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CN113509439A - Application of self-emulsifying delivery system in preparation of oral medicine for treating lymphatic metastasis tumor - Google Patents

Application of self-emulsifying delivery system in preparation of oral medicine for treating lymphatic metastasis tumor Download PDF

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CN113509439A
CN113509439A CN202110784259.XA CN202110784259A CN113509439A CN 113509439 A CN113509439 A CN 113509439A CN 202110784259 A CN202110784259 A CN 202110784259A CN 113509439 A CN113509439 A CN 113509439A
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self
delivery system
combination
emulsifier
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陈晓光
刘玉玲
叶军
杨艳芳
高越
季鸣
刘东东
冯遇
李仁杰
徐晓燕
廖恒锋
李燕
金晶
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Borui Pioneer Beijing Biotechnology Co ltd
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Abstract

The invention relates to an application of a self-emulsifying delivery system in preparing an oral medicament for treating lymphatic metastasis tumor, wherein the self-emulsifying delivery system comprises an oil phase, an emulsifier, a co-emulsifier and an immunomodulator lipid material compound. The self-emulsifying delivery system is a lipid carrier mainly composed of an oil phase, an emulsifying agent and an auxiliary emulsifying agent, can be diluted by gastrointestinal fluid and emulsified into an oil-in-water (o/w) nano-emulsion after being taken orally, is targeted and gathered in mesenteric lymph nodes through a lymph transport path, activates immune cells in the mesenteric lymph nodes, and finally exerts the immune effect of resisting tumors (particularly lymphatic metastasis tumors). The self-emulsifying delivery system can not only improve the compliance of patients, but also has more treatment advantages on tumors which are transferred by lymph, especially tumors which are sensitive to tumor immunotherapy.

Description

Application of self-emulsifying delivery system in preparation of oral medicine for treating lymphatic metastasis tumor
Technical Field
The invention belongs to the technical field of biological medicines, relates to a novel pharmaceutical application of a self-emulsifying delivery system, and particularly relates to an application of the self-emulsifying delivery system in preparing an oral medicine for treating lymphatic metastasis tumors.
Background
Tumor metastasis is a process in which tumor cells are shed from primary foci, migrate to other parts through lymphatic vessels or blood vessels, and continue to grow, and is the leading cause of death of tumor patients. Metastasis of tumor cells tends to be somewhat directional, like "seeds", migrating selectively towards a microenvironment more suitable for their growth. For example, breast cancer is susceptible to lung, bone and brain metastases, colon cancer is susceptible to lung and liver metastases, and pancreatic cancer is susceptible to liver metastases. Tumor metastasis is mainly divided into two pathways, namely hematogenous metastasis and lymphatic metastasis. Malignant tumors are more prone to metastasize via the lymphatic system, which is thus the primary route of spread for many solid tumors (e.g., melanoma, breast cancer, etc.), than transvascular metastasis. The main reasons are as follows: (1) compared with the vascular structure, the endothelial cells of the lymphatic vessels are loosely connected, and the basement membrane is not complete enough, so that the tumor cells can enter the lymphatic vessels more easily; (2) the flow rate of lymph fluid is slow, so that tumor cells can survive in the lymphatic system more easily; (3) the serum-free lymphatic environment allows the cells to have higher viability in the lymphatic fluid.
Surgical resection, chemotherapy, radiotherapy and tumor immunotherapy are four major current therapies for tumor treatment. However, when the tumor is metastasized, there may be multiple metastases (e.g., lymph node metastasis), and it is difficult to eradicate all metastases by surgical resection and radiotherapy, with the resulting damage to the patient being greater. While chemotherapy drugs or immunotherapy drugs which are systemically administered are often resident in blood or visceral organs and are difficult to enter the lymphatic system, which seriously affects the treatment effect on lymphatic metastases. Therefore, inhibiting the lymphatic metastasis of tumors is one of the major research points in the field of tumor therapy today. For caffeoylquinic acid immunomodulators such as chlorogenic acid, good tumor immunotherapy effect is difficult to be achieved by oral administration, and only injection administration can be adopted clinically. However, the stimulation effect of injection administration on immune cells such as T cells, DC cells, macrophages and the like is not very ideal, so that the long-time frequent injection and the intramuscular injection for several months and once a day are needed clinically, so that the patient compliance is poor, and the clinical treatment and application are limited.
