CN114652683A - Mdivi-1 nano long-circulating liposome and preparation method and application thereof - Google Patents
Mdivi-1 nano long-circulating liposome and preparation method and application thereof Download PDFInfo
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- CN114652683A CN114652683A CN202210295382.XA CN202210295382A CN114652683A CN 114652683 A CN114652683 A CN 114652683A CN 202210295382 A CN202210295382 A CN 202210295382A CN 114652683 A CN114652683 A CN 114652683A
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- 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
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- 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
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses a nano long-circulating liposome which is formed by coating a medicament active ingredient with a lipid membrane material, wherein the medicament active ingredient is Mdivi-1, and the molar mass ratio of Mdivi-1 to the lipid membrane material is 1: 80-20. The lipid membrane material comprises phospholipid, cholesterol and a long circulating material, wherein the long circulating material is DSPE-mPEG 2000. The Mdivi-1 nano long-circulating liposome provided by the invention has small hepatotoxicity and fewer side effects, has an obvious effect of improving hepatocyte injury compared with free drugs, and also has a better anti-hepatic fibrosis effect.
Description
Technical Field
The invention belongs to the field of medicinal preparations, and particularly relates to an Mdivi-1 nano long-circulating liposome as well as a preparation method and application thereof.
Background
Mdivi-1 is a selective cell penetration inhibitor of the mitochondrion Dynamin-associated GTPase (Drp1) and mitochondrion Dynamin I (Dnm 1). In vitro experiments prove that inhibition of mitochondrial outer membrane permeabilization after treatment of cells with Mdivi-1 results in reduced cytochrome C release and inhibition of apoptosis. In the study of a circulatory system, Mdivi-1 can improve the prognosis of cerebral apoplexy, protect cells against ischemia-reperfusion injury, and prompt that the Mdivi-1 has a protective effect on the cells, and can be applied to resisting the cerebral apoplexy and protecting nerves.
In addition, Mdivi-1 has been reported to be a small molecule compound with anti-hepatic fibrosis activity. However, Mdivi-1 is difficult to dissolve in water, has low bioavailability, short half-life and large toxic and side effects, and limits the clinical application of the medicine. Therefore, there is a need to provide a new dosage form of Mdivi-1 drug to overcome these disadvantages, thereby expanding its clinical applications.
Liposomes are a drug carrier that entraps drugs within a lipid bilayer. The liposome can improve the solubility of the drug, control the release of the drug, improve the effect of the drug and reduce the toxicity of the drug. The long-circulating liposome is a liposome modified by polyethylene glycol, and can reduce the uptake of the liposome by a reticuloendothelial system, so that the clearance rate of the liposome in vivo is slowed, the residence time in blood is prolonged, and the half-life period of the loaded medicine is prolonged.
Disclosure of Invention
In the prior art, reports about the nano long-circulating liposome encapsulating the Mdivi-1 medicament are rare. The invention aims to provide an Mdivi-1 nano long-circulating liposome, which can effectively reduce the hepatotoxicity of Mdivi-1 medicaments, has the effect of improving liver cell injury and can improve the bioavailability of medicaments.
In a first aspect, the invention provides a nano long-circulating liposome, which is characterized in that the liposome is composed of a lipid membrane material coated with a drug active ingredient, wherein the drug active ingredient is Mdivi-1.
Preferably, the molar mass ratio of the Mdivi-1 to the lipid membrane material is 1: 80-20.
More preferably, the molar mass ratio of Mdivi-1 to the lipid membrane material is 1: 40-20.
In the most preferred embodiment of the present invention, the molar mass ratio of Mdivi-1 to lipid membrane material is 1: 20.
The lipid membrane material comprises phospholipid, cholesterol and a long circulating material, wherein the molar mass ratio of the phospholipid to the cholesterol to the long circulating material is (5.5-9.5): (1-4): (0.5-1).
Preferably, the molar mass ratio of the phospholipid to the cholesterol to the long-circulating material is (7.5-8.5): (1-2): 0.5.
the phospholipid is selected from one or more of soybean phospholipid, hydrogenated soybean phospholipid, lecithin, cephalin, phosphatidylethanolamine, phosphatidic acid and phosphatidylcholine.
