Anti-cancer body cavity effusion targeting tablet and preparation method thereof

Abstract

The invention discloses an anti-cancer body cavity effusion targeting tablet and a preparation method thereof, the tablet adopts a multi-layer structure design and comprises a quick release layer, a slow release layer and a targeting layer, and a traditional Chinese medicine active component is composed of extracts of twelve medicinal materials such as poria cocos, semen lepidii and radix pseudostellariae. The preparation method comprises the following steps: preparing the traditional Chinese medicine active components by combining ultrasonic-assisted extraction with a macroporous resin purification technology; preparing a folic acid modified mesoporous silica nano drug delivery system by a sol-gel method; the preparation method comprises the following steps: respectively preparing each layer of particles, carrying out layered tabletting by adopting a three-time feeding and three-time tabletting process, and finally carrying out film coating. Through combination of a multi-layer structure and a nano drug-loading technology, rapid onset, sustained release and active targeting of the drug are realized, the bioavailability and the treatment effect of the drug are remarkably improved, meanwhile, the process is simple and feasible, special equipment is not needed, and the preparation method is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of traditional Chinese medicine preparation, and relates to an anticancer body cavity effusion targeting tablet and a preparation method thereof. BACKGROUND

[0002] Cancerous body cavity effusion is a common serious complication of patients with advanced tumors. Traditional Chinese medicine has accumulated rich experience in treating this disease. The basic treatment formula of Huangjia Medicine Circle shows good efficacy in clinical application, but traditional decoction has the disadvantages of poor stability and inconvenience for taking.

[0003] Modern pharmaceutical preparation technology provides a new solution for the modernization of traditional Chinese medicine. Multi-layer tablet technology can achieve programmed release of different drugs; nano drug delivery system can improve drug targeting and bioavailability; ultrasonic extraction technology can improve extraction efficiency and reduce energy consumption.

[0004] However, the existing technology has the following problems: the traditional extraction method has low efficiency and large loss of effective components; ordinary tablets are difficult to achieve long-acting sustained release and targeted delivery of drugs; the complex process equipment requires high requirements and is difficult to popularize and apply. In addition, the existing technology lacks scientific verification of the necessity of each medicinal material in the formula and systematic optimization of modern preparation process. SUMMARY

[0005] The purpose of the present application is to provide an anticancer body cavity effusion targeting tablet and a preparation method thereof, which are simple in process, low in equipment requirement and suitable for industrial production. The necessity and synergy of the formula are verified through systematic experiments, and the intelligent release and targeted treatment of drugs are achieved through the combination of multi-layer tablet structure and nano technology.

[0006] According to the purpose of the present application, the present application provides an anticancer body cavity effusion targeting tablet, which is composed of traditional Chinese medicine active components, modern antitumor active components and pharmaceutical excipients, adopts a multi-layer sustained release tablet structure, and comprises a rapid release layer, a sustained release layer and a targeting layer; the traditional Chinese medicine active components comprise extracts of Poria cocos, Semen Platycladi, Radix Pseudostellariae, Herba Hedyotis Diffusae, Herba Belamcandae, Fructus Jujubae, Radix Morindae Officinalis, Rhizoma Atractylodis Macrocephalae, Cortex Mori, Radix Astragali, Herba Agrimoniae, Radix Notoginseng.

[0007] Further, the weight ratio of the traditional Chinese medicine active components to the excipients in the rapid release layer is (30-50):(70-50), the weight ratio of the traditional Chinese medicine active components to the excipients in the sustained release layer is (20-40):(80-60), and the weight ratio of the traditional Chinese medicine active components to the excipients in the targeting layer is (10-30):(90-70).

[0008] Further, the immediate-release layer comprises cross-linked povidone 3-8%, microcrystalline cellulose 40-60%, lactose 20-30%; the sustained-release layer comprises hydroxypropyl methylcellulose K100M 15-25%, calcium hydrogen phosphate 30-50%; and the targeting layer comprises mesoporous silica nanoparticles 5-15%, mannitol 50-70%.