Oral administration has superior compliance compared to invasive administration by injection. However, it is difficult for caffeoylquinic acid immunomodulators to exhibit good immunotherapeutic effects when administered orally. According to the recognition of those skilled in the art, even if the bioavailability is increased by absorption-promoting techniques, the effect of administration by injection is far from being achieved, and an oral preparation useful for clinical treatment cannot be obtained. For the immunoregulation active ingredients, a specific nano delivery tool is adopted, so that the oral absorption is improved, the functions of activating T cells and other immune cells in intestinal tracts and enhancing the immunotherapy effect are realized, and the preparation of an oral preparation for transferring tumors through lymph is developed.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a novel pharmaceutical application of a self-emulsifying delivery system, and particularly provides an application of the self-emulsifying delivery system containing an oil phase, an emulsifier, a co-emulsifier and an immunomodulator lipid material complex in preparing an oral medicament for treating lymphatic metastasis tumors.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides an application of a self-emulsifying delivery system in preparing an oral medicament for treating lymphatic metastasis tumor, wherein the self-emulsifying delivery system comprises an oil phase, an emulsifier, a co-emulsifier and an immunomodulator lipid material compound.
The self-emulsifying delivery system is a lipid carrier mainly composed of an oil phase, an emulsifying agent and an auxiliary emulsifying agent, can be diluted by gastrointestinal fluid and emulsified into an oil-in-water (o/w) nano-emulsion after being taken orally, is targeted and gathered in mesenteric lymph nodes through a lymph transport path, activates immune cells in the mesenteric lymph nodes, and finally exerts the immune effect of resisting tumors (particularly lymphatic metastasis tumors). The self-emulsifying delivery system can not only improve the compliance of patients, but also has more treatment advantages on tumors which are transferred by lymph, especially tumors which are sensitive to tumor immunotherapy.
Preferably, the lymphatic metastatic tumor is a tumor that can be treated by activating immune cells in the lymphatic system and/or lymphatic organs.
Preferably, the immune cells comprise any one or a combination of at least two of DC cells, T cells, B cells, NK cells or macrophages.
The combination of at least two of the above-mentioned combinations, such as the combination of DC cells and T cells, the combination of B cells and NK cells, the combination of NK cells and macrophages, etc., can be selected in any other combination manner, and is not repeated herein.
Preferably, the lymphoid metastatic tumour comprises brain glioma, lung cancer or leukaemia.
The brain glioma is the most common and fatal primary malignancy in the central nervous system, with a 5-year relative survival rate of less than 5%, and eventually relapses. The conventional therapy of brain glioma is to combine the resection with radiotherapy and temozolomide chemotherapy, and the effect is still not ideal. The limitations of conventional surgery are mainly due to the diffuse infiltrative nature of tumors, preventing complete resection of normal brain parenchymal infiltrating cells, and new therapies are urgently needed clinically to improve patient prognosis.
The incidence and mortality of lung cancer are high in the first place worldwide. Since early symptoms of lung cancer are not obvious, most patients have been diagnosed with locally diffuse or distant metastasis, leading to poor prognosis. Traditional therapies (surgery, radiation therapy and chemotherapy) have limited efficacy in controlling the progression of advanced lung cancer. Molecular targeted therapy is effective against specific molecular types of lung cancer, but acquired resistance usually occurs after 8-12 months of administration. The tumor immunotherapy, especially the related immune checkpoint inhibitor, has a rapid progress in the field of lung cancer treatment, and the adaptive syndrome is continuously approved at home and abroad, so that the tumor immunotherapy has an excellent clinical treatment prospect.
The leukemia is a hematological malignancy caused by differentiation disorder, apoptosis obstruction and clonal proliferation of hematopoietic stem cells at different differentiation stages, and the existing leukemia treatment methods comprise chemotherapy, radiotherapy, immunotherapy, targeted therapy, stem cell transplantation and the like. Leukemia is the first in the morbidity and mortality of malignant tumors in the population of 0-35 years old, and with the development of treatment methods, the complete remission rate is improved, but the recurrence rate is high. Immunotherapy of leukemia is based on the effect of a cell graft that can cure the disease on leukemia or can be defined as using the host's own cellular immunity against underlying disease, which can be accomplished by either enhancing the host's immune system or suppressing negative regulators. With the research and development of immunotherapy, the number of immune cells and immune pathways utilized by the immunotherapy is increasing, so that the clinical curative effect of leukemia is gradually improved.
The glioma, the lung cancer and the leukemia have high morbidity and mortality, poor prognosis and are easy to transfer through lymph.
Preferably, the emulsifier comprises any one or a combination of at least two of polyethylene glycol glyceride, caprylic/capric polyethylene glycol glyceride, oleic polyethylene glycol glyceride or linoleic polyethylene glycol glyceride; caprylic capric acid polyethylene glycol glyceride is preferred.
Compared with other types of emulsifiers, the caprylic capric acid polyethylene glycol glyceride as the emulsifier enables the finally formed self-emulsifying delivery system to have better emulsifying efficiency, tissue penetrability and safety, and further enables the self-emulsifying delivery system to have better absorption and lower gastrointestinal tract irritation in vivo.
