WO2022116987A1 - 阿昔替尼的自微乳组合物 - Google Patents

阿昔替尼的自微乳组合物 Download PDF

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WO2022116987A1
WO2022116987A1 PCT/CN2021/134705 CN2021134705W WO2022116987A1 WO 2022116987 A1 WO2022116987 A1 WO 2022116987A1 CN 2021134705 W CN2021134705 W CN 2021134705W WO 2022116987 A1 WO2022116987 A1 WO 2022116987A1
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axitinib
self
surfactant
microemulsion composition
oil phase
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PCT/CN2021/134705
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English (en)
French (fr)
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易木林
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湖南慧泽生物医药科技有限公司
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Priority claimed from CN202011391509.5A external-priority patent/CN112618488B/zh
Priority claimed from CN202011388653.3A external-priority patent/CN112516315B/zh
Application filed by 湖南慧泽生物医药科技有限公司 filed Critical 湖南慧泽生物医药科技有限公司
Publication of WO2022116987A1 publication Critical patent/WO2022116987A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the technical field of medicine, in particular to a self-microemulsion composition of axitinib.
  • Axitinib is a multi-targeted tyrosine kinase inhibitor developed by Pfizer, which can inhibit vascular endothelial cell growth factor receptors VEGFR1, VEGFR2, VEGFR3, platelet-derived growth factor receptor and c-KIT for Advanced renal cancer for which other systemic therapy fails, was approved by the FDA on January 27, 2012.
  • Axitinib is currently marketed as a tablet.
  • Axitinib is a white powder with a melting point of 218.4°C. It is slightly soluble in polyethylene glycol 400, slightly soluble in methanol or ethanol, very slightly soluble in acetonitrile, and almost insoluble in water. It is unstable to light, heat and humidity. Degradation easily occurs.
  • the solubility is 0.8 mg/mL in pH 1.2 hydrochloric acid solution at 20°C and 0.2 ⁇ g/mL in pH 6.8 phosphate buffer solution, which are typical pH-dependent drugs.
  • axitinib tablets The content of axitinib tablets is relatively low, usually 1 mg/tablet and 5 mg/tablet. Therefore, when axitinib is mixed with excipients, it is easy to cause uneven mixing, which threatens the safety of clinical medication. Secondly, axitinib has extremely low solubility and is a poorly soluble drug, which is prone to the problem of unqualified dissolution. Axitinib is a poorly soluble drug, and its particle size needs to be small enough to ensure that the dissolution rate meets the requirements. However, at the same time, the smaller the particle size of axitinib, the more difficult it is to mix uniformly.
  • axitinib is most prone to adverse reactions in the digestive system during use, and its diarrhea incidence rate exceeds 80%. When persistent diarrhea occurs, it may cause other problems such as dehydration. Gastrointestinal adverse reactions may be due to drug stimulation of the gastrointestinal tract and changes in bowel motility, resulting in diarrhea. Therefore, there is a need to reduce or even eliminate the side effects of the drug by changing the dosage form.
  • the self-microemulsifying composition forms microemulsions in the gastrointestinal tract.
  • the drug exists in these small oil droplets and is rapidly distributed throughout the gastrointestinal tract.
  • the drug is distributed between the oil/water two items, relying on the huge surface area of the small oil droplets.
  • Self-microemulsion compositions have been shown to improve the stability of drugs in the blood circulation, prolong the drug action time, and because of their uniform particle size and particle size distribution, they can deliver drugs to specific cells and tissues.
  • the self-microemulsion composition not only has a small particle size, but also can prevent the microemulsion from agglomerating into agglomerates, and can penetrate deeper into the lesion site, change the drug distribution, improve the efficacy of the drug, and reduce side effects.
  • the patent with the application number CN201710156853.8 provides a preparation method of XLI crystal form axitinib.
  • the axitinib and a protic solvent are mixed, recrystallized, and recrystallized by adding crystal seeds in an anhydrous solvent to obtain XLI crystal form axitinib.
  • axitinib is a poorly soluble small-dose drug, it is usually pulverized during preparation to improve the dissolution rate. However, if the particle size is too fine, the uniformity will exceed the standard, which will cause various adverse reactions.
  • the purpose of the present invention is to provide a self-microemulsion composition of axitinib to alleviate the adverse reactions of axitinib.
  • Making axitinib into a self-microemulsion composition can make the drug release smoothly and slowly, avoid serious adverse reactions in the digestive system caused by high blood drug concentration after taking the drug, and also avoid the impact of unqualified dissolution. Reduce adverse reactions and improve efficacy.
  • the present invention adopts the following technical solutions:
  • the present invention provides a self-microemulsion composition of axitinib, comprising at least 1) axitinib; 2) an oil phase; 3) a surfactant.
  • the self-microemulsion composition further includes 4) a co-surfactant.
  • the self-microemulsion composition in terms of the mass percentage of the total mass of the self-microemulsion composition, comprises 0.1-10% axitinib, 1-70% oil phase, and 10-90% surface activity agent and 0-60% co-surfactant.
  • the self-microemulsion composition in terms of the mass percentage of the total mass of the self-microemulsion composition, includes 0.1%, 0.2%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.82%, 0.83%, 0.99%, 1%, 1.23%, 1.5%, 1.64%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% axitinib.
  • the self-microemulsion composition in terms of the mass percentage of the total mass of the self-microemulsion composition, includes 1%, 1.23%, 1.5%, 1.64%, 2%, 3%, 4%, 4.96%, 5%, 9.91%, 10%, 14.14%, 14.17%, 14.88%, 15%, 16.34%, 16.39%, 16.42%, 16.53%, 16.56%, 19.75%, 19.83%, 20%, 23.11%, 24.69% , 25%, 26.48%, 29.75%, 30%, 33.06%, 35%, 39.6%, 39.67%, 40%, 44.63%, 45%, 49.59%, 50%, 60% or 70% of the oil phase.
  • the self-microemulsion composition in terms of the mass percentage of the total mass of the self-microemulsion composition, includes 10%, 20%, 25%, 29.7%, 29.75%, 30%, 39.67%, 40%, 42.43%, 42.5%, 44.63%, 45%, 46.31%, 49.38%, 49.59%, 50%, 52.29%, 52.43%, 52.46%, 52.64%, 52.86%, 55%, 59.5%, 60%, 64.46% , 65%, 66.94%, 69.42%, 70%, 79.34%, 80%, 89.52% or 90% surfactant.
  • the self-microemulsion composition in terms of the mass percentage of the total mass of the self-microemulsion composition, includes 0%, 5%, 9.91%, 10%, 15%, 19.83%, 20%, 24.69%, 25%, 26.37%, 26.48%, 29.42%, 29.51%, 29.7%, 29.75%, 30%, 33.06%, 35%, 40%, 42.43%, 42.5%, 45%, 50%, 54.54% or 55% co-surfactant.
  • the self-microemulsion composition includes 0.5-2% axitinib in terms of mass percentage of the total mass of the self-microemulsion composition. Further, the self-microemulsion composition, in terms of the mass percentage of the total mass of the self-microemulsion composition, comprises 1%-65%, 5%-50% or 10%-40% of the oil phase. Further, the self-microemulsion composition includes 40%-70%, 45-60% or 25-90% of surfactant in terms of mass percentage of the total mass of the self-microemulsion composition. Further, the self-microemulsion composition, in terms of mass percentage of the total mass of the self-microemulsion composition, includes 0-45% or 20-35% of a co-surfactant.
  • the self-microemulsion composition further includes one or both of antioxidants and preservatives; the antioxidants or preservatives account for 0.005-0.1% of the total mass of the self-microemulsion composition.
  • the antioxidant is selected from one or two of tert-butyl-p-hydroxyanisole BHA, butylated hydroxytoluene BHT, vitamin C, and vitamin E (dl- ⁇ -tocopherol).
  • oil phase is a variety of pharmaceutically acceptable oil phases, selected from natural vegetable oil, vegetable oil after structural modification and hydrolysis, or medium chain length fatty acid glycerides with chain length between C8-C10. one or more.
  • the oil phase is selected from: corn oil, sunflower oil (such as 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 Sesame Oil, coconut Oil C8/C10 Mono- or Diglycerides (Capmul MCM), Coconut Oil C8/C10 Propylene Glycol Diester (Captex 200), coconut Oil C8/C10 Triglycerides (Captex 355), coconut Oil Aminopropyl Beet Base, Purified Acetylated Monoglyceride (Miglyol 812), Purified Sunflower Oil Monoglyceride, Macrogol Glyceryl Laurate, Glycerol Monooleate, Glycerol Monolinoleate, Medium Chain Triglyceride, Polyglycerol Glycol Glyceryl Oleate, Macrogol Glyceryl Linoleate, Macrogol Caprylic Glyceryl Caprate, Caprylic
  • the oil phase is selected from sunflower oil, soybean oil, oleic acid, castor oil, glycerol monolinoleate, medium chain triglyceride (MCT), caprylic acid, ethyl oleate, isopropyl myristate , Propylene Glycol Monolaurate, Medium Chain Glycerate, Macrogol Glyceryl Linoleate, Macrogol-6 Oleate, Medium Chain Triglyceride, Glyceryl Monooleate, Ethyl Oleate , the mixed oil phase (the mass ratio of the two is 1 ⁇ 9:1 ⁇ 9, further is 8: 2 or 6:4), the 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 gly
  • the surfactant is selected from nonionic, anionic, cationic and zwitterionic surfactants.
  • the surfactant is selected from 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/oleoylphosphatidylcholine, stearoyl/palmitoyl/oleoylphosphatidylethanolamine, phosphatidylcholine , hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol and phosphatidylinositol, distearoylphosphatidylethanolamine, oleoylphosphatidylcho
  • poloxamers 188 and 407) polyoxyethylene glycerides, polyoxyethylene sorbitan trioleate, polyoxyethylene Triolein, polyoxyethylene sorbitan fatty acid ester, sodium octyl succinate, calcium octyl succinate, potassium succinate, sodium lauryl sulfate, sodium lauryl sulfate, dipalmitoyl phosphatidic acid, Ethoxylated castor oil, mannitol oleate polyoxyethylene ether, polyethylene glycol glycerides, oleoyl polyoxyethylene glycerides, polyethylene glycol fatty acid esters, polyethylene glycol fatty acid esters, poly Ethylene Glycol-15 Hydroxystearate (Solutol), Macrogol-8-Glycerol Caprylic/Capric Acid, Macrogol-32 Glyceryl Laurate, Glyceryl Lauroyl Macrogol-32, Caprylic acid polyethylene glycol glyceride,
  • the surfactant is selected from polyoxyethylene castor oil (Cremophor EL 35, EL35), polyoxyethylene hydrogenated castor oil (Cremophor RH 40), Tween 80, caprylic acid macrogol glyceride, caprylic acid Capric macrogol glyceride, propylene glycol monocaprylate, polyglycerol fatty acid ester, lauroyl macrogol-32 glyceride, caprylic capric macrogol glyceride (Labrasol), oleoyl polyoxyethylene Glycerides, Macrogolglycerides, Polysorbates (eg, Polysorbate 20, Polysorbate 80), Polyoxyethylene Castor Oil, Propylene Glycol Monolaurate, Polyethylene Glycol Caprylate, and Polyoxyethylene Mixed surfactant of ethylene hydrogenated castor oil (the mass ratio of the two is 1 ⁇ 9:1, further is 2 ⁇ 3:1, 1:2, 1:1, 2:1 or 3:1), caprylic acid capric acid In the mixed surfactant of acid macro
  • the co-surfactant is selected from one or more of medium/short chain alcohols and ethers.
