CN112516315B

CN112516315B - Self-microemulsion composition of tyrosine kinase inhibitor

Info

Publication number: CN112516315B
Application number: CN202011388653.3A
Authority: CN
Inventors: 周群; 黄建国; 罗熙; 周旋; 彭丽
Original assignee: Hunan Huize Bio Pharmaceutical Co ltd
Current assignee: Hunan Huize Bio Pharmaceutical Co ltd
Priority date: 2020-12-02
Filing date: 2020-12-02
Publication date: 2022-07-08
Anticipated expiration: 2040-12-02
Also published as: CN112516315A

Abstract

The invention belongs to the technical field of medicines, and discloses a self-microemulsion composition of a tyrosine kinase inhibitor, which comprises the following components in part by weight: 0.1-40% of tyrosine kinase inhibitor; 60-99.9% of a carrier; the carrier comprises an oil phase, a surfactant and a cosurfactant; the self-microemulsion composition spontaneously forms a microemulsion with the particle size of less than 50nm when meeting water medium. The dissolution rate and the mixing uniformity of the prepared tyrosine kinase inhibitor meet the requirements, the prepared tyrosine kinase inhibitor can be spontaneously dispersed under gastrointestinal peristalsis when meeting gastrointestinal fluid after oral administration to form O/W type nano-emulsion, drug molecules are wrapped in a carrier, the particle size of the drug molecules is correspondingly increased, the membrane penetration mode of the nano-emulsion is changed after the nano-emulsion is contacted with small intestine epidermal cells, the original passive diffusion transport is changed into endocytosis transport, and the stimulation of the nano-emulsion on the gastrointestinal tract is reduced through active endocytosis or endocytosis absorption, so that the stimulation of the drug caused by overhigh local concentration and long-time contact with the gastrointestinal wall is reduced, and the side effect of the drug on the gastrointestinal tract can be reduced.

Description

Self-microemulsion composition of tyrosine kinase inhibitor

Technical Field

The invention relates to the technical field of medicines, in particular to a self-microemulsion composition of a tyrosine kinase inhibitor.

Background

Tyrosine kinase inhibitors have common problems in clinical use, and firstly have great toxic and side effects and reactions such as nausea, vomiting or diarrhea. Secondly, poor resistance, such as high doses used for a long period of time, will tend to develop. Clinical data of the tyrosine kinase inhibitor show that in the treatment process of the oral tyrosine kinase inhibitor, adverse reactions occur in systems such as endocrine, digestive, cardiovascular and skin at a high rate, and multiple systems are possibly concurrent. Clinical analysis shows that the surface tyrosine kinase inhibitor is most prone to adverse reactions of the digestive system in the using process, the diarrhea incidence rate of the surface tyrosine kinase inhibitor exceeds 80 percent, and when persistent diarrhea occurs, dehydration and other problems can be caused. Adverse reactions in the digestive system may cause changes in intestinal motility by irritation of the gastrointestinal tract by the drug, resulting in diarrhea. Therefore, there is a need to reduce or even eliminate the side effects of drugs by modifying the dosage form.

The self-microemulsion composition forms microemulsion in gastrointestinal tract, the medicine exists in the fine oil drops and is rapidly distributed in the whole gastrointestinal tract, the medicine is distributed between oil and water, the dissolution of the water-insoluble medicine is greatly improved by depending on the huge surface area of the fine oil drops, and the bioavailability is improved. The self-microemulsion composition has been proved to be capable of improving the stability of the drug in blood circulation, prolonging the duration of action of the drug, and in addition, delivering the drug to specific cells and tissues due to its uniform particle size and particle size distribution. The self-microemulsion composition has small particle size, can prevent the microemulsion from aggregating into a cluster, can penetrate into a pathological change part, changes the distribution of the medicament, improves the curative effect of the medicament and reduces side effects.

The application number is CN201711358022.5, which discloses a lurasidone hydrochloride self-microemulsion composition and a preparation method thereof, wherein the lurasidone hydrochloride, an oil phase, an emulsifier and an auxiliary emulsifier form a liquid self-microemulsion composition, or the obtained liquid self-microemulsion composition is further prepared with an excipient to form a solid self-microemulsion composition.

Application number CN201010285368.9 discloses an anticancer pharmaceutical composition, which contains arctigenin and a tyrosine kinase inhibitor. Compared with single medicine, the provided pharmaceutical composition has synergistic anticancer activity in the aspect of inhibiting the non-small cell lung cancer; microemulsion formulations of the pharmaceutical compositions are also provided.

Therefore, there is a need to provide a tyrosine kinase inhibitor that is simple, reliable, and reduces adverse effects.

Disclosure of Invention

The invention aims to provide a self-microemulsion composition of a tyrosine kinase inhibitor, so as to relieve adverse reactions of the tyrosine kinase inhibitor. The tyrosine kinase inhibitor is prepared into the self-microemulsion composition, so that the medicament can be stably and slowly released, serious adverse reaction of a digestive system caused by overhigh blood concentration after the medicament is taken can be avoided, the influence caused by unqualified dissolution can also be avoided, the adverse reaction is obviously reduced, and the curative effect is improved.

In order to solve the technical problems, the invention adopts the following technical scheme:

in one aspect, the present invention provides a self-microemulsifying composition of a tyrosine kinase inhibitor, comprising, based on the total weight of the composition:

0.1-40% of a tyrosine kinase inhibitor;

20-99.9% of a carrier;

the carrier includes an oil phase, a surfactant, and a co-surfactant.

