CN113230346B - A Chinese medicinal composition with anticancer effect and anticancer Chinese medicinal implant - Google Patents
A Chinese medicinal composition with anticancer effect and anticancer Chinese medicinal implant Download PDFInfo
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Abstract
A traditional Chinese medicine composition with anticancer function and an anticancer traditional Chinese medicine implant relate to a traditional Chinese medicine composition and an implant. Aiming at solving the problems of low inhibition rate of the existing traditional Chinese medicine composition on the proliferation of lung cancer cells and unstable release rate of an implant. The Chinese medicinal composition comprises Chinese medicinal extract, atractylenolide I and crocin. Preparing an implant: dissolving PLGA and mannitol in organic solvent, adding the Chinese medicinal composition, drying, molding, packaging, and sterilizing. The auxiliary release device containing the anticancer traditional Chinese medicine implant is composed of a medicine storage bin, foam plastics, a sheet anticancer traditional Chinese medicine implant and a mesh, the traditional Chinese medicine composition can inhibit the proliferation of tumor cells and has low toxic and side effects, and the auxiliary release device ensures the constant release rate.
Description
Technical Field
The invention relates to a traditional Chinese medicine composition with an anticancer effect and an anticancer traditional Chinese medicine implant.
Background
Primary bronchogenic carcinoma, lung cancer for short, is a malignant tumor originating from the bronchial mucosa or glands. In recent years, the incidence and mortality of lung cancer have both increased rapidly. Lung cancer is classified into non-small cell lung cancer and small cell lung cancer according to histopathology. Wherein, the non-small cell lung cancer accounts for 80 to 85 percent of the total number of the lung cancer, and comprises squamous carcinoma, adenocarcinoma, large cell carcinoma, adenosquamous carcinoma, carcinoid and the like. There are many lung cancer treatment methods, and although the diagnosis and treatment methods of lung cancer are continuously making new progress, due to the problems of tumor metastasis and multidrug resistance, the prognosis of lung cancer patients is still not good, and the five-year survival rate is only 8-15%. Chemotherapy is one of the main means for treating middle and late stage lung cancer at present, and the patients in middle and late stages can be generally treated by systemic chemotherapy to prevent the recurrence and metastasis of tumors and achieve the purpose of prolonging the survival time of the patients. The curative effect of chemotherapy is mainly related to the effective drug concentration in tumor tissues and the duration of action on tumors, and the dosage required for achieving the local effective concentration of tumor tissues by using the chemotherapy drugs intravenously is usually larger, so that the drug concentration of the whole body is high, and the adverse reaction of the whole body is serious. When the chemotherapy kills tumor cells, the chemotherapy also has a killing effect on normal tissue cells, has more side effects, such as bone marrow hematopoietic function inhibition, severe gastrointestinal reaction and the like, and influences the life quality of patients. Therefore, the search for new and effective lung cancer treatment drugs to further improve clinical efficacy has become one of the clinical problems to be solved urgently.
The combined medication becomes a new trend in the future, the combined medication can play the role of the synergistic treatment of the medicaments, improve the curative effect of the medicaments, relieve the toxic and side effect and delay or avoid the medicament resistance, but the prior Chinese medicinal composition has low anticancer activity and low proliferation inhibition rate on lung cancer cells, and influences the application of the Chinese medicament in the treatment of the lung cancer. The implant has long-acting effect, the drug release time is long, the drug use times can be reduced, but after the implant is released in vivo for a certain time, along with the dissolution of the implant, cavities are easily generated when the release speed of local drugs on the implant body is too high, so that the drug release rate is unstable.
Disclosure of Invention
The invention aims to solve the problems that the existing traditional Chinese medicine composition has low inhibition rate on lung cancer cell proliferation and the release rate of an implant medicine is unstable, and provides a traditional Chinese medicine composition with an anticancer effect and an anticancer traditional Chinese medicine implant.