  • the co-surfactant is selected from ethanol, propylene glycol, isopropanol, n-butanol, polyethylene glycol (molecular weight range is 100Da-10kDa, 300Da-2000Da, or 400Da-1000Da) such as polyethylene glycol 200 ⁇ 600 (eg: PEG400, polyethylene glycol 600), polyethylene glycol vitamin E succinate, propylene carbonate, propylene carbonate, tetrahydrofurfuryl alcohol, ethylene glycol furfuryl alcohol, glycerol furfural, dimethyl isopropyl alcohol Sorbitan, dimethylacetamide, N-methylpyrrolidone, diethylene glycol monoethyl ether (Transcutol or Transcutol P or Transcutol HP or TP), ethylene glycol monoethyl ether, docosahexaenoic acid , Cholesterol, Azone, Glycerin, Ethyl acetate, Polyethylene glyco
  • the co-surfactant is selected from: ethanol, propylene glycol, isopropanol, diethylene glycol monoethyl ether, polyethylene glycol 400, glycerin, polyethylene glycol 60, polyethylene glycol 400 and diethylene glycol
  • One or at least two of the mixed co-surfactants of ethylene glycol monoethyl ether is 2:1.
  • the mass ratio of the oil phase:surfactant:cosurfactant is: 10 ⁇ 35:45 ⁇ 60:20 ⁇ 35, and the further mass ratios are 10.1:59.9:30, 19.62:45.38:35, 16.7 : 53.3:30, 29.84:50:20.16 or 30:45.38:24.62; further, the oil phase is ethyl oleate; the surfactant is polyoxyethylene castor oil; the co-surfactant is two Ethylene glycol monoethyl ether.
  • the particle size of the microemulsion formed by dispersing the self-microemulsion composition into the aqueous medium is less than 500 nm. Further, the particle size of the microemulsion formed by dispersing the self-microemulsion composition into the aqueous medium is less than 300 nm. Further, the particle size of the microemulsion formed by dispersing the self-microemulsion composition into the aqueous medium is less than 100 nm. Further, the particle size of the microemulsion formed by dispersing the self-microemulsion composition into the aqueous medium is less than 50 nm.
  • the particle size of the microemulsion formed by dispersing the self-microemulsion composition into the aqueous medium is less than 30 nm. Further, the particle size of the microemulsion formed by dispersing the self-microemulsion composition into the aqueous medium is less than 500 nm, 450 nm, 400 nm, 350 nm, 300 nm, 250 nm, 200 nm, 150 nm, 100 nm, 90 nm, 80 nm, 60 nm, 55 nm, 53 nm , 52 nm, 51.5 nm, 51 nm, 50.5 nm, 50 nm, 49.5 nm, 49 nm, 48 nm, 47 nm, 46 nm, 45 nm, 43 nm, 42 nm, 40 nm, 35 nm, 30 nm, 25 nm, 20 nm, 15 nm, 10 nm or even smaller.
  • the particle size of the microemulsion formed by dispersing the self-microemulsion composition into the 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 present invention is prepared by mixing and dissolving each component material, and there are various ways of mixing and dissolving, such as: micro-jet, stirring, shaking, etc.
  • the purpose is to help improve the stability of the self-microemulsion composition and reduce the self-emulsion. Particle size of nanoemulsions dispersed by microemulsions in aqueous media.
  • the active ingredients of axitinib may include crystals or amorphous forms, salts, anhydrates or hydrates, solvates, prodrugs, metabolites, etc. of axitinib, all of which can be used in the present invention. Invented preparations.
  • the present invention provides the use of the aforementioned self-microemulsion composition in the preparation of a medicament for preventing, treating or protecting tumor diseases.
  • the tumor diseases include cancer and metastatic cancer, further including but not limited to, cancer such as bladder cancer, breast cancer, colon cancer, kidney cancer, renal cell cancer, liver cancer, lung cancer (including small cell lung cancer), esophageal cancer , gallbladder, ovarian, pancreatic, gastric, cervical, thyroid, prostate, and skin cancers (including squamous cell carcinoma); hematopoietic tumors of the lymphatic system (including leukemia, acute lymphocytic 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 bone marrow system (including acute chronic myelogen
  • the present 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, powders, granules, and the like.
  • the self-microemulsion composition is a capsule, and the capsule comprises a self-microemulsion composition and a capsule shell, wherein the self-microemulsion composition is as described in the present invention; the capsule shell is made of hard capsules or soft capsule material.
  • the capsule shells are hard capsules and/or soft capsule materials well known in the art, such as hard gelatin capsules or soft gelatin capsules, which can be purchased or prepared through commercial channels, and are not particularly limited here.
  • the invention adopts the self-micro-emulsifying technology to make it into self-micro-emulsifying soft capsule, which can rapidly form micro-emulsion after oral administration, greatly improves the dissolution rate of the drug and the permeability of the gastrointestinal mucosa, thereby improving the bioavailability of the drug , reduce adverse reactions.
  • the present invention provides a pharmaceutical composition, including one of the self-microemulsion composition of the present invention or the self-microemulsion composition capsule of the present invention, and other antitumor drugs.
  • the other antitumor drugs include, but are by no means limited to, Asparaginase, Bleomycin, Carboplatin, Carmustine, Chlorambucil ), cisplatin, L-asparaginase (Colaspase), cyclophosphamide, cytarabine (Cytarabine), dacarbazine (Dacarbazine), actinomycin D (Dactinomycin), daunorubicin (Daunorubicin) , doxorubicin (doxorubicin), epirubicin (Epirubicin), etoposide (Etoposide), 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, sub Folic acid, cyclohexyl nitrosourea, nitrogen mustard, 6-mercaptopurine, Mesna, Methotrexate, Mitomycin C, Mitoxantrone, Pred
  • the pharmaceutical composition of the present invention is used in the preparation of a medicament for preventing, treating or protecting tumor diseases.
  • the oil phase optimizes the internal structure between the particles of the self-microemulsion composition, which can improve the stability of the system.
  • the existence of the surfactant of the present invention makes the nanoemulsion have water-like properties, and the uniform particle size is conducive to carrying the drug through the static water layer and in close contact with the small intestinal epithelial cell membrane.
  • the self-microemulsion composition prepared by the invention can significantly improve the bioavailability of the drug by solving the dissolution and transmembrane transport of the drug in the body, improve the problems of low bioavailability, large in vivo variation and high safety risk of the original preparation, and reduce the cost of medication for patients.
  • self-microemulsifying soft capsules are easy to scale up and produce, self-emulsifying speed is fast, and has good reproducibility.
  • the emulsifier in the self-microemulsion composition is amphiphilic and can dissolve in the oil phase and the water phase, which can prevent the drug in the O/W nanoemulsion from depositing in the gastrointestinal tract and prolong the dissolution state of the drug molecule, which is beneficial to improve the biological Availability while reducing adverse reactions.
  • Co-emulsifiers are both hydrophilic and lipophilic, helping active ingredients to form uniform nanoemulsions and maintaining emulsion stability during storage.
  • the present invention has the following beneficial effects:
  • Axitinib has the characteristics of poor solubility, small dosage and easy to be decomposed by visible light, and provides a self-microemulsion composition. After dissolving and dispersing the oil phase, surfactant and co-surfactant, Axitinib was added so that the dissolution and mixing uniformity of the prepared axitinib met the requirements.
  • the prepared self-microemulsion composition After the prepared self-microemulsion composition enters the gastrointestinal tract orally, it can self-microemulsify into O/W nanoemulsion in the presence of gastrointestinal fluid. After the milk contacts the small intestinal epidermal cells, the membrane permeation mode changes, from the original passive diffusion transport to endocytosis. Through active pinocytosis or endocytosis absorption, the stimulation of the gastrointestinal tract by the nanoemulsion is reduced, thereby reducing the local concentration of drugs due to The irritation caused by too high and prolonged contact with the gastrointestinal wall can reduce the gastrointestinal side effects of the drug.
  • axitinib in the nanoemulsion is encapsulated in the emulsion droplets, it protects axitinib from being degraded by the gastrointestinal tract and overcomes the enzyme barrier and membrane barrier. At the same time, the lower surface tension of the nanoemulsion can make the emulsion droplets grow for a longer time.
  • Contact with the gastrointestinal mucosa increases the transmembrane transport of the drug.
  • the nanoemulsion is pinocytosed by the small intestinal cells in a whole form, which increases the lymphatic absorption of the drug, avoids the first-pass effect, and further improves the bioavailability.
  • the formed O/W nanoemulsion is less than 500nm or even less than 100nm, which can make the drug quickly distribute in the entire gastrointestinal tract, making it easier for the drug to directly contact the small intestinal epithelial cells, and can promote the drug to pass through the small intestine through pinocytosis or endocytosis.
  • Absorption by mucosal epithelial cells makes the dissolution process of the drug no longer the rate-limiting step of in vivo absorption, significantly improves the solubility and dissolution rate of axitinib in gastrointestinal fluid, increases the oral absorption rate and bioavailability of the drug, and improves the permeability, reduce gastrointestinal reactions, and reduce adverse reactions; the self-microemulsion composition is emulsified to form nanoemulsion, which promotes the transmembrane absorption of the drug.
  • the drug release speed is stable, which can prevent the blood drug concentration from fluctuating too much, improve the curative effect of the drug, and reduce adverse reactions.