The long-circulating material is selected from cholesterol modified by polyethylene glycol or distearoyl phosphatidyl ethanolamine modified by polyethylene glycol.
Preferably, the long-circulating material is polyethylene glycol modified distearoyl phosphatidyl ethanolamine, in particular DSPE-mPEG 2000.
In a preferred embodiment of the invention, the molar mass ratio of phospholipid to cholesterol is 4-9:1, most preferably the molar mass ratio of phospholipid to cholesterol is 9: 1.
In a preferred embodiment of the invention, the DSPE-mPEG2000 has a molar mass fraction of 5%.
In a second aspect, the present invention provides a method for preparing a nano-sized long circulating liposome, the method comprising: dissolving Mdivi-1, phospholipid, cholesterol and long-circulating materials in a solution, forming a film, hydrating, performing ultrasonic treatment, centrifuging, and passing the film to obtain the nano long-circulating liposome.
Specifically, the method comprises the following steps:
(1) dissolving Mdivi-1, phospholipid, cholesterol and long-circulating materials in a chloroform-methanol solution;
(2) performing reduced pressure rotary evaporation at 37 ℃ to form a film;
(3) adding normal saline, and hydrating at 37 deg.C;
(4) the unencapsulated drug was removed by sonication on ice, centrifugation and filtration through a 0.22 μm pore size filter.
In a third aspect, the present invention provides a pharmaceutical composition, wherein the pharmaceutical composition comprises the nano-sized circulating liposome of the present invention, and optionally, further comprises a pharmaceutically acceptable carrier.
In a fourth aspect, the invention provides the nano long-circulating liposome and application of a pharmaceutical composition in preparation of a medicament for preventing and/or treating liver fibrosis.
The Mdivi-1 nano long-circulating liposome provided by the invention has the following advantages: has small hepatotoxicity and less side effects, has obvious effect of improving hepatocyte damage compared with free medicaments, and simultaneously has better effect of resisting hepatic fibrosis.
Drawings
FIG. 1 particle size distribution diagram of liposomes
FIG. 2 Effect of liposomes and free drugs on survival of liver fibrosis mice
FIG. 3 Effect of liposomes and free drugs on the rate of weight change in liver fibrosis mice
FIG. 4 Effect of liposomes and free drugs on liver weight ratio of liver fibrosis mice
FIG. 5 the effect of liposomes and free drugs on the pathological changes of liver tissue and collagen content in liver fibrosis mice
FIG. 6 Effect of liposomes and free drugs on serological indices of hepatic fibrosis mice
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only some embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Lecithin, cholesterol, and DSPE-mPEG2000 used in the examples of the present invention were purchased from Aivianto (Shanghai) pharmaceutical science and technology Limited; mdivi-1 is available from MedChemexpress.
Preparation of Mdivi-1 nano long-circulating liposome
Example 1
The method of reference [1], which uses a thin film hydration method to prepare liposomes. Dissolving lecithin, cholesterol, DSPE-mPEG2000 and Mdivi-1 in chloroform methanol solution (4: 1V/V of chloroform: methanol), making the concentration of lecithin 7.5mM, cholesterol 2mM, DSPE-mPEG2000 0.5mM and Mdivi-1 0.125mM, and rotary evaporating at 37 deg.C in a eggplant-shaped bottle to form a film; adding physiological saline, hydrating at 37 deg.C for 2 hr, and sonicating on ice using a sonicator. Subsequently, the unencapsulated drug was removed by centrifugation at 18000g for 3 minutes. Then filtering with a filter membrane with the aperture of 0.22 mu m to obtain the Mdivi-1 nano long-circulating liposome.
Example 2
The preparation method and the raw materials are the same as example 1, except that the concentration of Mdivi-1 in the chloroform-methanol solution is 0.25 mM.
Example 3
The preparation method and the raw materials are the same as example 1, except that the concentration of Mdivi-1 in the chloroform-methanol solution is 0.5 mM.
Example 4
The preparation method and the raw materials are the same as example 1, except that the concentration of Mdivi-1 in the chloroform-methanol solution is 1 mM.