The combination of at least two of the above-mentioned combinations, for example, the combination of macrogol glyceride and caprylic/capric macrogol glyceride, the combination of caprylic/capric macrogol glyceride and oleic macrogol glyceride, the combination of oleic macrogol glyceride and linoleic macrogol glyceride, etc., and any other combination mode can be selected, and thus, the description thereof is omitted.
Preferably, the coemulsifier comprises any one of propylene carbonate, ethylene glycol monoethyl ether, glycerol furfural, dimethyl isosorbide, diethylene glycol monoethyl ether, PEG400, glycerol or benzyl alcohol or a combination of at least two of them; a combination of dimethyl isosorbide and diethylene glycol monoethyl ether is preferred.
The combination of at least two of the above-mentioned compounds, such as the combination of propylene carbonate and ethylene glycol monoethyl ether, the combination of furfural glycerol and dimethyl isosorbide, the combination of glycerol and benzyl alcohol, etc., can be selected in any combination manner, and will not be described herein again.
Preferably, the oil phase comprises oleic acidEthyl ester, sorbitol oleate, glyceryl linoleate,
Figure BDA0003158482510000051
1944cs, Maisine35-1, ethyl linoleate, C8/C10 monoglyceride, coconut oil C8/C10 diglyceride, coconut oil C8/C10 triglyceride, caprylic diglyceride, caprylic monoglyceride, capric diglyceride, capric triglyceride, caprylic capric monoglyceride, caprylic capric triglyceride, isopropyl myristate, linoleic acid macrogol glyceride, Gelucire or Capryol 90; a combination of ethyl oleate, sorbitol oleate and glyceryl oleate is preferred.
The combination of at least two of the above-mentioned compounds, for example, the combination of ethyl oleate and sorbitol oleate, the combination of glyceryl oleate and glyceryl linoleate, the combination of ethyl linoleate and C8/C10 monoglyceride, etc., may be selected in any combination manner, and thus, the details are not repeated herein.
Preferably, the immunomodulator lipid material complex consists of an immunomodulator and a lipid material, the molar ratio of the immunomodulator to the lipid material is 1 (0.25-8), such as 1:0.25, 1:0.5, 1:0.75, 1:1, 1:2, 1:3, 1:4, 1:6, 1:8 and the like, and any specific value in the numerical range can be selected, so that the details are not repeated. Preferably 1 (0.25-4).
Preferably, the complexing rate of the immunomodulator and the lipid material is greater than 90%, for example, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, etc., and any other specific value within the range of values can be selected, which is not described herein again.
Preferably, the immunomodulator comprises any one or combination of at least two of chlorogenic acid, neochlorogenic acid, cryptochlorogenic acid, isochlorogenic acid A, isochlorogenic acid B, isochlorogenic acid C or silymarin; chlorogenic acid is preferred.
The combination of at least two of the chlorogenic acid and the neochlorogenic acid, the combination of the cryptochlorogenic acid and the isochlorogenic acid A, the combination of the isochlorogenic acid B and the isochlorogenic acid C, and the like can be selected in any combination mode, and are not described in detail herein.
Preferably, the lipid material comprises any one or a combination of at least two of soybean phospholipid, egg yolk phospholipid, phosphatidyl glycerol, distearoyl phosphatidylcholine, dipalmitoyl phosphatidylethanolamine, dimyristoyl phosphatidylcholine or ceramide; preferably a combination of soy phospholipids and egg phospholipids.
The combination of at least two of the above-mentioned components, such as the combination of soybean phospholipid and egg yolk phospholipid, the combination of phosphatidyl glycerol and distearoyl phosphatidylcholine, the combination of dipalmitoyl phosphatidylethanolamine and dimyristoyl phosphatidylcholine, etc., can be selected in any combination manner, and will not be described in detail herein.
Preferably, the content of the immunomodulator in the self-emulsifying delivery system is 5-200mg/g, such as 5mg/g, 10mg/g, 20mg/g, 50mg/g, 60mg/g, 80mg/g, 100mg/g, 120mg/g, 150mg/g, 180mg/g, 200mg/g, etc., and any specific value within the value range can be selected, and thus, the details are not repeated herein.
Preferably, the mass ratio of the oil phase, the emulsifier and the co-emulsifier is (1-5) to (3-6) to (2-6).
Wherein, the specific value in (1-5) can be 1, etc.
The specific values in (3-6) can be 3, 3.5, 4, 4.5, 5, 5.5, 6, etc.
The specific values in (2-6) can be 2, 3, 4, 5, 6, etc.