  • Test 1 The preparation process of the self-emulsifying preparation is as follows:
  • SMEDDS carrier i.e. oil phase, surfactant, co-surfactant
  • SMEDDS carrier i.e. oil phase, surfactant, co-surfactant
  • SMEDDS carrier i.e. oil phase, surfactant, cosurfactant
  • add axitinib according to the recipe quantity and fill it after fully dissolving. in soft capsules.
  • the axitinib formulation was diluted 100-fold with an aqueous medium of pH 6.8, and then measured with a nanoparticle analyzer. Each sample is tested at least three times to ensure the accuracy of the results.
  • the prescription is as follows: Axitinib: 5mg;
  • the total mass of the SMEDDS carrier is 600 mg: the mass ratio of oil phase: surfactant: co-surfactant is: 16.7:53.3:30; the oil phase is ethyl oleate; the surfactant is polyoxyethylene castor oil ; Described co-surfactant is diethylene glycol monoethyl ether.
  • the preparation process was referred to Experiment 1, and the particle size test was referred to Experiment 2.
  • the particle size of the nanoemulsion of the obtained axitinib preparation was 18.45 nm.
  • the prescription is as follows: Axitinib: 5mg;
  • the total mass of the SMEDDS carrier is 600 mg: the oil phase: the mass ratio of the surfactant is: 1:9; the oil phase is glycerol monolinoleate; the surfactant is caprylic acid capric acid polyethylene glycol glyceride 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 nanoemulsion of the obtained axitinib preparation was 114.54 nm.
  • the prescription is as follows: Axitinib: 5mg;
  • the total mass of the SMEDDS carrier is 600mg: the mass ratio of oil phase: surfactant: co-surfactant is: 1:8:1; the oil phase is medium chain triglyceride; the surfactant is caprylic acid capric acid polymer
  • the mixed emulsifier of ethylene glycol glyceride and polyoxyethylene castor oil, the mass ratio of the two is 3:1; the co-surfactant is PEG400.
  • the preparation process was referred to Experiment 1, and the particle size test was referred to Experiment 2.
  • the particle size of the nanoemulsion of the obtained axitinib preparation was 170.45 nm.
  • the prescription is as follows: Axitinib: 5mg;
  • the total mass of the SMEDDS carrier is 600mg: the mass ratio of oil phase: surfactant: co-surfactant is: 1:7:2; the oil phase is medium chain triglyceride; the surfactant is caprylic acid capric acid polymer.
  • the preparation process was referred to Experiment 1, and the particle size test was referred to Experiment 2.
  • the particle size of the nanoemulsion of the obtained axitinib preparation was 120 nm.
  • the prescription is as follows: Axitinib: 5mg;
  • the total mass of the SMEDDS carrier is 600 mg: the mass ratio of oil phase: surfactant: co-surfactant is: 1:13:6; the oil phase is linoleic acid macrogol glyceride; the surfactant is Caprylic acid capric acid macrogol glyceride; the co-surfactant is diethylene glycol monoethyl ether.
  • the preparation process was referred to Experiment 1, and the particle size test was referred to Experiment 2.
  • the particle size of the nanoemulsion of the obtained axitinib preparation was 145 nm.
  • the prescription is as follows: Axitinib: 5mg;
  • the total mass of SMEDDS carrier is 600mg: the mass ratio of oil phase: surfactant: co-surfactant is: 1:6:3; the oil phase is medium chain triglyceride; the surfactant is caprylic acid capric acid polymer
  • the preparation process was referred to Experiment 1, and the particle size test was referred to Experiment 2.
  • the particle size of the nanoemulsion of the obtained axitinib preparation was 200 nm.
  • the prescription is as follows: Axitinib: 5mg;
  • the total mass of the SMEDDS carrier is 600 mg: the oil phase is ethyl oleate; the surfactant is Tween 80, and the remaining parameters are as follows:
  • the prescription is as follows: Axitinib: 5mg;
  • the total mass of the SMEDDS carrier is 600 mg: the mass ratio of oil phase: surfactant: co-surfactant is: 4:4:2; the oil phase is glycerol monooleate, and the surfactant is propylene glycol monocaprylic acid ester; the co-surfactant is PEG600.
  • the preparation process was referred to Experiment 1, and the particle size test was referred to Experiment 2.
  • the particle size of the nanoemulsion of the obtained axitinib preparation was 150 nm.
  • the prescription is as follows: Axitinib: 5mg;
  • the total mass of the SMEDDS carrier is 300 mg: the mass ratio of oil phase: surfactant: co-surfactant is: 1:6:3; the oil phase is oleic acid; the surfactant is polyglycerol fatty acid ester; Described cosurfactant is Transcutol P.
  • the preparation process was referred to Experiment 1, and the particle size test was referred to Experiment 2.
  • the particle size of the nanoemulsion of the obtained axitinib preparation was 145 nm.
  • the prescription is as follows: Axitinib: 5mg;
  • the total mass of the SMEDDS carrier is 400 mg: the mass ratio of oil phase: surfactant: co-surfactant is: 4.5:4.5:1; the oil phase is polyethylene glycol-6 glycerol oleate; the surfactant is propylene glycol monolaurate; the co-surfactant is propylene glycol.
  • the preparation process was referred to Experiment 1, and the particle size test was referred to Experiment 2.
  • the particle size of the nanoemulsion of the obtained axitinib preparation was 230 nm.
  • the prescription is as follows: Axitinib: 5mg;
  • the total mass of the SMEDDS carrier is 400 mg: the mass ratio of oil phase: surfactant: co-surfactant: 5:4:1; the oil phase is medium chain glyceride; the surfactant is polyoxyethylene hydrogenated Castor oil (RH40); the co-surfactant is polyethylene glycol 400.
  • the preparation process was referred to Experiment 1, and the particle size test was referred to Experiment 2.
  • the particle size of the nanoemulsion of the obtained axitinib preparation was 256 nm.
  • the prescription is as follows: Axitinib: 5mg;
  • the total mass of the SMEDDS carrier is 500 mg: the mass ratio of oil phase: surfactant: co-surfactant is: 4:3:3; the oil phase is ethyl oleate; the surfactant is Tween 80; The co-surfactant is ethylene glycol monoethyl ether.
  • the preparation process was referred to Experiment 1, and the particle size test was referred to Experiment 2.
  • the particle size of the nanoemulsion of the obtained axitinib preparation was 320 nm.
  • the prescription is as follows: Axitinib: 5mg;
  • the total mass of the SMEDDS carrier is 500 mg: the mass ratio of oil phase: surfactant: co-surfactant is: 1:3:3; the oil phase is glycerol monooleate; the surfactant is polyoxyethylene castor Sesame oil (EL35); the co-surfactant is ethylene glycol monoethyl ether.
  • the preparation process was referred to Experiment 1, and the particle size test was referred to Experiment 2.
  • the particle size of the nanoemulsion of the obtained axitinib preparation was 154 nm.
  • the prescription is as follows: Axitinib: 5mg;
  • the total mass of the SMEDDS carrier is 600 mg: the mass ratio of oil phase: surfactant: co-surfactant is: 1:3:2; the oil phase is glycerol monolinoleate; the surfactant is polyoxyethylene Castor oil (EL35); the cosurfactant is Transcutol P.
  • the preparation process was referred to Experiment 1, and the particle size test was referred to Experiment 2.
  • the particle size of the nanoemulsion of the obtained axitinib preparation was 220 nm.
  • the prescription is as follows: Axitinib: 5mg;
  • the total mass of the SMEDDS carrier is 300 mg: the mass ratio of oil phase: surfactant: co-surfactant is: 16.7:53.3:30; the oil phase is glycerol monolinoleate; the surfactant is polyoxyethylene Castor oil (EL35); the cosurfactant is diethylene glycol monoethyl ether.
  • the preparation process was referred to Experiment 1, and the particle size test was referred to Experiment 2.
  • the particle size of the nanoemulsion of the obtained axitinib formulation was 172 nm.
  • the prescription is as follows: Axitinib: 5mg;
  • the total mass of the SMEDDS carrier is 400 mg: the mass ratio of oil phase: surfactant: co-surfactant is: 2.5:5:2.5; the oil phase is glycerol monooleate and ethyl oleate, and the specific mass ratio is as follows:
  • Described surfactant is RH40; Described cosurfactant is Transcutol HP.
  • the preparation process was referred to Experiment 1, and the particle size test was referred to Experiment 2.
  • the prescription is as follows: Axitinib: 10 mg;
  • the total mass of the SMEDDS carrier is 600 mg: the mass ratio of oil phase: surfactant: co-surfactant is: 5:16:9; the oil phase is a mixed oil phase of glycerol monooleate and ethyl oleate, two The mass ratio is 2:3; the surfactant is polyoxyethylene castor oil; the co-surfactant is diethylene glycol monoethyl ether.
  • the preparation process was referred to Experiment 1, and the particle size test was referred to Experiment 2.
  • the particle size of the nanoemulsion of the obtained axitinib preparation was 21.36 nm.
  • the prescription is as follows: Axitinib: 15mg;
  • the total mass of the SMEDDS carrier is 750 mg: the mass ratio of oil phase: surfactant: co-surfactant is: 5:16:9; the oil phase is a mixed oil phase of glycerol monooleate and ethyl oleate, and two The surfactant mass ratio is 2:3; the surfactant is a mixed surfactant of caprylic acid caprylic acid polyethylene glycol glyceride and polyoxyethylene hydrogenated castor oil, and the specific ratio is as follows.
  • the prescription is as follows: Axitinib: 5mg;
  • the preparation process was referred to Experiment 1, and the particle size test was referred to Experiment 2.
  • the particle size of the obtained nanoemulsion was 36.02 nm.
  • the prescription is as follows: Axitinib: 5mg;
  • the particle size of the obtained nanoemulsion was 23.42 nm.
  • the prescription is as follows: Axitinib: 5mg;
  • the total mass of the SMEDDS carrier is 600 mg: the oil phase is ethyl oleate; the surfactant is polyoxyethylene castor oil; the cosurfactant is diethylene glycol monoethyl ether.
  • the preparation process was referred to Experiment 1, and the particle size test was referred to Experiment 2.
  • any self-microemulsion composition prepared in the above-mentioned embodiment is uniformly mixed with an antioxidant, it is packed in a soft capsule or a hard capsule, and obtained from the microemulsion capsule.
  • the dosage of antioxidants can be adjusted reasonably according to the dosage of axitinib.
  • the axitinib self-microemulsion composition and the commercially available reference preparation provided in the examples of the present invention Disperse in 250mL aqueous medium to measure the dispersibility and solubility of the drug, and observe whether there is drug precipitation.
  • Aqueous media include water and phosphate buffer (pH 6.8).