Effect example 1 Effect of lipid ratio on Liposome encapsulation efficiency
The encapsulation efficiency of Mdivi-1 nano-sized long-circulating liposomes prepared in examples 1 to 4 was examined by the method disclosed in reference [2 ]. Mu.l of the liposomes were taken, mixed with 1980. mu.l of ethanol and centrifuged at 20000g for 45 minutes at 4 ℃. The liposomes were lysed and the entrapped drug was released into solution, and the amount of Mdivi-1 in the solution was quantitatively determined by UV spectrophotometry at 295 nm. The encapsulation efficiency was calculated by the following formula: EE% ═ mass of entrapped drug/mass of drug initially added 100%. The results are shown in the following table:
TABLE 1 measurement of liposome encapsulation efficiency at different drug-to-lipid ratios
Encapsulation efficiency is an important indicator of liposomal drugs. As can be seen from the above table, when the drug-lipid ratio is in the range of 1:80 to 1:20, the encapsulation efficiency is about 70%, the encapsulation efficiency is slightly increased with the increase of the drug-lipid ratio, and the highest drug-lipid ratio is reached when the drug-lipid ratio is 1:20, but the drug-lipid ratio is continuously increased to 1: 10, the encapsulation efficiency is reduced to about 15%. The inventor selects the drug-to-lipid ratio to be 1:20 for subsequent experiments.
Example 5
The preparation method and the raw materials are the same as example 3, except that the concentration of lecithin in the chloroform-methanol solution is 9.5mM, and the concentration of cholesterol is 0 mM.
Example 6
The preparation method and raw materials are the same as example 3, except that the concentration of lecithin in the chloroform-methanol solution is 8.5mM, and the concentration of cholesterol is 1 mM.
Example 7
The preparation method and raw materials are the same as example 3, except that the concentration of lecithin in the chloroform-methanol solution is 5.5mM, and the concentration of cholesterol is 4 mM.
Effect example 2 Effect of phospholipid Cholesterol ratio on Liposome encapsulation efficiency
The encapsulation efficiency of Mdivi-1 nano long-circulating liposomes prepared in examples 3 and 5-7 was examined according to the method shown above. The results are shown in the following table:
TABLE 2 detection of liposome encapsulation efficiency at different phospholipid-cholesterol ratios
Cholesterol is an important component for preparing the liposome, can adjust the fluidity of the phospholipid bilayer membrane, and can influence the encapsulation efficiency, so that the proportion of phospholipid cholesterol needs to be optimized. As can be seen from the above table, the encapsulation efficiency was higher, both reaching 75% or more, when the phospholipid cholesterol ratio was 9:1 and 8:2 compared to the group without cholesterol. But the cholesterol content continues to increase to a phospholipid cholesterol ratio of 6: 4, the encapsulation efficiency is greatly reduced. We chose a phospholipid cholesterol ratio of 9:1 for subsequent experiments.
Example 8
The preparation method and raw materials are the same as example 6, except that the concentration of lecithin in the chloroform-methanol solution is 8.25mM, and the concentration of DSPE-mPEG2000 is 0.75 mM.
Example 9
The preparation method and raw materials are the same as example 6, except that the concentration of lecithin in the chloroform-methanol solution is 8mM, and the concentration of DSPE-mPEG2000 is 1 mM.
Effect example 3 Effect of DSPE-mPEG2000 on Liposome encapsulation efficiency
The encapsulation efficiency of Mdivi-1 nano long-circulating liposomes prepared in examples 6 and 8-9 was examined according to the method shown above. The results are shown in the following table:
TABLE 3 detection of Liposome encapsulation efficiency for different DSPE-mPEG2000 contents
DSPE-mPEG2000 is an essential component of liposomes to achieve long circulation. The DSPE-mPEG2000 content in the first long-circulating liposome adriamycin liposome approved by FDA is 5%[3]The content of the DSPE-mPEG2000 in the liposome can reach 10 percent[1]. The effect of the content of the DSPE-mPEG2000 on the Mdivi-1 liposome is detected, and the encapsulation rate is gradually reduced when the content of the DSPE-mPEG2000 is increased from 5% to 10%. Therefore, the DSPE-mPEG2000 content in the present invention is preferably 5%. In conclusion, the preferred method for preparing Mdivi-1 nano long-circulating liposomes according to the present invention is the example 6.