[0009] Further, the extraction process of the active components of traditional Chinese medicine is as follows: water or ethanol is used as a solvent, the ratio of material to liquid is 1:8-12, extraction is carried out for 2-3 times, each time for 30-60 minutes, plate and frame filtration is combined with 0.45 μm microporous filter membrane for filtration, AB-8 type macroporous resin is used for purification, the eluent is 50-70% ethanol, the volume of eluent is 3-5 times the column volume, and the flow rate is 2-3 BV / h.

[0010] Further, the targeting layer comprises folate-modified mesoporous silica nanoparticle drug delivery systems, the nanoparticle has a particle size of 50-100 nm, a drug loading capacity of ≥25%, and pH-responsive release characteristics.

[0011] According to another object of the present application, the present application provides a preparation method of the above-mentioned anticancer body cavity effusion targeting tablet, comprising the following steps: (1) extraction and purification of active components of traditional Chinese medicine; (2) preparation of a nanoparticle drug delivery system; (3) preparation of each layer of particles; (4) layered tabletting and coating; In step (4), the layered tabletting is carried out by a three-time feeding and three-time tabletting process, the immediate-release layer is first pressed, then the sustained-release layer is added and lightly pressed, and finally the targeting layer is added and finally pressed.

[0012] Further, the tabletting process environment conditions in step (4) are as follows: temperature 20-25℃, relative humidity 40-60%, particle size distribution 80-100 mesh, water content 2-4%, and tabletting speed 20-30 rpm.

[0013] The present application has the following advantages: The present application uses ultrasonic-assisted extraction combined with macroporous resin purification technology to prepare active components of traditional Chinese medicine, uses a sol-gel method to prepare folate-modified mesoporous silica nanoparticle drug delivery systems, carries out layered tabletting by a three-time feeding and three-time tabletting process after preparing each layer of particles, and finally carries out film coating. The present application realizes rapid onset, sustained release and active targeting of drugs by the combination of a multi-layer structure and nanoparticle drug delivery technology, significantly improves the bioavailability and therapeutic effect of drugs, and the process is simple and feasible, does not require special equipment, and is suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0014] Figure 1Process flow chart for the embodiment of the present application; Figure 2 Detailed process flow chart for the embodiment of the present application. DETAILED DESCRIPTION

[0015] The specific embodiments of the present application are further described below. It is to be noted that the description of these embodiments is intended for the purpose of aiding in the understanding of the present application, and is not intended to constitute a limitation of the present application. Moreover, the technical features involved in the various embodiments of the present application described below can be combined with each other as long as there is no conflict.

[0016] Embodiment 1 An anticancer body cavity effusion targeting tablet is composed of traditional Chinese medicine active components, modern antitumor active components, and pharmaceutical excipients, adopts a three-layer structure design, and includes a quick-release layer, a sustained-release layer, and a targeting layer. The traditional Chinese medicine active components include extracts of Poria cocos, Semen Platycladi, Radix Pseudostellariae, Herba Hedyotis Diffusae, Herba Belamcanda Chinensis, Fructus Jujubae, Radix Morindae Officinalis, Rhizoma Atractylodis Macrocephalae, Cortex Morae Radicis, Radix Paeoniae Albus, Herba Lycopodii, and Radix Notoginseng.

[0017] The components and proportions of each layer of the tablet are optimized as follows: Quick-release layer: the weight ratio of traditional Chinese medicine active components to excipients is (30-50):(70-50), and includes crospovidone (3-8%), microcrystalline cellulose (40-60%), and lactose (20-30%); Sustained-release layer: the weight ratio of traditional Chinese medicine active components to excipients is (20-40):(80-60), and includes hydroxypropyl methyl cellulose K100M (15-25%) and calcium hydrogen phosphate (30-50%); Targeting layer: the weight ratio of traditional Chinese medicine active components to excipients is (10-30):(90-70), and includes mesoporous silica nanoparticles (5-15%) and mannitol (50-70%).