Further, the self-microemulsion composition spontaneously forms a microemulsion with the particle size of less than 50nm when meeting a water medium.

Further, the tyrosine kinase inhibitor is selected from: the composition comprises a pharmaceutically acceptable carrier and a pharmaceutically acceptable carrier, wherein the carrier is selected from the group consisting of axitinib, erlotinib, gefitinib, vandetanib, imatinib, canertinib, vartanib, sorafenib, sunitinib, leflunomide, apatinib, crizotinib, erlotinib, lapatinib, dasatinib, nilotinib, panitumumab, panitinib, lauratinib, cabozitinib, erlotinib, lurasidone hydrochloride, lurasidone, tiratinib, laratinib, oxitinib, afatinib, pezotinib, pazopanib, apatinib, pyrroltinib, rivatinib, olatinib, olanitib, periertinib, canatinib and mixtures thereof.

Further, the self-microemulsion composition comprises 0.1-20% of tyrosine kinase inhibitor.

Further, the self-microemulsion composition comprises 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 15%, 16%, 18%, 19% or 20% of a tyrosine kinase inhibitor.

Furthermore, the weight ratio of the surfactant to the cosurfactant in the carrier is 1-2: 1.

Further, the carrier comprises 5-70% of an oil phase, 10-90% of a surfactant and 5-45% of a cosurfactant by weight of the total carrier.

Further, the carrier comprises 5%, 10%, 12%, 15%, 18%, 20%, 25%, 30%, 40%, 45%, 50%, 60% or 70% of an oil phase by total weight of the carrier.

Further, the oil phase comprises polyethylene glycol glyceryl oleate

M 1944CS)、

CC (glyceryl monolinoleate), capryol90 (propylene glycol caprylate), coconut oil C8/C10 monoglyceride or diester (Capmul MCM),

(caprylic capric polyglycol glyceride), oleic acid, ethyl oleate, glyceryl monooleate (Peceol), or combinations thereof.

Further, the carrier comprises 10%, 20%, 25%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 80% or 90% of the surfactant by total weight of the carrier.

Further, the surfactant includes tween 80, caprylic capric polyethylene glycol glyceride (Labrasol), polyoxyethylene castor oil (Cremophor EL35), polyoxyethylene hydrogenated castor oil (Cremophor RH 40), or a combination thereof.

Further, the carrier comprises 0, 0.5%, 1%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 40%, 45% or 50% of a co-surfactant, based on the total weight of the carrier.

Further, the cosurfactant comprises polyethylene glycol (with molecular weight ranging from 100Da to 10kDa, 300Da to 2000Da, or 400Da to 1000Da) such as polyethylene glycol 200-600 (e.g. PEG400, polyethylene glycol 600), propylene glycol, diethylene glycol monoethyl ether (Transcutol or Transcutol P or Transcutol HP or TP), or combinations thereof.

Further, in the carrier, the oil phase: surfactant (b): the mass ratio of the cosurfactant is as follows: 20:53.3:26.7 or 1:6:3 or 3:4.66:2.34 or 4:4:2 or 5:3.66: 1.34.

Further, in the carrier, the oil phase is 1) a mixed oil phase of propylene glycol caprylate and polyethylene glycol glyceryl oleate, and the mass ratio of the propylene glycol caprylate to the polyethylene glycol glyceryl oleate is as follows: 1:1, 2:1 or 1: 2; 2) propylene glycol caprylate; or 3) Capmul MCM.

Further, in the carrier, the surfactant is 1) polyoxyethylene hydrogenated castor oil; 2) the mixed surfactant of RH40 and tween 80, the mass ratio of the two is 5:5, 6:4, 7:3, 8:2 and 9: 1.

Further, in the carrier, the cosurfactant is 1) a mixed cosurfactant of polyethylene glycol 400 and diethylene glycol monoethyl ether, and the mass ratio of the cosurfactant to the mixed cosurfactant is 2:1, 1:1, 3:1 or 2: 8; 2) diethylene glycol monoethyl ether or propylene glycol or PEG 400.

Further, the carrier is ((propylene glycol caprylate: polyethylene glycol glyceryl oleate): polyoxyethylene hydrogenated castor oil: (polyethylene glycol 400: diethylene glycol monoethyl ether)) - (13.3:6.7):53.3: (17.8: 8.9).

Further, the carrier is Capmul MCM Cremophor RH40 diethylene glycol monoethyl ether 20:53.3: 26.7.