Other specific point values within the above numerical ranges can be selected, and are not described in detail herein.
Preferably, the medicament further comprises pharmaceutically acceptable auxiliary materials.
Preferably, the auxiliary materials comprise any one or a combination of at least two of a carrier, a diluent, an excipient, a filler, a binder, a wetting agent, a disintegrating agent, an emulsifier, a cosolvent, a solubilizer, an osmotic pressure regulator, a surfactant, a coating material, a coloring agent, a pH regulator, an antioxidant, a bacteriostatic agent or a buffering agent.
The combination of at least two of the above components, such as the combination of a filler and a binder, the combination of an emulsifier and a cosolvent, the combination of an osmotic pressure regulator and a surfactant, the combination of a pH regulator and an antioxidant, and the like, can be selected in any combination manner, and are not described in detail herein.
Preferably, the carrier comprises a liposome, micelle, dendrimer, microsphere or microcapsule.
In the present invention, the self-emulsifying delivery system is prepared by a preparation method comprising the following steps:
mixing oil phase, emulsifier, co-emulsifier and lipid material complex of immunomodulator uniformly.
In the invention, the immune regulator lipid material compound is prepared by a preparation method comprising the following steps:
weighing immunomodulator and lipid material at a certain ratio, dissolving in organic solvent, mixing, standing for 15-30min (such as 15min, 17min, 20min, 22min, 25min, 28min, 30min, etc.), rotary evaporating or spray drying to remove organic solvent, and drying under reduced pressure.
Compared with the prior art, the invention has the following beneficial effects:
the self-emulsifying delivery system is a lipid carrier mainly composed of an oil phase, an emulsifying agent and an auxiliary emulsifying agent, can be diluted by gastrointestinal fluid and emulsified into an oil-in-water (o/w) nano-emulsion after being taken orally, is targeted and gathered in mesenteric lymph nodes through a lymph transport path, activates immune cells in the mesenteric lymph nodes, and finally exerts the immune effect of resisting tumors (particularly lymphatic metastasis tumors). The self-emulsifying delivery system can not only improve the compliance of patients, but also has more treatment advantages on tumors which are transferred by lymph, especially tumors which are sensitive to tumor immunotherapy (such as leukemia).
Drawings
FIG. 1 is a graph showing the volume results of in situ brain gliomas of each group of mice in test example 1 (wherein A is an observed nuclear magnetic resonance image and B is a statistical image of the volume of each group of tumors);
FIG. 2 is a graph showing statistics of CD40 and CD86 expression levels in mesenteric lymph nodes of each group of mice in test example 1;
FIG. 3 is a graph showing statistics of CD40 and CD86 expression levels in peripheral blood of each group of mice in test example 1;
FIG. 4 is a graph showing statistics of the proportion of central memory type CD3+ T cells in mesenteric lymph nodes of each group of mice in test example 1;
FIG. 5 is a graph showing the statistics of the analysis of immune cells in situ tumors of each group of mice in test example 1;
fig. 6 is an appearance of tumors of each group of mice in test example 3.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
The following method for determining the compounding rate of chlorogenic acid and lipid materials comprises the following steps:
(1) control solution: weighing a chlorogenic acid standard substance 25mg to 25ml volumetric flask, performing constant volume with ethanol solution, precisely weighing 1ml to 50ml volumetric flask, and performing constant volume with 30% ethanol water to obtain a reference substance solution;
(2)Wgeneral assembly: weighing 80mg of chlorogenic acid lipid material compound into a 25ml volumetric flask, carrying out constant volume shaking with absolute ethyl alcohol, precisely weighing 1ml to 50ml volumetric flask, and carrying out constant volume shaking with 30% ethanol water solution to obtain a total solution of a sample W;
(3)Wcompounding: weighing 80mg chlorogenic acid lipid material complex into 25mL volumetric flask, dissolving with chloroform, diluting to constant volume, filtering with 0.22 μm filter membrane, precisely weighing 1mL filtrate, blowing nitrogen to remove solvent (chloroform), diluting with 30% ethanol water to 50mL, and taking as sample WCompoundingAnd (3) solution.
Based on the above samples, the following HPLC conditions were used for the determination:
mobile phase: 0.4% phosphoric acid acetonitrile 82:18(v/v)
Detection wavelength: 328nm
Flow rate: 1.0mL/min
Column temperature: 25 deg.C
Sample introduction amount: 10 μ L
Stopping time: and 8 min.
The following method for determining the particle size of the self-emulsifying delivery system was used: 100 μ L of the self-emulsifying delivery system was added to 10mL of purified water, stirred for 1 minute, and the particle size was measured using a laser particle sizer.