Characterization of Mdivi-1 nanometer Long-circulating liposomes
The particle size of the liposome prepared in example 6 was measured using a particle size analyzer, and the average particle size was 59.8nm as shown in FIG. 1.
In vivo efficacy experiment of Mdivi-1 nano long-circulating liposome
Female C57BL/6J mice, 8 weeks old (approximately 20g body weight), were used and randomized into 4 groups. Wherein 3 groups pass through CCl4Inducing to establish a hepatic fibrosis mouse model in CCl4Two weeks after induction, one group of mice was given free Mdivi-1 (drug dose 3mg/kg), labeled CCl, by tail vein injection4+ M; a group of mice was administered the Mdivi-1 nanocirculatory liposomes prepared in example 6 (drug dose 3mg/kg, calculated as drug loading in liposomes), labeled CCl4+ PLM; a group of mice was given an equal volume of PBS, labeled CCl4. The administration group was administered 2 times per week for 2 weeks. An Olive oil induction group, labeled Olive oil, was also set up as a negative control.
1. Survival rate of mice
The survival of mice in each group during the treatment period is shown in FIG. 2, and the results show that in the 2-week treatment period, negative control group (Olive oil), untreated hepatic fibrosis group (CCl)4) Liposomal therapeutic group (CCl)4+ PLM) was 100% in mice, but the free Mdivi-1 dose group (CCl) was the same dose as liposomes4+ M) the survival rate of the mice decreased by 66% after 2 weeks of treatment, indicating that free Mdivi-1 had toxic side effects at a dose of 3mg/kg, whereas the toxicity of the drug was significantly reduced when Mdivi-1 was formulated into liposomes according to the present invention.
2. Body weight changes in mice
The body weight change of the mice in each group after treatment is shown in figure 3. The results showed that the weight of the negative control group (Olive oil) increased about 10%, and that of the untreated liver fibrosis group (CCl)4) Weight loss of approximately 3%, free Mdivi-1 treatment group (CCl)4+ M) did not alter the degree of weight loss, whereas the liposome drug treated group (CCl)4+ PLM) increased body weight by > 10% compared to pre-treatment.
3. Change in liver weight ratio in mice
The liver weight ratio of each group of mice is calculated, the result is shown in figure 4, and the untreated liver fibrosis group (CCl) can be found4) The liver tissue of the mouse is swollen, and the liver weight ratio is obviously increased; free Mdivi-1 treatment group (CCl)4+ M) liver weight ratio close to untreated liver fibrosis group. Treatment with liposomal drug (CCl) compared to negative control group (Olive oil)4+ PLM) the liver-to-weight ratio of the mouse liver tissue was significantly restored.
4. Liver tissue section staining
Liver tissues of each group of experimental mice were stained in sections using a conventional method. Untreated liver fibrosis group (CCl) was found by HE staining and sirius red staining of liver tissue4) Liver tissue of mice developed significant collagen deposition, free Mdivi-1 treatment group (CCl)4+ M) collagen content is slightReduced, liposomal drug therapy (CCl)4+ PLM) collagen amount was further decreased, and the results are shown in fig. 5. The Mdivi-1 nano long-circulating liposome prepared by the invention has better anti-hepatic fibrosis effect than the free medicament.
5. Mouse serum ALT assay
By examining serum ALT reflecting hepatocyte injury, as shown in FIG. 6, the untreated liver fibrosis group (CCl)4) Mice, with significantly increased ALT compared to the normal group, free Mdivi-1 treated group (CCl)4+ M) ALT was further increased compared to untreated, suggesting that free drug at this dose further aggravated hepatocyte damage, whereas liposome drug treated (CCl)4+ PLM) was decreased relative to the ALT value of the untreated group, suggesting that the Mdivi-1 nm long circulating liposomes prepared by the present invention have the effect of improving liver cell damage.