The traditional Chinese medicine composition with the anticancer effect consists of a traditional Chinese medicine extract, atractylenolide I and crocin, wherein the mass ratio of the traditional Chinese medicine extract to the atractylenolide I to the crocin is 4:1 (8-10);
the preparation method of the traditional Chinese medicine extract comprises the following steps:
weighing 2-10 parts of pinellia ternate, 3-8 parts of snakegourd fruit, 10-20 parts of dried orange peel, 3-12 parts of allium macrostemon, 5-15 parts of coptis chinensis, 6-10 parts of semen lepidii and 3-8 parts of solanum dulcamara in parts by weight as raw materials;
secondly, crushing the raw materials weighed in the step one and uniformly mixing to obtain a mixture;
adding distilled water and cellulase into the mixture, and performing ultrasonic enzymolysis to obtain an enzymolysis solution;
adding absolute ethyl alcohol into the enzymatic hydrolysate, standing at room temperature, and filtering to obtain a precipitate;
fifthly, repeatedly purifying the precipitate obtained in the fourth step for 3-5 times;
the purification process comprises the following steps: adding 10-20 times of 60-90 ℃ distilled water in volume into the precipitate, stirring, filtering again, discarding the precipitate to obtain a supernatant, adding absolute ethyl alcohol into the supernatant, standing at room temperature, and filtering to obtain a precipitate;
sixthly, drying the product obtained by purification in the fifth step to obtain a traditional Chinese medicine extract; the drying temperature is 40-60 ℃.
The method for preparing the sheet-shaped anticancer traditional Chinese medicine implant by using the traditional Chinese medicine composition with the anticancer effect comprises the following steps: weighing 12-19 parts of the traditional Chinese medicine composition, 77-79 parts of PLGA (polylactic-co-glycolic acid) and 3-5 parts of mannitol in parts by weight, dissolving the PLGA and the mannitol in an organic solvent, adding the traditional Chinese medicine composition, uniformly mixing, carrying out vacuum drying to remove the organic solvent, then placing in a forming mold to prepare a sheet-shaped anticancer traditional Chinese medicine implant, and finally subpackaging and sterilizing;
the PLGA is PLGA (50: 50) with the molecular weight of 15000-25000, and the dosage of the organic solvent is based on the full dissolution of PLGA and mannitol.
An auxiliary release device containing the anticancer Chinese medicinal implant comprises a medicinal storage bin, foamed plastic, a sheet anticancer Chinese medicinal implant and a mesh sheet; the main body of the medicine storage bin is in a hollow oblate column shape, the upper end of the medicine storage bin is open, an annular limiting flange is arranged on the inner side wall of the opening at the upper end of the medicine storage bin, the foamed plastic is placed in the medicine storage bin, the volume of the foamed plastic is the same as that of the medicine storage bin, the flaky anti-cancer traditional Chinese medicine implant is placed on the foamed plastic, a mesh sheet covers the flaky anti-cancer traditional Chinese medicine implant, the mesh sheet is arranged on the lower portion of the limiting flange, and the aperture of the mesh sheet is 50-80 microns; the height of the medicine storage bin is 3-8 mm, and the inner diameter of the medicine storage bin is 4-13 mm; the volume of the medicine storage bin is 2-3 times of the volume of the sheet-shaped anticancer traditional Chinese medicine implant; the medicine storage bin, the foam plastic and the mesh sheet are made of polylactic acid with the molecular weight of 10.0-20.0 ten thousand.
The invention has the following beneficial effects:
the traditional Chinese medicine composition prepared by the invention can inhibit the proliferation of tumor cells, shows a better anticancer effect and has low toxic and side effects. When the mass ratio of the traditional Chinese medicine extract to the atractylenolide I to the crocin is 4:1 (8-10), the proliferation of lung cancer cells can be obviously inhibited, and the inhibition effect is better than that of the single traditional Chinese medicine extract to one of the atractylenolide I and the crocin.
When the auxiliary release device containing the anticancer traditional Chinese medicine implant is used, the auxiliary release device is implanted into tumor tissues, tissues around tumor, tumor beds after tumor resection or other parts needing drug delivery, so that targeted drug delivery is realized, the drug concentration of local tissues is higher, the drug concentration of the whole body is not high, the curative effect is improved, and the adverse reaction of the whole body is reduced.
The upper end of an auxiliary release device containing the anticancer traditional Chinese medicine implant is open, the foam plastic 2, the sheet anticancer traditional Chinese medicine implant 3 and the mesh 4 are arranged in the medicine storage bin 1, and the foam plastic 2, the sheet anticancer traditional Chinese medicine implant 3 and the mesh 4 are limited in the medicine storage bin 1 by an annular limiting flange 5; the pore diameter of the mesh 4 is 50-80 mu m, the pore diameter of the mesh is similar to the size of pores formed by interweaving fibers in interstitial tissue, so that the mesh is favorably combined with and adhered to in vivo tissues, and meanwhile, the foam plastic 2 is in a compressed state, so that the sheet-shaped anticancer traditional Chinese medicine implant 3 is in close contact with the mesh 4 and the tissues in a medicine release period, and the constant release rate is ensured; and interruption of drug release caused by cavity formation after drug release is also avoided.
