CN116159026A - Ursolic acid vesicle and preparation and application thereof - Google Patents

Ursolic acid vesicle and preparation and application thereof Download PDF

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CN116159026A
CN116159026A CN202310191455.5A CN202310191455A CN116159026A CN 116159026 A CN116159026 A CN 116159026A CN 202310191455 A CN202310191455 A CN 202310191455A CN 116159026 A CN116159026 A CN 116159026A
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drug
ursolic acid
pentacyclic triterpene
vesicle
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CN116159026B (en
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王永军
范文雯
袁畅鸿
刘洪卓
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Shenyang Pharmaceutical University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
    • A—HUMAN NECESSITIES
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
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    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to an ursolic acid vesicle and preparation and application thereof. The vesicle contains pentacyclic triterpene drug and nonionic surfactant, wherein the pentacyclic triterpene drug is ursolic acid, and the nonionic surfactant is polysorbate 80. The method of the invention obviously increases the solubility of the ursolic acid, improves the drug loading rate of the preparation, has good stability and encapsulation efficiency in vitro, and has prolonged biological half-life, obvious liver disease treatment effect and good safety in vivo.

Description

Ursolic acid vesicle and preparation and application thereof
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to an ursolic acid vesicle and preparation and application thereof.
Background
Pentacyclic triterpene ursolic acid is a compound extracted from plants, is classified into class IV in a Biopharmaceutical Classification System (BCS), belongs to low-solubility and low-permeability drugs, and clinically has the effect of remarkably reducing serum turnoverAmmonianase, liver protection and liver function recovery. Ursolic Acid (UA) has antiinflammatory, antibacterial, and antitumor pharmacological activities, and can induce Ca by inhibiting DNA replication 2+ Releasing, down regulating anti-apoptosis gene, inhibiting cyclooxygenase-2 and inducible nitric oxide synthase to induce apoptosis. However, the poor solubility makes the bioavailability of the ursolic acid lower, which greatly limits the clinical application of the ursolic acid.
The nano-drug delivery system has the advantages of increasing the solubility of the drug, improving the targeted delivery effect of the drug, prolonging the circulation time of the drug in the body and the like. The vesicles generally comprise nonionic surfactants, lipid components such as cholesterol and charge inducers, and in vivo experiments show that the vesicles act like liposomes, can prolong the circulation time of the embedded drugs, change the organ distribution and metabolic stability of the embedded drugs, and have the disadvantage that the inclusion of the lipid component cholesterol reduces the encapsulation rate of the hydrophobic drugs on the membrane. The cholesterol-free vesicles prepared by screening active pharmaceutical ingredients with proper structures and loading the active pharmaceutical ingredients into membranes of the vesicles can maximally improve the drug loading rate of the preparation, and meanwhile, the fluidity of the membranes can be regulated to a certain extent, so that the stability of the membranes is improved. However, it is not always possible to circulate any kind of structure of the drug which can interact well with the surfactant to form stable vesicles.
Disclosure of Invention
Aiming at the technical background, the invention aims to provide an ursolic acid vesicle and a preparation method and application thereof.
In order to achieve the above purpose, the invention adopts the technical scheme that:
a pentacyclic triterpene drug vesicle is characterized in that the vesicle contains a pentacyclic triterpene drug and a nonionic surfactant, wherein the pentacyclic triterpene drug is ursolic acid, and the nonionic surfactant is polysorbate 80.
The molar ratio of the pentacyclic triterpene drug to the nonionic surfactant is 1-4:1-2.
A preparation method of pentacyclic triterpene drug vesicles comprises the steps of dissolving the components in organic solvents with water according to the proportion, mixing, and removing the organic solvents by dialysis.
The water phase is sucrose and/or glucose.
The application of the pentacyclic triterpene drug vesicle, which has targeted accumulation in the liver, is used as a drug for treating liver diseases.
