CN110974972B - Weakly acidic derivatives of poorly soluble drugs and liposome preparations thereof - Google Patents
Weakly acidic derivatives of poorly soluble drugs and liposome preparations thereof Download PDFInfo
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Abstract
The invention relates to the technical field of medicines, in particular to a weakly acidic derivative of an insoluble medicine and a liposome preparation thereof. The weak acidic derivative is prepared by taking a drug containing hydroxyl as a raw material, and connecting the drug with acid anhydrides or dibasic acids which are saturated or unsaturated (the middle of a carbon chain can contain elements such as oxygen, sulfur, nitrogen, silicon and the like) in chains with different carbon lengths through esterification reaction, so that the drug presents weak acidity with different strengths. The weakly acidic derivative can be actively loaded into the liposome by a pH gradient method. The prepared liposome obviously improves the maximum drug resistance of the compound, prolongs the half-life period, can improve the bioavailability of the drug and achieves the purposes of synergy and attenuation.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a weakly acidic derivative of an insoluble medicine and a liposome preparation thereof.
Background
In the process of drug development and screening, many drugs with high in vitro pharmacological activity have the problem of poor water solubility. Due to its solubilityThe problem greatly limits the clinical application of the traditional Chinese medicine preparation and also brings challenges to the development of the preparation of the traditional Chinese medicine preparation. The traditional solubilization technology, such as adding a surfactant or absolute ethyl alcohol, can cause a series of adverse reactions such as anaphylactic reaction and the like when being injected and administered to a human body. Various preparation techniques are applied to the research of the pharmaceutical formulation of insoluble drugs for improving the pharmacy of the insoluble drugs, such as a nano suspension technology, a micro emulsion technology, a cyclodextrin-based inclusion compound technology, a solid dispersion technology and a liposome technology. Liposomes, the most successful nanoformulation at present, have been approved and marketed by the U.S. FDA for a number of products, including doxorubicin hydrochloride liposomes
Elitaxicam hydrochloride liposome
Vincristine sulfate liposome
Cytarabine-daunorubicin co-carried liposome
And the like.
Greatly reduces the cardiotoxicity of the adriamycin free drug, and increases the circulation time and the accumulation of tumor sites.
The liposome technology is applied to the field of research and development of pharmaceutical preparations, and the drugs can be encapsulated in lipid carrier phospholipid bilayers or an internal water phase environment, namely passive drug carrying and active drug carrying technologies. The ability of a drug to be entrapped in liposomes and whether it is present in the phospholipid bilayer or in the internal aqueous environment depends on the physicochemical properties of the drug. Generally, both water-soluble drugs and fat-soluble drugs can be made into liposome technology by passive drug loading technology, and the water-soluble drugs are encapsulated in an inner water phase by interaction with a phospholipid polar head and an inner water phase environment, and the fat-soluble drugs can exist in a lipid bilayer, but many drugs have complex solubility characteristics and are difficult to be encapsulated in the liposome, or have the problems of low encapsulation efficiency, poor stability and the like.
A method for encapsulating poorly water-soluble drugs in liposomes is to modify the chemical structure of the drug to change its lipid solubility and solubility. For example, paclitaxel can be inserted into liposome phospholipid bilayer by modifying fatty acid carbon chain with paclitaxel, but there still exists limitation of passive drug loading. Compared with the passive drug loading technology, the active drug loading technology greatly overcomes the problems of the passive drug loading liposome, such as obviously improving the encapsulation efficiency and the preparation stability. The active drug loading technology requires that drugs have appropriate lipophilic hydrophilicity and pKa, and weak acidity or weak alkalinity can be encapsulated in the water phase environment in the liposome through transmembrane power formed by pH gradient difference inside and outside the liposome phospholipid bilayer. Active drug loading is difficult to achieve with drugs that are very water soluble or poorly water soluble. In addition to pH gradients, metal ion gradients are also used in liposome active drug delivery techniques, where drugs are retained in liposomes by forming stable poorly soluble complexes with metal ions in the internal aqueous environment, but active drug delivery techniques based on metal ion gradients require the presence of metal ion binding sites in the drug structure or the formation of stable coordination complexes with metal ions. Clinically applied antitumor drugs such as adriamycin, irinotecan, vincristine sulfate and the like are prepared into the active drug-carrying liposome by a pH gradient method due to the proper chemical characteristics.
A series of important broad-spectrum active drugs such as taxanes have extremely poor water solubility, do not have weak acid or weak base characteristics, are difficult to develop liposome preparations, and currently, taxol serving as three taxane preparations for clinical application
Docetaxel
Cabazitaxel
By prescriptionThe absolute ethyl alcohol and the surfactant are added for solubilization, and meanwhile, obvious adverse reaction and toxic and side effects are caused, so that the application of the broad-spectrum anti-tumor drug with high activity is limited.
Therefore, the development of the preparation technology of the drug-active liposome preparation can improve the difficulty of the development of the current drug preparations with poor insolubility or water solubility and lipophilicity, fully develop the utilization value of the drugs, and hopefully reduce toxicity, weaken or eliminate adverse reactions, and improve tolerance, bioavailability and therapeutic effect in clinical application.
