CN117771176A - Self-microemulsion composition of lenatinib, drug delivery system and solid preparation - Google Patents

Self-microemulsion composition of lenatinib, drug delivery system and solid preparation Download PDF

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CN117771176A
CN117771176A CN202211161718.XA CN202211161718A CN117771176A CN 117771176 A CN117771176 A CN 117771176A CN 202211161718 A CN202211161718 A CN 202211161718A CN 117771176 A CN117771176 A CN 117771176A
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lenatinib
self
oil
oleic acid
glyceride
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易木林
曾也
周叶文
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Hunan Huize Bio Pharmaceutical Co ltd
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Hunan Huize Bio Pharmaceutical Co ltd
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Abstract

The invention discloses a self-microemulsion composition of lenatinib, a drug delivery system and a solid preparation, which are prepared by screening oil phases, emulsifying agents and auxiliary emulsifying agents in specific types and dosage proportions; the self-microemulsion composition can improve the solubility and bioavailability of the lenatinib, reduce the dosage of the lenatinib under the condition of keeping the same curative effect with the original ground tablet, further improve various adverse reactions and improve medication compliance. Further provides a lenatinib self-microemulsion drug delivery system and a solid preparation, and improves the stability of the pharmaceutical preparation.

Description

Self-microemulsion composition of lenatinib, drug delivery system and solid preparation
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a self-microemulsion composition, a drug delivery system and a solid preparation of lenatinib, and especially relates to a self-microemulsion drug delivery system of lenatinib.
Background
Lenatinib maleate (neratinib maleate) is an orally active, irreversible pan-human Epidermal Growth Factor Receptor (EGFR) inhibitor that inhibits HER1, HER2 and HER4 receptors and their associated tyrosine kinases. The method is used for assisting in treating early HER2 over-expression and amplified breast cancer adult patients, prevents the signal paths of the HER1, HER2 and HER4 from transduction, and achieves the purpose of resisting cancer.
Lenatinib maleate was originally developed by the wheatstone company and, after being purchased by the gabion pharmaceutical company, was licensed to PUMA biotechnology company in the united states for development, marketing, production and sales. The product is approved by the United states Food and Drug Administration (FDA) for marketing at 7.17.2017 under the trade name Nerlynx. The lenatinib is marketed in the form of tablets, with a specification of 40mg per tablet. The recommended oral dose is 240 mg.d-1 (6 tablets), the dose is 1 time per day, the dosage is large, adverse reactions are obvious, especially gastrointestinal adverse reactions are mainly diarrhea, nausea and vomiting, and clinical test results show that the incidence rate of 1-3 grade diarrhea in the lenatinib administration group is obviously higher than that of a placebo group (95% vs 36%). Lenatinib has poor water solubility, particularly in neutral and alkaline environments, and studies have shown that lenatinib has a faster degradation rate in aqueous solutions with pH greater than 3, which results in its lower bioavailability (17%); the lenatinib has poor water solubility, is degraded in an aqueous solution with the pH value of more than 3, has poor stability, is metabolized by CYP3A4 in vivo, is discharged and transported by P-glycoprotein, and has low bioavailability, large dosage and obvious gastrointestinal adverse reaction after long-term administration.
Lenatinib is used as a breast cancer potentiation adjuvant chemotherapy for the treatment of early HER2 positive adult breast cancer patients, which is the first approved "potentiation adjuvant therapy" medication by the FDA for trastuzumab (trastuzumab) treatment with complete injections, and the disease has not progressed, but there are still high risk factors for breast cancer patients. Lenatinib has high anti-tumor activity, can prolong the survival time of HER2 positive breast cancer patients without disease progression, and reduces the risk of cancer recurrence.
CN201080060547.0 discloses enteric coated drug spheroids for reducing or eliminating adverse effects of drugs associated with side effects such as emesis and diarrhea, but without significantly improving the bioavailability.
In view of the low bioavailability of lenatinib tablets and serious gastrointestinal adverse reactions, and the fact that only one tablet formulation is currently marketed, the clinical use of the tablet formulation is greatly limited, and therefore, the development of new formulations is urgently needed.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a self-microemulsion composition, a drug delivery system and a solid preparation of lenatinib, in particular to a self-microemulsion drug delivery system of lenatinib. According to the invention, through screening oil phase, emulsifier and co-emulsifier in specific types and dosage proportions, the solubility and bioavailability of the lenatinib can be improved, and the dosage of the lenatinib can be reduced under the condition of keeping the same curative effect as that of an original ground tablet, so that various adverse reactions are improved, and medication compliance is improved.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
according to a first embodiment of the present invention there is provided a self-microemulsion composition of lenatinib comprising lenatinib, an oil phase and an emulsifier.
Further, a co-emulsifier is included.
Further, the self-microemulsion composition comprises, by weight, 0.1-15% of lenatinib, 10-60% of an oil phase, 10-70% of an emulsifier and 0-60% of a co-emulsifier.
Further, the mass percentage of the lenatinib is 0.5-10%, and the mass percentage of the lenatinib is 0.5%, 1%, 1.64%, 1.96%, 2%, 2.78%, 3%, 3.29%, 3.37%, 3.45%, 4%, 4.23%, 5.0%, 6%, 6.40%, 6.86%, 7%, 7.79%, 8%, 9% or 10%.
Further, the mass percentage of the oil phase is 15-60%, and the mass percentage of the oil phase is 15%, 19.44%, 20%, 21.86%, 25%, 28.97%, 29.17%, 29.56%, 30%, 30.92%, 33.75%, 33.77%, 34.31%, 35%, 37.99%, 38.62%, 38.89%, 39.08%, 39.44%, 40%, 50%, 55% or 60%. In the self-microemulsifying drug delivery system, when two auxiliary materials are respectively contained in the oil phase, the mass ratio of the two auxiliary materials is 1:9-9:1; the ratio of the two oil phases is: 1:1, 1:1.1, 1:1.3, 1:1.5, 1:2, 1:2.5, 1:3, 1:4, 1:5, 1.1:1, 1.2:1, 2:1, 3:1, 3:2, 3.5:1, 4:1, 5:1, 5.2:1 or 5.5:1.
Further, the mass percentage of the emulsifier is 10-70%, and the mass percentage of the emulsifier is 10%, 15%, 18%, 20%, 22.48%, 22.64%, 24%, 25%, 25.97%, 28.97%, 29.41%, 30%, 31.25%, 34.48%, 35%, 36%, 37.5%, 38.62%, 38.63%, 38.89%, 40%, 42%, 43.45%, 43.72%, 44.07%, 44.28%, 45%, 45.10%, 46.05%, 46.34%, 48%, 50%, 54%, 55% or 56.72%. In the self-microemulsifying drug delivery system, when two auxiliary materials are respectively contained in the emulsifying agent, the mass ratio of the two auxiliary materials is 1:9-9:1; the mass ratio of the two emulsifying agents is 1:1, 1:1.1, 1:1.3, 1:1.5, 1:2, 1:2.5, 1:3, 1:4, 1:5, 1.1:1, 1.2:1, 2:1, 3:1, 3.5:1, 4:1, 5:1, 5.2:1 or 5.5:1.