The following method for determining the drug loading of a self-emulsifying delivery system was used: chromatography column packed with octadecylsilane bonded silica, Agilent SB-C18 (4.6X 250mm, 5 μm); mixing 1% glacial acetic acid: acetonitrile 90:10(v: v) is used as a mobile phase, and the detection wavelength is 328 nm; the column temperature was 25 ℃; the flow rate is 1 mL/min; sample introduction amount: 5 mu L of the solution; stopping time: and 15 min. Taking 833mg of a sample from an emulsion delivery system, precisely weighing, placing in a 10mL measuring flask, adding methanol for dissolving, diluting to a scale, shaking up, precisely weighing 1mL, placing in a 50mL measuring flask, diluting with methanol to a scale, and shaking up to obtain a test solution. Precisely weighing 10mg of chlorogenic acid reference substance, placing in a 10mL measuring flask, adding methanol for dissolving, diluting to scale, shaking, precisely weighing 1mL, placing in a 10mL measuring flask, adding solvent for diluting to scale, and shaking to obtain reference substance solution. And (4) measuring the solutions of the test sample and the reference substance, and calculating the content of the sample by peak area according to an external standard method.
Chlorogenic acids referred to below were purchased from ninthlo, Sichuan, Biotech, Inc.
The following ICR and C57BL/6 mice were purchased from Experimental animals technology, Inc., Viton, Beijing.
The following G422 cells, Lewis lung cancer cells and L1210 leukemia cells are all from the national cell resource center of the basic medical research institute of Beijing cooperative medical college.
Example 1
The invention provides a self-emulsifying delivery system, which is prepared by the following steps:
(1) taking soybean lecithin as a lipid material, feeding chlorogenic acid and the soybean lecithin according to a drug-lipid ratio of 1:1, adding the materials into a 1L round-bottom flask together, taking absolute ethyl alcohol as a solvent, controlling the drug concentration to be 60mg/ml, standing at 25 ℃ for 15min after the chlorogenic acid and the soybean lecithin are completely dissolved, then carrying out rotary evaporation at 100rpm and 40 ℃ in a rotary evaporator, carrying out reduced pressure drying to remove the absolute ethyl alcohol, and after the ethyl alcohol is evaporated to dryness, continuing to carry out reduced pressure drying at 100rpm at 25 ℃ for 1h to remove the ethyl alcohol completely, thus obtaining the chlorogenic acid lipid material compound. The recombination rate was determined to be 101.52% according to the above method.
(2) Weighing ethyl oleate, caprylic capric acid polyethylene glycol glyceride and diethylene glycol monoethyl ether according to the mass ratio of 2:5:3, and uniformly stirring and mixing to obtain a blank self-emulsifying concentrated solution.
(3) Adding the chlorogenic acid lipid material compound into the blank self-emulsifying concentrated solution according to the mass ratio of the compound to the blank self-emulsifying concentrated solution of 1.2:5, and placing the mixture into an air bath oscillator at the temperature of 25 ℃ and the rotating speed of 210rpm to obtain the self-emulsifying delivery system. The drug loading rate is measured to be 60mg/g, and the particle size is measured to be 60nm after the drug is diluted by 100 times of water.
Example 2
The invention provides a self-emulsifying delivery system, which is prepared by the following steps:
(1) taking soybean lecithin as a lipid material, feeding chlorogenic acid and the soybean lecithin according to a drug-lipid ratio of a molar ratio of 1:2, adding the chlorogenic acid and the soybean lecithin into a 1L round-bottom flask together, taking absolute ethyl alcohol as a solvent, controlling the drug concentration to be 60mg/ml, standing at 25 ℃ for 15min after the chlorogenic acid and the soybean lecithin are completely dissolved, then carrying out rotary evaporation at 100rpm and 40 ℃ in a rotary evaporator, carrying out reduced pressure drying to remove the absolute ethyl alcohol, drying the ethanol by evaporation, and continuing to carry out reduced pressure drying at 100rpm at 25 ℃ for 1h to remove the ethanol completely, thereby obtaining the chlorogenic acid-lipid material compound. The recombination rate was determined to be 100.89% according to the above method.
(2) Weighing ethyl oleate, caprylic capric acid polyethylene glycol glyceride and diethylene glycol monoethyl ether according to the mass ratio of 3:4:3, and uniformly stirring and mixing to obtain a blank self-emulsifying concentrated solution. And the antioxidant vitamin E (added in an amount of 0.04%) was added to the blank self-emulsifying concentrate.
(3) Adding the chlorogenic acid lipid material compound into the blank self-emulsifying concentrated solution according to the mass ratio of the compound to the blank self-emulsifying concentrated solution of 3.45:10, and placing the mixture into an air bath oscillator at the temperature of 25 ℃ and the rotating speed of 210rpm to obtain the self-emulsifying delivery system. The drug loading rate is measured to be 48mg/g, and the particle size is measured to be 100nm after the drug is diluted by 100 times of water.