The 'oil phase' referred to in the invention is defined as various pharmaceutically acceptable oil phases, and is selected from one or more of natural vegetable oil, vegetable oil after structural modification and hydrolysis, or fatty acid glyceride with medium chain length between C8-C10. The oil phase is selected from: corn oil, sunflower oil (e.g., refined sunflower oil), sesame oil, peanut oil, soybean oil, safflower oil, olive oil, palm oil, cottonseed oil, coix seed oil, castor oil, hydrogenated castor oil, coconut oil C8/C10 monoglyceride or diester (Capmul MCM), coconut oil C8/C10 propylene glycol diester (Captex 200), coconut oil C8/C10 triglyceride (Captex 355), coconut oil aminopropyl betaine, purified acetylated monoglyceride (Miglyol 812), purified sunflower oil monoglyceride, macrogol laurate, glyceryl monooleate, glyceryl monolinoleate, medium chain triglyceride, macrogol oleate, macrogol linoleate, macrogol caprylate capric glyceride, caprylic capric glyceride, polyoxyethylene oleate, polyoxyethylene linoleate, polyoxyethylene caprylate capric glyceride, palm capric glyceride, coconut oil, palm oil, cottonseed oil, coconut oil, castor oil, hydrogenated castor oil, coconut oil C8/C10 monoglyceride (Capacity MCM), coconut oil C8/C10 propylene glycol diester (Capacity 200), coconut oil, Camellia glyceride, almond oil oleic acid PEG-6 glyceride, corn oil linoleic acid PEG-6 glyceride, and olein: propylene glycol (90:10 vol/vol), egg yolk lecithin, soybean lecithin, dioleoyl lecithin, dilauroyl lecithin, dimyristoyl lecithin, dipalmitoyl lecithin, distearoyl lecithin, cephalin, creatinine, inositol phospholipid, lysophospholipid, phosphatidic acid, phosphatidylglycerol, stearoyl/palmitoyl/oleoyl phosphatidylcholine, stearoyl/palmitoyl/oleoyl phosphatidylethanolamine, phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol and phosphatidylinositol, distearoyl phosphatidylethanolamine, oleoyl phosphatidylcholine, hexanoic acid, octanoic acid, oleic acid, vitamin E, stearic acid, isopropyl laurate, isopropyl palmitate, isopropyl myristate, polyethylene glycol-6-oleate, medium chain glycerides, medium chain triglycerides, fatty acids, Linoleic acid polyethylene glycol glyceride, propylene glycol monolaurate, propylene glycol monocaprylate, sorbitan oleate, ethyl laurate, ethyl myristate, ethyl oleate (some examples are abbreviated as EO), and ethyl linoleate or at least two thereof. Optionally, the oil phase is selected from one or at least two of sunflower oil (e.g. refined sunflower oil), soybean oil, oleic acid, castor oil, glycerol monolinoleate, Medium Chain Triglycerides (MCT), caprylic acid, ethyl oleate, isopropyl myristate, propylene glycol monolaurate, medium chain glycerides, polyethylene glycol glycerol linoleate, polyethylene glycol-6 glycerol oleate, medium chain triglycerides, glycerol monooleate, ethyl oleate. Wherein the oil phase is selected from glycerol monolinoleate, medium-chain triglyceride, polyethylene glycol glycerol linoleate, glycerol monooleate, ethyl oleate, medium-chain triglyceride, polyethylene glycol-6-glyceride oleate, ethyl oleate, isopropyl myristate, caprylic acid, a mixed oil phase of oleic acid and medium-chain triglyceride (the mass ratio of the two is 1-9: 1-9, further 8:2 or 6:4), a mixed oil phase of glycerol monooleate and caprylic acid (the mass ratio of the two is 1-9: 1-9, further 4:1), oleic acid and glycerol monolinoleate (the mass ratio of the two is 1-9: 1-9, further 1:4), ethyl oleate and glycerol monolinoleate (the mass ratio of the two is 1-9: 1-9, further 1:3), isopropyl myristate and glycerol monolinoleate (the mass ratio of the two is 1-9: 1-9, further 1:1), glycerol monooleate and ethyl oleate (the mass ratio of the glycerol monooleate to the ethyl oleate is 1-9: 1-9, further 2: 3).

The "surfactant" referred to in the present invention is selected from nonionic, anionic, cationic and zwitterionic surfactants. Further, the surfactant is selected from the group consisting of egg yolk lecithin, soybean lecithin, dioleoyl lecithin, dilauroyl lecithin, dimyristoyl lecithin, dipalmitoyl lecithin, distearoyl lecithin, cephalin, creatinine, inositol phospholipid, lysophospholipid, phosphatidic acid, phosphatidylglycerol, stearoyl/palmitoyl/oleoyl phosphatidylcholine, stearoyl/palmitoyl/oleoyl phosphatidylethanolamine, phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol and phosphatidylinositol, distearoyl phosphatidylethanolamine, oleoyl phosphatidylcholine, dimyristoyl phosphatidylethanolamine, dipalmitoyl phosphatidylethanolamine, distearoyl phosphatidylethanolamine, dimyristoyl phosphatidylserine, acetylated monoglyceride, sorbitan fatty acid ester, and mixtures thereof, Polyethylene glycol glyceryl amygdala oleate, coconut oil C8/C10 polyethylene glycol glycerides, polyoxyethylene lauryl stearate, polyethylene glycol 100 vitamin E succinate, polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene castor oil (Cremophor EL35), polyoxyethylene hydrogenated castor oil (Cremophor RH 40), polyoxyethylene polyoxypropylene copolymer (e.g., poloxamers 188 and 407), polyoxyethylene glycerides, polyoxyethylene sorbitan trioleate, polyoxyethylene glycerol trioleate, polyoxyethylene sorbitan fatty acid esters, sodium octyl succinate, calcium octyl succinate, potassium octyl succinate, sodium lauryl sulfate, dipalmitoyl phosphatidic acid, ethoxylated castor oil, mannitol oleate polyoxyethylene ether, polyethylene glycol glycerides, oleoyl polyoxyethylene glycerides, polyethylene glycol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, and the like, Polyethylene glycol fatty acid ester, polyethylene glycol-15 hydroxystearate (Solutol), polyethylene glycol-8-glyceryl caprylate/caprate, lauric acid polyethylene glycol-32 glyceride, lauroyl polyethylene glycol-32 glyceride, caprylic/capric acid polyethylene glycol glyceride, sorbitan sesquioleate, polysorbates (such as polysorbate 20 and polysorbate 80), water-soluble natural vitamin E, span 80, Tween 80, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), caprylic acid, sodium caprylate, bile acid and its salt, ursodeoxycholic acid, sodium cholate, sodium taurocholate, sodium glycocholate, N-hexadecyl-N, N-dimethyl-3-ammonia (amonio) -1-propane sulfonate, palmitoyl lysophosphatidyl-L-serine, Lysophospholipids (e.g., 1-acyl-SN-glycero-3-phosphate ester of ethanolamine, choline, serine or threonine), N-alkyl-N, N-dimethylamino-1-propanesulfonate, 3-cholamido-1-propyldimethylamino-1-propanesulfonate, dodecyl choline phosphate, myristoyl lysophosphatidylcholine, egg lysolecithin, polyglycerol fatty acid ester, propylene glycol monocaprylate, propylene glycol monolaurate, hexadecyl-trimethylammonium bromide, hexadecyl pyridinium chloride, polyethylene oxide/polypropylene oxide block copolymer (Pluronics/Tetronics, Triton X-100, dodecyl beta-D-glucopyranoside), sodium taurocholate, oleic acid, threonine, and mixtures thereof, One or at least two of acylcarnitine, lysine, arginine, histidine and lysine.