The amount of the anticancer agent of the present invention to be used depends on many factors such as tumor volume, patient weight, patient age, progress of disease and therapeutic response. But the principle is that the proliferation of lung cancer cells can be inhibited, the release rate is ensured to be constant, and the toxic reaction of the medicine is not obviously increased.
The use method of the implant comprises the following steps: the auxiliary release device containing the anticancer traditional Chinese medicine implant can be implanted into the tumor, the periphery of the tumor or the position needing administration by the operation; the tumor which can be cut off in the operation can be implanted into the tumor bed after the tumor is cut off, so as to prevent the tumor from relapse.
Drawings
FIG. 1 is a schematic view of the structure of an auxiliary release device containing an anticancer Chinese medicinal implant according to example 4;
FIG. 2 is the in vitro release profile of the drug of example 4;
FIG. 3 is a graph showing the in vivo release rate of the drug in example 4.
Detailed Description
The technical scheme of the invention is not limited to the specific embodiments listed below, and any reasonable combination of the specific embodiments is included.
The first embodiment is as follows: the traditional Chinese medicine composition with the anticancer effect consists of a traditional Chinese medicine extract, atractylenolide I and crocin, wherein the mass ratio of the traditional Chinese medicine extract to the atractylenolide I to the crocin is 4:1 (8-10);
the preparation method of the traditional Chinese medicine extract comprises the following steps:
weighing 2-10 parts of pinellia ternate, 3-8 parts of snakegourd fruit, 10-20 parts of dried orange peel, 3-12 parts of allium macrostemon, 5-15 parts of coptis chinensis, 6-10 parts of semen lepidii and 3-8 parts of solanum dulcamara in parts by weight as raw materials;
secondly, crushing the raw materials weighed in the step one and uniformly mixing to obtain a mixture;
adding distilled water and cellulase into the mixture, and performing ultrasonic enzymolysis to obtain an enzymolysis solution;
adding absolute ethyl alcohol into the enzymatic hydrolysate, standing at room temperature, and filtering to obtain a precipitate;
fifthly, repeatedly purifying the precipitate obtained in the fourth step for 3-5 times;
the purification process comprises the following steps: adding 10-20 times of 60-90 ℃ distilled water in volume into the precipitate, stirring, filtering again, discarding the precipitate to obtain a supernatant, adding absolute ethyl alcohol into the supernatant, standing at room temperature, and filtering to obtain a precipitate;
sixthly, drying the product obtained by purification in the fifth step to obtain a traditional Chinese medicine extract; the drying temperature is 40-60 ℃.
The embodiment has the following beneficial effects:
the traditional Chinese medicine composition can inhibit the proliferation of tumor cells, shows a better anticancer effect and has low toxic and side effects. When the mass ratio of the traditional Chinese medicine extract to the atractylenolide I to the crocin is 4:1 (8-10), the proliferation of lung cancer cells can be obviously inhibited, and the inhibition effect is better than that of the single traditional Chinese medicine extract to one of the atractylenolide I and the crocin.
The second embodiment is as follows: the first difference between the present embodiment and the specific embodiment is: the traditional Chinese medicine composition with the anticancer effect consists of a traditional Chinese medicine extract, atractylenolide I and crocin, wherein the mass ratio of the traditional Chinese medicine extract to the atractylenolide I to the crocin is 4:1: 8.
The third concrete implementation mode: the present embodiment differs from the first or second embodiment in that: the traditional Chinese medicine composition with the anticancer effect consists of a traditional Chinese medicine extract, atractylenolide I and crocin, wherein the mass ratio of the traditional Chinese medicine extract to the atractylenolide I to the crocin is 4:1: 10.
The fourth concrete implementation mode: the difference between this embodiment mode and one of the first to third embodiment modes is: the temperature of ultrasonic enzymolysis in the third step is 37 ℃, and the time of ultrasonic enzymolysis is 2-5 h; the volume ratio of the mass of the mixture to the distilled water is 1g (3 mL-5 mL).
The fifth concrete implementation mode: the difference between this embodiment and one of the first to fourth embodiments is: the volume ratio of the enzymolysis liquid to the absolute ethyl alcohol in the fourth step is (5-10) to (90-95); the standing time is 10-20 h.
The sixth specific implementation mode: the difference between this embodiment and one of the first to fifth embodiments is: in the fifth step, the volume ratio of the supernatant to the absolute ethyl alcohol is (5-10) to (90-95).