  • Dissolution apparatus TDT-08L, aqueous medium: 250 mL, rotation speed 50 rpm, temperature 37 °C.
  • This test example provides the stability test of the axitinib soft capsules provided in the examples.
  • the soft capsule of axitinib prepared by the present invention has good stability.
  • Normal rats with no symptoms such as diarrhea and abnormal liver and kidney function were selected and randomly divided into two groups, 20 rats in the experimental group and 20 in the control group, and there was no statistical difference in age, sex, body weight, body surface area, etc. 0.05).
  • the experimental group was given the samples of the examples, and the control group was given the commercially available axitinib tablets, both of which were conventionally treated.
  • the rats were given free food and water support according to their body weight, age and activity level. There was basically no significant change in the activity level and state. On the 5th, 10th and 30th days, the rats with diarrhea, abdominal distension and vomiting were observed. The results are shown in Table 4.
  • Test Example 4 Tissue distribution of axitinib self-microemulsion composition
  • Healthy rats were selected and randomly divided into groups, with 9 rats in each group.
  • the specific mode of administration is:
  • the first group of rats was orally administered axitinib tablet suspension (reference preparation, R) at a dose of 5 mg/kg;
  • the other groups of rats were orally administered axitinib self-emulsifying solution (test preparation, T, Example 1, Example 3, Example 7-4, Example 14, Example 18-1, Example 21-1). , Example 21-3), the dose is 5mg/kg.
  • the collected blood samples were anticoagulated with heparin sodium. Within 1 h after collection, centrifuge at 3500 rpm for 10 min at 2-8 °C, and the separated plasma was stored in a -80 °C refrigerator for testing. The red blood cells in the lower layer should also be recovered and stored in a -80°C refrigerator for testing.
  • LC-MS/MS method was used to detect the concentration of axitinib in rat plasma samples, tissue samples and fecal samples, respectively.
  • tissue distributions of the test and reference formulations of axitinib are shown in Table 5 below.
  • Group 1 rats were orally administered axitinib tablet suspension (reference preparation, R) at a dose of 1 or 5 mg/kg;
  • the other groups of rats were orally administered axitinib self-emulsifying solution (test preparation, Example 1, Example 3, Example 7-4, Example 14, Example 18-1, Example 21-1, Example Example 21-3), the dose was 1 or 5 mg/kg.
  • the collected blood samples were anticoagulated with heparin sodium. Within 1 h after collection, centrifuge at 3500 rpm for 10 min at 2-8 °C, and the separated plasma was stored in a -80 °C refrigerator for testing.
  • the Tmax of the axitinib self-emulsifying group was decreased compared with the reference preparation, and the Cmax was increased, and increased by 5-6 times;
  • the AUC of the test preparation is 2 to 3 times that of the reference preparation.
  • the self-microemulsion compositions prepared in the examples of the present application can significantly improve the bioavailability of axitinib in rats.

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Abstract

一种阿昔替尼的自微乳组合物，按自微乳组合物的总质量的质量百分比计，包括0.1～10％阿昔替尼、1～70％的油相、10～90％的表面活性剂和0～60％的助表面活性剂。制备的阿昔替尼制剂的溶出度、混合均一度均满足要求，在口服后遇胃肠液在胃肠蠕动下自发分散形成O/W型纳米乳，通过将药物分子包裹在载体内，药物分子的粒径相应变大，使得纳米乳与小肠表皮细胞接触后透膜方式发生变化，由原本的被动扩散转运变成胞吞转运，通过主动胞饮或胞吞吸收，减少纳米乳对胃肠道的刺激，从而减少药物因局部浓度过高及与胃肠壁长时间接触而引起的刺激，可减少药物胃肠道副作用。

Description

阿昔替尼的自微乳组合物 技术领域
本发明涉及医药技术领域，具体涉及一种阿昔替尼的自微乳组合物。
背景技术
阿昔替尼(Axitinib)是Pfizer公司开发的多靶点酪氨酸激酶抑制剂，可以抑制血管内皮细胞生长因子受体VEGFR1、VEGFR2、VEGFR3、血小板衍生生长因子受体和c-KIT，用于其它系统治疗无效的晚期肾癌，2012年1月27日FDA批准上市。目前上市的阿昔替尼产品为片剂。
阿昔替尼为白色粉末，熔点218.4℃，略溶于聚乙二醇400，微溶于甲醇或乙醇，极微溶于乙腈，几乎不溶于水，本身对光、热、湿都不稳定，容易发生降解。在20℃pH1.2盐酸溶液中溶解度为0.8mg/mL，pH6.8磷酸盐缓冲溶液中溶解度为0.2微克/mL，为典型的pH依赖型药物。
阿昔替尼片剂规格含量较低，通常有1mg/片和5mg/片两种规格含量，因此，阿昔替尼与辅料混合时容易产生混合不均匀的问题，威胁临床用药安全。其次，阿昔替尼溶解度极低，属于难溶性药物，容易存在溶出度不合格的问题。阿昔替尼属于难溶性药物，其粒径需要足够小才能保证溶出度符合要求。但是同时，阿昔替尼的粒径越小，越不容易混合均匀。第三，临床资料显示，在口服阿昔替尼治疗过程中，在内分泌(6.5％)、消化(7.2％)、心血管(6.9％)、皮肤(14.4％)等系统中不良反应发生率较高，且可能多系统并发。临床分析表面阿昔替尼在使用过程中最易发生消化系统不良反应，其腹泻发生率超过80％，当出现持续性腹泻，可能引起脱水等其他问题。消化系统不良反应可能为药物刺激胃肠道而引起肠蠕动改变，从而导致腹泻。因此，需要通过改变剂型来降低甚至消除药物的副作用。