A method for improving solubility of pentacyclic triterpene substance comprises mixing pentacyclic triterpene substance with nonionic surfactant to form vesicle containing pentacyclic triterpene substance, and further improving its solubility; wherein the pentacyclic triterpene is ursolic acid, and the nonionic surfactant is polysorbate 80.
The molar ratio of the pentacyclic triterpene drug to the nonionic surfactant is 1-4:1-2.
The beneficial technical effects of the invention are as follows:
(1) The vesicle realizes high drug loading rate of the ursolic acid on the vesicle membrane, improves the solubility of the ursolic acid in water, and has high drug loading rate of the preparation;
(2) The vesicle has smaller and very uniform particle size, simple preparation method, easy realization of large-scale industrial production, good stability, freeze-drying and convenient storage and transportation of the preparation;
(3) The vesicle can slow down the in vitro release of the medicine, prolong the half life of the medicine in vivo and improve the AUC;
(4) The vesicle disclosed by the invention has a good liver targeting effect, and the drug effect result shows that the vesicle has an obvious liver disease treatment effect and is good in safety.
Drawings
FIG. 1 shows the effect of drug loading on the particle size and PDI of ursolic acid vesicles according to an embodiment of the invention.
FIG. 2 shows the effect of the ratio of organic phase to aqueous phase on the particle size and PDI of ursolic acid vesicles according to the example of the invention.
FIG. 3 shows the effect of temperature on the particle size and PDI of ursolic acid vesicles provided in the examples of the present invention.
Fig. 4-1 shows the storage stability of ursolic acid vesicles at 4 ℃ according to the embodiment of the invention.
Fig. 4-2 show the stability of ursolic acid vesicles at 37 ℃ provided by the embodiment of the invention.
FIG. 5-1 is a tissue distribution study of each formulation at 4 hours post-administration.
Fig. 5-2 is a tissue distribution study of each formulation 12 hours after administration.
Fig. 5-3 are tissue distribution studies of each formulation 24 hours after administration.
FIG. 6-1 shows the change in liver function index Total Bilirubin (TBIL) after administration of each formulation in a cholestatic hepatitis model.
FIG. 6-2 shows changes in the liver function index glutamic oxaloacetic transaminase (AST) after administration of each formulation in a cholestatic hepatitis model.
Fig. 6-3 are changes in the liver function index glutamic pyruvic transaminase (ALT) after administration of each formulation in a cholestatic hepatitis model.
Figures 6-4 are changes in animal body weight following administration of each formulation in a cholestatic hepatitis model.
FIG. 7-1 shows changes in liver function index Total Bilirubin (TBIL) after administration of each formulation in an acute hepatitis model.
FIG. 7-2 shows changes in the liver function index glutamic-oxaloacetic transaminase (AST) after administration of each formulation in an acute hepatitis model.
Fig. 7-3 show changes in the liver function index glutamic pyruvic transaminase (ALT) after administration of each formulation in an acute hepatitis model.
Figures 7-4 show changes in body weight of animals following administration of each formulation in an acute hepatitis model.
FIG. 8-1 shows the change in survival rate after administration of each formulation in an in situ liver cancer model.
Fig. 8-2 shows the change in body weight of animals after administration of each formulation in an in situ liver cancer model.
Detailed Description
The technical scheme of the invention is further specifically described below through specific embodiments and with reference to the accompanying drawings.
The ursolic acid vesicle not only solves the problem of low solubility of the indissoluble medicine, but also can increase the accumulation of the preparation at the target position, thereby better playing the curative effect of the medicine; the method comprises the following steps: the ursolic acid and the polysorbate 80 are used as main membrane structural components of the vesicle, so that the solubility of the ursolic acid is obviously increased, the bioavailability of the medicine and the medicine carrying capacity of the preparation are improved, the preparation has good stability and encapsulation efficiency, the in vivo biological half-life of the preparation is prolonged, and the accumulation and treatment effects of the medicine at a target position are improved.
EXAMPLE 1 examination of ursolic acid vesicles
1. Preparation of ursolic acid vesicles