The seventh embodiment: the difference between this embodiment and one of the first to sixth embodiments is: the stirring time in the fifth step is 20min to 40 min; the room temperature standing time is 10-20 h.
The specific implementation mode is eight: the method for preparing the sheet-shaped anticancer traditional Chinese medicine implant by using the traditional Chinese medicine composition with the anticancer effect is carried out according to the following steps:
weighing 12-19 parts of the traditional Chinese medicine composition, 77-79 parts of PLGA (polylactic-co-glycolic acid) and 3-5 parts of mannitol in parts by weight, dissolving the PLGA and the mannitol in an organic solvent, adding the traditional Chinese medicine composition, uniformly mixing, carrying out vacuum drying to remove the organic solvent, then placing in a forming mold to prepare a sheet-shaped anticancer traditional Chinese medicine implant, and finally subpackaging and sterilizing;
the molecular weight of the PLGA is 15000-25000. The amount of organic solvent is such that PLGA and mannitol are sufficiently dissolved.
The specific implementation method nine: the auxiliary release device containing the anticancer traditional Chinese medicine implant in the embodiment is composed of a medicine storage bin 1, foam plastic 2, a sheet-shaped anticancer traditional Chinese medicine implant 3 and a mesh 4; the main body of the medicine storage bin 1 is in a hollow oblate column shape, the upper end of the medicine storage bin 1 is open, an annular limiting flange 5 is arranged on the inner side wall of the upper end opening of the medicine storage bin 1, the foamed plastic 2 is placed in the medicine storage bin 1, the volume of the foamed plastic 2 is the same as that of the medicine storage bin 1, the flaky anti-cancer traditional Chinese medicine implant 3 is placed on the foamed plastic 2, the foamed plastic is in a compressed state, a net piece 4 covers the flaky anti-cancer traditional Chinese medicine implant 3, the net piece 4 is arranged on the lower portion of the limiting flange 5, and the aperture of the net piece 4 is 50-80 micrometers; the height of the medicine storage bin 1 is 3-8 mm, and the inner diameter is 4-13 mm; the volume of the medicine storage bin 1 is 2-3 times of the volume of the sheet-shaped anticancer traditional Chinese medicine implant 3; the medicine storage bin 1, the foam plastic 2 and the net piece 4 are made of polylactic acid with the molecular weight of 10.0-20.0 ten thousand; the molecular weight of PLGA in the sheet-shaped anticancer traditional Chinese medicine implant is 15000-25000; the molecular weights of the medicine storage bin 1, the foam plastic 2 and the mesh 4 are larger than that of PLGA in the flaky anticancer traditional Chinese medicine implant, and the medicine storage bin, the foam plastic 2 and the mesh 4 can be completely degraded after the flaky anticancer traditional Chinese medicine implant 3 is released for a period of time.
When the auxiliary release device containing the anticancer traditional Chinese medicine implant is used, the auxiliary release device is implanted into tumor tissues, tissues around tumor, tumor beds after tumor resection or other parts needing drug delivery, so that targeted drug delivery is realized, the drug concentration of local tissues is higher, the drug concentration of the whole body is not high, the curative effect is improved, and the adverse reaction of the whole body is reduced.
The upper end of an auxiliary release device containing the anticancer traditional Chinese medicine implant is open, the foam plastic 2, the sheet anticancer traditional Chinese medicine implant 3 and the mesh 4 are arranged in the medicine storage bin 1, and the foam plastic 2, the sheet anticancer traditional Chinese medicine implant 3 and the mesh 4 are limited in the medicine storage bin 1 by an annular limiting flange 5; the pore diameter of the mesh 4 is 50-80 mu m, the pore diameter of the mesh is similar to the size of pores formed by interweaving fibers in interstitial tissue, so that the mesh is favorably combined with and adhered to in vivo tissues, and meanwhile, the foam plastic 2 is in a compressed state, so that the sheet-shaped anticancer traditional Chinese medicine implant 3 is in close contact with the mesh 4 and the tissues in a medicine release period, and the constant release rate is ensured; and interruption of drug release caused by cavity formation after drug release is also avoided.
The detailed implementation mode is ten: the present embodiment differs from the ninth embodiment in that: the volume of the medicine storage bin 1 is 3 times of the volume of the sheet-shaped anticancer traditional Chinese medicine implant 3.
