CN108113976B - TH-302 preparation, preparation method and application thereof - Google Patents
TH-302 preparation, preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a microsphere preparation of TH-302, a preparation method and application thereof. The carrier material polylactic acid or polylactic acid/glycolic acid copolymer with the degradation product of lactic acid or glycolic acid is used for encapsulating TH-302 or pharmaceutical salt thereof to prepare the embolic microsphere, on one hand, the physical barrier of the microsphere can be utilized to obstruct the blood supply of tumor tissues, on the other hand, the active product of TH302 can be slowly released under the action of acid generated by the degradation of the carrier material, thereby further enhancing the anti-tumor effect.
Description
Technical Field
The invention relates to a medicinal preparation for treating liver cancer, in particular to a TH-301 preparation for treating a liver cancer patient who cannot be treated by an operation at an advanced stage, a preparation method and application.
Background
Liver cancer (Hepatocellular carcinoma HCC) is one of malignant tumors worldwide, has hidden onset, rapid progression and short life cycle, and seriously harms human health. More than 50 million patients appear each year and are the third cancer-related cause of death worldwide. The incidence rate in Europe is 3.6/10 ten thousand-10.6/10 ten thousand, and the incidence rate in the world is 16.0/10 ten thousand. At present, the main treatment method for liver cancer patients is surgical operation, but the effect is good only for early liver cancer, and most liver cancer patients are diagnosed in middle and late stages and have no operation chance.
The vascularity of tumor tissue is different from that of normal tissue, disorganized, resulting in a microenvironment interspersed with hypoxic and normoxic regions. In the normoxic region, tumor cells are rapidly formed and are extremely sensitive to conventional chemotherapy, while in the hypoxic region, tumor cells are in a dormant state and are resistant to standard chemotherapy and radiotherapy, thus becoming a major obstacle to tumor treatment.
TH-302 is a prodrug of a dinitroimidazole, a highly cytotoxic selective hypoxia-activated DNA alkylating agent designed and synthesized by researchers from Threshold pharmaceutical companies. Can be converted into dibromo-ifosfamide mustard with alkylating agent activity in a tumor hypoxia area or in acid activation, but has little activity under the condition of normal oxygen or normal pH.
At present, the reports of TH-302 at home and abroad are reports of oral dosage forms, and the publication numbers are as follows: US20140072624A1, no other reports have been made on TH-302 dosage forms. Oral administration belongs to systemic administration, and only a part of the medicine reaches cancer cells, so that the toxic and side effects are great.
Disclosure of Invention
In view of the above, the present invention aims to propose a TH-302 formulation which can be administered in a lower dosage, so that the toxic side effects of the drug on the subject to be administered are reduced.
The TH-302 formulation of the present invention comprises an active agent and a carrier material; the active drug is coated by the carrier material to form microspheres;
wherein the active drug is TH-302 or a pharmaceutically acceptable salt of TH-302; the carrier material is a material of which the degradation product is lactic acid or glycolic acid.
Preferably, the carrier material is polylactic acid, polylactic acid-glycolic acid copolymer, or a mixture of the two.
Preferably, the polylactic acid is an ester-terminated or carboxyl-terminated polylactic acid; the polylactic acid-glycolic acid copolymer is an ester-terminated or carboxyl-terminated polylactic acid-glycolic acid copolymer.
Preferably, the percentage lactic acid/glycolic acid in the ester-terminated or carboxy-terminated polylactic acid-glycolic acid copolymer is 75: 25.
Preferably, the particle size of the microspheres is within 75 μm-300 μm.
For the TH-302 preparation, the invention also provides a preparation method thereof, which comprises the following steps:
firstly, adding an active drug and a carrier material into an organic solvent, and completely dissolving and uniformly mixing the drug and the carrier material;
secondly, injecting the medicine and the carrier material which are completely dissolved in the organic solvent and uniformly mixed into a water phase containing the emulsifier with the first concentration to form emulsion;
and thirdly, transferring the emulsion into a water phase containing an emulsifier with a second concentration, stirring at a low speed, volatilizing an organic solvent, and then centrifuging and washing to obtain the TH-302 microsphere preparation.