自微乳组合物在胃肠道中形成微乳，药物存在于这些细小的油滴中，快速分布于整个胃肠道内，药物在油/水两项之间分配，依靠细小油滴的巨大表面积大大提高水不溶出性药物的溶出，提高生物利用度。自微乳组合物已被证明能够提高药物在血液循环中的稳定性，延长药物作用时间，另外由于其粒径和粒径分布均一，可以将药物输送到特定的细胞和组织。自微乳组合物不仅粒径小，而且能够避免微乳聚集成团，更能深入病变部位，改变药物分布，提高药物疗效，降低副作用。
申请号为CN201710156853.8的专利提供了一种XLI晶型阿昔替尼的制备方法，将阿昔替尼、质子性溶剂混匀，重结晶，在无水溶剂中进行加晶种重结晶得到XLI晶型阿昔替尼。由 于阿西替尼属于难溶性小剂量药物，因此在制备制剂时通常将其粉碎，以提高溶出度。但是粒度太细，会导致均匀度超标，进而引起各种不良反应。
因此，需要提供一种简单、可靠、降低不良反应的阿昔替尼自微乳组合物。
发明内容
本发明的目的在于提供一种阿昔替尼的自微乳组合物，以缓解阿昔替尼的不良反应。将阿昔替尼制成自微乳组合物可以使药物平稳缓慢的释放，避免服药后血药浓度过高而引起严重的消化系统不良反应，也可避免溶出度不合格带来的影响，显著降低不良反应，提高疗效。
为了解决上述技术问题，本发明采用如下技术方案：
一方面，本发明提供一种阿昔替尼的自微乳组合物，至少包括1)阿昔替尼；2)油相；3)表面活性剂。
进一步地，所述自微乳组合物还包括4)助表面活性剂。
进一步地，所述自微乳组合物，按自微乳组合物的总质量的质量百分比计，包括0.1～10％阿昔替尼、1～70％的油相、10～90％的表面活性剂和0～60％的助表面活性剂。
进一步地，所述自微乳组合物，按自微乳组合物的总质量的质量百分比计，包括0.1％、0.2％、0.4％、0.5％、0.6％、0.7％、0.8％、0.82％、0.83％、0.99％、1％、1.23％、1.5％、1.64％、2％、3％、4％、5％、6％、7％、8％、9％或10％的阿昔替尼。进一步地，所述自微乳组合物，按自微乳组合物的总质量的质量百分比计，包括1％、1.23％、1.5％、1.64％、2％、3％、4％、4.96％、5％、9.91％、10％、14.14％、14.17％、14.88％、15％、16.34％、16.39％、16.42％、16.53％、16.56％、19.75％、19.83％、20％、23.11％、24.69％、25％、26.48％、29.75％、30％、33.06％、35％、39.6％、39.67％、40％、44.63％、45％、49.59％、50％、60％或70％的油相。进一步地，所述自微乳组合物，按自微乳组合物的总质量的质量百分比计，包括10％、20％、25％、29.7％、29.75％、30％、39.67％、40％、42.43％、42.5％、44.63％、45％、46.31％、49.38％、49.59％、50％、52.29％、52.43％、52.46％、52.64％、52.86％、55％、59.5％、60％、64.46％、65％、66.94％、69.42％、70％、79.34％、80％、89.52％或90％的表面活性剂。进一步地，所述自微乳组合物，按自微乳组合物的总质量的质量百分比计，包括0％、5％、9.91％、10％、15％、19.83％、20％、24.69％、25％、26.37％、26.48％、29.42％、29.51％、29.7％、29.75％、30％、33.06％、35％、40％、42.43％、42.5％、45％、50％、54.54％或55％的助表面活性剂。
进一步地，所述自微乳组合物，按自微乳组合物的总质量的质量百分比计，包括0.5～2％的阿昔替尼。进一步地，所述自微乳组合物，按自微乳组合物的总质量的质量百分比计，包括1％～65％、5％～50％或10％～40％的油相。进一步地，所述自微乳组合物按自微乳组合物的总质量的质量百分比计，包括40％～70％、45～60％或25～90％的表面活性剂。进一步地，所述 自微乳组合物，按自微乳组合物的总质量的质量百分比计，包括0～45％或20～35％的助表面活性剂。
进一步地，所述自微乳组合物还包括抗氧化剂、防腐剂中的一种或两种；所述抗氧化剂或防腐剂占所述自微乳组合物的总质量的0.005～0.1％。
进一步地，所述抗氧化剂选自叔丁基对羟基茴香醚BHA、丁羟基甲苯BHT、维生素C、维生素E(dl-α-生育酚)中的一种或两种。
进一步地，所述油相为药学上可接受的各种油相，选自天然植物油、经结构改造和水解后的植物油、或链长在C8-C10之间的中等链长脂肪酸甘油酯中的一种或多种。
进一步地，所述油相选自：玉米油、葵花油(如精制葵花油)、芝麻油、花生油、大豆油、红花油、橄榄油、棕榈油、棉籽油、薏仁油、蓖麻油、氢化蓖麻油、椰子油C8/C10甘油单酯或双酯(Capmul MCM)、椰子油C8/C10丙二醇双酯(Captex 200)、椰子油C8/C10甘油三酯(Captex 355)、椰子油氨丙基甜菜碱、纯化乙酰化的单甘油酯(Miglyol 812)、纯化向日葵油单甘油酯、聚乙二醇月桂酸甘油酯、单油酸甘油酯、单亚油酸甘油酯、中链甘油三酯、聚乙二醇油酸甘油酯、聚乙二醇亚油酸甘油酯、聚乙二醇辛酸癸酸甘油酯、辛酸癸酸甘油酯、聚氧乙烯油酸甘油酯、聚氧乙烯亚油酸甘油酯、山茶酸甘油酯、杏仁油油酸PEG-6甘油酯、玉米油亚油酸PEG-6甘油酯、油酸甘油酯：丙二醇(90:10体积比)、蛋黄卵磷脂、大豆卵磷脂、二油酰基卵磷脂、二月桂酰基卵磷脂、二肉豆蔻酰基卵磷脂、二棕榈酰基卵磷脂、二硬脂酰基卵磷脂、脑磷脂、肌酐、肌醇磷脂、溶血磷脂、磷脂酸、磷脂酰甘油、硬脂酰/棕榈酰/油酰磷脂酰胆碱、硬脂酰/棕榈酰/油酰磷脂酰乙醇胺、磷脂酰胆碱、氢化磷脂酰胆碱、磷脂酰丝氨酸、磷脂酰乙醇胺、磷脂酰甘油和磷脂酰肌醇、二硬脂酰磷脂酰乙醇胺、油酰磷脂酰胆碱、己酸、辛酸、油酸、维生素E、硬脂酸、月桂酸异丙酯、棕榈酸异丙酯、肉豆蔻酸异丙酯、油酸聚乙二醇-6甘油酯、中链甘油酸酯、亚油酸聚乙二醇甘油酯、丙二醇单月桂酸酯、油酸聚乙二醇甘油酯、丙二醇辛酸酯、油酸山梨醇酯、月硅酸乙酯、肉豆蔻酸乙酯、油酸乙酯(EO)、亚油酸乙酯中的一种或至少两种。
进一步地，所述油相选自葵花油、大豆油、油酸、蓖麻油、单亚油酸甘油酯、中链甘油三酯(MCT)、辛酸、油酸乙酯、肉豆蔻酸异丙酯、丙二醇单月桂酸酯、中链甘油酸酯、亚油酸聚乙二醇甘油酯、油酸聚乙二醇-6甘油酯、中链甘油三酯、单油酸甘油酯、油酸乙酯、丙二醇辛酸酯、油酸聚乙二醇甘油酯、Capmul MCM、油酸和中链甘油三酯的混合油相(二者的质量比为1～9:1～9，进一步地为8:2或6:4)、单油酸甘油酯和辛酸的混合油相(二者的质量比为1～9:1～9，进一步地为4:1)、油酸和单亚油酸甘油酯(二者的质量比为1～9:1～9，进一步地为1:4)、油酸乙酯和单亚油酸甘油酯(二者的质量比为1～9:1～9，进一步地为1:3)、 肉豆蔻酸异丙酯和单亚油酸甘油酯(二者的质量比为1～9:1～9，进一步地为1:1)、单油酸甘油酯和油酸乙酯(二者的质量比为1～9:1～9，进一步地为2:3、1:9、2:3、2:8、3:7、4:6或5:5)、丙二醇辛酸酯和油酸聚乙二醇甘油酯的混合油相(二者质量比为2:1)中的一种或至少两种。
进一步地，所述表面活性剂选自非离子型、阴离子型、阳离子型和两性离子表面活性剂。
进一步地，所述表面活性剂选自蛋黄卵磷脂、大豆卵磷脂、二油酰基卵磷脂、二月桂酰基卵磷脂、二肉豆蔻酰基卵磷脂、二棕榈酰基卵磷脂、二硬脂酰基卵磷脂、脑磷脂、肌酐、肌醇磷脂、溶血磷脂、磷脂酸、磷脂酰甘油、硬脂酰/棕榈酰/油酰磷脂酰胆碱、硬脂酰/棕榈酰/油酰磷脂酰乙醇胺、磷脂酰胆碱、氢化磷脂酰胆碱、磷脂酰丝氨酸、磷脂酰乙醇胺、磷脂酰甘油和磷脂酰肌醇、二硬脂酰磷脂酰乙醇胺、油酰磷脂酰胆碱、二肉豆蔻酰基磷脂酰乙醇胺、二棕榈酰基磷脂酰乙醇胺、二硬脂酰基磷脂酰乙醇胺、二肉豆蔻酰基磷脂酰丝氨酸、乙酰化单甘油酯、脱水山梨糖醇脂肪酸酯、杏仁油酸聚乙二醇甘油酯、椰子油C8/C10聚乙二醇甘油酯、聚氧乙烯十二羟硬脂酸酯、聚乙二醇100维生素E琥珀酸酯、聚氧乙烯-聚氧丙烯共聚物、聚氧乙烯蓖麻油(Cremophor EL 35)、聚氧乙烯氢化蓖麻油(Cremophor RH 40)、聚氧乙烯聚氧丙烯共聚物(例如泊洛沙姆188和407)、聚氧乙烯甘油酯、聚氧乙烯山梨醇酐三油酸脂、聚氧乙烯甘油三油酸脂、聚氧乙烯脱水山梨糖醇脂肪酸酯、琥珀辛酯钠、琥珀辛酯钙、琥珀辛酯钾、十二烷基硫酸钠、月桂基硫酸钠、二棕榈酰磷脂酸、乙氧基化蓖麻油、甘露醇油酸脂聚氧乙烯醚、聚乙二醇甘油酯类、油酰聚氧乙烯甘油酯、聚乙二醇脂肪酸酯、聚乙二醇脂肪酸酯、聚乙二醇-15羟基硬脂酸酯(Solutol)、聚乙二醇-8-甘油辛酸/癸酸酯、月桂酸聚乙二醇-32甘油酯、月桂酰聚乙二醇-32甘油酯、辛癸酸聚乙二醇甘油酯、山梨醇酐倍半油酸脂、聚山梨酯(如聚山梨酯20、聚山梨酯80)、水溶性天然维生素E、司盘80、吐温80、聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物(Soluplus)、辛酸、辛酸钠、胆汁酸、胆汁酸盐、熊果脱氧胆酸、胆酸钠、脱氧胆酸钠、牛磺胆酸钠、甘胆酸钠、N-十六烷基-N,N-二甲基-3-氨(ammonio)-1-丙烷磺酸盐、棕榈酰溶血磷脂酰-L-丝氨酸、溶血磷脂(例如，乙醇胺、胆碱、丝氨酸或苏氨酸的1-酰基-SN-甘油-3-磷酸酯)、N-烷基-N,N-二甲基氨-1-丙烷磺酸盐、3-胆酰胺-1-丙基二甲基氨-1-丙烷磺酸盐、十二烷基磷酸胆碱、肉豆蔻酰溶血磷脂酰胆碱、鸡蛋溶血卵磷脂、聚甘油脂肪酸酯、丙二醇单辛酸酯、丙二醇单月桂酸酯、十六烷基-三甲基铵溴化物、十六烷基吡啶氯化物、聚环氧乙烷/聚环氧丙烷嵌段共聚物(Pluronics/Tetronics、曲通X-100、十二烷基β-D-吡喃葡糖苷)、牛磺二氢梭链孢酸钠、油酸、酰基肉毒碱、赖氨酸、精氨酸、组氨酸、赖氨酸中的一种或至少两种。