Example 3
The present invention provides a self-emulsifying delivery system, the method of preparation of which differs from example 1 only in that: soybean lecithin was replaced with soybean lecithin and egg yolk lecithin in a mass ratio of 2:1 (the total amount of lipid material remained unchanged). Other conditions were kept consistent. The drug loading rate is measured to be 60mg/g, and the particle size is measured to be 50nm after 100 times of dilution by water.
Example 4
The present invention provides a self-emulsifying delivery system, the method of preparation of which differs from example 1 only in that: the diethylene glycol monoethyl ether was replaced with dimethyl isosorbide and diethylene glycol monoethyl ether in a mass ratio of 1:1 (the total amount of co-emulsifier was kept constant). Other conditions were kept consistent. The drug loading rate is measured to be 60mg/g, and the particle size is measured to be 60nm after the drug is diluted by 100 times of water.
Example 5
The present invention provides a self-emulsifying delivery system, the method of preparation of which differs from example 1 only in that: the ethyl oleate was replaced with ethyl oleate, sorbitol oleate and glycerol oleate in a mass ratio of 5:2:1 (the total amount of the oil phase remained unchanged). Other conditions were kept consistent. The drug loading rate is measured to be 60mg/g, and the particle size is measured to be 70nm after the drug is diluted by 100 times of water.
Example 6
The present invention provides a self-emulsifying delivery system, the method of preparation of which differs from example 1 only in that: the caprylic capric acid polyethylene glycol glyceride is replaced by linoleic acid polyethylene glycol glyceride with the same quantity. Other conditions were kept consistent. The drug loading rate is measured to be 60mg/g, and the particle size is measured to be 70nm after the drug is diluted by 100 times of water.
Test example 1
An ICR mouse inoculated with brain glioma in situ is taken as a model, and the construction method comprises the following steps: female ICR mice were anesthetized with sodium pentobarbital and placed in a stereotactic instrument. 2X 10 at a rate of 10. mu.L/min6One G422 cell was injected into the brain.
24 ICR mice (female, 18-20g) inoculated in situ with brain gliomas were randomly divided into 3 groups of 8 mice each, a model group, a CHA group and a CHA-SME group. Physiological saline, chlorogenic acid (CHA, intraperitoneal injection, 20 mg/kg/day, 9 consecutive days) and the sample of example 1 (CHA-SME, oral administration, 35 mg/kg/day, 9 consecutive days) were administered separately. After the administration, the tumor size in the mouse brain is observed by nuclear magnetic resonance to evaluate the anti-tumor effect of the chlorogenic acid self-emulsifying delivery system.
The experimental result is shown in figure 1 (wherein A is an observed nuclear magnetic resonance image, and B is a statistical image of the tumor volume of each group), and the chlorogenic acid self-emulsifying delivery system (CHA-SME) can obviously inhibit the growth of the brain glioma in situ of the mouse at the dosage of 35 mg/kg. Compared with the model group, the tumor volumes of the chlorogenic acid (CHA) and the chlorogenic acid self-emulsifying delivery system (CHA-SME) are respectively reduced to 54 percent and 46 percent, which indicates that the chlorogenic acid self-emulsifying delivery system (CHA-SME) has stronger tumor inhibition effect.
The mice were subjected to immunoassays for mesenteric lymph nodes, peripheral blood and in situ tumors after administration, including mainly DC and T cell analysis. Experimental results as shown in fig. 2 and 3, characteristic mature proteins of DC surface in mesenteric lymph nodes and peripheral blood were significantly up-regulated compared to the model group after administration of chlorogenic acid self-emulsifying delivery system (CHA-SME). As shown in fig. 2, CD40 and CD86 were increased 2.4 and 1.4 fold, respectively, in the mesenteric lymph nodes of the chlorogenic acid self-emulsifying delivery system (CHA-SME) group compared to the model group, whereas no significant change was observed in the chlorogenic acid (CHA) group. Furthermore, the CD86 in mesenteric lymph nodes of the chlorogenic acid self-emulsifying delivery system (CHA-SME) group was 1.4 times higher than that of the chlorogenic acid (CHA) group. As shown in fig. 3, CD40 and CD86 in peripheral blood of the chlorogenic acid self-emulsifying delivery system (CHA-SME) group were increased by 1.3 and 13.4 times, respectively, compared to the model group, while no significant change was observed in the chlorogenic acid (CHA) group. In addition to stimulating DC maturation, as shown in FIG. 4, the ratio of central memory CD3+ T cells in mesenteric lymph nodes was increased 1.6 fold in the chlorogenic acid self-emulsifying delivery system (CHA-SME) group compared to the model group, whereas no significant change was observed in the chlorogenic acid (CHA) group.