Further, the mass percentage of the auxiliary emulsifier is 0-60%, and the mass percentage of the auxiliary emulsifier is 0, 5%, 6%, 8%, 10%, 11%, 12%, 12.5%, 13%, 13.66%, 14.08%, 14.48%, 15%, 16%, 16.7%, 17.5%, 18%, 19%, 20%, 24%, 25%, 28.97%, 29.56%, 30%, 30.64%, 32.47%, 32.79%, 34.31%, 35%, 36%, 38%, 40%, 42%, 45%, 48% or 50%. In the self-microemulsifying drug delivery system, when two auxiliary materials are respectively contained in the auxiliary emulsifying agent, the mass ratio of the two auxiliary materials is 1:9-9:1; the mass ratio of the two auxiliary emulsifying agents is 1:1, 1:1.1, 1:1.3, 1:1.5, 1:2, 1:2.5, 1:3, 1:4, 1:5, 1.1:1, 1.2:1, 2:1, 3:1, 3.5:1, 4:1, 5:1, 5.2:1 or 5.5:1.
Further, the oil phase is various pharmaceutically acceptable oil phases and is selected from one or more of natural vegetable oil, vegetable oil after structural modification and hydrolysis, or medium-chain-length fatty glyceride with the chain length of C8-C10.
Further, 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 mono-or diglycerides, caprylic capric mono-diglycerides (Capmul MCM), coconut oil C8/C10 propylene glycol diglycerides (Captex 200), coconut oil C8/C10 triglycerides (Captex 355), coconut oil aminopropyl betaine, purified acetylated monoglycerides (Miglyol 812), purified sunflower oil monoglycerides, propylene glycol caprylate (capryol 90), polyethylene glycol laurate, glyceryl monooleate (Pecelol), glyceryl monolinoleate (Maisine CC), medium chain triglycerides (MCT, labrafac lipophile WL 1349), polyethylene glycol glyceryl oleate, polyethylene glycol glyceryl linoleate polyethylene glycol capryl caprate glyceride, polyoxyethylene glyceryl oleate, polyoxyethylene glyceryl linoleate, camellia glyceryl oleate, almond oil PEG-6 glyceride, corn oil PEG-6 glyceride, glyceryl oleate, egg yolk lecithin, soybean lecithin, dioleoyl lecithin, dilauroyl lecithin, dimyristoyl lecithin, dipalmitoyl lecithin, distearoyl lecithin, cephalin, creatine, inositol phospholipid, lysophospholipid, phosphatidic acid, phosphatidylglycerol, stearoyl/palmitoyl/oleoyl phosphatidylcholine, stearoyl/palmitoyl/oleoyl phosphatidylethanolamine, phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol and one or at least two of phosphatidylinositol, distearoyl phosphatidylethanolamine, oleoyl phosphatidylcholine, caproic acid, caprylic acid, oleic acid, star anise oil, vitamin E, stearic acid, isopropyl laurate, isopropyl palmitate, isopropyl myristate, polyglycerol oleate (Caprol PGE-860), polyethylene glycol-6 glyceride oleate, medium chain glycerides, polyethylene glycol glyceride linoleate, propylene glycol monolaurate (Capmul PG-12), propylene glycol caprylate, sorbitol oleate, ethyl laurate, ethyl myristate, ethyl oleate, ethyl linoleate, tocopherol, glyceryl monolinoleate (map CC), glyceryl tricaprylate (e.g., captex 8000), and polyoxyethylene glyceride oleate (LABRARIL M1944 CS).
Further, the oil phase is selected from one or at least two of tricaprylin, caprylic capric mono-di-glyceride, mono-caprylic glyceride, mono-capric glyceride, caprylic glyceride, propylene glycol mono-caprylate, caprylic capric mono-di-triglyceride, medium chain triglyceride, ethyl oleate, corn oil, oleic acid, star anise oil, capmul MCM, mono-linoleic glyceride, propylene glycol caprylate, mono-oleic glyceride, propylene glycol monolaurate, caprylic capric polyethylene glycol glyceride, oleoyl polyoxyethylene glyceride, polyglycerol oleate (Caprol PGE-860).
Further, the oil phase is selected from the following combinations: the mixed oil phase of oleic acid and corn oil, the mixed oil phase of oleic acid and glyceryl trioleate, the mixed oil phase of oleic acid and medium chain triglyceride, the mixed oil phase of oleic acid and propylene glycol caprylate, the mixed oil phase of oleic acid and Capmul MCM, the mixed oil phase of oleic acid and glyceryl monolinoleate, and the mixed oil phase of glyceryl tricaprylate and propylene glycol monocaprylate.
Further, the emulsifier is selected from one or at least two of nonionic, anionic, cationic and zwitterionic emulsifiers.
Further, the method comprises the steps of, the emulsifier is selected from egg yolk lecithin, soybean lecithin, di-oleoyl lecithin, dilauroyl lecithin, dimyristoyl lecithin, dipalmitoyl lecithin, distearyl lecithin, cephalin, creatinine, inositol phosphatide, lysophosphatide, 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 monoglycerides, sorbitan fatty acid esters, polyethylene glycol glycerol amygdalinates, C8/C10 polyethylene glycol glycerol cocoates, polyoxyethylene lauryl stearate, polyethylene glycol 100 vitamin E succinate, polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene castor oil (Cremophor EL 35), polyoxyethylene hydrogenated castor oil (Cremophor RH 40), polyoxyethylene polyoxypropylene copolymers (e.g., poloxamers 188 and 407), polyoxyethylene glycerol esters, vitamin E polyethylene glycol succinate (TPGS), 15-hydroxystearic acid glycerol ester (SH 15), polyoxyethylene sorbitan trioleate, polyoxyethylene glycerol trioleate, polyoxyethylene sorbitan fatty acid esters, sodium docusate, calcium docusate, potassium docusate, 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-15 hydroxystearates (Solutol), polyethylene glycol-8-glyceroloctanoate/decanoate, polyethylene glycol-32 glycerol laurate, lauroyl polyethylene glycol-32 glycerol esters, polyethylene glycol glycerol caprylate, sorbitan sesquioleate, polysorbates (such as polysorbate 20, polysorbate 80), water-soluble natural vitamin E, span 80, tween 80, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers (Soluplus), caprylic acid, sodium caprylate, bile acids, ursodeoxycholic acid, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-hexadecyl-N, N-dimethyl-3-amino (ammonio) -1-propane sulfonate, palmitoyl lysophosphatidyl-L-serine, lysophospholipids (e.g., 1-acyl-SN-glycerol-3-phosphate of ethanolamine, choline, serine, or threonine), N-alkyl-N, N-dimethylamino-1-propane sulfonate, 3-cholamide-1-propyldimethylamino-1-propane sulfonate, dodecyl phosphorylcholine, myristoyl lysophosphatidylcholine, egg lysolecithin, polyglycerol fatty acid ester, propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol monocaprylate, cetyl-trimethylammonium bromide, cetyl pyridinium chloride, polyethylene oxide/polypropylene oxide block copolymers (Pluronics/Tetronics, triton X-100, dodecyl beta-D-glucopyranoside), sodium taurinate, polyethylene glycol glyceryl capryldecanoate (Labrasol), oleic acid, acyl carnitine, lysine, arginine, histidine, lysine, or at least two thereof.
Further, the emulsifier is selected from one or at least two of polyoxyethylated castor oil (Cremophor EL 35), polyoxyethylated hydrogenated 40 castor oil (Cremophor RH 40), oleoyl polyoxyethylene glyceride (LABRARIL M1944 CS), tween80, caprylic capric acid polyethylene glycol glyceride (Capmul MCM), monocapric acid glyceride (Capmul MCM C10), vitamin E polyethylene glycol succinate (TPGS), propylene glycol monocaprylate (Capryol 90), polyglycerol fatty acid ester, lauroyl polyethylene glycol-32 glyceride, caprylic acid polyethylene glycol glyceride (Labrasol), 15-hydroxystearin (SH 15), oleoyl polyoxyethylene glyceride, polyethylene glycol glyceride, polysorbate (such as polysorbate 20, polysorbate 80), propylene glycol monolaurate (Capmul PG-12).