Reference documents
[1]Li Y,Pu S,Liu Q,Li R,Zhang J,Wu T,Chen L,Li H,Yang X,Zou M,Xiao J,Xie W,He J,An integrin-based nanoparticle that targets activated hepatic stellate cells and alleviates liver fibrosis.J Control Release.2019；303:77-90.
[2]Parvathaneni V,Kulkarni NS,Shukla SK,Farrales PT,Kunda NK,Muth A,Gupta V,Systematic Development and Optimization of Inhalable Pirfenidone Liposomes for Non-Small Cell Lung Cancer Treatment.Pharmaceutics.2020；12(3):206.
[3]Gabizon A,Shmeeda H,Barenholz Y,Pharmacokinetics of pegylated liposomal Doxorubicin:review of animal and human studies.Clin Pharmacokinet.2003；42(5):419-36.
The above detailed description is merely illustrative of the present disclosure and does not represent a limitation thereof. Other variations of the specific structure of the invention will occur to those skilled in the art.
Claims (10)
1. The nano long-circulating liposome is characterized by consisting of a liposome membrane material coated with active pharmaceutical ingredients, wherein the active pharmaceutical ingredients are Mdivi-1, and the molar mass ratio of the Mdivi-1 to the liposome membrane material is 1: 80-20.
2. The nano-sized long-circulating liposome of claim 1, wherein the molar mass ratio of Mdivi-1 to the lipid membrane material is 1: 40-20.
3. The nano-long circulating liposome of claim 2, wherein the molar mass ratio of Mdivi-1 to the lipid membrane material is 1: 20.
4. The nano-sized long-circulating liposome of claim 1, wherein the lipid membrane material comprises phospholipids, cholesterol and long-circulating material, wherein the molar mass ratio of phospholipids to cholesterol to long-circulating material is (5.5-9.5): (1-4): (0.5-1); the phospholipid is selected from one or more of soybean phospholipid, hydrogenated soybean phospholipid, lecithin, cephalin, phosphatidylethanolamine, phosphatidic acid and phosphatidylcholine; the long-circulating material is selected from cholesterol modified by polyethylene glycol or distearoyl phosphatidyl ethanolamine modified by polyethylene glycol.
5. The Nanotrycirculating liposome of claim 4, wherein the molar mass ratio of phospholipid, cholesterol and long-circulating material is (7.5-8.5): (1-2): 0.5, the long-circulating material is polyethylene glycol modified distearoyl phosphatidyl ethanolamine.
6. The nano-long circulating liposome according to claim 5, wherein the long circulating material is DSPE-mPEG2000, and the molar mass fraction of the DSPE-mPEG2000 is 5%.
7. A method of preparing the nano-long circulating liposome of claim 1, the method comprising: dissolving Mdivi-1, phospholipid, cholesterol and a long-circulating material in a solution, forming a film, hydrating, performing ultrasonic treatment, centrifuging, and passing the film to obtain the nano long-circulating liposome.
8. The method for preparing according to claim 7, characterized in that it comprises the steps of:
(1) dissolving Mdivi-1, phospholipid, cholesterol and long-circulating material in chloroform-methanol solution;
(2) rotary evaporation at 37 deg.C under reduced pressure to form film;
(3) adding normal saline, and hydrating at 37 deg.C;
(4) the unencapsulated drug was removed by sonication on ice, centrifugation and filtration through a 0.22 μm pore size filter.
9. A pharmaceutical composition comprising the nano-sized long-circulating liposome of any one of claims 1 to 6, optionally further comprising a pharmaceutically acceptable carrier.
10. Use of the nano-sized long-circulating liposome according to any one of claims 1 to 6 and the pharmaceutical composition according to claim 9 in the preparation of a medicament for preventing and/or treating liver fibrosis.
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| CN116585304A (en) * | 2023-04-25 | 2023-08-15 | 四川大学华西医院 | Acute liver injury protecting medicine and preparation method thereof |
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| CN116585304B (en) * | 2023-04-25 | 2024-04-05 | 四川大学华西医院 | Acute liver injury protecting medicine and preparation method thereof |
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