进一步地，所述表面活性剂选自聚氧乙烯蓖麻油(Cremophor EL 35，EL35)、聚氧乙 烯氢化蓖麻油(Cremophor RH 40)、吐温80、辛癸酸聚乙二醇甘油酯、辛酸癸酸聚乙二醇甘油酯、丙二醇单辛酸酯、聚甘油脂肪酸酯、月桂酰聚乙二醇-32甘油酯、辛癸酸聚乙二醇甘油酯(Labrasol)、油酰聚氧乙烯甘油酯、聚乙二醇甘油酯、聚山梨酯(如聚山梨酯20、聚山梨酯80)、聚氧乙烯蓖麻油、丙二醇单月桂酸酯、辛癸酸聚乙二醇甘油酯和聚氧乙烯氢化蓖麻油的混合表面活性剂(二者的质量比为1～9:1，进一步地为2～3:1、1:2、1:1、2:1或3:1)、辛酸癸酸聚乙二醇甘油酯和聚氧乙烯蓖麻油的混合表面活性剂(二者质量比为3:1、4:1)、聚山梨酯80和RH40的混合表面活性剂(3:1)中的一种或至少两种。
进一步地，所述助表面活性剂选自中/短链醇、醚中的一种或多种。
进一步地，所述助表面活性剂选自乙醇、丙二醇、异丙醇、正丁醇、聚乙二醇(分子量范围为100Da-10kDa，300Da-2000Da，或400Da-1000Da)如聚乙二醇200～600(如：PEG400、聚乙二醇600)、聚乙二醇维生素E琥珀酸酯、碳酸丙二酯、碳酸亚丙酯、四氢糠醇、乙二醇糠醇、甘油糠醛、二甲基异山梨酯、二甲基乙酰胺、N-甲基吡咯烷酮、二乙二醇单乙基醚(Transcutol或Transcutol P或Transcutol HP或TP)、乙二醇单乙基醚、二十二碳六烯酸、胆固醇、氮酮、甘油、乙酸乙酯、聚氧化乙烯、辛癸酸聚乙二醇甘油酯、丙烯碳酸酯、丙烯碳酸酯、单硬脂酸甘油酯、双硬脂酸甘油酯、聚甘油-6-二油酸脂中的一种或至少两种。
进一步地，所述助表面活性剂选自：乙醇、丙二醇、异丙醇、二乙二醇单乙基醚、聚乙二醇400、甘油、聚乙二醇60、聚乙二醇400和二乙二醇单乙基醚的混合助表面活性剂(二者质量比为2:1)0中的一种或至少两种。
进一步地，所述油相：表面活性剂：助表面活性剂的质量比为：10～35:45～60:20～35，进一步质量比为10.1:59.9:30、19.62:45.38:35、16.7:53.3:30、29.84:50:20.16或30:45.38:24.62；进一步地，所述油相为油酸乙酯；所述表面活性剂为聚氧乙烯蓖麻油；所述助表面活性剂为二乙二醇单乙醚。
进一步地，所述自微乳组合物分散到水性介质中形成的微乳的粒径小于500nm。进一步地，所述自微乳组合物分散到水性介质中形成的微乳的粒径小于300nm。进一步地，所述自微乳组合物分散到水性介质中形成的微乳的粒径小于100nm。进一步地，所述自微乳组合物分散到水性介质中形成的微乳的粒径小于50nm。进一步地，所述自微乳组合物分散到水性介质中形成的微乳的粒径小于30nm。进一步地，所述自微乳组合物分散到水性介质中形成的微乳的粒径小于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或甚至更小。进一步地，所述自微乳组合物分散到水性介质中形 成的微乳的粒径为5～500nm或5～400nm或5～300nm或5～200nm或5～100nm或5～60nm或5～30nm。
本发明的制剂通过将各组分物料进行混合溶解制备得到，混合溶解的方式可以有多种，例如：微射流、搅拌、震荡等，目的在于利于提高自微乳组合物的稳定性和降低自微乳在水介质中分散的纳米乳的粒径。
进一步地，所述阿昔替尼的活性成分可包括阿昔替尼的晶体或无定型、盐、无水合物或水合物、溶剂化物、前药、代谢产物等，所有形式都可以用于本发明制剂。
一方面，本发明提供一种前述自微乳组合物在制备预防、治疗或防护肿瘤类疾病的药物中的用途。其中，所述肿瘤类疾病包括癌症和转移癌，进一步包括但并不限于，癌症如膀胱癌，乳腺癌，结肠癌，肾癌，肾细胞癌，肝癌，肺癌(包括小细胞肺癌)，食道癌，胆囊癌，卵巢癌，胰腺癌，胃癌，宫颈癌，甲状腺癌，前列腺癌，和皮肤癌(包括鳞状细胞癌)；淋巴系统造血肿瘤(包括白血病，急性淋巴囊肿性白血病，急性成淋巴细胞性白血病，B细胞淋巴瘤，T细胞淋巴瘤，何杰金(氏)淋巴瘤，非何杰金(氏)淋巴瘤，多毛细胞白血病和伯基特淋巴瘤)；骨髓系统造血肿瘤(包括急慢性骨髓性粒细胞性白血病，骨髓增生异常综合症，和前髓细胞白血病)；间充质细胞起源的肿瘤(包括纤维肉瘤和横纹肌肉瘤，和其他肉瘤，如软组织和软骨)；中枢末梢神经系统瘤(包括星形细胞瘤，成神经细胞瘤，神经胶质瘤，和神经鞘瘤)；和其他肿瘤(包括黑素瘤，精原细胞瘤，畸胎癌，骨肉瘤，xenoderoma pigmentosum，keratoctanthoma，甲状腺滤泡瘤和卡波济(氏)肉瘤)。
一方面，本发明提供一种剂型，将所得自微乳组合物灌装入软或硬胶囊中，也可以加入吸收剂制成固体自乳化片剂、丸剂、散剂、颗粒剂等。
进一步地，所述自微乳组合物为胶囊剂，所述胶囊剂包括自微乳组合物和胶囊壳，其中，所述自微乳组合物如本发明所述；所述胶囊壳由硬胶囊或软胶囊材料制得。所述胶囊壳均为本领熟知的硬胶囊和/或软胶囊材料，如明胶硬胶囊或明胶软胶囊，均可以通过商业途径购得或制备，在此不做特殊限定。
本发明采用自微乳化技术将其制成自微乳化软胶囊，口服后可迅速形成微乳，大大地提高了药物的溶出度和胃肠道粘膜的通透性，从而提高药物的生物利用度，降低不良反应。
一方面，本发明提供一种药物组合物，包括本发明所述自微乳组合物或本发明所述自微乳组合物胶囊剂中的一种，以及其他抗肿瘤药物。
进一步地，所述其他抗肿瘤药物包括，但绝不限于，门冬酰胺酶(Asparaginase)，博来霉素(Bleomycin)，卡铂，卡莫司汀(Carmustine)，苯丁酸氮芥(Chlorambucil)，顺铂，L-天冬酰胺酶(Colaspase)，环磷酰胺，阿糖胞苷(Cytarabine)，达卡巴嗪(Dacarbazine)，放线菌素 D(Dactinomycin)，柔红霉素(Daunorubicin)，阿霉素(多柔比星)，表柔比星(Epirubicin)，依托泊苷(Etoposide)，5-氟脲嘧啶，六甲基三聚氰胺，羟基脲，异环磷酰胺，伊立替康，亚叶酸，环己亚硝脲，氮芥，6-巯基嘌呤，美司钠(Mesna)，甲氨蝶呤(Methotrexate)，丝裂霉素C(MitomycinC)，米托蒽醌(Mitoxantrone)，泼尼松龙(Prednisolone)，泼尼松(Prednisone)，丙卡巴肼(Procarbazine)，雷洛昔芬(Raloxifen)，链唑霉素(Streptozocin)，他莫昔芬(Tamoxifen)，硫鸟嘌呤(Thioguanine)，托泊替康，长春碱，长春新碱，长春地辛，氨鲁米特(Aminoglutethimide)，L-门冬酰胺酶，硫唑嘌呤，5-氮杂胞苷，克拉屈滨(Cladribine)，白消安(Busulfan)，己烯雌酚，2′,2′-二氟去氧胞二磷胆碱，多西紫杉醇，赤羟基壬烷基腺嘌呤(Erythrohydroxynonyl adenine)，乙炔雌二醇，5-氟尿嘧啶脱氧核苷，5-氟脱氧尿苷单磷酸，磷酸氟达拉滨(Fludarabine phosphate)，氟甲睾酮(Fluoxymesterone)，氟他胺(Flutamide)，己酸羟孕酮，伊达比星(Idarubicin)，干扰素，醋酸甲羟孕酮，醋酸甲地孕酮，美法仑(Melphalan)，米托坦(Mitotane)，紫杉醇，喷司他丁(Pentostatin)，N-磷酸乙酰基-L-天冬氨酸(PALA)，普卡霉素(Plicamycin)，甲基环己亚硝脲(Semustine)，替尼泊苷(Teniposide)，丙酸睾丸酮，塞替派(Thiotepa)，三甲基三聚氰胺，尿核苷和长春瑞滨。
一方面，本发明所述药物组合物在制备预防、治疗或防护肿瘤类疾病的药物中的用途。
油相优化自微乳组合物颗粒之间的内部结构，可以提升体系的稳定性。
本发明表面活性剂的存在使纳米乳具有向水性，粒径均一有利于携带药物通过静态水层，与小肠上皮细胞膜亲密接触。本发明制备的自微乳组合物通过解决药物在体内溶解和跨膜转运能显著提高药物生物利用度，改善原制剂生物利用度低、体内变异大和安全风险大的问题，并降低患者用药成本。同时，自微乳软胶囊易于放大生产，自乳化速度快，具有很好的重现性。
自微乳组合物中的乳化剂是双亲性的，本身能溶于油相和水相，可防止O/W纳米乳中的药物在胃肠道内沉积和延长药物分子的溶解状态，有利提高生物利用度同时降低不良反应。
助乳化剂既有亲水性又有亲油性，有助于活性组分形成均一的纳米乳且保持乳剂在贮存过程中的稳定性。
与现有技术相比，本发明具有如下的有益效果：
本发明针对阿昔替尼本身溶解性差、使用剂量小且易见光分解的特点，提供一种自微乳组合物，通过将油相、表面活性剂、助表面活性剂进行溶解分散后，再加入阿昔替尼，使得制备的阿昔替尼的溶出度、混合均一度均满足要求。
制备的自微乳组合物经口服进入胃肠道后，遇胃肠液能够自微乳化成O/W纳米乳，通过将药物分子包裹在载体内，药物分子的粒径相应变大，使得纳米乳与小肠表皮细胞接触后透 膜方式发生变化，由原本的被动扩散转运变成胞吞转运，通过主动胞饮或胞吞吸收，减少纳米乳对胃肠道的刺激，从而减少药物因局部浓度过高及与胃肠壁长时间接触而引起的刺激，可减少药物胃肠道副作用。
由于纳米乳中阿昔替尼包裹在乳滴内，保护阿昔替尼避免受胃肠的降解，克服了酶障和膜障，同时纳米乳较低的表面张力可使乳滴较长时间的与胃肠道粘膜接触，增加了药物的跨膜转运。纳米乳以整体形式被小肠细胞胞饮，增加药物的淋巴吸收，避免了首过效应，进一步提高生物利用度。
所形成的O/W型纳米乳小于500nm甚至小于100nm，可使药物快速分布于整个胃肠道中，使得药物更容易和小肠上皮细胞直接接触，通过胞饮或胞吞等作用能够促进药物经小肠粘膜上皮细胞吸收，使得药物的溶出过程不再成为体内吸收的限速步骤，显著提高了阿昔替尼在胃肠液中的溶解度和溶出速率，增加药物口服吸收率和生物利用度，提高了渗透率，降低胃肠道反应，降低不良反应；自微乳组合物经乳化后形成纳米乳，促进药物的跨膜吸收，同时阿昔替尼被空白微乳载体包裹，实现药物的缓释，药物释放速度平稳，可防止血药浓度起伏过大，提高了药物的疗效同时，降低不良反应。
附图说明
图1各组胃肠不良反应总发生情况对比结果
具体实施方式
下面结合具体实施例，进一步阐述本发明。这些实施例仅用于说明本发明而不用于限制本发明的范围。
