles is 310±11nm (Malvern Zetaszier Nano-S900);

The drug encapsulation rate is 77.9±4.8% (encapsulation rate=drug amount in nanoparticles (mg)/administration amount (mg)×100%);

The drug loading amount was 8.8±0.7% (drug loading = drug amount in nanoparticles (mg)/total weight of nanoparticles (lyophilized powder, mg) × 100%).

Example 6: Preparation of asiatic acid glyceryl monostearate-triolein lipid nanoparticles (mass ratio of main drug to lipid material is 1:9)

Accurately weigh 5 mg of asiatic acid, 36 mg of glyceryl monostearate (commercially available, purity > 90%) and 9 mg of liquid lipid triolein (commercially available, purity > 95%; The mass ratio of the lipid material is 20%), dissolved in 5mL of absolute ethanol under heating in a water bath at (70±2)°C, and used as the organic phase, the solution concentration of the lipid material is 9mg/mL. With water as the dispersed phase, heat to (70±2)°C. Under mechanical stirring at 400 rpm, inject the organic phase into 50 mL of the dispersed phase, and continue stirring for 5 min to obtain a cloudy liquid with opalescence. After the turbid solution was cooled to room temperature, the pH was adjusted to 1.2 with hydrochloric acid, centrifuged, the precipitate was washed with a small amount of deionized water, centrifuged again, and the upper liquid was discarded to obtain asiatic acid lipid nanoparticles. The nanoparticles can be dispersed in an aqueous solution of poloxamer 188 with a mass volume ratio of 0.001 g/mL to obtain a lipid nanoparticle dispersion of asiatic acid.

After measurement, the particle size of the lipid nanoparticles is 293±9nm (Malvern Zetaszier Nano-S900);

The drug encapsulation rate is 63.3±5.7% (encapsulation rate = drug amount in nanoparticles (mg)/administration amount (mg) × 100%);

The drug loading amount was 8.2±0.4% (drug loading amount=drug amount in nanoparticles (mg)/total weight of nanoparticles (lyophilized powder, mg)×100%).

Example 7: Investigation of Drug Absorption of Lipid Nanoparticles in Rats in Body Intestinal Perfusion Model

Prepare a phenol red solution with a concentration of 20 μg/ml according to the literature method (Wu Peisheng, et al. Study on the difference in the absorption of L-tetrahydropalmatine and its racemate in rat intestines [J]. Acta Pharmaceutica Sinica, 2007, 42(5): 534-537.). Precisely pipette an appropriate amount of the lipid nanoparticle dispersions in Example 2 and Example 5, and then disperse them in the phenol red solution to prepare nanoparticle intestinal perfusates with asiatic acid concentrations of 30 μg/mL, and at the same time use asiatic acid raw materials As a control group (medicine solution concentration 30 μg/mL, prepared in phenol red solution), it was placed at 37°C for later use.

Rat in vivo unidirectional perfusion absorption model was used to investigate the absorption of rat small intestine. That is, SD rats fasted overnight under natural drinking water conditions, weighing (200±20) g, were randomly divided into 3 groups, 5 rats in each group. Anesthetized by intraperitoneal injection of pentobarbital sodium, and the back was immobilized. The abdominal cavity was opened along the abdominal midline, and the small intestine segment was carefully separated. After making an incision at both ends of the small intestine, rinse the intestinal contents with saline preheated to 37°C, then empty the saline with air, intubate and ligate, and connect to a constant flow pump. After flushing with the prepared intestinal perfusate (preheated to 37 ℃) at a flow rate of 1.0 mL/min for 50 min, adjust the flow rate to 0.2 mL/min and start timing, respectively at 15-30, 30-45, 45- Collect the perfusate at 60, 60-75, 75-90, 90-105, 105-120, and 120-135 minutes, measure the concentration of Asiatic acid and phenol red at each time point, and calculate the concentration of Asiatic acid and its lipid. Drug absorption percentage of plasma nanoparticles at each time point (absorption percentage=absorption amount

/ initial amount × 100%). The _{absorption characteristics of the drug were evaluated by the lumenal effective absorption coefficient (Peff} ) , absorption rate constant ( Ka ₎ and drug absorbed dose fraction ( fa ₎ (Table 1). The results showed that the P _eff and f _a of the two lipid nanoparticles were significantly different from those of the raw materials (P<0.05), and the prepared lipid nanoparticles could significantly improve the drug penetration rate in the intestinal tract.

Table 1: P _eff , K _a and f _a of rat small intestine with different lipid nanoparticles (n=5)

the P _eff /×10 ^-4 ·cm ^{- 1} ·s ^{- 1} K _a /×10 ^-3 ·s ^{- 1} f _a % Asiatic acid 0.48±0.04 0.34±0.06 52.50±3.08 Lipid Nanoparticles (Glyceryl Monostearate) 0.57±0.03 ^* 0.41±0.03 62.06±3.97 ^* Lipid Nanoparticles (Glyceryl Monostearate-Oleic Acid) 0.66±0.10 ^* 0.45±0.07 ^* 67.64±6.51 ^*

^* P<0.05, compared with Asiatic acid raw material group.