Preferably, the method further comprises the following steps: and fourthly, freeze-drying the obtained TH-302 microsphere preparation to obtain microsphere freeze-dried powder.
Preferably, the organic solvent is selected from dichloromethane, ethyl acetate, acetone, ethanol, methanol, benzyl alcohol and a mixture of two or more thereof;
the emulsifier is selected from polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, sodium polymethacrylate, polypropylene, gelatin, tragacanth and a mixture of two or more of the above.
Preferably, the emulsifier of the first concentration and the emulsifier of the second concentration are 0.2 to 10 percent of the weight of the emulsifier in water, and more preferably, the second concentration is lower than the first concentration.
The invention also provides application of the TH-302 preparation, which is used for treating liver cancer alone or in combination with other chemoradiotherapy medicaments.
Based on the characteristics of TH-302, the carrier material polylactic acid or polylactic acid/glycolic acid copolymer with the degradation product of lactic acid or glycolic acid is used for encapsulating and preparing the embolism microsphere, on one hand, the physical barrier of the microsphere can be utilized to block the blood supply of tumor tissues, on the other hand, the active product of TH302 can be slowly released under the action of acid generated by the degradation of the carrier material, and the anti-tumor effect is further enhanced.
Drawings
Figure 1 is a graph showing the in vitro release profile of the TH-302 formulation of the present invention when formed into microspheres of varying particle size.
Detailed Description
The invention provides TH-302 in the form of sustained-release embolization microspheres which comprise TH-302, P L GA or P L A. P L GA/P L A is used as a matrix material to prepare TH-302 hepatic artery embolization microspheres which have smooth and round surfaces, regular and non-adhesion particles, 75-100 μm, 100-200 μm and 200-300 μm (table 1), high drug loading and encapsulation efficiency (table 2) and sustained release half a month (figure 1) and a preparation method thereof.
The invention also relates to a preparation method of the TH-302 hepatic artery embolism microsphere, which adopts a single emulsification-solvent volatilization method to prepare the microsphere, and the active medicament and the biodegradable medicinal high molecular material are dissolved in one or more organic solvents to form an oil phase, wherein the organic solvent is selected from dichloromethane, ethyl acetate, acetone, ethanol, methanol, benzyl alcohol or more than one mixed organic solvent. In addition, a continuous water phase is prepared, and the nonionic surfactants are dissolved in water, wherein the weight percentage of the nonionic surfactants in the water is 2-5%. The non-ionic surfactant is selected from polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, sodium polymethacrylate, polypropylene, gelatin and tragacanth. The single emulsification-solvent evaporation method for preparing the microspheres comprises the following steps: adding a high molecular auxiliary material and an active drug TH-302 into dichloromethane or a mixed solvent, after completely dissolving and uniformly mixing, injecting the mixed solution into a water phase with a proper concentration by using an injection meter under the stirring condition of 250-500rpm, continuously stirring at 4 ℃ to form an emulsion, transferring the emulsion into the water phase with a lower concentration, stirring at a low speed for 4-5h, and volatilizing the organic solvent; and then centrifuging at 4000-.
The microsphere carrier material is selected from P L GA with the molecular weight of 9800 daltons, the mass percentage of L A to GA in P L GA is 75:25, the microsphere carrier material is selected from P L A, and the microsphere carrier material can also be a mixture of P L GA and P L A.
The invention adopts a common electromagnetic stirrer or a mechanical stirrer, and the stirring speed is 250rpm-500 rpm. The nonionic emulsifier accounts for 2-5 wt% of the water phase.
The microsphere prepared by the method has smooth and round surface, regular and non-adhesive particles, and the particle size distribution is in three ranges of 75-100 μm, 100-200 μm and 200-300 μm (table 1). The encapsulation efficiency is higher (table 2), and the slow release period is half a month (figure 1).
The TH-302 formulation of the present invention, its preparation method and use are described in detail below with reference to the accompanying drawings.
The TH-302 formulation of the present invention formed as an embolic microsphere.