Further, the auxiliary emulsifier is selected from one or more of medium/short chain alcohol and ether.
Further, the co-emulsifier is selected from one or more of ethanol, propylene glycol, isopropanol, N-butanol, polyethylene glycol (molecular weight range of 100Da-10kDa,300Da-2000Da, or 400Da-1000 Da) such as polyethylene glycol 200-600 (such as PEG400, PEG 600), polyethylene glycol vitamin E succinate, propylene carbonate, tetrahydrofurfuryl alcohol, ethylene glycol furalcohol, glycerylfurfural, dimethyl isosorbide, dimethylacetamide, N-methylpyrrolidone, diethylene glycol monoethyl ether (Transcutol or Transcutol P or Transcutol HP or TP), ethylene glycol monoethyl ether, docosahexaenoic acid, cholesterol, azone, glycerol, ethyl acetate, polyethylene oxide, caprylic/capric polyethylene glycol glyceride, propylene carbonate, glyceryl monostearate, glyceryl distearate, polyglycerol-6-dioleate.
The products of the self-microemulsifying drug delivery systems developed today are flexible. On the one hand, the drug molecules can influence the emulsification effect of the self-microemulsifying drug delivery system, different drugs have different effects, and only special auxiliary materials can form an effective self-microemulsifying system, so that the characteristics of the drugs are combined, the types and the proportions of the oil, the emulsifier and the auxiliary emulsifier are determined through a large number of experimental screening for a long time, and the risk of screening failure is extremely high; on the other hand, the self-microemulsifying drug delivery system contains a large amount of emulsifying agent, and the high concentration of emulsifying agent may cause irritation or even toxic and side effects of the preparation to human body.
Further, the self-microemulsion composition comprises lenatinib, oleic acid, corn oil, polyoxyethylene hydrogenated castor oil and benzyl alcohol.
Further, the self-microemulsion composition comprises lenatinib, oleic acid, corn oil, polyoxyethylene hydrogenated castor oil and diethylene glycol monoethyl ether. Further, the self-microemulsion composition comprises, by weight, 1.5% of lenatinib, 7.7% of oleic acid, 7.7% of corn oil, 9.2% of polyoxyethylene hydrogenated castor oil and 13.8% of diethylene glycol monoethyl ether.
Further, the self-microemulsion composition comprises lenatinib, oleic acid, corn oil, polyoxyethylene hydrogenated castor oil and caprylic/capric polyethylene glycol glyceride.
Further, the self-microemulsion composition comprises lenatinib, oleic acid, corn oil, polyoxyethylene castor oil and caprylic/capric polyethylene glycol glyceride.
Further, the self-microemulsion composition comprises lenatinib, oleic acid, corn oil, polyoxyethylated castor oil, and diethylene glycol monoethyl ether.
Further, the self-microemulsion composition comprises lenatinib, oleic acid, corn oil, polyoxyethylated castor oil, and benzyl alcohol.
Further, the self-microemulsion composition comprises lenatinib, oleic acid, corn oil, vitamin E polyethylene glycol succinate and benzyl alcohol.
Further, the self-microemulsion composition comprises lenatinib, oleic acid, corn oil, polyoxyethylene hydrogenated castor oil, oleoyl polyoxyethylene glyceride and benzyl alcohol.
Further, the lenatinib forms and releases a microemulsion from the microemulsion composition when contacted with an aqueous medium, and the particle size of the microemulsion is 2-500 nm. Further, the lenatinib forms and releases a microemulsion from the microemulsion composition upon contact with an aqueous medium, the microemulsion having a particle size of less than 500nm, 450nm, 400nm, 350nm, 300nm, 250nm, 200nm, 150nm, 100nm, 95nm, 90nm, 85nm, 80nm, 75nm, 70nm, 65nm, 60nm, 55nm, 50nm, 45nm, 40nm, 35nm, 30nm, 25nm, 20nm, 15nm, 10nm or even less. Further, the lenatinib forms and releases a microemulsion from the microemulsion composition when in contact with an aqueous medium, and the particle size of the microemulsion is 50-500 nm or 10-300 nm or 10-250 nm or 10-200 nm or 10-150 nm or 10-60 nm or 10-100 nm or 10-50 nm.
According to a second embodiment of the present invention there is provided a lenatinib self-microemulsifying delivery system comprising a lenatinib self-microemulsion composition.
Further, the self-microemulsifying drug delivery system further comprises a solid adsorbent.
Further, the self-microemulsifying drug delivery system comprises, by weight, 4-70% of a lenatinib self-microemulsion composition and 30-95% of a solid adsorbent.
Further, the mass percentage of the solid adsorbent is 30%, 30.64%, 32.47%, 32.79%, 33.3%, 34.31%, 35%, 36%, 38%, 40%, 42%, 45%, 48%, 50%, 55%, 60%, 65%, 66.7%, 70%, 80%, 90% or 95%. In the self-microemulsifying drug delivery system, when two auxiliary materials are respectively contained in the solid adsorbent, the mass ratio of the two auxiliary materials is 1:9-9:1; the mass ratio of the two solid adsorbents is 1:1, 1:1.1, 1:1.3, 1:1.5, 1:2, 1:2.5, 1:3, 1:4, 1:5, 1.1:1, 1.2:1, 2:1, 3:1, 3.5:1, 4:1, 5:1, 5.2:1 or 5.5:1.
Further, the method comprises the steps of, the solid adsorbent is selected from mannitol, xylitol, dextrin, sucrose, sorbitol, sodium saccharin, pantoprazole, xylitol, aspartame, erythritol, dextran 80, lactose, microcrystalline cellulose, pregelatinized starch, lactose, starch, gelatinized starch, corn starch, hydroxypropyl methylcellulose (HPMC-K100 LV), calcium sulfate, sodium carboxymethyl starch, carboxymethyl cellulose (carboxymethyl cellulose), carboxymethyl cellulose calcium, cross-linked sodium carboxymethyl cellulose (sodium cross-linked carboxymethyl cellulose), soybean lecithin, low substituted hydroxypropyl cellulose, tragacanth powder, bentonite, cross-linked povidone or cross-linked sodium carboxymethyl starch, adipic acid, alginic acid, sodium carboxymethyl cellulose, calcium hydrogen phosphate, calcium carbonate, silicon dioxide, calcium citrate, light anhydrous silicic acid, synthetic aluminum silicate wheat starch, rice starch, cellulose acetate phthalate, calcium stearate, tragacanth, potato starch, hydroxyethyl methylcellulose, hydroxypropyl starch, monosodium fumarate, povidone, anhydrous citric acid, methylcellulose, monocalcium phosphate, anhydrous dibasic calcium phosphate, magnesium aluminum silicate, gum arabic, isopropyl citrate, polyvinyl acetate resin, cellulose acetate phthalate, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl starch, vinylpyrrolidone-vinyl acetate copolymer, hydroxypropyl methylcellulose, micronized silica gel, pluronic, hydroxypropyl methylcellulose, dextran 70, aerosil 200, magnesium aluminum metasilicate, hydroxypropyl-beta-cyclodextrin, oxalic acid, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl cellulose, polyacrylic resin, methylcellulose, chitin, carboxymethyl cellulose, polyvinylpyrrolidone, dextran, acacia, dextrin, maltose, metal silicate, metal carbonate, isopropyl citrate, anhydrous calcium chloride, calcium chloride dihydrate, zinc oxide, zinc hydroxide, magnesium carbonate, magnesium oxide, microcrystalline cellulose, lactose, aluminum hydroxide gel powder, sodium chloride, pregelatinized starch, sucrose powder, glucose powder, mannitol, sorbitol starch, cyclodextrin, sodium carbonate, sodium bicarbonate, calcium sulfate, polyethylene glycol 4000, polyethylene glycol 6000, diatomite and glycolide-lactide copolymer with a molecular weight of 2-4 ten thousand and a network structure with multiple folds inside.