Example 1
The preparation method of the traditional Chinese medicine extract is carried out according to the following steps:
weighing 5 parts of pinellia ternate, 5 parts of snakegourd fruit, 15 parts of dried orange peel, 7 parts of allium macrostemon, 6 parts of coptis chinensis, 8 parts of semen lepidii and 4 parts of solanum dulcamara in parts by weight as raw materials, wherein the raw materials are dry products;
secondly, crushing the raw materials weighed in the step one and uniformly mixing to obtain a mixture;
adding distilled water and cellulase into the mixture, and performing ultrasonic enzymolysis to obtain an enzymolysis solution; the temperature of ultrasonic enzymolysis in the third step is 37 ℃, and the time of ultrasonic enzymolysis is 4 hours; the volume ratio of the mass of the mixture in the third step to the distilled water is 1g:4 mL;
adding absolute ethyl alcohol into the enzymatic hydrolysate, standing at room temperature, and filtering to obtain a precipitate; the volume ratio of the enzymolysis liquid to the absolute ethyl alcohol in the step four is 8: 93; the standing time in the fourth step is 11 hours;
fifthly, repeatedly purifying the precipitate obtained in the fourth step for 4 times;
the purification process comprises the following steps: adding 17 times volume of 70 deg.C distilled water into the precipitate, stirring, filtering, discarding precipitate to obtain supernatant, adding anhydrous ethanol into the supernatant, standing at room temperature, and filtering to obtain precipitate;
in the fifth step, the volume ratio of the supernatant to the absolute ethyl alcohol is 8: 93; the stirring time in the fifth step is 30 min; the standing time at room temperature is 11 h;
sixthly, drying the product obtained by purification in the fifth step at the drying temperature of 50 ℃ to obtain the traditional Chinese medicine extract.
Example 2
This example is an experiment of the effect of the Chinese medicinal composition on the in vitro proliferation of human lung cancer A549 cells:
this example was carried out by MTT method, and human lung cancer A549 cells (gift from anatomical textroom of Harbin medical university) in logarithmic growth phase were collected and adjusted to a cell concentration of 1X 10 in RPMI1640 medium containing 10% FBS5one/mL, then seeded into 96 well cell culture plates at 200 μ L per well. When the cells adhere to 70% -80%, the culture solution is discarded. Blank groups (without cells), control groups and experimental groups 1-8 are set for 10 groups, and each group is set for 5 replicates. Adding 200 μ L of culture solution into each well of the blank group and the control group, adding 200uL of culture solution containing the drug into each well of each group of the experimental group, wherein the drug components and the concentration of the experimental group are shown in Table 1, preparing the traditional Chinese medicine extract adopted by the experimental group as the example 1, adding 20 μ L MTT (5mg/mL) into each well after culturing for 48h, culturing for 4h in a dark place, sucking and removing the supernatant, adding 150 μ L DMSO into each well, oscillating at a low speed for 10min, and measuring the OD value at 490nm by using a microplate reader. The inhibition rate of each experimental group medicament on A549 cell proliferation is calculated according to the following formula: the inhibition rate was 1- (drug OD value-blank OD value)/(control OD value-blank OD value) × 100%.
The experimental results are as follows:
as can be seen from Table 1, the traditional Chinese medicine extract, the atractylenolide I and the crocin which are independently used have the effect of inhibiting the in vitro proliferation of the human lung cancer A549 cells, and when the mass ratio of the traditional Chinese medicine extract to the atractylenolide I to the crocin is 4:1 (8-10), the growth of the lung cancer cells can be significantly inhibited, the inhibition rate of the proliferation of the lung cancer cells is improved, and the synergistic inhibition effect is achieved.
TABLE 1 inhibition of A549 cell proliferation by drugs (n ═ 5)
Example 3
The embodiment is the preparation of the anticancer traditional Chinese medicine implant:
the preparation of the anticancer traditional Chinese medicine implant is carried out according to the following steps: weighing 4 parts of traditional Chinese medicine extract (obtained in example 1), 1 part of atractylenolide I and 8 parts of crocin according to parts by weight, and uniformly mixing to obtain a traditional Chinese medicine composition;
weighing 18 parts of the traditional Chinese medicine composition, 78 parts of PLGA and 4 parts of mannitol in parts by weight, dissolving the PLGA and the mannitol in dichloromethane, adding the traditional Chinese medicine composition, uniformly mixing, carrying out vacuum drying to remove the dichloromethane, then placing in a forming mold to prepare a sheet-shaped anticancer traditional Chinese medicine implant, and finally subpackaging and sterilizing; the PLGA is PLGA (50: 50) with the molecular weight of 15000-25000, and the dosage of the dichloromethane is based on the full dissolution of the PLGA and the mannitol.