Preparing ursolic acid vesicles by adopting a DMSO injection method, dissolving polysorbate 80 and ursolic acid in a molar ratio of 1:2 into DMSO to obtain an organic phase, preparing an aqueous phase of 5% glucose injection, preparing an organic phase and an aqueous phase in a volume ratio of 1:8, slowly injecting the organic phase into the aqueous phase at a constant speed at 37 ℃, stirring for 5 minutes, dialyzing to remove DMSO, and standing in an ice bath for 5 minutes to obtain the ursolic acid vesicles (V-UA).
The drug-loaded vesicles are characterized by using a Markov particle size analyzer, the particle size of the ursolic acid vesicles is about 100nm, the PDI is less than 0.1, and the zeta potential is about-14 mV; the encapsulation rate of ursolic acid vesicles is above 95% by ultrafiltration centrifugation-high performance liquid chromatography.
Further carry out the stability test of ursolic acid vesicles
Placing the prepared ursolic acid vesicles at 4 ℃ for storage, and measuring the particle size and PDI (pulse packet identifier) on different days; the prepared ursolic acid vesicles are buffered with PBS containing 10% fetal bovine serum according to the ratio of 1:10 dilution, incubation at 37 ℃ for 16h, particle size and PDI changes were recorded, and experimental results are shown in fig. 4.
The results show that the ursolic acid vesicles have good stability in blood plasma at 4 ℃ and 37 ℃.
2. Examination of pentacyclic triterpene drug Structure
The oleanolic acid vesicle is prepared by adopting a DMSO injection method, wherein the molar ratio of polysorbate 80 to oleanolic acid is 1:2 as an organic phase, the aqueous phase is 5% glucose injection, the volume ratio of the organic phase to the aqueous phase is 1:8, the preparation temperature is 37 ℃, and the oleanolic acid vesicle is obtained after being placed in an ice bath for 5 minutes.
The experimental results show that: oleanolic acid and polysorbate 80 can also be prepared in a 2:1 molar ratio, but have poor shelf stability and begin to precipitate after one week.
3. Investigation of drug loading
According to the preparation process of the ursolic acid vesicles described in the step 1, the vesicles containing different amounts of the ursolic acid are prepared by the ursolic acid and the polysorbate 80 according to the molar ratio of 1:2, 1:1, 2:1 and 3:1, and then the vesicles obtained by the preparation are characterized according to the description, and the experimental result is shown in figure 1.
The results show that: the preparation of the ursolic acid and the polysorbate 80 in a molar ratio of 2:1 can realize effective encapsulation of the medicine, and the particle size and PDI of the preparation are optimal.
4. Investigation of the ratio of organic to aqueous phase
According to the preparation process of the ursolic acid vesicle recorded in the step 1, polysorbate 80 and ursolic acid with the molar ratio of 1:2 are taken as organic phases, and the vesicles are prepared by selecting the organic phase to water phase ratios of 1:7, 1:8 and 1:9 (v/v). The vesicles obtained were then characterized as described above and the experimental results are shown in fig. 2.
The results show that: the particle size and PDI of the formulations prepared at a ratio of 1:8 organic to aqueous phase are optimal.
5. Investigation of temperature
According to the preparation process of the ursolic acid vesicles recorded in the step 1, the preparation temperature is 25 ℃,37 ℃ and 45 ℃ to prepare the vesicles. The vesicles obtained were then characterized as described above and the experimental results are shown in fig. 3.
The results show that: the vesicle size and PDI prepared at 37℃are optimal.
Example 2 pharmacokinetic experiments on ursolic acid vesicles
10 SD rats weighing 180-200g were randomly divided into two groups, fasted for 12h before dosing and weighed 1h before dosing. The composition is an ursolic acid passive drug-loaded liposome group (wherein ursolic acid and yolk phospholipids are dissolved in DMSO and then slowly injected into water for dispersion to obtain the ursolic acid passive drug-loaded liposome, namely Lipo-UA,1mg/mL ursolic acid passive drug-loaded liposome (the concentration of the ursolic acid in the liposome is 1 mg/mL), and the ursolic acid vesicle group (V-UA, the concentration of the ursolic acid in the vesicles is 1 mg/mL) prepared in the step 1 of the embodiment, wherein the administration dosage is 5mg/kg. Whole blood was collected in heparin sodium coated EP tubes at time point 0.08,0.25,0.5,1,2,4,8, 12h post-dose, centrifuged at 13000rpm for 5min and the supernatant was stored at-80 ℃. UPLC-MS/MS measures the drug concentration in plasma and calculates the pharmacokinetic parameters.
TABLE 1 pharmacokinetic parameters of ursolic acid vesicles
PK parameters V-UA Lipo-UA
AUC 0-∞ (μg/L*h) 3654.664±388.127 2320.211±260.120
V Z (L/Kg) 11.004±3.442 5.386±1.885