Further, the surfactant is selected from one or at least two of polyoxyethylene castor oil (Cremophor EL35, EL35), polyoxyethylene hydrogenated castor oil (Cremophor RH 40), Tween 80, polyethylene glycol caprylate capric acid, propylene glycol monocaprylate, polyglycerol fatty acid ester, lauroyl polyethylene glycol-32 glyceride, polyethylene glycol caprylic capric acid (Labrasol), oleoyl polyoxyethylene glyceride, polyethylene glycol glyceride, polysorbate (such as polysorbate 20, polysorbate 80), and propylene glycol monolaurate. Further, the surfactant is one or at least two selected from polyoxyethylene castor oil (Cremophor EL35, EL35), polyoxyethylene hydrogenated castor oil (Cremophor RH 40), Tween 80, caprylic/capric polyethylene glycol glyceride, propylene glycol monocaprylate, polyglycerol fatty acid ester, propylene glycol monolaurate, oleoyl polyoxyethylene glyceride, polyoxyethylene castor oil, lauric acid polyethylene glycol-32 glyceride, caprylic/capric polyethylene glycol glyceride, and a mixed surfactant of polyoxyethylene hydrogenated castor oil (the mass ratio of the two is 1-9: 1, and further is 2-3: 1, and 3:1), polysorbate 80 and RH 40.

The cosurfactant is one or more selected from medium/short chain alcohol and ether. Further, the cosurfactant is selected from ethanol, propylene glycol, isopropanol, N-butanol, polyethylene glycol (molecular weight range of 100Da-10kDa, 300Da-2000Da, or 400Da-1000Da) such as polyethylene glycol 200-600 (such as PEG400, polyethylene glycol 600), polyethylene glycol vitamin E succinate, propylene carbonate, tetrahydrofurfuryl alcohol, ethylene glycol furfuryl alcohol, glycerol furfurol, dimethyl isosorbide, dimethyl acetamide, N-methyl pyrrolidone, one or at least two of diethylene glycol monoethyl ether (Transcutol or Transcutol P or Transcutol HP or TP), ethylene glycol monoethyl ether, docosahexaenoic acid, cholesterol, azone, glycerol, ethyl acetate, polyoxyethylene, polyethylene glycol caprylate/capric acid glyceride, propylene carbonate, glyceryl monostearate, glyceryl distearate and polyglycerol-6-dioleate. Further, the co-surfactant is selected from: one or at least two of ethanol, propylene glycol, isopropanol, diethylene glycol monoethyl ether, polyethylene glycol 400, glycerol and polyethylene glycol 600. Further, the cosurfactant is one or at least two selected from propylene glycol, glycerol, polyethanol 400 and diethylene glycol monoethyl ether.

Further, the particle size of the microemulsion formed by dispersing the self-microemulsion composition into an aqueous medium is less than 500 nm. Further, the particle size of the microemulsion formed by dispersing the self-microemulsion composition into an aqueous medium is less than 300 nm. Further, the particle size of the microemulsion formed by dispersing the self-microemulsion composition into an aqueous medium is less than 100 nm. Further, the particle size of the microemulsion formed by dispersing the self-microemulsion composition into an aqueous medium is less than 50 nm. Further, the particle size of the microemulsion formed by dispersing the self-microemulsion composition into an aqueous medium is less than 30 nm. Further, the particle size of the microemulsion formed from the microemulsion composition dispersed into an aqueous medium is less than 500nm, 450nm, 400nm, 350nm, 300nm, 250nm, 200nm, 150nm, 100nm, 90nm, 80nm, 60nm, 55nm, 53nm, 52nm, 51.5nm, 51nm, 50.5nm, 50nm, 49.5nm, 49nm, 48nm, 47nm, 46nm, 45nm, 43nm, 42nm, 40nm, 35nm, 30nm, 25nm, 20nm, 15nm, 10nm, or even less. Furthermore, the particle size of the microemulsion formed by dispersing the self-microemulsion composition into an aqueous medium is 5-500 nm or 5-400 nm or 5-300 nm or 5-200 nm or 5-100 nm or 5-60 nm or 5-30 nm.