Results of immunocytoanalysis in situ tumors as shown in fig. 5, the chlorogenic acid self-emulsifying delivery system (CHA-SME) group can significantly up-regulate the proportion of T cells (including CD3+, CD4+, CD8+, and memory T cells) in tumor tissues, compared to the model group and the chlorogenic acid (CHA) group. Compared with the chlorogenic acid (CHA) group, the tumor immunotherapy effect of the T cells is enhanced by 1.3, 2.4, 4.1, 1.6, 3.0, 4.1, 3.7 and 3.8 times respectively for CD3+, CD4+, CD8+, effector memory CD3+ T cells, effector memory CD4+ T cells, central memory CD4+ T cells, effector memory CD8+ T cells and central memory CD8+ T cells in the tumor tissues of the chlorogenic acid self-emulsifying delivery system (CHA-SME) group.
Test example 2
An ICR mouse with subcutaneous brain glioma transplantation is taken as a model, and the construction method comprises the following steps: 2 x 10 to6One G422 cell was injected subcutaneously into the right forelimb underarm area of female ICR mice.
18 ICR mice (female, 18-20g) with subcutaneously transplanted brain gliomas were randomly divided into 3 groups of 6 mice each, model, CHA and CHA-SME groups.
Physiological saline, chlorogenic acid (CHA, oral, 35 mg/kg/day, 19 consecutive days) and the sample of example 2 (CHA-SME, oral, 35 mg/kg/day, 19 consecutive days) were administered separately. Subcutaneous tumors were stripped and weighed after dosing to evaluate tumor suppression.
The experimental results are shown in table 1, compared with the model group and chlorogenic acid, the chlorogenic acid self-emulsifying delivery system (CHA-SME) can obviously inhibit the growth of the brain glioma of the mouse at the dosage of 35 mg/kg.
TABLE 1
Group of Tumor weight (g)
Model set 2.28±0.71
CHA group 2.40±0.21
CHA-SME group 0.82±0.55
Test example 3
The construction method takes a Lewis lung cancer C57BL/6 mouse transplanted under the skin as a model and comprises the following steps: will be 5X 105One Lewis lung carcinoma cell was injected subcutaneously into the right hind limb of male C57BL/6 mice.
6 Lewis lung carcinoma C57BL/6 mice (male, 16-18g) implanted subcutaneously were randomly divided into 2 groups of 3, a model group and a CHA-SME group.
Physiological saline, the sample of example 1 (CHA-SME, oral, 30 mg/kg/day, 14 consecutive days) were administered separately. Subcutaneous tumors were stripped and weighed after dosing to evaluate tumor suppression.
The experimental results are shown in fig. 6, compared with the model group, the chlorogenic acid self-emulsifying delivery system (CHA-SME) can significantly inhibit the growth of the lung cancer of the mice at the dosage of 30 mg/kg.
Test example 4
The construction method takes a subcutaneously transplanted L1210 leukemia DBA/2 mouse as a model and comprises the following steps: will be 6X 105One L1210 leukemia cell was injected subcutaneously into the right hind limb medial side of female DBA/2 mice.
48 ICR mice (female, 18-20g) were randomly divided into 8 groups of 6 mice each, model, CHA low, CHA high and CHA-SME 1-5 groups, respectively.
Chlorogenic acid (CHA, intraperitoneal injection, 20 and 40 mg/kg/day, continuous administration for 12 days) and the samples prepared in examples 1, 3-6 (CHA-SME, oral administration, 35 mg/kg/day, continuous administration for 12 days) were administered sequentially and separately. Subcutaneous tumors were stripped and weighed after dosing to evaluate tumor suppression.
The experimental results are shown in table 2, compared with the model group, the oral chlorogenic acid self-emulsifying delivery system (CHA-SME) can significantly inhibit the growth of murine leukemia, the tumor growth inhibition rate is more than 44.4%, and the tumor growth inhibition rate is respectively 29.8% and 40.5% better than that of the chlorogenic acid intraperitoneal injection group (20 and 40 mg/kg). Meanwhile, the data in the table show that the selection of the emulsifier, the co-emulsifier, the oil phase and the lipid material in the self-emulsifying delivery system can influence the anti-leukemia effect.