In this example, a tablet-shaped anticancer traditional Chinese medicine implant with a drug content of 9mg and a tablet-shaped anticancer traditional Chinese medicine implant with a drug content of 3mg are prepared for an in vitro release degree test, an in vivo release degree test and a pharmacodynamic test, and the drug content refers to the mass of a traditional Chinese medicine composition contained in the tablet-shaped anticancer traditional Chinese medicine implant.
Example 4
This example is an in vitro release test, an in vivo release test and a pharmacodynamic test.
In vitro release test:
1. weighing 12 pieces of the sheet-shaped anticancer traditional Chinese medicine implant with the medicine content of 9mg prepared in the embodiment 3 respectively;
2. measuring the content of crocin in 6 sheets of the anticancer Chinese medicinal implant by spectrophotometry, and calculating the average content of crocin;
3. respectively placing the other 6 sheet-shaped anticancer traditional Chinese medicine implants in the weighed auxiliary release devices to obtain the auxiliary release devices containing the anticancer traditional Chinese medicine implants;
4. placing the auxiliary release devices containing the anticancer traditional Chinese medicine implant into 10mL test tubes with plugs respectively, adding 5mL of purified water with the pH value of 7.0 into each test tube, placing the test tubes into a water bath at the temperature of (37 +/-0.5) DEG C, taking out all liquid in the test tubes respectively every day, supplementing the purified water with the same temperature and volume, continuing to place the test tubes into the water bath at the temperature of (37 +/-0.5) DEG C, respectively detecting the amount of crocin in the liquid taken out every day by a spectrophotometry method, and calculating the release degree, wherein the result is shown in figure 2. As seen from FIG. 2, the cumulative release reached 21.7% on day 3, the release rate was relatively constant from day 6 to day 44, and the release was complete without lag phase.
In vivo release test:
1. weighing 42 pieces of the sheet-shaped anticancer traditional Chinese medicine implant with the medicine content of 9mg prepared in the embodiment 3 respectively;
2. detecting the content of crocin in 3 tablets by high performance liquid chromatography, and calculating the average content of crocin as the content of crocin before implantation.
3. Respectively placing the other 39 pieces of the sheet-shaped anticancer traditional Chinese medicine implant into weighed auxiliary release devices to obtain the auxiliary release devices containing the anticancer traditional Chinese medicine implant;
4. taking 39 Wistar rats (purchased from Beijing Wittingle laboratory animal technology Co., Ltd.), and implanting 1 auxiliary release device containing an anticancer traditional Chinese medicine implant into the inner side of the right hind limb of each rat respectively by adopting an operation after anesthesia;
5. 3 rats were sacrificed at 1, 3, 5, 7, 10, 15, 20, 25, 30, 35, 40, 45, and 50 days after implantation, the remaining auxiliary release device containing the anticancer Chinese medicinal implant was removed, the remaining sheet-like anticancer Chinese medicinal implant was separated and the residual amount of crocin in the implant was detected by high performance liquid chromatography, and the release degree was calculated based on the content and residual amount of crocin before implantation, and the results are shown in fig. 3. The weight of the auxiliary release device taken out on the 50 th day is reduced by 20.7% in average compared with that before the implantation, the auxiliary release device starts to degrade from the outer surface, but the strength is not obviously reduced, and the auxiliary release device can be completely degraded in vivo after the sheet-shaped anticancer traditional Chinese medicine implant is released for a period of time;
the in vivo release rate result is shown in figure 3, the crocin can be released in rats for 50 days continuously, the initial release rate is higher, the effective concentration can be reached in a short time, and the occurrence of drug resistance of tumor cells is reduced, the accumulated release on day 1 reaches 8.9%, the accumulated release on day 3 reaches 20.6%, the release on day 5 reaches 29.3%, the release rate on day 7 reaches 36.5%, the later release rate is more stable, the release rate on day 10 reaches 41.0%, the release rate on day 15 reaches 50.1%, the release rate on day 20 reaches 56.9%, the release rate on day 25 reaches 67.5%, the release rate on day 30 reaches 77.1%, the release rate on day 35 reaches 82.9%, the release rate on day 40 reaches 88.0%, the release rate on day 45 reaches 94.0%, and the release rate on day 50 reaches 97.3%.