[0018] The extraction of the traditional Chinese medicine active components adopts a unified process: water or ethanol is used as a solvent, the solid-liquid ratio is 1:8-12 (g / mL), extraction is performed for 2-3 times, each time for 30-60 minutes, plate-and-frame filtration is combined with 0.45 μm microporous filter membrane for filtration, AB-8 type macroporous resin is used for purification, the eluent is 50-70% ethanol, the eluent volume is 3-5 times the column volume, and the flow rate is 2-3 BV / h.

[0019] The tabletting process environmental conditions are a temperature of 20-25°C and a relative humidity of 40-60%, the particle size distribution of the granules is 80-100 mesh, the water content is 2-4%, and the tabletting speed is 20-30 revolutions / minute.

[0020] Formulation screening experiment and rationality analysis of the present embodiment The necessity of 12 medicinal materials was verified by orthogonal experimental design (L16(4^5)). The whole prescription (12 ingredients) was significantly better than any reduced-ingredient group (p<0.01) in reducing the amount of pleural effusion, tumor inhibition rate and comprehensive score. The synergistic effects of each medicinal material are as follows: Poria cocos (monarch drug): water excretion and dampness, modern pharmacology has diuretic, immunomodulatory effect; Tinglizi (ministerial drug): lung and asthma, enhance diuresis; Ban Zhilian, Baihuasheshecail (ministerial drug): clearing heat and detoxifying, synergistic anti-tumor; Radix Astragali (assistant drug): Qi and solid table, enhance immunity; Sanqi (ministerial drug): stasis and hemostasis, direct drugs to the disease.

[0021] The process is simple and feasible, and conventional equipment is adopted, which is suitable for industrial production; the extraction efficiency is high, the ultrasonic extraction technology improves the yield of effective components; the drug release is intelligent, the three-layer structure realizes rapid effect, continuous action and target therapy; the bioavailability is high, the nano drug delivery system improves the solubility of the poorly soluble components; the targeting is strong, the folate-modified nanoparticles actively target tumor cells; the formula is scientifically verified, and the synergistic effect of each medicinal material significantly improves the curative effect.

[0022] Example 2 An anticancer body cavity effusion targeting tablet is composed of traditional Chinese medicine active components, modern anti-tumor active components and pharmaceutical excipients, adopts a multi-layer sustained-release tablet structure, and comprises a quick-release layer, a sustained-release layer and a targeting layer; the traditional Chinese medicine active components comprise extracts of Poria cocos, Tinglizi, Taizishen, Ban Zhilian, Baihuasheshecail, Jujube, Hei Chou, Baizhu, Sangbaipi, Huangqi, Xianhecao and Sanqi.

[0023] The weight ratio of the traditional Chinese medicine active components to the excipients in the quick-release layer is (30-50):(70-50), the weight ratio of the traditional Chinese medicine active components to the excipients in the sustained-release layer is (20-40):(80-60), and the weight ratio of the traditional Chinese medicine active components to the excipients in the targeting layer is (10-30):(90-70).

[0024] The quick-release layer comprises cross-linked povidone 3-8%, microcrystalline cellulose 40-60% and lactose 20-30%; the sustained-release layer comprises hydroxypropyl methyl cellulose K100M 15-25% and calcium hydrogen phosphate 30-50%; and the targeting layer comprises mesoporous silica nanoparticles 5-15% and mannitol 50-70%.

[0025] The traditional Chinese medicine active components are extracted by ultrasonic wave and purified by macroporous resin technology, wherein Ban Zhilian and Baihuasheshecail are extracted by ultrasonic wave at 50-60 DEG C, the frequency is 40 kHz, the power is 500 W, and the extraction time is 30 minutes, and then the AB-8 type macroporous resin is used for purification, and the yield is greater than or equal to 15.2%.