Disclosure of Invention
Aiming at the technical background, the invention aims to provide a method for weakly acidic modification of a medicament and development of an active medicament-carrying liposome preparation thereof.
The invention realizes the purpose through the following technical scheme:
the invention provides a weakly acidic derivative of a poorly soluble drug, which is a weakly acidic derivative of a poorly soluble drug, wherein the weakly acidic derivative is prepared by connecting a drug containing a hydroxyl group as a raw material with acid anhydrides or dibasic acids which are saturated or unsaturated (the middle of a carbon chain can contain oxygen, sulfur, nitrogen, silicon and other elements) with chains with different carbon lengths through an esterification reaction, so that the drug has weak acidity with different strengths, namely the weakly soluble drug;
the structure of the weakly acidic derivative of the poorly soluble drug can be represented by the following general formula:
R 1 -O-CO-R 2 -COOH
wherein R is 1 Represents a poorly soluble drug moiety-O-CO-is a linking ester bond, R 2 Represents a spacer group which can be a C1-C8 saturated alkane carbon chain, a C2-C8 alkene carbon chain or a C1-C8 alkane carbon chain containing heteroatoms such as O, S, N, se, si;
further, R 2 Preferably C1-C6 alkanes or C2-C6 alkenes;
further, R 2 Preferably C1-C4 alkanes or C2-C4 alkenes;
still further, R 2 Preferably C2-C3 alkanes or C4 alkenes;
the weakly acidic derivatives of the drugs should have a pKa of 3 or more,
furthermore, the weak acid derivative of the medicine has pKa less than or equal to 12;
the insoluble drug can be, but not limited to, antineoplastic agents such as taxanes, camptothecins, podophyllotoxins, triptolide, tripterine, steroidal anti-inflammatory drugs, non-steroidal anti-inflammatory drugs, lipid-lowering statins, targeted blood vessel growth inhibitor combretastatin, etc.
The weakly acidic derivatives of the drugs according to the above may be, but are not limited to, the following structures:
(1) Weak acidification derivative of podophyllotoxin
(2) Etoposide weakly acidified derivatives
(3) Combretastatin weakly-acidified derivatives
(4) Docetaxel weakly acidic derivatives
(5) Cabazitaxel weakly-acidified derivative
The slightly soluble drug weakly acidic derivative is suitable for being actively loaded into a liposome with an internal water phase environment.
Furthermore, the weakly acidic derivatives of the poorly soluble drugs are suitable for loading into the aqueous internal environment of the liposomes.
Furthermore, the drug weakly acidic derivative can be stabilized in the internal water phase environment through electrostatic interaction with cations or the formation of insoluble precipitates of metal cations.
The active drug-carrying liposome of the drug weakly acidic derivative comprises the following main components: phospholipid, cholesterol (Chol), slightly-soluble drug weakly-acidic derivatives (dissolved by organic solvent), buffer salt and acetate solution.
Preparing the slightly-soluble drug weakly-acidic derivative active drug-loaded liposome: the blank liposome is prepared by taking acetate or phosphate as an internal water phase through a pH gradient method, and the drug weakly acidic derivative and the blank liposome are incubated together to realize active drug loading.
The medicinal weakly acidic derivative liposome is mainly characterized in that the derivative is actively loaded into an inner water phase solution by a pH gradient active drug loading technology, wherein the establishment of the pH gradient can be realized by that acetate with different concentrations in the inner water phase diffuses to the outside of a double-layer membrane through acetic acid molecules so as to cause the pH of the inner water phase to rise, preferably calcium acetate, and the preferred concentration of the calcium acetate is 50-200mM;
the phospholipid used for the preparation of the liposomes described above may be selected from Phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidic acid (phosphatidic acid), phosphatidylethanolamine (PE), phosphatidylserine (PS), glycolipid (glycolipid), sphingolipids (sphingolipids), such as sphingosine (sphingosine), sphingomyelin (sphingomyelin), glycosphingolipids (glycolipides) such as one or more of the classes of gangliosides such as gangliosides and their derivatives or targeted modified phospholipids such as polyethylene glycol (polyethylene glycol) modified single components or combinations, polypeptides, monoclonal antibodies or monoclonal antibody fragments, etc., phospholipids modified to include a phospholipid derivative modified by various types of stimuli responsive linkages.
Further preferred phospholipids include one or more of hydrogenated soy lecithin (HSPC), distearoylphosphatidylcholine (DSPC), distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG 2000);
further, the phospholipid is a combination of DSPC and DSPE-PEG 2000;
when the selected phospholipid combination is the combination of DSPC and DSPE-PEG2000, the weight ratio is 3-60.
The content of cholesterol contained in the liposome is 10-45 mol% of lipid components other than the drug, and the preferable mol ratio is 30-45%.
The mass ratio of the slightly acidic derivative of the slightly soluble drug to the phospholipid is 0.05-0.2.