The embolism microsphere carrier can be divided into natural, synthetic and semisynthetic high molecular materials, wherein the natural high molecular materials mainly comprise gelatin, alginate, chitosan and proteins, the semisynthetic natural high molecular materials comprise cellulose derivatives, the synthetic high molecular materials comprise polylactic acid (P L A) and polylactic glycolic acid copolymer (P L GA), and the synthetic high molecular materials are ideal microsphere carriers due to good biocompatibility, degradability and good stability in organisms.
Example 1 Effect of ester-terminated P L GA on microsphere encapsulation efficiency
Weighing 0.6g of ester-terminated P L GA, dissolving the ester-terminated P L GA in an organic solvent to prepare an oil phase, wherein the organic solvent is dichloromethane or a mixture of dichloromethane and methanol, precisely weighing a certain amount of TH-302 active drug, dissolving the TH-302 active drug in the oil phase, uniformly mixing the mixture by ultrasonic waves to obtain a drug-containing organic phase, weighing a proper amount of PVA in distilled water with a certain volume, repeatedly heating and dissolving the PVA in a microwave oven, complementing the weight loss, obtaining a 3% aqueous phase solution, injecting the oil phase into 15ml and 3% PVA solution at a certain speed by using an injection pump, stirring the mixture at 350rpm for 7min, transferring the emulsion into 250ml and 2% PVA solution, stirring the mixture at 250rpm and 4 ℃ for 4-5h, volatilizing the organic solvent, centrifuging, washing and drying to obtain the ester-terminated P L GA microspheres, and measuring the microsphere encapsulation rate, wherein the results are shown in Table 1.
Example 2 Effect of carboxyl terminal P L GA on microsphere encapsulation efficiency
Weighing 0.6g of carboxyl-terminal P L GA, dissolving in an organic solvent to prepare an oil phase, wherein the organic solvent is dichloromethane or a mixture of dichloromethane and methanol, precisely weighing a certain amount of TH-302 active drug, dissolving in the oil phase, ultrasonically mixing uniformly to obtain a drug-containing organic phase, weighing a proper amount of PVA in distilled water with a certain volume, repeatedly heating and dissolving the PVA in a microwave oven, complementing weight loss, and obtaining a 3% aqueous phase solution, injecting the oil phase into 15ml and 3% PVA solution at a certain speed by using an injection pump, stirring at 350rpm for 7min, transferring the emulsion into 250ml and 2% PVA solution, stirring at 250rpm and 4 ℃ for 4-5h, volatilizing the organic solvent, centrifuging, washing and drying to obtain carboxyl-terminal P L GA microspheres, and determining the microsphere encapsulation rate, wherein the results are shown in Table 1.
Example 3 Effect of hydroxyl terminated P L GA on microsphere encapsulation efficiency
Weighing 0.6g of hydroxyl-terminated P L GA, dissolving the hydroxyl-terminated P L GA in an organic solvent to prepare an oil phase, wherein the organic solvent is dichloromethane or a mixture of dichloromethane and methanol, precisely weighing a certain amount of TH-302 active drug, dissolving the TH-302 active drug in the oil phase, uniformly mixing the mixture by ultrasonic waves to obtain a drug-containing organic phase, weighing a proper amount of PVA in distilled water with a certain volume, repeatedly heating and dissolving the PVA in a microwave oven, complementing the weight loss, obtaining a 3% aqueous phase solution, injecting the oil phase into 15ml of 3% PVA solution at a certain speed by using an injection pump, stirring the mixture at 350rpm for 7min, transferring the emulsion into 250ml of 2% PVA solution, stirring the mixture at 250rpm and 4 ℃ for 4-5h, volatilizing the organic solvent, centrifuging, washing and drying to obtain the hydroxyl-terminated P L GA microspheres, and determining the microsphere encapsulation rate, wherein the results are shown in Table 1.