The preparation of the invention is prepared by mixing and dissolving the component materials, and the mixing and dissolving mode can be various, such as: micro-jetting, stirring, shaking and the like, and aims to improve the stability of the self-microemulsion composition and reduce the particle size of the nano-emulsion dispersed in an aqueous medium.

Further, the active ingredient of the tyrosine kinase inhibitor may include crystalline or amorphous forms, salts, anhydrous or hydrated forms, solvates, prodrugs, metabolites, etc. of the tyrosine kinase inhibitor, all of which may be used in the formulations of the present invention.

In one aspect, the invention provides an application of the self-microemulsion composition in preparing a medicament for preventing, treating or protecting tumor diseases. Wherein, the tumor-like diseases include cancers and metastatic cancers, further including, but not limited to, cancers such as bladder cancer, breast cancer, colon cancer, kidney cancer, renal cell carcinoma, liver cancer, lung cancer (including small cell lung cancer), esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer (including squamous cell carcinoma); hematopoietic tumors of the lymphatic system (including leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell leukemia and Burkitt's lymphoma); hematopoietic tumors of the myeloid system (including acute and chronic myelogenous leukemias, myelodysplastic syndromes, and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcomas and rhabdomyosarcomas, and other sarcomas such as soft tissue and cartilage); central peripheral nervous system tumors (including astrocytomas, neuroblastomas, gliomas, and schwannomas); and other tumors (including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pimentosum, keratocotanthoma, thyroid follicular tumor, and kaposi's sarcoma).

In one aspect, the invention provides a dosage form, the obtained self-emulsifying composition is filled into soft or hard capsules, and an absorbent can also be added to prepare solid self-emulsifying tablets, pills, powder, granules and the like.

Further, the self-microemulsion composition is a capsule, and comprises a self-microemulsion composition and a capsule shell, wherein the self-microemulsion composition is described in the invention; the capsule shell is made of hard capsule or soft capsule materials. The capsule shell is a hard capsule and/or soft capsule material well known in the art, such as a gelatin hard capsule or a gelatin soft capsule, and can be commercially obtained or prepared, and is not particularly limited herein.

The invention adopts self-microemulsifying technology to prepare the self-microemulsifying soft capsule, can quickly form microemulsion after being taken, and greatly improves the dissolution rate of the medicament and the permeability of gastrointestinal mucosa, thereby improving the bioavailability of the medicament and reducing adverse reactions.

In one aspect, the invention provides a pharmaceutical composition comprising one of the self-microemulsion composition of the invention or the self-microemulsion composition capsule of the invention, and other anti-tumor drugs.

Further, the other antineoplastic agents include, but are in no way limited to, Asparaginase (Asparaginase), Bleomycin (Bleomycin), carboplatin, Carmustine (Carmustine), Chlorambucil (Chlorambucil), cisplatin, L-Asparaginase (Colaspase), cyclophosphamide, Cytarabine (Cytarabine), Dacarbazine (Dacarbobazine), actinomycin D (Dactinomycin), Daunorubicin (Daunomycin), doxorubicin (doxorubicin), Epirubicin (Epirubicin), Etoposide (Etoposide), 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, folinic acid, lomustine, nitrogen mustard, 6-mercaptopurine, Mesna (Mesna), Methotrexate (Methotrexate), mitomycin C (mitomycin C), Mitoxantrone (Mitoxantrone), Prednisolone (Preprednisolone (Preloxazine), Prednisone (Profenone), streptozotocin (Streptozocin), Tamoxifen (Tamoxifen), Thioguanine (Thioguanine), topotecan, vinblastine, vincristine, vindesine, Aminoglutethimide (Aminoglutethimide), L-asparaginase, azathioprine, 5-azacytidine, Cladribine (Cladribine), Busulfan (Busufan), diethylstilbestrol, 2 ', 2' -difluorodeoxycytidine, docetaxel, erythrohydroxynonanyladenine (Erythroxynyladienine), ethinylestradiol, 5-fluorouracil deoxynucleoside, 5-fluorodeoxyuridine, Fludarabine phosphate (Flarataferine), fluoromethyltestosterone (Fluoxymatriplex), Flutamide (Flutathionine), hydroxyprogesterone hexanoate, Idarubicin (Idarubicin), interferon, medroxyprogesterone acetate (Metastine), paclitaxel-phosphate (Melothalamethionine), Melothalamethionine (Melothione), Melothione (Melothione), Melothalamethionine (Melothione, Melothalamethionine), Melothione (Melothione, Melothalamicine, Melothalamethionine, Melothricin (E), plicamycin (Plicamycin), methylcyclohexanone (Semustine), Teniposide (Teniposide), testosterone propionate, Thiotepa (Thiotepa), trimethylmelamine, uridine and vinorelbine.

In one aspect, the pharmaceutical composition of the invention is used for preparing a medicament for preventing, treating or protecting tumor diseases.