When the phospholipid is the combination of DSPC and DSPE-PEG2000, the weight ratio of DSPC to DSPE-PEG2000 is 10-50, the molar ratio of cholesterol content in lipid components except for the drug is 30-45%, the mass ratio of the slightly-soluble drug weakly-acidic derivatives to the phospholipid is 0.05-0.2, the preferable internal water phase calcium acetate is selected, the concentration of the internal water phase calcium acetate is 120mM, the drug and blank liposome are incubated at 65 ℃, the drug loading is carried for 30min, and the active drug loading entrapment rate can reach more than 95%.
According to the above preferred conditions, three weakly acidic derivatives of cabazitaxel, cabazitaxel-succinic acid derivative (SA-CTX), cabazitaxel-succinic acid derivative (GA-CTX), cabazitaxel-trans-dibutene-1, 4-dicarboxylic acid derivative (DA-CTX) are respectively according to the drug weakly acidic derivatives: the phospholipid proportion is 1, 20, 1.
The invention has the advantages that:
(1) the drug is endowed with certain faintly acid through simple drug faintly acid derivatization, and the development of a drug active drug-carrying liposome preparation can be realized;
(2) the weakly acidic derivative is synthesized by the hydroxyl-containing drug and the anhydride or the dibasic acid through esterification reaction, the process is simple and convenient, the purification and the separation are easy, and the yield is high;
(3) the slightly-soluble drug weakly-acidic derivative liposome prepared by an active drug loading mode remarkably improves the maximum drug resistance of the compound, and improves the safety and the therapeutic index;
(4) the slightly-soluble medicine weakly-acidic derivative liposome prepared by the active medicine carrying mode can prolong the half-life period of the corresponding medicine, increase AUC (oral administration coefficient), improve the bioavailability of the medicine and fully exert the medicine effect.
Drawings
FIGS. 1A, B, C are Cabazitaxel succinic acid derivatives (SA-CTX [ M + K ], respectively] + ) Cabazitaxel glutaric acid derivative (GA-CTX [ M + Na ]] + ) Cabazitaxel-trans-dibutene-1, 4-dicarboxylic acid derivative (DA-CTX [ M + Na ]] + Mass spectrograms of three carbateside weakly acidic derivatives
FIG. 2A is a schematic representation of the Cabazitaxel-diglycolic acid derivative [ M-H ]] - Mass spectrogram; b is a cabazitaxel-thioglycolic acid derivative [ M-H] - Mass spectrum of
FIG. 3A is a mass spectrum of docetaxel-succinic acid derivative [ M-H ]] - (ii) a B is docetaxel-glutaric acid derivative mass spectrum [ M-H] -
FIG. 4A Podophyllotoxin-succinic acid derivative mass spectrum [ M-H](ii) a B Podophyllotoxin-glutaric acid derivative mass spectrum [ M + Na ]] +
FIG. 5A Etoposide-succinic acid derivative Mass Spectrum [ M-H] - (ii) a B is the mass spectrum [ M-H ] of the etoposide-glutaric acid derivative] - FIG. 6A Combrestatin-succinic acid derivative Mass Spectroscopy [ M + Na ]] + (ii) a B combretastatin-glutaric acid derivative mass spectrum [ M + Na ]] +
FIG. 7 shows the effect of drug lipid ratio on the encapsulation efficiency of three cabazitaxel weakly acidic derivatives
FIG. 8 shows the effect of aqueous phase concentration on the encapsulation efficiency of three cabazitaxel weakly acidic derivatives
FIGS. 9A and B are graphs showing the influence of cholesterol content on the particle size and encapsulation efficiency of three cabazitaxel weakly acidic derivative liposomes
FIG. 10 is a graph of the encapsulation efficiency of three cabazitaxel liposomes as a function of time
FIG. 11 is a graph showing the antitumor effect results and body weight change of three Cabazitaxel weakly acidic derivatives.
Detailed Description
The invention is further illustrated by the following examples, which are not to be construed as limiting the scope of the claims.
The related nouns are:
entrapment Efficiency (EE), which refers to the ratio of the drug loading in the liposome to the drug dosage during drug loading;
calculating the formula:
EE＝W inside of liposome /W total of input X100％
drug Loading (DL), which is the ratio of the mass of Drug loaded in the liposome to the total mass of the liposome preparation;
calculating the formula:
DL＝W inside of liposome /W total X100％
the Drug-to-Lipid ratio (D: L) refers to the mass ratio of the Drug to the total phospholipid
Specific examples
EXAMPLE 1 Synthesis of Cabazitaxel-succinic/glutaric acid derivatives (SA-CTX, GA-CTX)
0.12mmol of cabazitaxel, 0.024mmol of DMAP,0.24mmol of succinic anhydride or glutaric anhydride was put into a 25ml eggplant-shaped bottle, dissolved by adding 5ml of dichloromethane, reacted at room temperature for 5 hours, and detected by thin layer chromatography (developing agent dichloromethane: methanol =10, added with 0.1% glacial acetic acid). After the reaction, the solvent was evaporated to dryness to obtain a white oily viscous liquid, which was dissolved in dichloromethane, washed twice with 0.5M HCl, once with water, evaporated to dryness to obtain a white solid, which was purified by column chromatography with dichloromethane to methanol 100:1 (containing one thousandth of glacial acetic acid), eluting, separating and purifying, measuring the purity of a sample by a high performance liquid chromatography method, and identifying a product by mass spectrum and nuclear magnetism. The nuclear magnetic results were as follows:
SA-CTX:1H NMR(400MHz,DMSO-d6)δ12.25(s,1H),8.06–7.55(m,6H),7.5–7.3(m, 5H),7.18(t,J＝7.2Hz,1H),5.86–5.72(m,1H),5.37(d,J＝7.1Hz,1H),5.07(d,J＝3.5Hz,2H), 4.69(s,1H),4.48(s,1H),4.01(s,2H),3.75(dd,J＝10.6,6.5Hz,1H),3.58(d,J＝7.0Hz,1H), 3.28(m,6H),3.21(s,3H),2.63(s,2H),2.53(m,J＝6.5Hz,5H),2.23(s,3H),1.77(s,3H),1.50(s, 4H),1.39(s,9H),0.97(d,J＝8.0Hz,3H).