Example 8: Investigation of Oral Absorption of Lipid Nanoparticles in Rats

After oral administration of Asiatic acid, its main metabolites are glucuronic acid conjugates and sulfate ester conjugates (the ratio of glucuronic acid conjugates to sulfate ester conjugates is about 4:1), and they are mainly excreted through bile. Asiatic acid is poorly absorbed from the gastrointestinal tract and has very low oral bioavailability. After oral administration of the drug (1.25mg) to rats, the peak plasma concentration (Cmax) is far lower than that of intravenous injection (about 1/60); after oral administration of Asiatic acid (12mg) to humans, the Cmax is only 0.098

μg·ml ^-1 , 0-12h area under the curve (AUC _0-12h ) is 0.61±0.25μg·h·mL ^-1 (Chasseaud L. F., et al.The metabolism of Asiatic Acid, Madecassic Acid and Asiaticoside in the Rat[ J]. Drug Res.,1971,21:1379-1384; Rush W. R., et al.The comparative steady-state bioavailability of the active ingredients of madecassol[J].Eur. J. Drug Metab. Pharmacokinet., 1993,18 (4):323-326.). The low oral bioavailability also brings great difficulties to evaluate drug absorption by detecting blood drug concentration. Because bile is the main excretion route of asiatic acid metabolites, and the concentration is relatively high for easy detection. The invention evaluates the oral absorption characteristics of nanoparticles by detecting the total concentration of asiatic acid (including asiatic acid glucuronic acid conjugate and sulfate ester conjugate, which is the main metabolite of asiatic acid) in rat bile at different times.

Healthy SD rats (weight (200±20) g) were randomly divided into 3 groups, 5 rats in each group, fasted overnight (without water), anesthetized with sodium pentobarbital, opened the abdominal cavity along the midline of the abdomen, intubated the bile duct, and Ligate and fix, collect blank bile. After the rats were awake, they were given lipid nanoparticles (asiatic acid lipid nanoparticles prepared by Example 2 and Example 5, dispersed in poloxamer with a mass-volume ratio of 0.001g/mL) by intragastric administration respectively. 188 in the aqueous solution, the drug concentration is 5mg/mL), and asiatic acid raw material is used as the control group (gastric administration of the suspension, prepared with 0.5% CMC-Na, the drug concentration is 5mg/mL), the dosage All are 50mg/kg, collected at 0~1h, 1~2h, 2~3h, 3~4h, 4~5h, 5~6h, 6~8h, 8~10h, 10~12h, 12~24h after administration Take a bile sample and record the bile volume.

Precisely pipette 50 μL of bile at different time points, hydrolyze with β-glucuronidase and sulfatase, and extract with liquid, and detect the total concentration of asiatic acid in bile by HPLC. Fig. 4 is bile asiatic acid excretion-time curve, and the result shows, take lipid as the two kinds of nanoparticles of carrier all can improve drug excretion, and drug excretion peak value is significantly higher than raw material control group (carrier is glycerol monostearate Ester Nanoparticle Group and Monostearin

Glyceride-oleic acid nanoparticles group was 1.6 times and 1.8 times that of the raw material control group, P<0.05), suggesting that the two lipid nanoparticles can significantly improve the bioavailability of Asiatic acid.

The invention uses insoluble asiatic acid (commercially available, with a chromatographic purity greater than 90%) as the main agent, adopts advanced lipid nano-preparation technology, and physically prepares a lipid nanoparticle of asiatic acid that can promote drug absorption. The preparation process adopted in the present invention is simple, easy to industrialized production, and the solvent only involves a small amount of three types of solvents, absolute ethanol (removed in the subsequent process) and water; the composition of the excipients in the prescription is also simple, only conventional lipid materials , does not involve emulsifiers. The lipid nanoparticles obtained by the formulation process are less affected by the gastrointestinal tract than self-emulsified emulsion droplets, and the absorption is more regular.

Claims (1)

1. a kind of asiatic acid lipid nanoparticle that can promote oral absorption, is characterized in that, the medicine that described nanoparticle encapsulates is asiatic acid, and carrier is lipid material, and described lipid material is solid lipid or by Composed of solid lipids and liquid lipids, the mass ratio of solid lipids and liquid lipids is 80-100:0-20; solid lipids are made of glyceryl monostearate or stearic acid, and liquid lipids are made of oleic acid or triolein; the particle size of the obtained lipid nanoparticles is less than 700nm, the encapsulation efficiency is 40-90%, and the drug loading is 7-11%; Described asiatic acid lipid nanoparticles are prepared by the following method: (1) Using absolute ethanol as a solvent, add lipid materials and asiatic acid with a chromatographic purity greater than 90%, heat and dissolve in a water bath at (70±2)°C, and use it as an organic phase, in which the mass of asiatic acid and lipid materials The ratio is 1:7~11, and the solution concentration of lipid material is 7~11mg/mL; (2) With water as the dispersed phase, heat to (70±2)°C; (3) Under 400r/min mechanical stirring, inject the organic phase into the dispersed phase, the volume ratio of absolute ethanol to water is 1:10; continue to stir for 5 minutes to obtain an opalescent cloudy liquid; let the cloudy liquid cool After reaching room temperature, adjust the pH to 1.2 with hydrochloric acid, centrifuge, wash the precipitate with a small amount of water, centrifuge again, and discard the upper liquid to obtain asiatic acid lipid nanoparticles.