The oil phase optimizes the internal structure among the self-microemulsion composition particles, and can improve the stability of the system. The existence of the surfactant enables the nanoemulsion to have water-based property, and the uniform particle size is beneficial to carrying the medicine to pass through a static water layer and be in close contact with the epithelial cell membrane of the small intestine. The self-microemulsion composition prepared by the invention can obviously improve the bioavailability of the medicament by solving the problems of dissolution and transmembrane transport of the medicament in vivo, improve the problems of low bioavailability, large in vivo variation and large safety risk of the original preparation, and reduce the administration cost of patients. Meanwhile, the self-microemulsion soft capsule is easy to be produced in an enlarged mode, and has high self-emulsifying speed and good repeatability.

The emulsifier in the self-microemulsion composition is amphiphilic and can be dissolved in an oil phase and a water phase, so that the drug in the O/W nanoemulsion can be prevented from being deposited in the gastrointestinal tract, the dissolution state of drug molecules can be prolonged, the bioavailability can be improved, and adverse reactions can be reduced.

The co-emulsifier has both hydrophilicity and lipophilicity, helps the active components to form a uniform nanoemulsion and maintains the stability of the emulsion during storage.

Compared with the prior art, the invention has the following beneficial effects:

the invention provides a self-microemulsion composition aiming at the characteristic of great toxic and side effects of a tyrosine kinase inhibitor.

After the prepared self-microemulsion composition enters the gastrointestinal tract by oral administration, the self-microemulsion composition can be self-microemulsified into O/W nanoemulsion when meeting gastrointestinal fluids, drug molecules are wrapped in a carrier, the particle size of the drug molecules is correspondingly enlarged, the transmembrane mode of the nanoemulsion is changed after the contact with small intestine epidermal cells, the original passive diffusion transport is changed into endocytosis transport, and the stimulation of the nanoemulsion to the gastrointestinal tract is reduced by active endocytosis or endocytosis absorption, so that the stimulation of the drug caused by overhigh local concentration and long-time contact with the gastrointestinal wall is reduced, and the side effect of the drug on the gastrointestinal tract can be reduced.

The tyrosine kinase inhibitor in the nanoemulsion is wrapped in the emulsion drop, so that the tyrosine kinase inhibitor is protected from being degraded by the stomach and intestine, enzyme barriers and membrane barriers are overcome, meanwhile, the emulsion drop can be contacted with the mucosa of the stomach and intestine for a long time due to the lower surface tension of the nanoemulsion, and the transmembrane transport of the drug is increased. The nanoemulsion is endocytosed by small intestinal cells in an integral form, so that the lymphatic absorption of the medicament is increased, the first-pass effect is avoided, and the bioavailability is further improved.

The formed O/W type nanoemulsion is smaller than 100nm and even smaller than 50nm, so that the medicine can be quickly distributed in the whole gastrointestinal tract, the medicine can be more easily and directly contacted with small intestinal epithelial cells, the medicine can be promoted to be absorbed by the small intestinal mucosal epithelial cells through endocytosis or the like, the dissolution process of the medicine is not a rate-limiting step of in vivo absorption any more, the solubility and dissolution rate of the tyrosine kinase inhibitor in gastrointestinal fluid are obviously improved, the oral absorption rate and bioavailability of the medicine are increased, the permeability is improved, the gastrointestinal tract reaction is reduced, and the adverse reaction is reduced; the self-microemulsion composition forms a nano-emulsion after emulsification, so that transmembrane absorption of the drug is promoted, and meanwhile, the tyrosine kinase inhibitor is wrapped by a blank microemulsion carrier, so that slow release of the drug is realized, the drug release speed is stable, overlarge fluctuation of blood concentration can be prevented, the curative effect of the drug is improved, and adverse reactions are reduced.

Drawings

In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the description of the embodiments will be briefly described below, and for those skilled in the art, other drawings can be obtained according to the drawings without any creative effort.

FIG. 1 shows the comparison of the total occurrence of adverse gastrointestinal reactions in each group

Detailed Description

The invention will be further illustrated with reference to the following specific examples. These examples are intended to illustrate the invention and are not intended to limit the scope of the invention.

Test one: the preparation process of the self-emulsifying preparation is as follows:

weighing SMEDDS carriers (namely an oil phase, a surfactant and a cosurfactant) according to the prescription amount, uniformly mixing, carrying out ultrasonic mixing at 37 ℃ under a light-shielding condition, carrying out mechanical stirring at the speed of 100-400 rpm to form a transparent and uniform self-emulsifying solution, adding a tyrosine kinase inhibitor according to the prescription amount, uniformly stirring, fully dissolving and then filling into soft capsules.

And (2) test II: determination of microemulsion size

The particle size of the tyrosine kinase inhibitors prepared in the examples was tested.

The tyrosine kinase inhibitor was diluted 100-fold with an aqueous medium having a pH of 6.8 and then measured by a nanometer particle size analyzer. At least three tests were performed per sample to ensure the accuracy of the results.

Example 1

The prescription is as follows: axitinib: 5 mg;

the total mass of the SMEDDS carrier is 600 mg: oil phase: surfactant (B): the mass ratio of the cosurfactant is as follows: 16.7:53.3: 30; the oil phase is ethyl oleate; the surfactant is polyoxyethylene castor oil; the cosurfactant is diethylene glycol monoethyl ether. The preparation process refers to test one, and the particle size test refers to test two. The particle size of the nanoemulsion of the obtained axitinib preparation is 18.45 nm.