GA-CTX：1H NMR(400MHz,DMSO-d6)δ12.11(s,1H),8.01–7.93(m,2H),7.85(d,J＝ 8.8Hz,1H),7.78–7.61(m,3H),7.47–7.32(m,4H),7.17(t,J＝7.3Hz,1H),5.80(t,J＝9.1Hz, 1H),5.36(d,J＝7.1Hz,2H),4.98–4.91(m,1H),4.69(s,1H),4.47(s,1H),4.01(s,2H),3.75(dd, J＝10.5,6.5Hz,3H),3.58(d,J＝7.0Hz,1H),3.28(s,3H),3.21(s,3H),2.45-2.34(m,J＝7.3Hz, 7H),2.32–2.19(m,6H),1.84–1.72(s,3H),1.38(s,9H),1.24(s,2H),0.97(s,J＝7.9Hz,6H).
example 2 Synthesis of Cabazitaxel-trans-dibutene-1, 4-dicarboxylic acid derivative (DA-CTX)
0.12mmol of cabazitaxel, 0.06mmol of DMAP,0.18mmol of trans-dibutene-1, 4-dicarboxylic acid was placed in a 25ml eggplant-shaped bottle, dissolved by adding 10ml of dry dichloromethane, stirred for 40min under ice-water bath conditions, added with 0.24mmol of EDCI, stirred for 1h further, and then transferred to room temperature for reaction for 2 hours, and the reaction was monitored by thin layer chromatography for completion (developing agent dichloromethane: methanol =10, added with 0.1% glacial acetic acid. After the reaction was completed, the reaction solution was placed in a separatory funnel, washed twice with 0.5M HCl, once with water, and evaporated to dryness to obtain a white solid. By column chromatography to sequentially extract the crude product with dichloromethane to methanol 100: 1. 50:1 (containing one thousandth of glacial acetic acid), eluting, separating and purifying, measuring the purity of a sample by high performance liquid chromatography, and identifying a product by mass spectrum and nuclear magnetism. The nuclear magnetic results were as follows:
DA-CTX：1H NMR(400MHz,DMSO-d6)δ12.2(s,1H)δ8.04–7.97(m,2H),7.90(s,1H), 7.81–7.64(m,3H),7.50–7.36(m,4H),7.21(t,J＝7.4Hz,1H),5.85(d,J＝8.3Hz,2H),5.81– 5.58(m,2H),5.40(dd,J＝7.1,2.1Hz,1H),5.11(t,J＝3.3Hz,2H),4.98(d,J＝9.6Hz,1H),4.73 (s,1H),4.51(s,1H),4.05(s,2H),3.78(dd,J＝10.6,6.5Hz,1H),3.61(d,J＝6.9Hz,1H),3.24(s, 4H),3.05(d,J＝6.6Hz,1H),2.27(d,J＝3.9Hz,3H),1.83(d,J＝4.9Hz,4H),1.54(t,J＝3.9Hz, 5H),1.42(s,9H),1.27(s,2H),1.19(s,3H),1.04–0.97(m,6H).
EXAMPLE 3 Synthesis of Cabazitaxel-diglycolic acid derivatives
0.12mmol of cabazitaxel, 0.024mmol of DMAP,0.24mmol of diethylene glycol dare are placed in a 25ml eggplant-shaped bottle, dissolved by adding 5ml of dichloromethane, reacted at room temperature for 5 hours, and detected by thin layer chromatography (developing solvent dichloromethane: methanol =10, added 0.1% glacial acetic acid. After the reaction was completed, the solvent was evaporated to dryness to obtain a white oily viscous liquid, which was dissolved in dichloromethane, washed twice with 0.5M HCl, once with water, evaporated to dryness to obtain a white solid, which was purified by column chromatography sequentially with dichloromethane to methanol 200: 1. 100, and (2) a step of: 1,50: eluting with an eluting solvent (containing one thousandth of glacial acetic acid) according to the proportion of 1, separating and purifying, measuring the purity, and confirming the structure by mass spectrum.