Further, the self-microemulsifying drug delivery system further comprises one or two of an antioxidant, a flavoring agent and a preservative; the mass percentage of the antioxidant, the flavoring agent or the preservative is respectively 0.005-1%, and further, the mass percentage of the antioxidant is 0.005%, 0.05%, 0.1%, 0.2%, 0.4%, 0.5%, 0.6%, 0.8% or 1%; the mass percentage of the flavoring agent is 0.005%, 0.05%, 0.1%, 0.2%, 0.4%, 0.5%, 0.6%, 0.8% or 1%; the mass percent of the preservative is 0.005%, 0.05%, 0.1%, 0.2%, 0.4%, 0.5%, 0.6%, 0.8% or 1%.
Further, the antioxidant is selected from one or two of tert-butyl p-hydroxyanisole BHA, butylhydroxytoluene BHT, vitamin C, vitamin E (dl-alpha-tocopherol), tocotrienol, rosemary extract, calcium lactate, sodium lactate, potassium sorbate, disodium ethylenediamine tetraacetate, disodium calcium ethylenediamine tetraacetate, sodium D-isoascorbate, sodium phytate, sodium ascorbate, calcium ascorbate, sodium benzoate, potassium benzoate, sodium sulfite, sodium bisulphite, sodium hyposulfite, potassium ascorbate, potassium isoascorbate, potassium ascorbate palmitate, sodium ascorbate palmitate, potassium phytate, sodium tert-butylhydroquinone, potassium tert-butylhydroquinone, sodium 2, 6-di-tert-butyl-4-methylphenol, potassium 4, 6-di-tert-butyl-4-methylphenol, sodium 4-methyl-2-tert-butylphenol, potassium sorbate, sodium 4-hexylresorcinol or potassium 4-hexylresorcinol.
Further, the flavoring agent is selected from one or more of saccharin sodium, sucrose, saccharin, aspartame, xylitol, sorbitol, mannitol, maltose, acesulfame potassium, glycyrrhizin, stevioside, orange essence, peppermint essence, strawberry essence, assorted essence or fruit essence.
Further, the oil phase is selected from one or more of oleic acid and corn oil.
Further, the emulsifier is selected from one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil and tween 80.
Further, the auxiliary emulsifier is selected from one or more of diethylene glycol monoethyl ether, caprylic/capric acid polyethylene glycol glyceride and benzyl alcohol.
Further, the adsorbent is silica. Further, the silica is selected from the group consisting of colloidal silica, mesoporous silica, ultrafine silica, hydrophobic silica, precipitated silica, amorphous silica, liquid silica, crystalline silica, and the like; further, the average particle diameter of the silicon dioxide is less than or equal to 4 mu m, and the specific surface area is more than or equal to 100m 2 /g。
Further, the antioxidant is selected from vitamin E.
Further, the flavoring agent is selected from sodium saccharin.
Further, the self-microemulsifying drug delivery system comprises, by weight, 0.1-5% of lenatinib, 3-30% of an oil phase, 5-30% of an emulsifying agent, 3-30% of a co-emulsifying agent, 50-75% of an adsorbing agent, 0.1-0.5% of an antioxidant and 0.1-0.5% of a flavoring agent.
Further, the lenatinib self-microemulsifying drug delivery system comprises, by weight, 0.1-5% of lenatinib, 3-15% of oleic acid, 3-15% of corn oil, 7-20% of an emulsifying agent, 3-20% of a co-emulsifying agent, 50-75% of silicon dioxide, 0.01-0.2% of vitamin E and 0.01-0.4% of saccharin sodium.
Further, the lenatinib self-microemulsifying drug delivery system comprises, by weight, 0.1-5% of lenatinib, 3-15% of oleic acid, 3-15% of corn oil, 7-20% of polyoxyethylene hydrogenated castor oil, 3-20% of diethylene glycol monoethyl ether, 50-75% of silicon dioxide, 0.01-0.2% of vitamin E and 0.01-0.4% of saccharin sodium. Further, the lenatinib self-microemulsifying drug delivery system comprises, by weight, 1.5% of lenatinib, 7.7% of oleic acid, 7.7% of corn oil, 9.2% of polyoxyethylene hydrogenated castor oil, 13.8% of diethylene glycol monoethyl ether, 59.8% of silicon dioxide, 0.1% of vitamin E and 0.2% of saccharin sodium.
According to a third embodiment of the present invention, there is provided a solid formulation of lenatinib.
Further, the self-microemulsifying drug delivery system is further dried to prepare the lenatinib self-microemulsion solid preparation.
Further, the drying conditions are: and drying at 40-60 deg.c for 2-6 hr under vacuum. Further, the drying condition is that the drying is carried out for 6 hours under vacuum at 60 ℃.
Further, the lenatinib self-microemulsion solid preparation comprises lenatinib, an oil phase, an emulsifier, a co-emulsifier, an adsorbent, an antioxidant and a flavoring agent.
In the invention, a preparation method of the self-microemulsifying drug delivery system is provided, which comprises the following steps:
evaluating the solubility of the carrier material oil phase, the emulsifier and the co-emulsifier for lenatinib;
dissolving the natatinib in a carrier material with high solubility, adding the carrier material with low solubility, and uniformly mixing to obtain a microemulsion composition;
adding solid adsorbent to obtain self-microemulsifying drug delivery system.
Further, in the process of uniform mixing, the lenatinib is uniformly mixed with a carrier substance with high solubility to obtain a mixed phase I; adding the carrier material with the second solubility into the first mixed phase, and uniformly mixing to obtain a second mixed phase; adding a carrier substance with low solubility into the mixed phase II, and uniformly mixing to obtain a mixed phase III; adding the carrier material with the lowest solubility into the mixed phase III to obtain the self-microemulsion composition.
Further, the self-microemulsion composition of the present invention may use crystalline or amorphous forms, salts, anhydrates or hydrates, solvates, prodrugs, metabolites, etc. of lenatinib.
According to a fourth embodiment of the present invention, there is provided a formulation of lenatinib.
A formulation of lenatinib comprising a solid formulation and a liquid formulation. Wherein the solid preparation comprises one or more of tablets, capsules, granules, powder, dripping pills and films. The liquid formulation includes, but is not limited to, one or more of injection, soft capsule, ointment, suppository, aerosol.
Further, the solid preparation is prepared from the content and auxiliary materials through one or more steps of crushing, sieving, mixing, granulating and tabletting. The auxiliary materials are selected from one or more of filler, adsorbent, adhesive, lubricant, dispersant, disintegrating agent, wetting agent, perfume and pigment. The content is the self-microemulsion system and lenatinib of the first embodiment, or the content is the composition containing lenatinib of the second embodiment.
In the invention, the self-microemulsion composition containing lenatinib can spontaneously form O/W nanoemulsion with high clarity, uniform particle size and stable property, and particle size of less than 250nm by mixing with water, biologically relevant mediums (such as SGF, SGF, fessiF and FassiF mediums) or gastrointestinal fluids; the contents can exist in a stable solution form when stored at room temperature; the self-microemulsion composition of the present invention is stable even under conditions of influence (e.g., 30.+ -. 2 ℃ C., 4 ℃ C., 10% by weight of water based on the composition is added, 15% by weight of water based on the composition is added).