TABLE 1 Effect of different end-capped P L GA support materials on microsphere encapsulation efficiency
EXAMPLE 4 Effect of ester-terminated P L A on microsphere encapsulation efficiency
Weighing 0.6g of ester-terminated P L A, dissolving in an organic solvent to prepare an oil phase, wherein the organic solvent is dichloromethane or a mixture of dichloromethane and methanol, precisely weighing a certain amount of TH-302 active drug, dissolving in the oil phase, ultrasonically mixing uniformly to obtain a drug-containing organic phase, weighing a proper amount of PVA in distilled water with a certain volume, repeatedly heating and dissolving the PVA in a microwave oven, complementing weight loss, obtaining a 3% aqueous phase solution, injecting the oil phase into 15ml and 3% PVA solution at a certain speed by using an injection pump, stirring at 350rpm for 7min, transferring the emulsion into 250ml and 2% PVA solution, stirring at 250rpm and 4 ℃ for 4-5h, volatilizing the organic solvent, centrifuging, washing and drying to obtain ester-terminated P L A microspheres, and determining the microsphere encapsulation rate, wherein the results are shown in Table 2.
Example 5 Effect of carboxyl terminal P L A on microsphere encapsulation efficiency
Weighing 0.6g of carboxyl terminal P L A, dissolving in an organic solvent to prepare an oil phase, wherein the organic solvent is dichloromethane or a mixture of dichloromethane and methanol, precisely weighing a certain amount of TH-302 active drug, dissolving in the oil phase, ultrasonically mixing uniformly to obtain a drug-containing organic phase, weighing a proper amount of PVA in distilled water with a certain volume, repeatedly heating and dissolving the PVA in a microwave oven, complementing weight loss, and obtaining a 3% aqueous phase solution, injecting the oil phase into 15ml and 3% PVA solution at a certain speed by using an injection pump, stirring at 350rpm for 7min, transferring the emulsion into 250ml and 2% PVA solution, stirring at 250rpm and 4 ℃ for 4-5h, volatilizing the organic solvent, centrifuging, washing and drying to obtain carboxyl terminal P L A microspheres, and determining the encapsulation rate of the microspheres, wherein the results are shown in Table 2.
Example 6 Effect of hydroxyl end P L A on microsphere encapsulation efficiency
Weighing 0.6g of hydroxyl-terminated P L A, dissolving in an organic solvent to prepare an oil phase, wherein the organic solvent is a mixture of dichloromethane and methanol, precisely weighing a certain amount of TH-302 active drug, dissolving in the oil phase, ultrasonically mixing uniformly to obtain a drug-containing organic phase, weighing a proper amount of PVA in distilled water with a certain volume, repeatedly heating and dissolving the PVA in a microwave oven, complementing weight loss to obtain a 3% aqueous phase solution, injecting the oil phase into 15ml of 3% PVA solution at a certain speed by using an injection pump, stirring at 350rpm for 7min, transferring the emulsion into 250ml of 2% PVA solution, stirring at 250rpm and 4 ℃ for 4-5h, volatilizing the organic solvent, centrifuging, washing and drying to obtain hydroxyl-terminated P L A microspheres, and determining the microsphere encapsulation rate, wherein the results are shown in Table 2.
TABLE 2 Effect of different end-capped P L A support materials on microsphere encapsulation efficiency
EXAMPLE 7 preparation of TH-302-P L GA hepatic artery embolization microspheres of different particle sizes
Weighing 0.6g of ester-terminated P L GA (molecular weight is 9800L A: GA is 75:25) and dissolving the ester-terminated P L GA in an organic solvent to prepare an oil phase, wherein the organic solvent is a mixture of dichloromethane and methanol, precisely weighing TH-302 active drugs with the amount of a prescription and dissolving the TH-302 active drugs in the oil phase, and ultrasonically mixing the drugs uniformly to obtain a drug-containing organic phase, weighing a proper amount of PVA in distilled water with a certain volume, repeatedly heating the distilled water in a microwave oven to dissolve the PVA and complement the weight loss to obtain a 5% PVA water phase solution, injecting the oil phase into 15ml of the PVA water phase solution at a certain speed by using an injection pump, stirring the mixture at 350rpm for 7min, transferring the emulsion into 250ml of 2% PVA solution at 250rpm and 4 ℃, stirring for 4-5h, volatilizing the organic solvent, centrifuging, washing and drying, and measuring the particle size of the microspheres by using a Malver.