Pharmacodynamic tests:
the human lung cancer A549 cells (donated by the anatomic textbook room of Harbin medical university) in logarithmic growth phase were collected and prepared to a cell concentration of 1X 10 with PBS solution7The cell suspension of each/mL is injected into the right back subcutaneous part of a 7-week-old male BALB/c nude mouse at a dose of 0.1mL for each, and the weight of the nude mouse is 18-20 g (purchased from Beijing Wintonlihua laboratory animal technology Co., Ltd.). After the nude mice are bred for 10 days conventionally, 20 nude mice with tumor body diameter about 0.5cm are selected and randomly divided into 2 groups of a control group and a drug group, and 10 mice in each group.
Implanting 1 auxiliary release device without a sheet-shaped anticancer traditional Chinese medicine implant into each nude mouse of a control group, implanting 1 auxiliary release device containing a sheet-shaped anticancer traditional Chinese medicine implant into each nude mouse of a drug group, wherein the sheet-shaped anticancer traditional Chinese medicine implant is the sheet-shaped anticancer traditional Chinese medicine implant with the drug content of 3mg prepared in example 3, implanting the implant by an operation after anesthesia, wherein the implantation parts are edges of dermatoma nodules of the nude mice, killing the nude mice after 21 days, stripping tumors, and weighing the tumor weight according to a formula: the tumor inhibition rate was (1-mean tumor weight in drug group/mean tumor weight in control group) × 100%, and the tumor inhibition rate was calculated. The results showed that the tumor weight of the control group was (2.73. + -. 0.28) g, the tumor weight of the drug group was (0.60. + -. 0.12) g, and the tumor inhibition rate was 78.02%.
The auxiliary release device containing the anticancer traditional Chinese medicine implant in the embodiment is composed of a medicine storage bin 1, foam plastic 2, a sheet-shaped anticancer traditional Chinese medicine implant 3 and a mesh 4; the main part in medicine storage 1 is hollow oblate column shape, the internal diameter in medicine storage 1 is the same with the external diameter of the anticancer traditional chinese medicine implant 3 of slice, the upper end in medicine storage 1 is uncovered, the open inside wall in upper end in medicine storage 1 is provided with annular spacing flange 5, foam 2 that is compression state places in medicine storage 1, the anticancer traditional chinese medicine implant 3 of slice is placed on foam 2, the anticancer traditional chinese medicine implant 3 of slice coats and is stamped net piece 4, net piece 4 sets up in spacing flange 5 lower part. The mesh has deformability, and when the device is installed, the mesh and the sheet anticancer traditional Chinese medicine implant are pressed into the lower part of the limiting flange, so that the foamed plastic is compressed, the mesh and the flange are tightly clamped, and the foamed plastic, the sheet anticancer traditional Chinese medicine implant and the mesh are limited in the medicine storage bin; the aperture of the mesh 4 is 50-80 μm; the medicine storage bin 1, the foamed plastic 2 and the mesh 4 are made of polylactic acid with the molecular weight (viscosity average molecular weight) of 10.0-20.0 ten thousand, the type is PLLA-40, the polylactic acid is purchased from Doudukang biomedical materials Co., Ltd, the type is PLLA-40, and the volume of the medicine storage bin 1 is 3 times of that of the sheet-shaped anticancer traditional Chinese medicine implant 3.
Claims (8)
1. A sheet-shaped anticancer traditional Chinese medicine implant containing an anticancer traditional Chinese medicine composition is characterized in that: consists of an anticancer traditional Chinese medicine implant and an auxiliary release device;
the anticancer traditional Chinese medicine implant is prepared according to the following steps: weighing 12-19 parts of the traditional Chinese medicine composition, 77-79 parts of PLGA and 3-5 parts of mannitol in parts by weight, dissolving the PLGA and the mannitol in an organic solvent, adding the traditional Chinese medicine composition, uniformly mixing, carrying out vacuum drying to remove the organic solvent, then placing in a forming mold to prepare a sheet-shaped anticancer traditional Chinese medicine implant, and finally subpackaging and sterilizing;
the molecular weight of the PLGA is 15000-25000;
the traditional Chinese medicine composition consists of a traditional Chinese medicine extract, atractylenolide I and crocin, wherein the mass ratio of the traditional Chinese medicine extract to the atractylenolide I to the crocin is 4:1 (8-10);
the preparation method of the traditional Chinese medicine extract comprises the following steps:
weighing 2-10 parts of pinellia ternate, 3-8 parts of snakegourd fruit, 10-20 parts of dried orange peel, 3-12 parts of allium macrostemon, 5-15 parts of coptis chinensis, 6-10 parts of semen lepidii and 3-8 parts of solanum dulcamara in parts by weight as raw materials;