Example 4 Synthesis of Cabazitaxel-Thiohydroxyacetic acid derivatives
0.12mmol of cabazitaxel, 0.024mmol of DMAP,0.24mmol of thiohydroxyacetic anhydride are placed in a 25ml eggplant-shaped bottle, dissolved by adding 5ml of dichloromethane, reacted at room temperature for 5 hours, and detected by thin-layer chromatography (developing solvent dichloromethane: methanol =10, 0.1% glacial acetic acid is added. After the reaction was completed, the solvent was evaporated to dryness to obtain a white oily viscous liquid, which was dissolved in dichloromethane, washed twice with 0.5M HCl, once with water, evaporated to dryness to obtain a white solid, purified by column chromatography using dichloromethane to methanol 200:1 (containing one thousandth of glacial acetic acid) is eluted, separated and purified, the purity is measured, and the mass spectrum confirms the synthetic structure.
Example 5 Synthesis of docetaxel succinic acid derivative (SA-DTX) and docetaxel glutaric acid derivative (GA-DTX)
0.12mmol of docetaxel, 0.024mmol of DMAP,0.24mmol of succinic anhydride and glutaric anhydride were placed in a 25ml eggplant-shaped bottle, dissolved by adding 5ml of dichloromethane, reacted at room temperature for 5 hours, and detected by thin layer chromatography (developing solvent dichloromethane: methanol =20, added 0.1% glacial acetic acid. After the reaction is finished, the solvent is evaporated to dryness to obtain a white oily viscous liquid, the white oily viscous liquid is dissolved in dichloromethane, washed twice by 0.5M HCl and once by water, and evaporated to dryness to obtain a white solid, and the white solid is prepared by column chromatography with dichloromethane, methanol 200:1 (containing one thousandth of glacial acetic acid), eluting, separating and purifying, determining the purity of the sample by high performance liquid chromatography, and identifying the product by mass spectrum and nuclear magnetism. The nuclear magnetic data are as follows:
SA-DTX:1H NMR(600MHz,Chloroform-d)δ8.09(s,2H),7.62(s,2H),7.51(t,J＝7.6Hz, 2H),7.39(t,J＝7.6Hz,2H),7.30(d,J＝7.7Hz,3H),6.21(s,1H),6.03(s,1H),5.66(s,1H),5.54 (s,1H),5.24(s,2H),4.96(s,1H),4.31(s,1H),4.25(s,1H),4.18(s,1H),3.90(s,1H),2.88(m,2H), 2.81–2.73(m,4H),2.62(m,2H),2.58–2.52(m,2H),2.42(s,2H),2.28(s,2H),1.98(m,3H), 1.93(s,2H),1.90–1.81(m,2H),1.74(s,9H),1.36–1.29(m,2H),1.28–1.18(s,1H),1.10(s,3H), 1.06(s,J＝13.2Hz,6H).
GA-DTX:1H NMR(600MHz,Chloroform-d)δ8.10(s,2H),7.62(s,2H),7.51(t,J＝7.7Hz, 2H),7.39(t,J＝7.6Hz,2H),7.34–7.27(m,3H),6.23(s,1H),5.67(s,1H),5.48(s,1H),5.23(s, 1H),4.97(d,J＝9.8Hz,1H),4.32(d,J＝8.4Hz,1H),4.26(dd,J＝10.9,6.8Hz,1H),4.19(d,J＝ 9.2Hz,1H),3.92(s,1H),2.44(s,3H),2.40–2.25(m,5H),1.96–1.85(m,6H),1.74(s,3H),1.35 (s,J＝17.7Hz,9H),1.24–1.16(m,3H),1.10(d,J＝23.5Hz,3H).
example 6 Synthesis of Podophyllotoxin succinic acid/glutaric acid derivative (PPT-SA/GA)
Adding podophyllotoxin 0.2mmol, succinic anhydride 0.8mmol or glutaric anhydride 0.3mol into 50ml eggplant-shaped bottle, adding anhydrous dichloromethane (about 15 ml) for dissolution, and adding 4-dimethylaminopyridine DMAP (24.2mg, 0.2mmol), 3 drops of triethylamine; after the feeding is finished, stirring at room temperature under the protection of nitrogen for reaction, monitoring the reaction process by TLC, and finishing the reaction for 12 hours; after the reaction is finished, 0.6g of 200-300 mesh silica gel is added, the sample is stirred by a dry method, and is separated and purified by silica gel column chromatography (eluent: dichloromethane: methanol = 270), monitoring is carried out by thin layer chromatography (developing agent: dichloromethane: methanol = 1), and finally, the turmeric toner powder compound PPT-SA is obtained, and the success of the synthesis is confirmed by mass spectrum.