试验一：自乳化制剂的制备过程如下：
按处方量称取SMEDDS载体(即油相、表面活性剂、助表面活性剂)，混合均匀，37℃且在避光条件下进行超声混合，辅以100～400rpm的速度进行机械搅拌，形成透明均一的自乳化溶液，按处方量加入阿昔替尼，搅拌均匀充分溶解后填充于软胶囊中。
或，按处方量称取SMEDDS载体(即油相、表面活性剂、助表面活性剂)，依次加入混合均匀，形成透明均一的自乳化溶液，按处方量加入阿昔替尼，充分溶解后填充于软胶囊中。
试验二：微乳大小的测定
对实施例所制备的阿昔替尼制剂的粒径进行测试。
将阿昔替尼制剂用pH6.8的水介质稀释100倍后，用纳米粒度仪进行测定。每一个样品进行至少三次测试，以确保结果的准确性。
实施例1
处方如下：阿昔替尼：5mg；
SMEDDS载体总质量为600mg：油相：表面活性剂：助表面活性剂的质量比为：16.7:53.3:30；所述油相为油酸乙酯；所述表面活性剂为聚氧乙烯蓖麻油；所述助表面活性剂为二乙二醇单乙醚。制备过程参照试验一，粒径测试参照试验二。所得阿昔替尼制剂的纳米乳的粒径为18.45nm。
实施例2
处方如下：阿昔替尼：5mg；
SMEDDS载体总质量为600mg：油相：表面活性剂的质量比为：1:9；所述油相为单亚油酸甘油酯；所述表面活性剂为辛酸癸酸聚乙二醇甘油酯和聚氧乙烯蓖麻油的混合乳化剂，二者质量比为3:1，制备过程参照试验一，粒径测试参照试验二。所得阿昔替尼制剂的纳米乳的粒径为114.54nm。
实施例3
处方如下：阿昔替尼：5mg；
SMEDDS载体总质量为600mg：油相：表面活性剂：助表面活性剂的质量比为：1:8:1；所述油相为中链甘油三酯；所述表面活性剂为辛酸癸酸聚乙二醇甘油酯和聚氧乙烯蓖麻油的混合乳化剂，二者质量比为3:1；所述助表面活性剂为PEG400。制备过程参照试验一，粒径测试参照试验二。所得阿昔替尼制剂的纳米乳的粒径为170.45nm。
实施例4
处方如下：阿昔替尼：5mg；
SMEDDS载体总质量为600mg：油相：表面活性剂：助表面活性剂的质量比为：1:7:2；所述油相为中链甘油三酯；所述表面活性剂为辛酸癸酸聚乙二醇甘油酯和聚氧乙烯蓖麻油的混合乳化剂，二者质量比为4:1；所述助表面活性剂为二乙二醇单乙醚。制备过程参照试验一，粒径测试参照试验二。所得阿昔替尼制剂的纳米乳的粒径为120nm。
实施例5
处方如下：阿昔替尼：5mg；
SMEDDS载体总质量为600mg：油相：表面活性剂：助表面活性剂的质量比为：1:13:6；所述油相为亚油酸聚乙二醇甘油酯；所述表面活性剂为辛酸癸酸聚乙二醇甘油酯；所述助表面活性剂为二乙二醇单乙醚。制备过程参照试验一，粒径测试参照试验二。所得阿昔替尼制剂的纳米乳的粒径为145nm。
实施例6
处方如下：阿昔替尼：5mg；
SMEDDS载体总质量为600mg：油相：表面活性剂：助表面活性剂的质量比为：1:6:3； 所述油相为中链甘油三酯；所述表面活性剂为辛酸癸酸聚乙二醇甘油酯和聚氧乙烯蓖麻油的混合乳化剂，二者质量比为4:1；所述助表面活性剂为二乙二醇单乙醚。制备过程参照试验一，粒径测试参照试验二。所得阿昔替尼制剂的纳米乳的粒径为200nm。
实施例7
处方如下：阿昔替尼：5mg；
SMEDDS载体总质量为600mg：所述油相为油酸乙酯；所述表面活性剂为吐温80，其余参数如下：
Figure PCTCN2021134705-appb-000001
制备过程参照试验一，粒径测试参照试验二。
实施例8
处方如下：阿昔替尼：5mg；
SMEDDS载体总质量为600mg：油相：表面活性剂：助表面活性剂的质量比为：4:4:2；所述油相为单油酸甘油酯，所述表面活性剂为丙二醇单辛酸酯；所述助表面活性剂为PEG600。制备过程参照试验一，粒径测试参照试验二。所得阿昔替尼制剂的纳米乳的粒径为150nm。
实施例9
处方如下：阿昔替尼：5mg；
SMEDDS载体总质量为300mg：油相：表面活性剂：助表面活性剂的质量比为：1:6:3；所述油相为油酸；所述表面活性剂为聚甘油脂肪酸酯；所述助表面活性剂为Transcutol P。制备过程参照试验一，粒径测试参照试验二。所得阿昔替尼制剂的纳米乳的粒径为145nm。
实施例10
处方如下：阿昔替尼：5mg；
SMEDDS载体总质量为400mg：油相：表面活性剂：助表面活性剂的质量比为：4.5:4.5:1；所述油相为油酸聚乙二醇-6甘油酯；所述表面活性剂为丙二醇单月桂酸酯；所述助表面活性剂为丙二醇。制备过程参照试验一，粒径测试参照试验二。所得阿昔替尼制剂的纳米乳的粒 径为230nm。
实施例11
处方如下：阿昔替尼：5mg；
SMEDDS载体总质量为400mg：油相：表面活性剂：助表面活性剂的质量比为：5:4:1；所述油相为中链甘油酸酯；所述表面活性剂为聚氧乙烯氢化蓖麻油(RH40)；所述助表面活性剂为聚乙二醇400。制备过程参照试验一，粒径测试参照试验二。所得阿昔替尼制剂的纳米乳的粒径为256nm。
实施例12
处方如下：阿昔替尼：5mg；
SMEDDS载体总质量为500mg：油相：表面活性剂：助表面活性剂的质量比为：4:3:3；所述油相为油酸乙酯；所述表面活性剂为吐温80；所述助表面活性剂为乙二醇单乙基醚。制备过程参照试验一，粒径测试参照试验二。所得阿昔替尼制剂的纳米乳的粒径为320nm。
实施例13
处方如下：阿昔替尼：5mg；
SMEDDS载体总质量为500mg：油相：表面活性剂：助表面活性剂的质量比为：1:3:3；所述油相为单油酸甘油酯；所述表面活性剂为聚氧乙烯蓖麻油(EL35)；所述助表面活性剂为乙二醇单乙基醚。制备过程参照试验一，粒径测试参照试验二。所得阿昔替尼制剂的纳米乳的粒径为154nm。
实施例14
处方如下：阿昔替尼：5mg；
SMEDDS载体总质量为600mg：油相：表面活性剂：助表面活性剂的质量比为：1:3:2；所述油相为单亚油酸甘油酯；所述表面活性剂为聚氧乙烯蓖麻油(EL35)；所述助表面活性剂为Transcutol P。制备过程参照试验一，粒径测试参照试验二。所得阿昔替尼制剂的纳米乳的粒径为220nm。
实施例15
处方如下：阿昔替尼：5mg；
SMEDDS载体总质量为300mg：油相：表面活性剂：助表面活性剂的质量比为：16.7:53.3:30；所述油相为单亚油酸甘油酯；所述表面活性剂为聚氧乙烯蓖麻油(EL35)；所述助表面活性剂为二乙二醇单乙醚。制备过程参照试验一，粒径测试参照试验二。所得阿昔替尼制剂的纳米乳的粒径为172nm。
实施例16
处方如下：阿昔替尼：5mg；
SMEDDS载体总质量为400mg：油相：表面活性剂：助表面活性剂的质量比为：2.5:5:2.5；所述油相为单油酸甘油酯和油酸乙酯，具体质量比如下：
实施例 单油酸甘油酯和油酸乙酯质量比 乳化时间(min) 粒径(nm)
16-1 1:9 1 19.58
16-2 2:8 1 18.87
16-3 3:7 1.5 18.92
16-4 4:6 0.8 19.24
16-5 5:5 1 20.91
所述表面活性剂为RH40；所述助表面活性剂为Transcutol HP。制备过程参照试验一，粒径测试参照试验二。
实施例17
处方如下：阿昔替尼：10mg；
SMEDDS载体总质量为600mg：油相：表面活性剂：助表面活性剂的质量比为：5:16:9；所述油相为单油酸甘油酯和油酸乙酯的混合油相，二者质量比为2:3；所述表面活性剂为聚氧乙烯蓖麻油；所述助表面活性剂为二乙二醇单乙醚。制备过程参照试验一，粒径测试参照试验二。所得阿昔替尼制剂的纳米乳的粒径为21.36nm。
实施例18
处方如下：阿昔替尼：15mg；
SMEDDS载体总质量为750mg：油相：表面活性剂：助表面活性剂的质量比为：5:16:9；所述油相为单油酸甘油酯和油酸乙酯的混合油相，二者质量比为2:3；所述表面活性剂为辛酸癸酸聚乙二醇甘油酯和聚氧乙烯氢化蓖麻油的混合表面活性剂，具体比值如下。
Figure PCTCN2021134705-appb-000002
制备过程参照试验一，粒径测试参照试验二。
实施例19
处方如下：阿昔替尼：5mg；
SMEDDS载体总质量为600mg：Capmul MCM:Cremophor RH40:二乙二醇单乙基醚＝20:53.3:26.7。制备过程参照试验一，粒径测试参照试验二。所得纳米乳的粒径为36.02nm。
实施例20
处方如下：阿昔替尼：5mg；
SMEDDS载体总质量为400mg：((丙二醇辛酸酯:油酸聚乙二醇甘油酯):聚氧乙烯氢化蓖麻油:(聚乙二醇400:二乙二醇单乙基醚))＝(13.3:6.7):53.3:(17.8:8.9)，制备过程参照试验一，粒径测试参照试验二。所得纳米乳的粒径为23.42nm。
实施例21
处方如下：阿昔替尼：5mg；
SMEDDS载体总质量为600mg：所述油相为油酸乙酯；所述表面活性剂为聚氧乙烯蓖麻油；所述助表面活性剂为二乙二醇单乙醚。制备过程参照试验一，粒径测试参照试验二。
具体比值如下表：
实施例 油相：表面活性剂：助表面活性剂的质量比
21-1 10.1:59.9:30
21-2 30:45.38:24.62
21-3 29.84:50:20.16
21-4 19.62:45.38:35
胶囊剂实施例1
将上述实施例制备的任一自微乳组合物与抗氧化剂混合均一后，装于软胶囊或硬胶囊中，得自微乳胶囊。其中抗氧化剂的用量根据阿昔替尼的用量进行合理调整即可。
试验例1 分散性和溶解性的测定
将本发明实施例所提供的阿昔替尼自微乳组合物和市售参比制剂
Figure PCTCN2021134705-appb-000003
分散于250mL水性介质中测定药物的分散性和溶解性，并观察是否有药物析出。
水性介质包括水和磷酸盐缓冲液(pH6.8)。
研究方法：美国药典方法II(浆法)。
溶出仪器：TDT-08L，水性介质：250mL，转速50rpm，温度37℃。
具体方法：将1g阿昔替尼自微乳组合物置于溶出杯中分散，分别于1，5，10，35，60min取样2mL，样品用0.45微米的聚丙烯过滤器过滤并稀释后进行HPLC分析。结果如下表：
表1 在水中阿昔替尼自微乳组合物和参比制剂的溶出度(％)