T 1/2 (h) 5.662±2.259 1.694±0.544
C max (μg/L) 8262.500±676.961 6871.520±709.305
CLz(L/h/Kg) 1.381±0.148 2.177±0.245
As can be seen from Table 3, the half-life of ursolic acid in V-UA is prolonged by about 2.4 times and the AUC is increased by about 0.6 times as compared with Lipo-UA.
EXAMPLE 3 tissue distribution study of ursolic acid vesicles
Healthy BALB/c mice were randomly divided into 3 groups (DiR group (DiR fluorescent probe group), V-UA-DiR group (DiR-labeled V-UA (V-UA is the ursolic acid vesicle prepared in step 1 of example 1, wherein the concentration of ursolic acid is 1 mg/mL)), lipo-UA-DiR group (DiR-labeled Lipo-UA (Lipo-UA is the ursolic acid passive drug-loaded liposome described in example 2, wherein the concentration of ursolic acid is 1 mg/mL)), and 9 groups each were administered by tail vein injection at a dose of V-UA-DiR group, lipo-UA-DiR group: 10mg/kg, diR:0.5mg/kg.
At 4, 12 and 24 hours after the administration, 3 mice were randomly sacrificed from each group, and after rapid dissection, the mice were collected for heart, liver, spleen, lung and kidney and placed in a culture dish in sequence, and the tissue organs of each group of mice were subjected to fluorescence photographing and quantitative analysis using a small animal living body imager, and the experimental results are shown in fig. 5.
The results show that the ursolic acid vesicles are accumulated in the liver more than the passive drug-loaded ursolic acid liposome preparation at 4, 12 and 24 hours after the drug administration.
Example 4 pharmacodynamics experiments with ursolic acid vesicles
1. Drug effect of ursolic acid vesicles on cholestatic hepatitis model
Male Balb/C mice (18-20 g) were selected, and mice were gavaged with 100mg/kg of alpha-naphthalene isothiocyanate (ANIT), and after 48h, the mice were randomly divided into five groups: blank (Blank), model (Model) (Blank and Model) control were given with 5% glucose solution, ursolic acid-loaded liposome (Lipo-UA, 10mg/kg, intravenous injection), ursolic acid vesicle (V-UA, 10mg/kg, intravenous injection) obtained in step 1 of example 1, and positive control ursodeoxycholic acid (UDCA, 75mg/kg, intragastric administration) were given once daily for 5 times, and liver function was measured by taking blood on day 1 and day 7 after the last administration, and body weight change during administration period of mice was recorded, and experimental results are shown in FIG. 6.
2. Efficacy of ursolic acid vesicles on acute hepatitis model
18-20g male Balb/C mice were selected and healthy Balb/C mice were randomly divided into five groups: blank (Blank), model (Model) (Blank and Model) and ursolic acid passive drug-loaded liposome (Lipo-UA, 10mg/kg, intravenous injection), ursolic acid vesicle (V-UA, 10mg/kg, intravenous injection) prepared in step 1 of example 1, and magnesium isoglycyrrhetate injection (MgIG, 15mg/kg, intravenous injection) as positive control were administered once daily for 5 times. After the end of the last administration, the mice were intraperitoneally injected with a mixed solution of D-galactosamine (D-gal) and Lipopolysaccharide (LPS) at a dose of 400mg/kg D-gal and 15. Mu.g/kg LPS, and the mice were induced to have an acute hepatitis model, and after 12 hours, blood was taken to determine liver function, and the weight change during the administration period of the mice was recorded, and the experimental results were shown in FIG. 7.
3. Efficacy of ursolic acid vesicles on in-situ liver cancer model
HepG2 (liver cancer) cells in the logarithmic growth phase were inoculated into 18-20g of male Balb/C-nu mouse livers, and the mice were immediately divided into four groups according to mouse serum AST/ALT values after 35 days: model control group (Model, 5% glucose solution), ursolic acid passive drug-loaded liposome group (Lipo-UA, 10mg/kg, intravenous injection), ursolic acid vesicle group (V-UA, 10mg/kg, intravenous injection) prepared in step 1 of example 1, and positive control drug paclitaxel (PTX, 8mg/kg, intravenous injection) were administered once daily for 5 times, and the mice survival period of each group was examined, and the weight change during the mice administration period was recorded, and the experimental results are shown in FIG. 8.
The results show that compared with the ursolic acid passive drug-loaded liposome preparation and the corresponding positive control preparation, the ursolic acid vesicle preparation has obvious advantages in different liver disease models. The vesicle can obviously reduce the values of aspartic acid Aminotransferase (AST), alanine Aminotransferase (ALT) and Total Bilirubin (TBIL) in serum of a hepatitis mouse and prolong the survival time of the in-situ liver cancer mouse.