Example 7 Synthesis of Etoposide succinic/glutaric acid derivatives (ETO-SA/GA)
Adding etoposide (58.8mg, 0.1mmol) into a 50ml eggplant-shaped bottle, adding 6ml dichloromethane for dispersion, adding acid-binding agent triethylamine (14ul, 0.1mmol) under ice bath condition, stirring and activating for 30min under the protection of nitrogen, wherein the solution is light yellow transparent solution; ultrasonically dissolving succinic anhydride (20mg, 0.2mol) or glutaric anhydride (17mg, 0.15mmol) and 4-dimethylamino pyridine (2.4 mg, 0.02 mmol) by using 5ml of anhydrous dichloromethane, then dropwise adding the solution into the activated ETO solution, after the dropwise adding is finished, moving the solution to room temperature for continuous reaction, monitoring the reaction process by TLC, and finishing the reaction for 7 hours; after the reaction was completed, 0.2g of 200-300 mesh silica gel was added, and the mixture was subjected to dry sample mixing, separation and purification by silica gel column chromatography (eluent: dichloromethane: methanol = 70), followed by monitoring by thin layer chromatography (developing solvent: dichloromethane: methanol = 20) to obtain a white powdery compound, and the synthetic structure was confirmed by mass spectrometry.
Example 8 Synthesis of combretastatin succinic acid derivative (CA 4-SA)
Combretastatin A0.2 mmol, succinic anhydride or glutaric anhydride 0.8mmol was added to a 50ml eggplant-shaped bottle, dissolved by addition of anhydrous dichloromethane (ca. 15 ml) and subsequently 4-dimethylaminopyridine DMAP (24.2 mg,0.2 mmol), 3 drops of triethylamine; after the feeding is finished, stirring at room temperature under the protection of nitrogen for reaction, monitoring the reaction process by TLC, and finishing the reaction for 12 hours; after the reaction, 0.6g of 200-300 mesh silica gel was added, the mixture was stirred by a dry method, and subjected to separation and purification by silica gel column chromatography (eluent: dichloromethane: methanol = 270).
Example 9 Effect of drug lipid ratio on active drug-loading encapsulation efficiency of Cabazitaxel weakly acidic derivatives
Weighing DSPC, chol and DSPE-PEG2000 with the mass ratio of 75. The obtained blank liposome. And (2) incubating blank liposomes for 30min at 65 ℃ according to a weak acid derivative ethanol solution with a mass ratio of phospholipid to cabazitaxel weak acid compound of 20, 10 and 5, stopping drug loading in an ice-water bath after the drug loading is finished, and measuring the liposome encapsulation efficiency.
The results show that when the mass ratio of phospholipid to drug is 20.
EXAMPLE 10 Effect of aqueous phase concentration on the Encapsulated efficiency of weakly acidic derivatives
Weighing DSPC, chol and DSPE-PEG2000 with the mass ratio of 75. The blank liposome was obtained. And (3) incubating the blank liposome at 65 ℃ for 30min according to a weak acid derivative ethanol solution with the mass ratio of phospholipid to the weak acid compound substance of cabazitaxel being 10, stopping drug loading in an ice-water bath after the drug loading is finished, and measuring the particle size and the entrapment rate of the liposome.
The results show that: the entrapment efficiency of the cabazitaxel weak acid derivative liposome is increased along with the increase of the concentration of the inner water phase, and the entrapment efficiency is not increased when the concentration of calcium acetate in the inner water phase is greater than or equal to 120mM, so that 120mM is selected as the optimal concentration of the inner water phase of the cabazitaxel weak acid derivative.
EXAMPLE 11 Effect of Cholesterol content on Liposome encapsulation efficiency
Weighing 100mg of total phospholipid (DSPC content is reduced when cholesterol is increased) with cholesterol mole fractions of 5%, 10%, 20%, 30%, 40% and 45%, dissolving in chloroform, performing rotary evaporation at 37 deg.C under reduced pressure to remove organic solvent to form phospholipid membrane, hydrating with 120mM calcium acetate solution at 65 deg.C for 30min, sequentially passing the obtained crude liposome solution through 0.4, 0.2 and 0.1 μm polycarbonate membrane in an extrusion device to obtain large single-chamber liposome with particle size of about 120nm, and exchanging outer water phase of liposome with sodium sulfate solution with concentration equal to that of inner water through dextran gel chromatographic column to obtain blank liposome. The blank liposomes were obtained. And (3) incubating blank liposome at 65 ℃ for 30min according to a weak acid derivative ethanol solution with a mass ratio of phospholipid to cabazitaxel weak acid compound of 10, stopping drug loading in an ice-water bath after the drug loading is finished, and measuring the particle size and the encapsulation efficiency of the liposome.
The results show that the encapsulation efficiency of three cabazitaxel weakly-acidic derivatives is gradually increased along with the increase of the cholesterol content, when the cholesterol content is more than or equal to 30%, the encapsulation efficiency can reach more than 95%, the particle size of the liposome is increased, the encapsulation efficiency is considered, the stability problem is considered, and the cholesterol content is not more than 45%.
Example 12 preparation of SA-CTX active drug-loaded liposomes (SA-CTX lipo)
Weighing 68.1mg DSPC, 22.2mg Chol and 1.2mg DSPE-PEG2000, dissolving in chloroform, carrying out rotary evaporation at 37 ℃ under reduced pressure to remove organic solvent to form a phospholipid membrane, hydrating with 120mM calcium acetate solution at 65 ℃ for 30min, sequentially passing the obtained primary emulsion liquid through 0.4, 0.2 and 0.1 mu m polycarbonate membranes in an extrusion device to obtain large single-chamber liposome with the particle size of about 120nm, and exchanging the outer water phase of the liposome with 120mM sodium sulfate solution through a sephadex chromatographic column to obtain the blank liposome. According to the mass ratio of the phospholipid to the medicine lipid of 1.