TABLE 2
Group of Tumor weight (g)
Model set 2.70±0.40
CHA Low dose group 1.90±0.75
CHA high dose group 1.61±0.90
CHA-SME 1 group (example 1) 1.40±0.25
CHA-SME 2 group (example 3) 0.95±0.20
CHA-SME 3 group (example 4) 1.05±0.15
CHA-SME 4 group (example 5) 1.10±0.30
CHA-SME 5 group (example 6) 1.50±0.10
The applicant states that the invention is illustrated by the above examples of the use of a self-emulsifying delivery system of the invention for the preparation of an oral medicament for the treatment of lymphatic metastases, but the invention is not limited to the above examples, i.e. it is not intended that the invention must be practiced in reliance thereon. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.

Claims (10)

1. Use of a self-emulsifying delivery system for the manufacture of an oral medicament for the treatment of lymphatic metastases, characterized in that the self-emulsifying delivery system comprises an oil phase, an emulsifier, a co-emulsifier and an immunomodulator lipid material complex.
2. The use of claim 1, wherein the lymphatic metastatic tumor is a tumor that can be treated by activating immune cells in the lymphatic system and/or lymphatic organs;
preferably, the immune cells comprise any one or a combination of at least two of DC cells, T cells, B cells, NK cells or macrophages;
preferably, the lymphoid metastatic tumour comprises brain glioma, lung cancer or leukaemia.
3. The use of claim 1 or 2, wherein the emulsifier comprises any one of or a combination of at least two of macrogol glyceride, caprylic/capric macrogol glyceride, oleic macrogol glyceride or linoleic macrogol glyceride; caprylic capric acid polyethylene glycol glyceride is preferred.
4. The use of any one of claims 1 to 3, wherein the co-emulsifier comprises any one or a combination of at least two of propylene carbonate, ethylene glycol monoethyl ether, glycerol furfural, dimethyl isosorbide, diethylene glycol monoethyl ether, PEG400, glycerol or benzyl alcohol; a combination of dimethyl isosorbide and diethylene glycol monoethyl ether is preferred.
5. The use of any one of claims 1 to 4, wherein the oil phase comprises ethyl oleate, sorbitol oleate, glycerol linoleate, glycerol,
Figure FDA0003158482500000011
1944cs, Maisine35-1, ethyl linoleate, C8/C10 monoglyceride, coconut oil C8/C10 diglyceride, coconut oil C8/C10 triglyceride, caprylic diglyceride, caprylic monoglyceride, capric diglyceride, capric triglyceride, caprylic capric monoglyceride, caprylic capric triglyceride, isopropyl myristate, linoleic acid macrogol glyceride, Gelucire or Capryol 90; a combination of ethyl oleate, sorbitol oleate and glyceryl oleate is preferred.
6. The use according to any one of claims 1 to 5, wherein the immunomodulatory lipid material complex consists of an immunomodulatory agent and a lipid material, the molar ratio of immunomodulatory agent to lipid material being 1 (0.25-8), preferably 1 (0.25-4);
preferably, the complexing rate of the immunomodulator with the lipid material is greater than 90%;
preferably, the immunomodulator comprises any one or combination of at least two of chlorogenic acid, neochlorogenic acid, cryptochlorogenic acid, isochlorogenic acid A, isochlorogenic acid B, isochlorogenic acid C or silymarin; preferably chlorogenic acid;
preferably, the lipid material comprises any one or a combination of at least two of soybean phospholipid, egg yolk phospholipid, phosphatidyl glycerol, distearoyl phosphatidylcholine, dipalmitoyl phosphatidylethanolamine, dimyristoyl phosphatidylcholine or ceramide; preferably a combination of soy phospholipids and egg phospholipids.
7. The use of any one of claims 1 to 6, wherein the amount of immunomodulator in the self-emulsifying delivery system is from 5 to 200 mg/g;
preferably, the mass ratio of the oil phase, the emulsifier and the co-emulsifier is (1-5) to (3-6) to (2-6).
8. The use of any one of claims 1-7, wherein the medicament further comprises a pharmaceutically acceptable excipient;
preferably, the auxiliary materials comprise any one or a combination of at least two of a carrier, a diluent, an excipient, a filler, a binder, a wetting agent, a disintegrating agent, an emulsifier, a cosolvent, a solubilizer, an osmotic pressure regulator, a surfactant, a coating material, a coloring agent, a pH regulator, an antioxidant, a bacteriostatic agent or a buffering agent.
9. Use according to any one of claims 1 to 8, wherein the self-emulsifying delivery system is prepared by a preparation method comprising the steps of:
mixing oil phase, emulsifier, co-emulsifier and lipid material complex of immunomodulator uniformly.
10. The use of claim 9, wherein the immunomodulatory lipid material complex is prepared by a method comprising:
weighing immunomodulator and lipid material according to a certain proportion, dissolving in organic solvent, mixing, standing for 15-30min, removing organic solvent by rotary evaporation or spray drying, and drying under reduced pressure.
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