Claims (7)

1. A pentacyclic triterpene drug vesicle is characterized in that the vesicle contains a pentacyclic triterpene drug and a nonionic surfactant, wherein the pentacyclic triterpene drug is ursolic acid, and the nonionic surfactant is polysorbate 80.
2. The pentacyclic triterpene drug vesicle according to claim 1, wherein: the molar ratio of the pentacyclic triterpene drug to the nonionic surfactant is 1-4:1-2.
3. A method for preparing pentacyclic triterpene drug vesicles according to claim 1, wherein the components according to claim 1 are dissolved in organic solvents which are mutually mixed with water according to a certain proportion, and the preparation method is obtained by dialysis to remove the organic solvents.
4. A method for preparing pentacyclic triterpene drug vesicles according to claim 3, wherein: the water phase is sucrose and/or glucose.
5. Use of a pentacyclic triterpene drug vesicle according to claim 1, wherein the pentacyclic triterpene drug vesicle has targeted accumulation in the liver for use as a medicament for the treatment of liver diseases.
6. A method for improving the solubility of pentacyclic triterpene substances, which is characterized in that: mixing pentacyclic triterpene substances with nonionic surfactant to form vesicles containing pentacyclic triterpene substances, thereby improving solubility; wherein the pentacyclic triterpene is ursolic acid, and the nonionic surfactant is polysorbate 80.
7. The method for improving the solubility of pentacyclic triterpene compounds according to claim 6, wherein: the molar ratio of the pentacyclic triterpene drug to the nonionic surfactant is 1-4:1-2.
CN202310191455.5A 2023-03-02 Ursolic acid vesicle and preparation and application thereof Active CN116159026B (en)

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Citations (3)

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CN1410066A (en) * 2002-11-21 2003-04-16 武汉利元亨药物技术有限公司 Ursolic acid poly lactic acid nano particle freeze dried powder for ampoule agent and its preparation method
US20040180082A1 (en) * 2002-10-09 2004-09-16 Amorepacific Corporation Submicron-liposome containing triterpenoid and a method for preparing the same
JP2013227284A (en) * 2012-03-26 2013-11-07 Ａｄａ Ｂｉｏ株式会社 Water-soluble agent of cyclic triterpene acid

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040180082A1 (en) * 2002-10-09 2004-09-16 Amorepacific Corporation Submicron-liposome containing triterpenoid and a method for preparing the same
CN1410066A (en) * 2002-11-21 2003-04-16 武汉利元亨药物技术有限公司 Ursolic acid poly lactic acid nano particle freeze dried powder for ampoule agent and its preparation method
JP2013227284A (en) * 2012-03-26 2013-11-07 Ａｄａ Ｂｉｏ株式会社 Water-soluble agent of cyclic triterpene acid

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
孙丹丹;闫雪生;徐新刚;于蓓蓓;生立嵩;: "熊果酸自微乳冻干制剂体外评价", 辽宁中医药大学学报, no. 01, 31 January 2016 (2016-01-31), pages 58 - 61 *

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