The SA-CTX lipo was determined to have a particle size of 120.4. + -. 3.2nm and an encapsulation efficiency of (98.7. + -. 1.4)%
EXAMPLE 13 preparation of GA-CTX active drug-loaded liposomes (GA-CTX lipo)
Weighing a prescription of 68.1mg DSPC, 22.2mg Chol and 1.2mg DSPE-PEG2000, dissolving in chloroform, performing rotary evaporation at 37 ℃ under reduced pressure to remove an organic solvent to form a phospholipid membrane, hydrating with 120mM calcium acetate solution at 65 ℃ for 30min, sequentially passing the obtained primary emulsion liquid through 0.4, 0.2 and 0.1 mu m polycarbonate membranes in an extrusion device to obtain large single-chamber liposomes with the particle size of about 120nm, and exchanging the external aqueous phase of the liposomes with 120mM sodium sulfate solution through a sephadex chromatographic column to obtain the blank liposomes. According to the weight ratio of the phospholipid to the medicinal lipid of 1.
The GA-CTX lipo has the particle size of about 123nm and the entrapment rate of about 97 percent
EXAMPLE 14 preparation of DA-CTX active drug-loaded liposomes (DA-CTX lipo)
Weighing 68.1mg DSPC, 22.2mg Chol and 1.2mg DSPE-PEG2000, dissolving in chloroform, performing rotary evaporation at 37 ℃ under reduced pressure to remove organic solvent to form a phospholipid membrane, hydrating with 120mM calcium acetate solution at 65 ℃ for 30min, sequentially passing the obtained primary emulsion liquid through 0.4, 0.2 and 0.1 mu m polycarbonate membranes in an extrusion device to obtain large single-chamber liposome with particle size of about 120nm, and exchanging the outer water phase of the liposome with 120mM sodium sulfate solution through a sephadex chromatographic column to obtain the blank liposome. According to the mass ratio of the phospholipid to the medicine lipid of 1.
The particle size of DA-CTX lipo is determined to be about 118nm, and the encapsulation efficiency is determined to be about 100 percent
Example 15 preparation of PPT-SA drug-loaded liposomes
Weighing 68.1mg DSPC, 22.2mg Chol and 1.2mg DSPE-PEG2000, dissolving in chloroform, carrying out rotary evaporation at 37 ℃ under reduced pressure to remove organic solvent to form a phospholipid membrane, hydrating with 200mM calcium acetate solution at 65 ℃ for 30min, sequentially passing the obtained primary emulsion liquid through 0.4, 0.2 and 0.1 mu m polycarbonate membranes in an extrusion device to obtain large single-chamber liposome with the particle size of about 120nm, and exchanging the outer water phase of the liposome with 200mM sodium sulfate solution through a sephadex chromatographic column to obtain the blank liposome. According to the mass ratio of the phospholipid to the medicine lipid being 1.
The particle size of PPT-SA lipo is determined to be about 118nm, and the encapsulation efficiency is about 95%.
Example 16 preparation of ETO-SA drug-loaded liposomes (ETO-SA)
Weighing 5:1: dissolving 0.02 DSPC, chol and DSPE-PEG2000 in chloroform, performing rotary evaporation at 37 deg.C under reduced pressure to remove organic solvent to obtain phospholipid membrane, hydrating with 120mM calcium acetate solution at 65 deg.C for 30min, sequentially passing the obtained primary emulsion solution through 0.4, 0.2 and 0.1 μm polycarbonate membrane in an extrusion device to obtain large single-chamber liposome with particle size of about 120nm, and passing through Sephadex chromatographic column to exchange the external water phase of liposome to 120mM sodium sulfate solution to obtain blank liposome. According to the mass ratio of the phospholipid to the medicinal lipid of 1.
The particle size of ETO-SA lipo is determined to be about 118nm, and the encapsulation efficiency is determined to be about 93.4 percent
EXAMPLE 17 stability test of three Cabazitaxel weakly acidic derivative liposomes
The three cabazitaxel weakly acidic derivative liposomes prepared according to examples 12, 13 and 14 were stored at 4 ℃ and the encapsulation efficiency was measured every 7 days.
Results show that the succinic acid-cabazitaxel liposome and the glutaric acid-cabazitaxel liposome in the three cabazitaxel weak-acid derivatives have relatively good stability, and the trans-dibutene-1, 4-dicarboxylic acid-cabazitaxel has relatively poor stability due to the fact that the structure of the trans-dibutene-1, 4-dicarboxylic acid-cabazitaxel contains double bonds.