In the invention, the self-microemulsion composition containing lenatinib is a solution system, and can spontaneously disperse to form O/W type nanoemulsion under gastrointestinal peristalsis when being taken orally, and has the advantages of high clarity, uniform particle size and stable property. The nanoemulsion has small particle size, can promote the dissolution of the medicine, increase the membrane permeability of the lenatinib in vivo, increase the penetrability of intestinal epithelial cells, further obviously promote the absorption and obviously improve the bioavailability of the medicine. The composition containing lenatinib can also remarkably reduce the influence of food on the absorption of the lenatinib and reduce the difference between meal and meal, so that the composition can be taken under the conditions of empty stomach and satiety, and the limitation of taking time is reduced.
In the invention, the formed uniform and stable drug system containing the lenatinib can be spontaneously dispersed to form nanoemulsion after entering a body, so that the problem of absorption and transmembrane of the lenatinib in the body can be effectively solved.
Through intensive research, the invention has the advantages that the oral bioavailability of the self-microemulsion composition containing lenatinib, the drug delivery system and the solid preparation is greatly improved, and the stability in a humid or over-humid environment is excellent.
Compared with the prior art, the invention has the following beneficial technical effects:
1: the self-microemulsion composition containing lenatinib, the drug delivery system and the solid preparation prepared by the invention have high solubility and strong stability for the lenatinib, and spontaneously disperse to form O/W type nanoemulsion under gastrointestinal peristalsis, and have high clarity, uniform particle size and stable property; the membrane permeability of the lenatinib in vivo is greatly improved, the penetrability of intestinal epithelial cells is increased, the absorption is further remarkably promoted, and the bioavailability of the medicine is improved.
2: compared with the original ground medicament, the medicament greatly reduces the stimulation of the medicament to the gastrointestinal tract, reduces the stimulation caused by the overhigh local concentration and the long-time contact with the gastrointestinal wall of the medicament, and reduces the side effects of the medicament to the gastrointestinal tract such as diarrhea, nausea and the like. On the other hand, the nanoemulsion is pinocytosis by small intestine cells in an integral form, so that the absorption of the medicine is promoted, the lymphatic transport path is triggered, the first pass effect is avoided, and the bioavailability is further improved. And compared with a liquid self-emulsifying preparation, the preparation method solves the problems of low stability, inconvenient storage and transportation and the like.
3: the self-emulsifying solid preparation of the lenatinib provided by the invention is simple in preparation process, the preparation process is simple, the medicament is only required to be dissolved in an oil phase, an emulsifying agent and a coemulsifier, the reinforcing body adsorbent is uniformly mixed, and the self-emulsifying solid preparation of the lenatinib is obtained after drying, so that the preparation is convenient for industrial mass production.
Drawings
FIG. 1 ternary phase diagram of oleic acid and corn oil mixed in different proportions.
FIG. 2 is a transmission electron micrograph of a droplet of the self-microemulsion composition prepared in example 77 after absorption.
Detailed Description
The following examples illustrate the technical aspects of the invention, and the scope of the invention claimed includes but is not limited to the following examples.
Test 1: preparation of self-emulsifying solid preparation:
according to the solubility of each component in the self-microemulsion system, dissolving lenatinib in a carrier component with high solubility in sequence from large to small, adding the next component after uniformly mixing the previous component, and finally obtaining clear and transparent yellow emulsion;
adding a solid adsorbent to obtain a self-microemulsifying drug delivery system;
and further drying to prepare the lenatinib self-microemulsion solid preparation.
Test 2: measurement test of microemulsion size:
the natatinib self-microemulsifying drug delivery system was diluted 100 times with water and then measured by a nanoparticle analyzer. Each sample was tested at least three times to ensure accuracy of the results.
Test 3: solubility investigation
Weighing 1g of adjuvant, adding excessive medicine into a centrifuge tube, swirling to disperse the medicine thoroughly, and placing into a gas bath vibrator (37deg.C, 100deg.C, 100deg.C.min) -1 ) Equilibrate for 48h.10 000 r.min -1 Centrifuging for 10min, collecting supernatant, measuring content by liquid chromatography, and calculating solubility.
Chromatographic conditions: chromatographic column: a Shim-pack GWS C18 column (4.6mm. Times.250 mm,5 μm); mobile phase a: b (40:60) (mobile phase A:2.72g of potassium dihydrogen phosphate in 1.0L of ultra-pure water, pH adjusted to 3.0 with phosphoric acid; mobile phase B: methanol); the detection wavelength is 260nm; the flow rate is 1.0 mL-min -1 The method comprises the steps of carrying out a first treatment on the surface of the Column temperature is 30 ℃; the sample injection amount was 10. Mu.L.
The results are shown in Table 1 below:
table 1 solubility of lenatinib in various excipients
Remarks: LABRAFIL M1944 CS: oleoyl polyoxyethylene glycerides; EL35: polyoxyethylene castor oil; capmul MCM: caprylic capric acid mono-diglycerides; capmul MCM C8: glycerol monocaprylate; labrasol: caprylic capric polyethylene glycol glyceride; RH40: polyoxyethylene hydrogenated 40 castor oil; capryol 90: propylene glycol monocaprylate; capmul MCM C10: glyceryl monocaprylate; caprol PGE-860: polyglycerol oleate; labrafac lipophile WL1349: medium chain triglycerides; peceol: glycerol monooleate; TP: diethylene glycol monoethyl ether; captex 8000: glyceryl trioctanoate; capmul PG-12: propylene glycol monolaurate; masine CC: glycerol monolinoleate; TPGS: vitamin E polyethylene glycol succinate; SH 15:15-glyceryl hydroxystearate;
As can be seen from Table 1, the solubility of lenatinib in oleic acid was highest, and the co-emulsifier was selected from Transcutol HP, which had a higher solubility.
Test 4: screening auxiliary materials
And selecting proper oil phase, emulsifying agent and auxiliary emulsifying agent for investigation according to the drug solubility test. Measuring absorbance at 600nm with an ultraviolet spectrophotometer by using pure water as a reference and calculating light transmittance (T,%); the color appearance of the dispersion after complete self-emulsification was observed and recorded, and the oil blend phase and emulsifier used were determined in combination with the light transmittance and emulsification status of each experimental group. The results are shown in Table 2.
The five self-emulsifying grade criteria are as follows:
(A) Rapidly emulsifying for less than 1min, and clarifying and transparent or light blue opalescence;
(B) Rapidly emulsifying for less than 2min, and making the emulsion slightly turbid than A and blue-white;
(C) The time is less than 3min, and the product is in a milky white liquid state;
(D) The emulsification is slow, the time is more than 3min, the emulsion is grey white and semi-solid coagulum is formed;
(E) The time is more than 3min, the dispersion is uneven, and the liquid level always has oil drops floating.
TABLE 2 compatibility of Mixed oil phase with emulsifiers
From Table 2, it is clear that oleic acid alone as an oil phase, and various emulsifiers were mixed in various proportions, did not achieve a good emulsifying effect. In terms of the emulsifying capacity of the emulsifier, RH40 is better in overall performance, and besides the mixture of oleic acid and Maisine CC, the light transmittance T is more than 90% after all the mixed oil phases are mixed with RH40 in the ratio of 1:2, and the emulsifying grade is above grade B, so that RH40 is selected as the emulsifier. Oleic acid and MCT, corn oil, capryol 90, captex 8000 and Capmul MCM are mixed in a ratio of 1:1 to form a mixed oil phase, and the mixed oil phase has good performance, particularly after oleic acid and corn oil are mixed, RH40 is used as an emulsifier, and the transmittance T=99.54% after the ratio of oleic acid to corn oil is 1:2 is the highest, and the emulsification grade is evaluated as A. The oleic acid and corn oil mixed oil phase and the emulsifier are mixed according to the high oil phase ratio of 1:1, T also reaches 86.10%, and the emulsification grade is evaluated as B. In addition, tween 80 and Labrasol are used as emulsifying agents, and the oleic acid and corn oil mixed oil phase is the best in all mixed oil phases. The oil phase was determined to be oleic acid mixed with corn oil, the emulsifier was RH40, and the co-emulsifier was Transcutol HP.