Example 2

The prescription is as follows: lurasidone hydrochloride: 5 mg;

the total mass of the SMEDDS carrier is 400 mg: (capryol90:

m1944 CS) RH40 (PEG400: TP) ═ 13.3:6.7 (53.3: (17.8:8.9), the preparation process refers to test one, and the particle size test refers to test two. The particle size of the obtained nano-emulsion is 26.24 nm.

Example 3

The prescription is as follows: lurasidone hydrochloride: 5 mg;

the total mass of the SMEDDS carrier is 600 mg: (propylene glycol caprylate: polyethylene glycol glyceryl oleate): polyoxyethylene hydrogenated castor oil: (polyethylene glycol 400: diethylene glycol monoethyl ether) ═ 13.3:6.7):53.3 (17.8: 8.9). The preparation process refers to test one, and the particle size test refers to test two. The particle size of the obtained nano-emulsion is 25.93 nm.

Example 4

The prescription is as follows: and (2) imatinib: 5 mg;

the total mass of the SMEDDS carrier is 400 mg: oil phase: surfactant (b): the mass ratio of the cosurfactant is as follows: 20:53.3: 26.7; wherein the oil phase is a mixed oil phase of propylene glycol caprylate and polyethylene glycol glyceryl oleate, and the mass ratio of the propylene glycol caprylate to the polyethylene glycol glyceryl oleate is as follows: 1: 1; the surfactant is polyoxyethylene hydrogenated castor oil; the cosurfactant is a mixed cosurfactant of polyethylene glycol 400 and diethylene glycol monoethyl ether, and the mass ratio of the two is 2: 1. The preparation process refers to test one, and the particle size test refers to test two. The particle size of the obtained nanoemulsion was 27.27 nm.

Example 5

The prescription is as follows: and (2) imatinib: 5 mg;

the total mass of the SMEDDS carrier is 600 mg: oil phase: surfactant (b): the mass ratio of the cosurfactant is as follows: 20:53.3: 26.7; wherein the oil phase is a mixed oil phase of propylene glycol caprylate and polyethylene glycol glyceryl oleate, and the mass ratio of the propylene glycol caprylate to the polyethylene glycol glyceryl oleate is as follows: 2: 1; the surfactant is polyoxyethylene hydrogenated castor oil; the cosurfactant is a mixed cosurfactant of polyethylene glycol 400 and diethylene glycol monoethyl ether, and the mass ratio of the two is 1: 1. The preparation process refers to test one, and the particle size test refers to test two. The particle size of the obtained nanoemulsion was 47.5 nm.

Example 6

The prescription is as follows: axitinib: 5 mg;

the total mass of the SMEDDS carrier is 600 mg: capmul MCM Cremophor RH40 diethylene glycol monoethyl ether 20:53.3: 26.7. The preparation process refers to test one, and the particle size test refers to test two. The particle size of the obtained nanoemulsion is 36.02 nm.

Example 7

The prescription is as follows: sunitinib: 5 mg;

the total mass of the SMEDDS carrier is 400 mg: oil phase: surfactant (b): the mass ratio of the cosurfactant is as follows: 1:6: 3; wherein the oil phase is a mixed oil phase of propylene glycol caprylate and polyethylene glycol glyceryl oleate, and the mass ratio of the propylene glycol caprylate to the polyethylene glycol glyceryl oleate is as follows: 1: 2; the surfactant is a mixed surfactant of RH40 and tween 80, and the mass ratio of the RH40 to the tween 80 is 5: 5; the cosurfactant is a mixed cosurfactant of polyethylene glycol 400 and diethylene glycol monoethyl ether, and the mass ratio of the cosurfactant to the diethylene glycol monoethyl ether is 2: 1. The preparation process refers to test one, and the particle size test refers to test two. The particle size of the obtained nanoemulsion is 25.36 nm.

Example 8

The prescription is as follows: sunitinib: 6 mg;

the total mass of the SMEDDS carrier is 400 mg: oil phase: surfactant (b): the mass ratio of the cosurfactant is as follows: 3:4.66: 2.34; the oil phase is a mixed oil phase of propylene glycol caprylate and polyethylene glycol glyceryl oleate, and the mass ratio of the propylene glycol caprylate to the polyethylene glycol glyceryl oleate is as follows: 1: 1; the surfactant is a mixed surfactant of RH40 and tween 80, and the mass ratio of the RH40 to the tween 80 is 6: 4; the cosurfactant is a mixed cosurfactant of polyethylene glycol 400 and diethylene glycol monoethyl ether, and the mass ratio of the two is 1: 1. The preparation process refers to test one, and the particle size test refers to test two. The particle size of the obtained nanoemulsion was 36.25 nm.

Example 9

The prescription is as follows: dasatinib: 6 mg;

the total mass of the SMEDDS carrier is 300 mg: oil phase: surfactant (b): the mass ratio of the cosurfactant is as follows: 4:4: 2; the oil phase is a mixed oil phase of propylene glycol caprylate and polyethylene glycol glyceryl oleate, and the mass ratio of the propylene glycol caprylate to the polyethylene glycol glyceryl oleate is 2: 1; the surfactant is a mixed surfactant of RH40 and tween 80, and the mass ratio of the RH40 to the tween 80 is 7: 3; the cosurfactant is a mixed cosurfactant of polyethylene glycol 400 and diethylene glycol monoethyl ether, and the mass ratio of the two is 3: 1.