Example 18 evaluation experiment of cytotoxicity of Cabazitaxel weakly acidic derivatives and liposome preparations thereof
RM-1 cells in logarithmic growth phase (prostate cancer cells) were added to a 96-well plate in a number of 1000 per well, after 24h cell attachment per well volume of 100 μ L, cabazitaxel (CTX), cabazitaxel succinic acid derivative (SA-CTX), cabazitaxel succinic acid derivative liposome (SA-CTX lipo), cabazitaxel glutaric acid derivative (GA-CTX), cabazitaxel glutaric acid derivative liposome (GA-CTX lipo), cabazitaxel trans-dibutylene-1, 4-dicarboxylic acid derivative liposome (DA-CTX lipo) were added to the well plate at a set concentration (n = 6), MTT was added after continuous culture for 48h, 72h, respectively, after 4h culture, crystal violet was generated in the well plate, after DMSO was added to dissolve the crystal violet, the absorbance was measured on an enzyme reader, the excitation wavelength was set at 490nm, and the cell absorbance was calculated as follows:
cell viability = (OD) Control group -OD Blank group )/(OD Administration set -OD Blank group )*100％
Half lethal dose IC was calculated by Graphpad software fitting according to cell viability 50
TABLE 1 IC of three Cabazitaxel weakly acidic derivatives and liposome preparations thereof 50
Note: unit ng/ml
Example 19 evaluation test of maximum tolerated dose of Cabazitaxel weakly acidic derivatives
Healthy male C56BL/6 mice of 4 weeks old were selected, and divided into 5 groups according to the control group, commercial preparations of Cabazitaxel (CTX), cabazitaxel succinic acid derivative liposome (SA-CTX lipo), cabazitaxel glutaric acid derivative liposome (GA-CTX lipo), and cabazitaxel trans-dibutylene-1, 4-dicarboxylic acid derivative liposome (DA-CTX lipo), and 3 mice in each group were administered with equivalent CTX doses of 6mg/kg, 10mg/kg, 20mg/kg, 30mg/kg, and 40mg/kg, and once every 3 days, and once every two days, and the state of the mice was observed, and the maximum tolerated dose evaluation index was made by reducing the body weight by more than 15% from the control group.
TABLE 2 maximum tolerated dose of three cabazitaxel weakly acidic derivative liposome preparations
Example 20 pharmacokinetic experiments on Carbozitaxel weakly acidic derivative liposomes
24 male rats weighing 200-230g were randomly divided into 4 groups, fasted for 12h before dosing and weighed 1h before dosing. 4 groups are respectively free medicine groups
Cabazitaxel succinic acid derivative liposome (SA-CTX lipo), cabazitaxel glutaric acid derivative liposome (GA-CTX lipo) and cabazitaxel trans-dibutene-1, 4-dicarboxylic acid derivative liposome (DA-CTX lipo) are injected into each rat, the dose of equivalent CTX is 5mg/kg, 0.083, 0.25, 0.5, 1, 2, 4, 8, 12 and 24h of ocular blood sampling is 0.3ml after the injection, the rat is placed into an EP tube coated with heparin, the rat is centrifuged at 13000rpm for 10min, a supernatant sample is taken and stored in a refrigerator at the temperature of-80 ℃, the blood concentration is determined by UPLC-MS/MS, and pharmacokinetic parameters are calculated
TABLE 3 pharmacokinetic parameters of cabazitaxel weakly acidic derivative liposome preparation
Example 21 pharmacodynamic experiment of Cabazitaxel weakly acidic derivative liposome
RM-1 cells in logarithmic growth phase were arranged at 5X 10 per mouse 6 The cells/0.2 ml are inoculated with 0.2ml volume on the right back side of male C57BL/6 mice of about 20g, and the tumor volume is observed and measured every day until the tumor volume reaches 100-130mm 3 Mice were randomly divided into 8 groups: a normal saline solution group,
SA-CTX lipo low dose group, SA-CTX lipo high dose group, GA-CTX lipo low dose group, GA-CTX lipo high dose group, DA-CTX lipo low dose group, DA-CTX lipo high dose group,
the administration dose was 6mg/kg, the other liposome low dose group was administered at an equivalent CTX of 6mg/kg, and the high dose group was administered at an equivalent dose of 30mg/kg, in a dose volume of 0.2mL, once every three days, for a total of four administrations. The body weight was measured every two days, the tumor major and minor diameters were measured, and the tumor volume was calculated. The results are shown in FIG. 11.
Tumor volume = major diameter × minor diameter 2 /2。
Claims (1)
1. The liposome of the weak acid derivative of the insoluble drug is characterized by comprising phospholipid, cholesterol, the weak acid derivative of the insoluble drug, an inner water phase solution and an outer water phase buffer salt solution, and a drug-loaded liposome is prepared by adopting a pH gradient active drug loading method; wherein the weak acid derivative of the slightly soluble drug is as follows:
the phospholipid is the combination of DSPC and DSPE-PEG2000, and the weight ratio of the DSPC to the DSPE-PEG2000 is 10-50:1, the cholesterol content accounts for 30-45% of the molar ratio of lipid components except the medicament;
the mass ratio of the slightly acidic derivative of the slightly soluble drug to the phospholipid is 1:5-20 parts of;
the inner water phase solution is calcium acetate solution with the concentration of 120mM;
in the preparation of the pH gradient active drug loading method, the weakly acidic derivative of the insoluble drug and the blank liposome are incubated together at 65 ℃, and the drug loading is 30mim.
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