Test 5: ternary phase diagram drawing
Oleic acid and corn oil are uniformly mixed according to the mass ratio of 1:3, 1:2, 1:1, 2:1 and 3:1 to be used as a mixed oil phase, then an emulsifier RH40 and a co-emulsifier Transcutol HP are uniformly mixed according to the mass ratio of 9:1, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8 and 1:9 to be used as a mixed emulsifier, and then mixed oil phases with different proportions and the mixed emulsifier are respectively compounded according to the mass ratio of 1:9, 2:8, 3:7, 4:6, 5:5 and 6:4. mu.L of each was removed and slowly added to 5mL of purified water (37 ℃ C., 100 r. Min) -1 ) Self-emulsifying, collecting emulsified solution, and measuring average particle diameter and polydispersity of emulsion drop by nanometer particle size analyzer.
And respectively taking the mixed oil phase, the emulsifier and the coemulsifier as three vertexes of a ternary phase diagram, and drawing the ternary phase diagram by using Origin 2019b software. A mixture of nanoemulsions capable of forming a clear or bluish appearance with an average particle size of < 100nm and a polydispersity of < 0.3 is recorded on a ternary phase diagram, the results of which are shown in FIG. 1. As can be seen from fig. 1, the ternary phase diagram satisfies the self-microemulsion condition most at the point when oleic acid: corn oil=1:1, so the ratio of oleic acid: corn oil=1:1 is selected as the mixed oil phase.
Test 6: prescription for screening liquid self-emulsifying preparation
40mg of lenatinib and 1000mg of carrier dosage of the self-microemulsion composition are taken as a benchmark, the content ratio of an oil phase, an emulsifier and a coemulsifier is adjusted, and a proper self-emulsification preparation prescription is screened, wherein the specific screening conditions are as follows:
TABLE 3 screening of formulation one
Table 4 screening of formulation two
Table 5 screening of formulation III
Table 6 screening of formulation IV
Table 7 screening of formulation five
Table 8 screening of formulation six
Table 9 screening of formulation seven
Table 10 screening of formulation eight
Test 7 adsorbent screening conditions
Preparing a lenatinib self-microemulsion composition by taking 40mg of lenatinib, 200mg of corn oil, 200mg of oleic acid, 240mg of polyoxyethylene hydrogenated castor oil and 360mg of diethylene glycol monoethyl ether as raw materials; adding adsorbent, grinding, and mixing to obtain the final product. The screening conditions of the specific adsorbent are as follows
TABLE 11 adsorbent screening case
Drug loading investigation
Dissolving the prepared self-microemulsifying drug delivery system in purified water, and dispersing the drug in air bath shaker (37deg.C, 100deg.C, r.min) -1 ) Equilibrate for 48h.10000 r.min -1 Centrifuging for 10min, collecting supernatant, measuring content by liquid chromatography, and calculating solubility.
Chromatographic conditions: chromatographic column: a Shim-pack GWS C18 column (4.6mm. Times.250 mm,5 μm); mobile phase a: b (40:60) (mobile phase A2.72 g of potassium dihydrogen phosphate in 1.0L of ultrapureIn water, phosphoric acid adjusts the pH to 3.0; mobile phase B: methanol); the detection wavelength is 260nm; the flow rate is 1.0 mL-min -1 The method comprises the steps of carrying out a first treatment on the surface of the Column temperature is 30 ℃; the sample injection amount was 10. Mu.L.
Determination of average particle size
Dissolving the prepared self-microemulsifying drug delivery system in purified water, and dispersing the drug in air bath shaker (37deg.C, 100deg.C, r.min) -1 ) Equilibrate for 48h.10 000 r.min -1 Centrifuging for 10min, collecting 50 μl of supernatant, slowly adding into 5mL of purified water (37deg.C, 100deg.C, r.min) -1 ) The emulsification time was measured by visual inspection and the average particle size was measured by a laser particle sizer.
From the results shown in Table 11, the silica was used as a solid adsorbent, and the drug loading and the emulsifying effect of the obtained microemulsified drug delivery system were both good.
Test 8 screening cases for different types of silica
Preparation of lenatinib self-microemulsion composition from 40mg of lenatinib, 200mg of corn oil, 200mg of oleic acid, 240mg of polyoxyethylene hydrogenated castor oil and 360mg of diethylene glycol monoethyl ether; adding adsorbent, and mixing to obtain the final product. Silica of different types is selected as an adsorbent, the state and the particle size condition of the silica are inspected, and different adsorption effects are obtained, and the specific results are shown in Table 12:
TABLE 12 screening cases for different types of silica
From the results in table 12, it can be seen that the silica with a large pore size and a large specific surface area can adsorb more self-microemulsion compositions, has higher drug-loading capacity and stronger drug adsorption capacity, effectively avoids the loss of drug molecules in the subsequent operation process, and is beneficial to the subsequent operation.
Run 9 investigation of the amount of silica
Preparation of lenatinib self-microemulsion composition from 40mg of lenatinib, 200mg of corn oil, 200mg of oleic acid, 240mg of polyoxyethylene hydrogenated castor oil and 360mg of diethylene glycol monoethyl ether; adding different amounts of adsorbents, mixing uniformly, and vacuum drying to obtain the self-microemulsifying solid preparation. 350FCP type silicon dioxide is selected as an adsorbent, the state and the particle size condition of the adsorbent are inspected, and different adsorption effects are obtained, and the specific results are shown in Table 13:
TABLE 13 screening of silica with different amounts of silica
From Table 13, it can be seen that the mass ratio of the adsorbent to the self-microemulsion composition is preferably in the range of 1:1 to 2:1, which is more advantageous for the optimum balance of drug loading, stability and drug release rate, based on comprehensive evaluation of particle size after rehydration, content after accelerated test and drug loading.
Test 10 investigation of drying conditions
The test formulations of examples 59-61 in test 9 were examined for different vacuum drying temperatures and times, and the water content in the resulting self-microemulsion solid formulations was determined. The results of the specific examination are shown in Table 14 below:
TABLE 14 screening conditions for drying conditions
As is clear from the results in Table 14, the drying temperature was 60℃under vacuum conditions for 2 to 6 hours, and the water content of the resulting solid preparation of a microemulsion was satisfactory.
Test 11 in vitro dissolution assay
Preparation of Mirabilib self-microemulsion composition from 40mg of lenatinib, 200mg of corn oil, 200mg of oleic acid, 240mg of polyoxyethylene hydrogenated castor oil and 360mg of diethylene glycol monoethyl ether; the solid adsorbent and the self-microemulsion composition are mixed in the ratio of 1.5 to 1, and silicon dioxide with different types is selected to prepare the self-microemulsion solid preparation by vacuum drying. 100mg of the lenatinib self-microemulsion solid preparation is weighed, 100ml of solution with pH of 1.2 is taken as a release medium at 37+/-0.1 ℃ by adopting a shaking table, the dissolution rate is inspected under the condition that the rotating speed is 100 revolutions per minute, 1ml is sampled for 30min, and the measurement is carried out by HPLC after filtration.