secondly, crushing the raw materials weighed in the step one and uniformly mixing to obtain a mixture;
adding distilled water and cellulase into the mixture, and performing ultrasonic enzymolysis to obtain an enzymolysis solution;
adding absolute ethyl alcohol into the enzymatic hydrolysate, standing at room temperature, and filtering to obtain a precipitate;
fifthly, repeatedly purifying the precipitate obtained in the fourth step for 3-5 times;
sixthly, drying the product obtained by purification in the fifth step to obtain a traditional Chinese medicine extract; the drying temperature is 40-60 ℃;
the purification process comprises the following steps: adding 10-20 times of 60-90 ℃ distilled water in volume into the precipitate, stirring, filtering again, discarding the precipitate to obtain a supernatant, adding absolute ethyl alcohol into the supernatant, standing at room temperature, and filtering to obtain a precipitate;
the auxiliary release device consists of a medicine storage bin (1), foam plastic (2), a sheet-shaped anticancer traditional Chinese medicine implant (3) and a mesh (4); the main body of the medicine storage bin (1) is in a hollow oblate column shape, the upper end of the medicine storage bin (1) is open, an annular limiting flange (5) is arranged on the inner side wall of the upper end opening of the medicine storage bin (1), the foamed plastic (2) is placed in the medicine storage bin (1), the volume of the foamed plastic (2) is the same as the volume of the medicine storage bin (1), the flaky anticancer traditional Chinese medicine implant (3) is placed on the foamed plastic (2), a mesh (4) covers the flaky anticancer traditional Chinese medicine implant (3), the mesh (4) is arranged on the lower portion of the limiting flange (5), and the aperture of the mesh (4) is 50-80 micrometers; the height of the medicine storage bin (1) is 3-8 mm, and the inner diameter is 4-13 mm; the volume of the drug storage bin (1) is 2-3 times of the volume of the sheet-shaped anticancer traditional Chinese medicine implant (3); the medicine storage bin (1), the foam plastic (2) and the net piece (4) are made of polylactic acid with the molecular weight of 10.0-20.0 ten thousand.
2. The sheet-shaped anticancer traditional Chinese medicine implant containing anticancer traditional Chinese medicine composition according to claim 1, characterized in that: the traditional Chinese medicine composition consists of a traditional Chinese medicine extract, atractylenolide I and crocin, wherein the mass ratio of the traditional Chinese medicine extract to the atractylenolide I to the crocin is 4:1: 8.
3. The sheet-shaped anticancer traditional Chinese medicine implant containing anticancer traditional Chinese medicine composition according to claim 1, characterized in that: the traditional Chinese medicine composition consists of a traditional Chinese medicine extract, atractylenolide I and crocin, wherein the mass ratio of the traditional Chinese medicine extract to the atractylenolide I to the crocin is 4:1: 10.
4. The sheet-shaped anticancer traditional Chinese medicine implant containing anticancer traditional Chinese medicine composition according to claim 1, characterized in that: the temperature of ultrasonic enzymolysis in the third step is 37 ℃, and the time of ultrasonic enzymolysis is 2-5 hours; the volume ratio of the mass of the mixture to the distilled water is 1g (3 mL-5 mL).
5. The sheet-shaped anticancer traditional Chinese medicine implant containing anticancer traditional Chinese medicine composition according to claim 1, characterized in that: the volume ratio of the enzymolysis liquid to the absolute ethyl alcohol in the fourth step is (5-10) to (90-95); the standing time is 10-20 h.
6. The sheet-shaped anticancer traditional Chinese medicine implant containing anticancer traditional Chinese medicine composition according to claim 1, characterized in that: in the fifth step, the volume ratio of the supernatant to the absolute ethyl alcohol is (5-10) to (90-95).
7. The sheet-shaped anticancer traditional Chinese medicine implant containing anticancer traditional Chinese medicine composition according to claim 1, characterized in that: fifthly, the stirring time is 20-40 min; the standing time at room temperature is 10-20 h.
8. The sheet-shaped anticancer traditional Chinese medicine implant containing anticancer traditional Chinese medicine composition according to claim 1, characterized in that: the volume of the medicine storage bin (1) is 3 times of that of the sheet-shaped anticancer traditional Chinese medicine implant (3).
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Application publication date: 20210810 Assignee: Harbin Pujitang Traditional Chinese Medicine Hall Co.,Ltd. Assignor: HEILONGJIANG University OF CHINESE MEDICINE Contract record no.: X2023980036235 Denomination of invention: A Chinese medicine composition with anticancer effects and an anticancer Chinese medicine implant Granted publication date: 20220401 License type: Common License Record date: 20230606 |
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