[0026] The extraction process of the active components of traditional Chinese medicine is as follows: water or ethanol is used as solvent, the ratio of material to liquid is 1:8-12 (g / mL), extraction is performed for 2-3 times, each time for 30-60 minutes, plate and frame filtration is combined with 0.45 μm microporous filter membrane for filtration, AB-8 type macroporous resin is used for purification, the eluent is 50-70% ethanol, the volume of eluent is 3-5 times the column volume, and the flow rate is 2-3 BV / h.

[0027] The immediate-release layer contains water-soluble components of traditional Chinese medicine and disintegrants, and can be rapidly released in gastric juice within 5-10 minutes; the sustained-release layer uses hydroxypropyl methylcellulose as a matrix material, and can achieve 12-24 hours of sustained release of the drug; and the targeting layer contains nanometer components wrapped by folate-modified liposomes.

[0028] In this embodiment, the modern anti-tumor active components include at least one of astragaloside, and panax notoginseng total saponins.

[0029] The anti-cancer body cavity effusion targeting tablet also contains a mesoporous silica-based nanocarrier drug delivery system, the nanocarrier has a particle size of 50-100 nm, a drug loading capacity of ≥25%, and pH-responsive release characteristics.

[0030] The anti-cancer body cavity effusion targeting tablet is prepared by using a conventional tablet press, the pressure is 10-20 kN, the tablet hardness is 8-12 kg / cm 2 , and the disintegration time is ≤30 minutes. The tabletting process environmental conditions are a temperature of 20-25 °C and a relative humidity of 40-60%, the particle size distribution of the granules is 80-100 mesh, the water content is 2-4%, and the tabletting speed is 20-30 revolutions / minute.

[0031] The formula of the active components of traditional Chinese medicine is selected based on orthogonal experimental design, and the optimal formula is as follows: 15 parts by weight of poria cocos, 15 parts by weight of semen platycladi, 15 parts by weight of pseudostellaria heterophylla, 30 parts by weight of herba barbatae, 30 parts by weight of belamcanda chinensis, 10 parts by weight of zizyphus jujuba, 10 parts by weight of black cohosh, 10 parts by weight of atractylodes macrocephala, 12 parts by weight of mulberry bark, 12 parts by weight of astragalus membranaceus, 20 parts by weight of herba potentillae rubri, and 3 parts by weight of panax notoginseng.

[0032] As shown in Figure 1 and Figure 2 , The preparation method of the anti-cancer body cavity effusion targeting tablet comprises the following steps: (1) extraction and purification of the active components of traditional Chinese medicine; (2) preparation of the nanocarrier drug delivery system; (3) preparation of the granules of each layer; (4) layered tabletting and coating.

[0033] The extraction in step (1) adopts ultrasonic-assisted technology, the extraction solvent is selected according to the polarity of the components, water or ethanol, the extraction temperature is 50-90℃, the extraction time is 30-60 minutes, and the purification adopts AB-8 type macroporous resin.

[0034] The nano drug delivery system in step (2) adopts a sol-gel method to prepare mesoporous silica nanoparticles, using tetraethyl orthosilicate as a silicon source and hexadecyl trimethyl ammonium bromide as a template agent, and is modified by folic acid.

[0035] The preparation of each layer of particles in step (3) includes: The fast-release layer particles: the water-soluble traditional Chinese medicine extract is mixed with microcrystalline cellulose and cross-linked polyvinylpyrrolidone to prepare granules; The slow-release layer particles: the fat-soluble traditional Chinese medicine extract is mixed with hydroxypropyl methyl cellulose and calcium hydrogen phosphate to prepare granules; The targeting layer particles: the drug-loaded nanoparticles are mixed with mannitol and microcrystalline cellulose.

[0036] The layered tabletting in step (4) adopts a three-time feeding and three-time tabletting process, that is, the fast-release layer is first pressed, then the slow-release layer is added and lightly pressed, and finally the targeting layer is added and finally pressed; the tabletting parameters are: pre-pressing pressure 4-6 kN, main pressing pressure 12-18 kN, and tabletting speed 20-30 rpm.

[0037] The coating in step (4) adopts a gastric-soluble film coating material, and the coating weight gain is 2-3%.