The preparation process refers to test one, and the particle size test refers to test two. The particle size of the obtained nanoemulsion is 45.21 nm.

Example 10

The prescription is as follows: laolatinib: 5 mg;

the total mass of the SMEDDS carrier is 400 mg: oil phase: surfactant (b): the mass ratio of the cosurfactant is as follows: 5:3.66: 1.34; the oil phase is a mixed oil phase of propylene glycol caprylate and polyethylene glycol glyceryl oleate, the mass ratio of the propylene glycol caprylate to the polyethylene glycol glyceryl oleate is 1:2, the surfactant is a mixed surfactant of RH40 and tween 80, and the mass ratio of the propylene glycol caprylate to the polyethylene glycol glyceryl oleate is 8: 2; the cosurfactant is a mixed cosurfactant of polyethylene glycol 400 and diethylene glycol monoethyl ether, and the mass ratio of the cosurfactant to the diethylene glycol monoethyl ether is 2: 8.

The preparation process refers to test one, and the particle size test refers to test two. The particle size of the obtained nano-emulsion is 23.05 nm.

Example 11

The prescription is as follows: lurasidone hydrochloride: 6 mg;

the total mass of the SMEDDS carrier is 400 mg: oil phase: surfactant (b): the mass ratio of the cosurfactant is as follows: 1:6: 3; the oil phase is propylene glycol caprylate, the surfactant is a mixed surfactant of RH40 and tween 80, and the mass ratio of the two is 6: 4; the co-surfactant is PEG 400.

The preparation process refers to test one, and the particle size test refers to test two. The particle size of the obtained nano-emulsion is 20 nm.

Example 12

The prescription is as follows: axitinib: 5 mg;

the total mass of the SMEDDS carrier is 400 mg: ((propylene glycol caprylate: polyethylene glycol glyceryl oleate): polyoxyethylene hydrogenated castor oil (polyethylene glycol 400: diethylene glycol monoethyl ether)) - (13.3:6.7):53.3 (17.8:8.9), preparation process reference test one, particle size test reference test two. The particle size of the obtained nano-emulsion is 23.42 nm.

Example 13

The prescription is as follows: axitinib: 5 mg;

the total mass of the SMEDDS carrier is 400 mg: ((propylene glycol caprylate: polyethylene glycol glyceryl oleate): polyoxyethylene hydrogenated castor oil (polyethylene glycol 400: diethylene glycol monoethyl ether)) - (13.3:6.7):53.3 (17.8:8.9), preparation process reference test one, particle size test reference test two. The particle size of the obtained nanoemulsion was 42.37 nm.

Example 14

The prescription is as follows: erlotinib: 5 mg;

the total mass of the SMEDDS carrier is 400 mg: capmul MCM Cremophor RH40 diethylene glycol monoethyl ether 20:53.3:26.7, preparation process reference run one, particle size test reference run two. The particle size of the obtained nano-emulsion is 29.01 nm.

Example 15

The prescription is as follows: dasatinib: 5 mg;

the total mass of the SMEDDS carrier is 400 mg: capmul MCM, surfactant diethylene glycol monoethyl ether 20:53.3:26.7, and mixed surfactant of RH40 and tween 80 in a mass ratio of 5: 5; the preparation process refers to test one, and the particle size test refers to test two. The particle size of the obtained nano-emulsion is 21.92 nm.

Capsule example 1

The self-microemulsion composition prepared in any of the above examples is mixed with an antioxidant uniformly and then filled into soft or hard capsules to obtain the self-microemulsion capsule. Wherein the dosage of the antioxidant is reasonably adjusted according to the dosage of the tyrosine kinase inhibitor.

Test example 1

Normal rats without symptoms such as diarrhea and liver and kidney dysfunction were selected and randomly divided into two groups, 20 rats in the experimental group and the control group, respectively, and there was no statistical difference in age, sex, body weight, body surface area, etc. (P > 0.05).

The method comprises the following steps: the experimental groups were treated with the example samples, the control group 1 with the commercially available lurasidone hydrochloride tablet, and the control group 2 with the commercially available axitinib tablet, all conventionally. Free diet and drinking water support are given according to the weight, age and activity degree of the rats, the activity degree and state are basically not obviously changed, and only rats with symptoms of diarrhea, abdominal distension and vomiting on the 5 th day, the 10 th day and the 30 th day are examined. The results are shown in Table 1.

TABLE 1 clinical test results of gastrointestinal adverse reaction occurrence in each group

The results in table 1 show that adverse reactions such as diarrhea, abdominal distension, and vomiting of rats administered with the example of the present invention were significantly improved at 5 days, 10 days, and 30 days, compared to the control group. Therefore, the safety of the medicine is obviously improved, and the compliance of taking the medicine are greatly improved.

Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A self-microemulsifying composition of a tyrosine kinase inhibitor, comprising, based on the total weight of the composition: 0.1% -40% of a tyrosine kinase inhibitor; 60-99.9% of a carrier;

the carrier is (propylene glycol caprylate: polyethylene glycol glyceryl oleate) polyoxyethylene hydrogenated castor oil (polyethylene glycol 400: diethylene glycol monoethyl ether) = (13.3:6.7) 53.3 (17.8: 8.9);

the self-microemulsion composition spontaneously forms a microemulsion with the particle size of less than 50nm when meeting water media;

the tyrosine kinase inhibitor is selected from: axitinib and lurasidone hydrochloride.