取样点 参比制 实施例 实施例 实施例7-3 实施例 实施例14
/min 剂 1 5   10  
1 0 57.4 62.0 56.8 60.2 59.2
5 19.9 87.5 82.4 79.8 84.9 86.0
10 47.2 99.3 99.6 94.6 98.1 100
35 75.2 100 100 100 100 100
60 85.3 100 100 100 100 100
表2 在磷酸盐缓冲液(pH6.8)中阿昔替尼自微乳组合物和参比制剂的溶出度(％)
Figure PCTCN2021134705-appb-000004
从表1、表2、图1中可知，本发明实施例分别分散于水(pH7.0)或磷酸盐缓冲液(pH6.8)中，在5min基本溶出完全，而上市的阿昔替尼参比制剂在60min仍不能完全溶出；本发明的阿昔替尼自微乳组合物的药物分散性和溶解性良好，37℃下在水介质中12h未见药物析出，有利于提高阿昔替尼的口服生物利用度，减小个体差异。
试验例2 稳定性测试
本试验例提供实施例所提供的阿昔替尼软胶囊的稳定性测试。
将阿昔替尼软胶囊装入聚乙烯塑料瓶后，分别在冷藏2-8℃、常温25℃±2℃、避光(25℃±2℃)、高温(60℃)和光照(4500lX)的条件下放样5天、10天、30天、2个月，将药物组合物用pH6.8的水介质稀释100倍后，取上清液测试阿昔替尼的含量，结果见表3。
表3 阿昔替尼软胶囊的稳定性
Figure PCTCN2021134705-appb-000005
Figure PCTCN2021134705-appb-000006
可见，本发明制备的阿昔替尼的软胶囊稳定性好。
试验例3
选取无腹泻和肝肾功能异常等症状的正常大鼠，将它们随机分为两组，实验组和对照组各20只，在年龄、性别、体重、体表面积等方面无统计学差异(P＞0.05)。
方法：实验组采用实施例样品，对照组采用市售阿昔替尼片剂，均常规治疗。按大鼠体重、年龄、活动程度给予自由饮食和饮水支持，活动程度和状态基本无明显变化，考察第5天、10天和30天时，发生腹泻、腹胀和呕吐症状的鼠只。结果见表4。
表4 各组胃肠不良反应发生情况临床试验结果
Figure PCTCN2021134705-appb-000007
Figure PCTCN2021134705-appb-000008
表4和图1结果显示，与对照组比较，在5天、10天和30天时，服用本发明实施例的大鼠的腹泻、腹胀和呕吐等不良反应显著得到改善。可见，药物的安全性明显得到提高，极大提高了服用的依从性和顺应性。
试验例4 阿昔替尼自微乳组合物的组织分布
1.给药
选择健康大鼠随机分组，每组9只。具体给药方式为：
第一组大鼠口服给予阿昔替尼片的混悬液(参比制剂，R)，剂量为5mg/kg；
其他组大鼠分别口服给予阿昔替尼自乳化溶液(受试制剂，T，实施例1、实施例3、实施例7-4、实施例14、实施例18-1、实施例21-1、实施例21-3)，剂量为5mg/kg。
2.样本采集及处理
阿昔替尼混悬液组在灌胃给药后0.25h、0.75h、4h每个时间点处死3只大鼠，而阿昔替尼自乳化溶液组则在灌胃给药后0.25h、0.75h、4h每个时间点处死3只大鼠。收集静脉血0.5mL，然后迅速解剖，取出心、肝、脾、肺、肾、胃、肠、脑组织。取出的组织使用生理盐水洗净表面血渍，再分别用滤纸吸干，称重。同时还需要采集大鼠肠道内的粪样，称重，用于测定未被吸收的药物量。
采集的血液样本使用肝素钠抗凝，收集后1h内，在2-8℃条件下3500rpm离心10min,分离血浆置于-80℃冰箱中保存待测。下层的红细胞也需回收至-80℃冰箱中保存待测。
取一定量(约0.2g)的各组织样品，按每1g组织加入3mL生理盐水，在冰浴条件下用电动匀浆机充分搅碎，置于-80℃冰箱中保存待测。其余的未进行匀浆的组织需回收并置于-80℃冰箱保存。
样本收集及处理过程全程避光。
3.样本检测
采用LC-MS/MS法分别检测大鼠血浆样本、组织样本和粪便样本中阿昔替尼药物浓度。
实验结果
阿昔替尼受试制剂和参比制剂的组织分布见下表5。
表5 阿昔替尼受试制剂和参比制剂的组织分布
Figure PCTCN2021134705-appb-000009
Figure PCTCN2021134705-appb-000010
从表5中结果可以看出，相比阿昔替尼参比制剂，阿昔替尼受试制剂在胃肠道中的药物浓度低，从表5数据中组织分布药物浓度可以看出药物在胃肠道中停留时间短且浓度低，能有效降低胃肠道的不良反应，从而减少药物因局部浓度过高及与胃肠壁长时间接触而引起的刺激，避免服药后血药浓度过高而引起的严重的消化系统不良反应。
试验例5 阿昔替尼自微乳组合物在大鼠中的药代动力学实验
1.给药
健康大鼠随机分组，每组6只。具体给药方式为：
第1组，6只大鼠口服给予阿昔替尼片的混悬液(参比制剂，R)，剂量为1或5mg/kg；
其他组大鼠分别口服给予阿昔替尼自乳化溶液(受试制剂，实施例1、实施例3、实施例7-4、实施例14、实施例18-1、实施例21-1、实施例21-3)，剂量为1或5mg/kg。
2.样本采集及处理
大鼠灌胃给药后0h、0.25h、0.5h、0.75h、1h、1.5h、2h、3h、4h、6h、8h、12h，采集静脉血0.5mL。
采集的血液样本使用肝素钠抗凝，收集后1h内，在2-8℃条件下3500rpm离心10min,分离血浆置于-80℃冰箱中保存待测。
3.结果
阿昔替尼受试制剂和参比制剂药动学参数见下表6-1和6-2。
表6-1 剂量1mg/kg，阿昔替尼受试制剂和参比制剂药动学参数
  t 1/2(h) T max(h) C max(ng/mL) AUC last(h*ng/mL)
参比制剂 3.06 0.46 1.26 2.12
实施例1 2.79 0.25 5.16 6.66
实施例3 2.74 0.25 8.66 7.31
实施例7-4 2.32 0.25 4.41 5.41
实施例14 2.25 0.25 2.42 6.48
实施例18-1 2.64 0.25 11.24 8.86
实施例21-1 2.37 0.25 3.31 6.01
实施例21-3 2.56 0.25 6.91 5.88
表6-2 剂量5mg/kg，阿昔替尼受试制剂和参比制剂药动学参数
  t 1/2(h) T max(h) C max(ng/mL) AUC last(h*ng/mL)
参比制剂 3.89 0.42 7.84 13.34
实施例1 3.89 0.29 45.12 31.07
实施例3 4.05 0.35 43.59 30.19
实施例7-4 3.43 0.25 28.58 24.39
实施例14 4.26 0.25 27.53 23.58
实施例18-1 4.88 0.25 40.87 25.39
实施例21-1 2.87 0.25 94.05 45.81
实施例21-3 3.09 0.25 36.13 29.32
从表中结果可以看出，在1mg/kg和5mg/kg的剂量下，阿昔替尼自乳化组相对参比制剂的Tmax均降低，Cmax均增大，且增加了5～6倍；受试制剂的AUC为参比制剂的2～3倍。本申请实施例制备的自微乳组合物能够显著提高阿昔替尼在大鼠体内的生物利用度。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，尽管参照前述实施例对本发明进行了详细的说明，对于本领域的技术人员来说，其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种阿昔替尼的自微乳组合物，其特征在于，按自微乳组合物的总质量的质量百分比计，包括0.1～10％阿昔替尼、1～70％油相、10～90％表面活性剂和0～60％助表面活性剂。
  2. 根据权利要求1所述的阿昔替尼的自微乳组合物，其特征在于，所述自微乳组合物，按自微乳组合物的总质量的质量百分比计，包括0.5～5％阿昔替尼、5～50％的油相、25～90％的表面活性剂和0～45％的助表面活性剂。
  3. 根据权利要求2所述的阿昔替尼的自微乳组合物，其特征在于，所述自微乳组合物，按自微乳组合物的总质量的质量百分比计，包括0.5～2％阿昔替尼、10％～40％的油相、45～60％的表面活性剂和20～35％的助表面活性剂。
  4. 根据权利要求1所述的阿昔替尼的自微乳组合物，其特征在于，所述油相为药学上可接受的各种油相，选自天然植物油、经结构改造和水解后的植物油、或链长在C8-C10之间的中等链长脂肪酸甘油酯中的一种或多种。
  5. 根据权利要求1所述的阿昔替尼的自微乳组合物，其特征在于，所述的表面活性剂选自非离子型、阴离子型、阳离子型和两性离子表面活性剂。
  6. 根据权利要求1所述的阿昔替尼的自微乳组合物，其特征在于，所述的助表面活性剂选自中/短链醇、醚中的一种或多种。
  7. 根据权利要求1所述的阿昔替尼的自微乳组合物，其特征在于，
    所述油相为单亚油酸甘油酯、单油酸甘油酯、油酸乙酯、中链甘油三酯、中链甘油酸酯、亚油酸聚乙二醇甘油酯、油酸聚乙二醇-6甘油酯、丙二醇辛酸酯、油酸聚乙二醇甘油酯、Capmul MCM、油酸中的一种或至少两种；
    所述表面活性剂为吐温80、丙二醇单辛酸酯、丙二醇单月桂酸酯、聚甘油脂肪酸酯、聚氧乙烯氢化蓖麻油、辛酸癸酸聚乙二醇甘油酯和聚氧乙烯蓖麻油中的一种或两种；
    所述助表面活性剂为PEG400、PEG600、丙二醇、二乙二醇单乙醚中的一种或两种。
  8. 一种剂型，其特征在于，将权利要求1～7任一项所述的自微乳组合物灌装入软或硬胶囊中，或加入吸收剂制成固体自乳化片剂、丸剂、散剂或颗粒剂。
  9. 一种药物组合物，包括权利要求1～7任一项所述的自微乳组合物或权利要求8所述剂型中的一种，以及其他抗肿瘤药物。
  10. 一种权利要求1～7任一项所述的自微乳组合物或权利要求8所述剂型或权利要求9所述药物组合物在制备预防、治疗或防护肿瘤类疾病的药物中的用途。
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