[0038] The application of the anti-cancer body cavity effusion targeting tablet in the preparation of a drug for treating malignant pleural effusion.

[0039] Example 3 Standardized extraction of active components of traditional Chinese medicine Take 15 g of poria cocos, 15 g of semen platycladi, 15 g of radix pseudostellariae, 30 g of herba barbatae, 30 g of herba belamcandaes, 10 g of fructus jujubae, 10 g of radix aconiti, 10 g of radix atractylodis macrocephalae, 12 g of cortex mori, 12 g of radix astragali, 20 g of herba potentillae, and 3 g of radix notoginseng, crush them through a 40-mesh sieve. Water-extract the medicinal materials (poria cocos, radix pseudostellariae, fructus jujubae, radix atractylodis macrocephalae, cortex mori, radix astragali, and herba potentillae) with water at a solid-liquid ratio of 1:10 (g / mL) and extract them 3 times at 80-90℃, each time for 45 minutes; alcohol-extract the medicinal materials (semen platycladi, herba barbatae, herba belamcandaes, radix aconiti, and radix notoginseng) with 70% ethanol at 70-80℃, and extract them 3 times, each time for 45 minutes. The extract is coarsely filtered through a 200-mesh sieve, precisely filtered through a 0.45-μm microporous filter, purified by AB-8 type macroporous resin (column diameter to height ratio 1:8), eluted with 5 times the column volume of 70% ethanol at a flow rate of 2.5 BV / h. The solvent is recovered, and the extract is vacuum-dried. The extraction rate is improved by 45-65%, and the effective component transfer rate is ≥85%.

[0040] Example 4 Preparation of nano-drug delivery systems 1 g of hexadecyltrimethylammonium bromide was dissolved in 100 mL of water, 2 mL of ammonia was added, and 5 mL of tetraethyl orthosilicate was added dropwise with stirring. The reaction was carried out at room temperature for 6 hours. The precipitate was collected by centrifugation and calcined at 550 °C for 6 hours to remove the template agent, yielding mesoporous silica nanoparticles (particle size 50-100 nm). The nanoparticles were dispersed in an astragaloside A solution (2 mg / mL) and stirred for 24 hours. The drug-loaded nanoparticles were collected by centrifugation, with a drug loading of ≥25%. Folic acid molecules were modified onto the surface of the nanoparticles using a silane coupling agent.

[0041] Example 5 Tablet preparation Immediate-release granules: 35g Astragalus polysaccharide extract, 45g microcrystalline cellulose, 5g crospovidone, 14g lactose, and 1g magnesium stearate are mixed and granulated, with a particle size controlled at 80-100 mesh and a moisture content of 2.5-3.5%. Slow-release granules: 30g total saponins of Panax notoginseng, 20g hydroxypropyl methylcellulose K100M, 45g dicalcium phosphate, 4.5g microcrystalline cellulose, 0.5g magnesium stearate, wet granulation; Targeting layer particles: 10g drug-loaded nanoparticles, 8g mesoporous silica, 65g mannitol, 16g microcrystalline cellulose, 0.5g colloidal silica, and 0.5g magnesium stearate, mixed together.

[0042] A rotary tablet press was used at a temperature of 23±2℃ and a relative humidity of 50±5%. First, the accelerated-release granules were lightly compressed (5kN), then the sustained-release granules were compressed at medium pressure (10kN), and finally the targeting granules were compressed at a final pressure (15kN). The tableting speed was 25 rpm. The tablet hardness was 10-12 kg / cm², with a tablet weight variation of ±3%.

[0043] Example 6 Quality evaluation Disintegration time limit: immediate-release layer ≤ 10 minutes, overall disintegration ≤ 25 minutes; Release rate: In pH 6.8 phosphate buffer, 35-45% is released after 2 hours and 75-85% is released after 12 hours; Content uniformity: RSD ≤ 3.0%; Stability: Accelerated test (40℃±2℃, RH75%±5%) for 6 months, all indicators meet the requirements.