EXAMPLE 8 preparation of TH-302-P L GA hepatic artery embolization microspheres of different particle sizes
Weighing 0.6g of ester-terminated P L GA (molecular weight is 9800L A: GA is 75:25) and dissolving the ester-terminated P L GA in an organic solvent to prepare an oil phase, wherein the organic solvent is a mixture of dichloromethane and methanol, precisely weighing TH-302 active drugs with the amount of a prescription and dissolving the TH-302 active drugs in the oil phase, and ultrasonically mixing the drugs uniformly to obtain a drug-containing organic phase, weighing a proper amount of PVA in distilled water with a certain volume, repeatedly heating the distilled water in a microwave oven to dissolve the PVA and complement the weight loss to obtain a 5% PVA water phase solution, injecting the oil phase into 15ml of the PVA water phase solution at a certain speed by using an injection pump, stirring the mixture at 350rpm for 5min, transferring the emulsion into 250ml of 2% PVA solution at 250rpm and 4 ℃, stirring for 4-5h, volatilizing the organic solvent, centrifuging, washing and drying, and measuring the particle size of the microspheres by using a Malvern.
EXAMPLE 9 preparation of TH-302-P L GA hepatic artery embolization microspheres of different particle sizes
Weighing 0.6g of ester-terminated P L GA (molecular weight is 9800L A: GA is 75:25) and dissolving the ester-terminated P L GA in an organic solvent to prepare an oil phase, wherein the organic solvent is a mixture of dichloromethane and methanol, precisely weighing TH-302 active drugs with the amount of a prescription and dissolving the TH-302 active drugs in the oil phase, and ultrasonically mixing the drugs uniformly to obtain a drug-containing organic phase, weighing a proper amount of PVA in distilled water with a certain volume, repeatedly heating the distilled water in a microwave oven to dissolve the PVA and then complementing the weight loss to obtain a 5% PVA water phase solution, injecting the oil phase into 15ml of the PVA water phase solution at a certain speed by using an injection pump, stirring the mixture at 250rpm for 5min, transferring the emulsion into 250ml of a 2% PVA solution at 250rpm and 4 ℃, stirring for 4-5h, volatilizing the organic solvent, centrifuging, washing and drying, and measuring the particle size of the microspheres by using a.
TABLE 3 TH-302-P L GA hepatic artery embolism microsphere with different particle size
Method for measuring particle size of TH-302-P L GA hepatic artery embolization microsphere
In the experiment, a Malvern particle size analyzer is used for determining the particle size of microspheres, a certain amount of prepared microspheres are weighed to 700m L in distilled water containing 5% of carboxymethylcellulose sodium as a suspending agent, a microsphere suspension with the concentration of 5% is prepared, the particle size of the microspheres is determined by the Malvern particle size analyzer, the particle size effect of the microspheres is evaluated mainly through two parameters of span and D50, and the particle size determination results of examples 7, 8 and 9 are shown in Table 3.
In vitro release method of TH-302-P L GA hepatic artery embolism microsphere
The in vitro release of the microspheres is investigated by a culture method, and the release medium is a phosphate buffer solution with the pH value of 7.4 and added with a surfactant. The specific method comprises the following steps: weighing a proper amount of microspheres into a 250ml conical flask, adding 100ml of release medium, placing the conical flask into a water bath constant temperature shaking table which is shaken at the frequency of 100rpm and the temperature of 37 ℃, taking a certain volume of sample at different time points, centrifuging, taking supernatant, simultaneously supplementing blank release medium with the same volume, pouring the lower layer of microsphere solution into the conical flask for continuous release, and slowly releasing the microspheres prepared in the experiment for half a month (figure 1). From the release profile, it can be seen that example 7, which has a smaller particle size, releases faster than examples 8 and 9, and the release trends of examples 8 and 9 are comparable.
The TH-302 preparation can be used as an arterial embolism microsphere, and embolizes a blood supply artery of a tumor of a liver cancer patient by means of a catheter intervention mode of a contrast agent. On the first hand, the blood supply of the tumor is blocked, and the tumor is kept in a hunger state for a long time; on the second aspect, the medicine stays at the tumor part for a long time, the medicine is slowly released, and the blood concentration of the medicine is improved; the third party has stronger cell killing power to the hypoxic region of the tumor microenvironment and has less side effect on the normal tissues of the organism.