TABLE 15 in vitro Release assay
Examples Solid adsorbent species Dissolution for 30min
62 SH-CD1 type silica 92.96％
63 SH-QX1 type silica 99.62％
64 350FCP type silica 99.85％
65 Aerosil 200 Phara model silica 90.44％
From the results in Table 15, it is clear that 350FCP type silica was used as a solid adsorbent, and the prepared self-emulsifying solid preparation meets the quality control requirements and the release degree meets the regulations.
Example 66
40mg of lenatinib 1.5%, 200mg of corn oil 7.7%, 200mg of oleic acid 7.7%, 240mg of polyoxyethylene hydrogenated castor oil 9.2%, 360mg of diethylene glycol monoethyl ether 13.8%, 0.1% of vitamin E2 mg, 4mg of saccharin sodium 0.2%, 1560mg of silicon dioxide 59.8%
The components are prepared into the lenatinib self-microemulsion solid preparation according to the mode of a test 1.
Example 67
Lenatinib 35mg 1.35%, corn oil 200mg 7.69%, oleic acid 200mg 7.69%, polyoxyethylene hydrogenated castor oil 255mg 9.8%, benzyl alcohol 345mg 13.26%, vitamin E2 mg 0.077%, saccharin sodium 4mg 0.15%, silica 1560mg 59.98%
The components are prepared into the lenatinib self-microemulsion solid preparation according to the mode of a test 1.
Example 68
40mg of lenatinib 1.42%, 100mg of corn oil 3.56%, 100mg of oleic acid 3.56%, 500mg of polyoxyethylene hydrogenated castor oil 17.78%, 500mg of diethylene glycol monoethyl ether 17.78%, 4mg of vitamin E0.14%, 8mg of saccharin sodium 0.28%, 1560mg of silicon dioxide 55.48%
The components are prepared into the lenatinib self-microemulsion solid preparation according to the mode of a test 1.
Example 69
40mg of lenatinib 1.45%, 350mg of corn oil 12.69%, 350mg of oleic acid 12.69%, 200mg of tween 80 7.25%, 150mg of caprylic-capric acid polyethylene glycol glyceride 5.44%, 0.11% of vitamin E3 mg, 4mg of saccharin sodium 0.15%, 60.21% of silicon dioxide 1660mg
The components are prepared into the lenatinib self-microemulsion solid preparation according to the mode of a test 1.
Example 70
40mg of lenatinib 1.5%, 200mg of corn oil 7.7%, 200mg of oleic acid 7.7%, 240mg of polyoxyethylene castor oil 9.2%, 360mg of benzyl alcohol 13.8%, 2mg of vitamin E0.1%, 4mg of saccharin sodium 0.2%, 1560mg of silicon dioxide 59.8%
The components are prepared into the lenatinib self-microemulsion solid preparation according to the mode of a test 1.
Example 71
40mg of lenatinib 1.28%, 9.62% of corn oil, 9.62% of oleic acid, 9.62% of polyoxyethylene castor oil, 200mg of diethylene glycol monoethyl ether, 6.42% of vitamin E5 mg 0.16%, 12mg of saccharin sodium, 0.38% of silicon dioxide 1960mg 62.88%
The components are prepared into the lenatinib self-microemulsion solid preparation according to the mode of a test 1.
Example 72
40mg of lenatinib 1.5%, 200mg of corn oil 7.7%, 200mg of oleic acid 7.7%, 240mg of polyoxyethylene hydrogenated castor oil 9.2%, 360mg of benzyl alcohol 13.8%, 2mg of vitamin E0.1%, 4mg of saccharin sodium 0.2%, 1560mg of silicon dioxide 59.8%
The components are prepared into the lenatinib self-microemulsion solid preparation according to the mode of a test 1.
Example 73
40mg of lenatinib 1.5%, 200mg of corn oil 7.7%, 200mg of oleic acid 7.7%, 240mg of polyoxyethylene hydrogenated castor oil 9.2%, 360mg of caprylic/capric acid polyethylene glycol glyceride 13.8%, 2mg of vitamin E0.1%, 4mg of saccharin sodium 0.2%, 1560mg of silicon dioxide 59.8%
The components are prepared into the lenatinib self-microemulsion solid preparation according to the mode of a test 1.
Example 74
40mg of lenatinib 1.5%, 200mg of corn oil 7.7%, 200mg of oleic acid 7.7%, 240mg of polyoxyethylene castor oil 9.2%, 360mg of caprylic/capric acid polyethylene glycol glyceride 13.8%, 0.1% of vitamin E2 mg, 4mg of saccharin sodium 0.2%, 1560mg of silicon dioxide 59.8%
The components are prepared into the lenatinib self-microemulsion solid preparation according to the mode of a test 1.
Example 75
40mg of lenatinib 1.5%, 200mg of corn oil 7.7%, 200mg of oleic acid 7.7%, 240mg of polyoxyethylene castor oil 9.2%, 360mg of benzyl alcohol 13.8%, 2mg of vitamin E0.1%, 4mg of saccharin sodium 0.2%, 1560mg of silicon dioxide 59.8%
The components are prepared into the lenatinib self-microemulsion solid preparation according to the mode of a test 1.
Example 76
40mg of lenatinib 1.5%, 200mg of corn oil 7.7%, 200mg of oleic acid 7.7%, 240mg of polyoxyethylene castor oil 9.2%, 360mg of diethylene glycol monoethyl ether 13.8%, 0.1% of vitamin E2 mg, 4mg of saccharin sodium 0.2%, 1560mg of silicon dioxide 59.8%
The components are prepared into the lenatinib self-microemulsion solid preparation according to the mode of a test 1.
Example 77
Lenatinib 35mg 3.38%, oleic acid 200mg 19.32%, corn oil 200mg 19.32%, polyoxyethylene hydrogenated castor oil 255mg 24.64%, diethylene glycol monoethyl ether 345mg 33.33%.
The particle size of the obtained lenatinib nanoemulsion is 36.08nm. After the lenatinib is diluted by adding water into the microemulsion, the Zeta potential is (-29.5+/-9.40) mV, and the micro emulsion is in a regular sphere shape under a transmission electron microscope, and is not aggregated, and the micro emulsion is shown in figure 2.
Effect example 1
The pharmacokinetic profile of either the self-microemulsion composition prepared according to the invention (test formulation) or the lenatinib tablet prepared according to the invention (reference formulation R) was examined for single oral administration in beagle dogs under fasting conditions.
The experiment adopts a two-period crossing design, beagle dogs are randomly grouped, and each group comprises 2 beagle dogs; the dosage of the suspension of the oral lenatinib tablet or the self-emulsifying solution of the lenatinib is 8mg/kg; after 4 hours after administration, water can be drunk at will. Pre-dose 0h, post-dose 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h were collected from the anterior saphenous vein by 1-2mL. The plasma was separated by centrifugation. The concentration of lenatinib in the plasma was determined by LC-MS/MS method. The results are shown in Table 16:
Table 16 pioglycan PK experimental plasma pharmacokinetic parameters
From the results in the table, it can be seen that, after the self-microemulsion composition prepared by the embodiment of the invention is administered at an equal dose, cmax and AUC are obviously improved, the AUC of the prepared self-microemulsion composition is about 3-8 times of that of a reference preparation (tablet), the relative bioavailability is improved by 3-8 times, and the inter-individual drug peak time, peak concentration and absorption level variation degree are low when the bioavailability is improved.
Effect example 2
The pharmacokinetic characteristics of the self-microemulsion solid formulation (test formulation) or the lenatinib tablet (reference formulation R) prepared by the present invention were examined for single oral administration to rats under fasting conditions.
The experiment adopts a two-period crossing design, rats are randomly grouped, and each group comprises 2 rats; the dosage of the suspension of the oral lenatinib tablet or the solid self-emulsifying solution of the lenatinib is 25mg/kg; after 4 hours after administration, water can be drunk at will.