[0044] Example 7 Pharmacodynamic evaluation A rat model of cancerous pleural effusion was established. Group experiments showed that the pleural effusion volume in the tablet group of this invention was 1.1±0.2ml, the tumor inhibition rate was 68.7±6.3%, and the survival time was 56.3±4.2 days, which were significantly better than those in the traditional decoction group (p<0.01).

[0045] The application adopts conventional pharmaceutical equipment, and the process is mature, stable, controllable in quality and suitable for large-scale industrial production.

[0046] Although embodiments of the present patent have been shown and described, it is to be understood that various modifications, substitutions, replacements and changes can be made to these embodiments without departing from the principles and spirit of the present patent, and the scope of the present patent is defined by the appended claims and their equivalents.

Claims

1. An anticancer body cavity effusion targeting tablet, characterized by, The active components of traditional Chinese medicine, modern anti-tumor active ingredients and pharmaceutical excipients are used to form a multi-layer sustained-release tablet structure, which comprises a quick-release layer, a sustained-release layer and a targeting layer; the active components of traditional Chinese medicine comprise extracts of Poria cocos, Semen Platycladi, Radix Pseudostellariae, Herba Hedyotis Diffusae, Herba Belamcanda Chinensis, Fructus Jujubae, Radix Morindae Officinalis, Rhizoma Atractylodis Macrocephalae, Radix Paeoniae Albus, Radix Paeoniae Rubra, Herba Agrimoniae Pilae and Radix Notoginseng.

2. The anti-cancer body cavity effusion targeting tablet according to claim 1, wherein, The weight ratio of the active components of traditional Chinese medicine to excipients in the quick-release layer is (30-50):(70-50), the weight ratio of the active components of traditional Chinese medicine to excipients in the sustained-release layer is (20-40):(80-60), and the weight ratio of the active components of traditional Chinese medicine to excipients in the targeting layer is (10-30):(90-70).

3. The anti-cancer body cavity effusion targeting tablet according to claim 1 or 2, characterized in that, The quick-release layer comprises cross-linked povidone 3-8%, microcrystalline cellulose 40-60% and lactose 20-30%; the sustained-release layer comprises hydroxypropyl methylcellulose K100M 15-25% and calcium hydrogen phosphate 30-50%; and the targeting layer comprises mesoporous silica nanoparticles 5-15% and mannitol 50-70%. 4.The anti-cancer body cavity effusion targeting tablet according to claim 1, characterized in that, The extraction process of the active components of traditional Chinese medicine is as follows: water or ethanol is used as the solvent, the solid-liquid ratio is 1:8-12, extraction is performed for 2-3 times, each time for 30-60 minutes, plate-and-frame filtration is combined with 0.45 μm microporous membrane filtration for filtration, AB-8 type macroporous resin is used for purification, the eluent is 50-70% ethanol, the eluent volume is 3-5 times the column volume, and the flow rate is 2-3 BV / h.

5. The anti-cancer body cavity effusion targeting tablet according to claim 1, wherein, The targeting layer comprises a folate-modified mesoporous silica nanoparticle drug delivery system, the nanoparticle has a particle size of 50-100 nm, a drug loading capacity of ≥25%, and pH-responsive release characteristics.

6. The method for preparing the anticancer cavity effusion-targeting tablet according to any one of claims 1-5, characterized in that, The method comprises the following steps: (1) extraction and purification of the active components of traditional Chinese medicine; (2) preparation of the nanoparticle drug delivery system; (3) preparation of each layer of particles; (4) layered tabletting and coating; In step (4), the layered tabletting is performed by using a three-time charging and three-time tabletting process, the quick-release layer is first pressed, then the sustained-release layer is added and lightly pressed, and finally the targeting layer is added and finally pressed.

7. The method of claim 6, wherein, In step (4), the tabletting process environmental conditions are as follows: temperature 20-25°C, relative humidity 40-60%, particle size distribution 80-100 mesh, water content 2-4%, and tabletting speed 20-30 rpm.

Images