TH-302 is prepared into microspheres, and the medicament is directly introduced into tumors for local administration, so that the action time of the medicament is prolonged in a sustained release manner, and the toxic and side effects of the medicament on a subject are reduced to the greatest extent while the treatment of the medicament on the tumors is ensured.
Claims (2)
1. A TH-302 formulation comprising an active agent and a carrier material; the active drug is coated by the carrier material to form the embolism microsphere;
wherein the active drug is TH-302 or a pharmaceutically acceptable salt of TH-302; the carrier material is a material of which the degradation product is lactic acid or glycolic acid, and the carrier material is polylactic acid, a polylactic acid-glycolic acid copolymer or a mixture of the polylactic acid and the polylactic acid, wherein the polylactic acid is ester-terminated or carboxyl-terminated polylactic acid, and the polylactic acid-glycolic acid copolymer is ester-terminated or carboxyl-terminated polylactic acid-glycolic acid copolymer; the mass percentage of lactic acid/glycolic acid in the ester-terminated or carboxyl-terminated polylactic acid-glycolic acid copolymer is 75: 25; the molecular weight of the polylactic acid-glycolic acid copolymer is 9800 daltons, the particle size of the embolism microsphere is 75-300 μm, and the preparation method of the embolism microsphere comprises the following steps:
firstly, adding an active drug and a carrier material into an organic solvent, and completely dissolving and uniformly mixing the drug and the carrier material;
secondly, injecting the medicine and the carrier material which are completely dissolved in the organic solvent and uniformly mixed into the water phase containing the emulsifier with the first concentration under the stirring condition of 250-500rpm, and continuously stirring at the temperature of 4 ℃ to form emulsion;
thirdly, transferring the emulsion to a water phase containing a second concentration emulsifier, stirring at a low speed for 4-5h, volatilizing the organic solvent, centrifuging at 4000-;
fourthly, freeze-drying the obtained TH-302 embolism microsphere preparation to obtain embolism microsphere freeze-dried powder;
the organic solvent is selected from dichloromethane, ethyl acetate, acetone, ethanol, methanol, benzyl alcohol and a mixture of more than two of the dichloromethane, the ethyl acetate, the acetone, the ethanol, the methanol and the benzyl alcohol;
the emulsifier is selected from polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, sodium polymethacrylate, polypropylene, gelatin, tragacanth and a mixture of more than two of the above;
the emulsifier with the first concentration and the emulsifier with the second concentration are both 0.2-10% of the proportion of the emulsifier in water, and the second concentration is lower than the first concentration.
2. The use of the TH-302 preparation of claim 1, alone or in combination with other chemoradiotherapy agents, in the preparation of a medicament for the treatment of liver cancer.
Priority Applications (1)
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| CN109675039A (en) * | 2018-12-21 | 2019-04-26 | 中国科学院长春应用化学研究所 | Pharmaceutical composition, anti-tumor drug and application |
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| CN107715169A (en) * | 2017-11-07 | 2018-02-23 | 南京林业大学 | The sodium alginate of the nanoparticle containing PLGA carries the preparation method and product of the compound embolism microball of medicine |
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| CN107715169A (en) * | 2017-11-07 | 2018-02-23 | 南京林业大学 | The sodium alginate of the nanoparticle containing PLGA carries the preparation method and product of the compound embolism microball of medicine |
Non-Patent Citations (3)
| Title |
|---|
| Preclinical Benefit of Hypoxia-Activated Intra-arterial Therapy with Evofosfamide in Liver Cancer;Rafael Duran,et al;《Clinical Cancer Research》;20160720;第23卷;536-548 * |
| 载药动脉栓塞微球DC Bead TM研究进展;金雪锋等;《药学与临床研究》;20120831;第20卷(第4期);319-325 * |
| 载药微球与空白微球栓塞治疗原发性肝癌的对比分析研究;王亚勋等;《影像诊断与介入放射学》;20171231;第26卷(第6期);445-450 * |
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