Pre-dose 0h, post-dose 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h were collected from the anterior saphenous vein by 1-2mL. The plasma was separated by centrifugation.
The concentration of lenatinib in the plasma was determined by LC-MS/MS method. The results are shown in Table 17:
Table 17 plasma pharmacokinetic parameters for rat PK experiments
From the results in the table, after the self-microemulsion solid preparation prepared by the embodiment of the invention is administrated at equal dosage, cmax and AUC are obviously improved, the AUC of the prepared self-microemulsion solid preparation is about 2.2-4.8 times of the AUC of a reference preparation (tablet), the relative bioavailability is improved by 2.2-4.8 times, and the inter-individual drug peak time, peak concentration and absorption level variation degree is low when the bioavailability is improved.
In addition, the solid preparation of lenatinib provided by the invention can effectively reduce the difference between before and after meal.

Claims (10)

1. The self-microemulsion composition of the lenatinib is characterized by comprising, by weight, 0.1-15% of the lenatinib, 10-60% of an oil phase, 10-70% of an emulsifying agent and 0-60% of a coemulsifier.
2. The self-microemulsion composition of claim 1, wherein said oil phase is selected from one or at least two of the group consisting of glyceryl tricaprylate, glyceryl caprylate mono-di-glyceride, glyceryl monocaprate, glyceryl caprylate, propylene glycol monocaprate, caprylic caprate mono-di-triglyceride, medium chain triglycerides, ethyl oleate, corn oil, oleic acid, star anise oil, capmul MCM, glyceryl monolinoleate, propylene glycol caprylate, glyceryl monooleate, propylene glycol monolaurate, caprylic capric polyethylene glycol glyceride, oleoyl polyoxyethylene glyceride, polyglyceryl oleate;
The emulsifier is one or at least two selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated 40 castor oil, oleoyl polyoxyethylene glyceride, tween80, capryl/capric acid polyethylene glycol glyceride, monocapric acid glyceride, vitamin E succinic acid polyethylene glycol ester, propylene glycol monocaprylate, polyglycerol fatty acid ester, lauroyl polyethylene glycol-32 glyceride, capryl/capric acid polyethylene glycol glyceride, 15-hydroxystearic acid glyceride, oleoyl polyoxyethylene glyceride, polyethylene glycol glyceride, polysorbate and propylene glycol monolaurate;
the auxiliary emulsifier is selected from one or at least two of ethanol, propylene glycol, isopropanol, N-butanol, polyethylene glycol vitamin E succinate, propylene carbonate, tetrahydrofurfuryl alcohol, ethylene glycol furfuryl alcohol, glycerylfurfural, dimethyl isosorbide, dimethylacetamide, N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol monoethyl ether, docosahexaenoic acid, cholesterol, azone, glycerol, ethyl acetate, polyethylene oxide, caprylic capric polyethylene glycol glyceride, propylene carbonate, glycerin monostearate, glycerin distearate and polyglycerol-6-dioleate.
3. The self-microemulsion composition of claim 1, wherein said oil phase is selected from one of the following combinations: the mixed oil phase of oleic acid and corn oil, the mixed oil phase of oleic acid and glyceryl trioleate, the mixed oil phase of oleic acid and medium chain triglyceride, the mixed oil phase of oleic acid and propylene glycol caprylate, the mixed oil phase of oleic acid and Capmul MCM, the mixed oil phase of oleic acid and glyceryl monolinoleate, and the mixed oil phase of glyceryl tricaprylate and propylene glycol monocaprylate.
4. A self-microemulsion composition according to any one of claims 1 to 3, wherein said self-microemulsion composition comprises lenatinib, oleic acid, corn oil, polyoxyethylated hydrogenated castor oil and benzyl alcohol;
or, the self-microemulsion composition comprises lenatinib, oleic acid, corn oil, polyoxyethylene hydrogenated castor oil and diethylene glycol monoethyl ether;
or, the self-microemulsion composition comprises lenatinib, oleic acid, corn oil, polyoxyethylene hydrogenated castor oil and caprylic/capric polyethylene glycol glyceride;
or, the self-microemulsion composition comprises lenatinib, oleic acid, corn oil, polyoxyethylene castor oil and caprylic/capric polyethylene glycol glyceride;
Or, the self-microemulsion composition comprises lenatinib, oleic acid, corn oil, polyoxyethylated castor oil and diethylene glycol monoethyl ether;
or, the self-microemulsion composition comprises lenatinib, oleic acid, corn oil, polyoxyethylated castor oil and benzyl alcohol;
or, the self-microemulsion composition comprises lenatinib, oleic acid, corn oil, vitamin E polyethylene glycol succinate and benzyl alcohol;
or, the self-microemulsion composition comprises lenatinib, oleic acid, corn oil, polyoxyethylene hydrogenated castor oil, oleoyl polyoxyethylene glyceride and benzyl alcohol.
5. A lenatinib self-microemulsifying delivery system comprising the lenatinib self-microemulsion composition of claim 1 and a solid adsorbent; preferably, one or two of antioxidants, flavoring agents and preservatives are also included.
6. The self-microemulsifying delivery system of claim 5, wherein the self-microemulsifying delivery system comprises, by weight, from 0.1% to 5% of lenatinib, from 3% to 30% of an oil phase, from 5% to 30% of an emulsifier, from 3% to 30% of a co-emulsifier, from 50% to 70% of an adsorbent, from 0.1% to 0.5% of an antioxidant, and from 0.1% to 0.5% of a flavoring agent.
7. The self-microemulsifying drug delivery system of claim 6, wherein the oil phase is selected from one or more of oleic acid and corn oil; the emulsifier is one or more selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil and tween 80; the auxiliary emulsifier is selected from one or more of diethylene glycol monoethyl ether, caprylic/capric acid polyethylene glycol glyceride and benzyl alcohol; the adsorbent is selected from one or more of mannitol, xylitol, lactose, corn starch, microcrystalline cellulose, pregelatinized starch, alginic acid, sodium carboxymethylcellulose, calcium hydrogen phosphate, calcium carbonate, silicon dioxide, dextrin and maltose; the antioxidant is selected from vitamin E; the flavoring agent is selected from saccharin sodium.
8. The self-microemulsifying drug delivery system of claim 7, comprising, by weight, 0.1-5% of lenatinib, 3-15% of oleic acid, 3-15% of corn oil, 7-20% of an emulsifying agent, 3-20% of a co-emulsifying agent, 50-70% of silica, 0.01-0.2% of vitamin E, and 0.01-0.4% of saccharin sodium; further, the composition comprises, by weight, 0.1 to 5% of lenatinib, 3 to 15% of oleic acid, 3 to 15% of corn oil, 7 to 20% of polyoxyethylene hydrogenated castor oil, 3 to 20% of diethylene glycol monoethyl ether, 50 to 75% of silicon dioxide, 0.01 to 0.2% of vitamin E and 0.01 to 0.4% of saccharin sodium.
9. The self-microemulsifying drug delivery system of claim 7, comprising, by weight, 1.5% lenatinib, 7.7% oleic acid, 7.7% corn oil, 9.2% polyoxyethylene hydrogenated castor oil, 13.8% diethylene glycol monoethyl ether, 59.8% silica, 0.1% vitamin E, and 0.2% saccharin sodium.
10. A solid formulation of lenatinib, characterized in that it is prepared by further drying the self-microemulsifying drug delivery system of claim 5.
CN202211161718.XA 2022-09-22 2022-09-22 Self-microemulsion composition of lenatinib, drug delivery system and solid preparation Pending CN117771176A (en)

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