CN112168781B - Tacrolimus self-microemulsion composition and preparation method thereof - Google Patents

Tacrolimus self-microemulsion composition and preparation method thereof Download PDF

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CN112168781B
CN112168781B CN202011206551.5A CN202011206551A CN112168781B CN 112168781 B CN112168781 B CN 112168781B CN 202011206551 A CN202011206551 A CN 202011206551A CN 112168781 B CN112168781 B CN 112168781B
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tacrolimus
self
mixture
microemulsion composition
surfactant
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CN112168781A (en
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黄建国
周群
周旋
罗熙
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Hunan Huize Bio Pharmaceutical Co ltd
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Hunan Huize Bio Pharmaceutical Co ltd
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    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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Abstract

The invention belongs to the technical field of medicines, and particularly discloses a tacrolimus self-microemulsion composition and a preparation method thereof. The tacrolimus self-microemulsion composition consists of the following components: tacrolimus, an oil phase, a surfactant, a cosurfactant, an organic acid and an antioxidant; the mass ratio of the tacrolimus, the oil phase, the surfactant, the cosurfactant, the organic acid and the antioxidant in the self-microemulsion composition is 1: 10-50: 50-150: 50-100: 1-5; the particle size of the microemulsion formed by dispersing the self-microemulsion composition into an aqueous medium is less than 200 nm. The invention prepares the tacrolimus self-microemulsion composition to improve the bioavailability of tacrolimus and relieve adverse reactions of tacrolimus and simultaneously reduces the problem of drug absorption difference of different individuals.

Description

Tacrolimus self-microemulsion composition and preparation method thereof
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a tacrolimus self-microemulsion composition and a preparation method thereof.
Background
Tacrolimus exists in the form of white crystals or crystalline powder, is hardly soluble in water, is easily soluble in ethanol, and is very easily soluble in methanol and chloroform.
Tacrolimus, sold under the name plecitalopram, is a potent immunosuppressive macrolide isolated in 1984 from the fermentation medium of streptomyces tsukubaensis (a fungus-like bacterium found in soil samples by Tsukuba) by Fujisawa corporation (Fujisawa). The immunosuppressive action of the tacrolimus is 10-100 times stronger than that of the cyclosporine A (CsA), so that the clinical dosage is greatly reduced, and the adverse reaction is also obviously reduced. Tacrolimus is a powerful immunosuppressant, is mainly used for preventing and treating rejection after organ transplantation of patients, has a similar and wider immunosuppressive effect as cyclosporin A, but has higher efficacy than cyclosporin A and lower toxic and side effects. Its mechanism of action may be related to its inhibition of T lymphocyte activation: tacrolimus forms a complex with T cytoplasmic FK-506 binding protein FKBP-12, calcium ions, calmodulin, calcineurin, thereby inhibiting the activity of calcineurin. This process inhibits the gene transcription of cytokines such as interleukin-1 and interferon-gamma by inhibiting dephosphorylation and nuclear translocation of nuclear factor of T cell, and finally inhibits the production of cytokines and activation of T lymphocytes, resulting in immunosuppression.
Tacrolimus can be used in various dosage forms including capsules, injections and ointments, and can be used for preventing organ rejection in patients transplanted in liver, kidney or heart. The pharmacokinetic profile of tacrolimus varies greatly among individuals due to differences in gastrointestinal function and food intake, tacrolimus is a substrate for cytochrome P450(CYP3A), resulting in large individual metabolic differences, significant hepatic first pass effects, poor bioavailability, and individual variability in bioavailability. This variability, coupled with its narrow therapeutic index, is necessary to monitor blood levels of tacrolimus for optimal therapeutic efficacy while minimizing the risk of toxicity. Wherein tacrolimus capsules are marketed in japan as early as 1993 under the trade name Prograf, and are immediate-release capsules that need to be taken twice a day; tacrolimus sustained-release capsules are marketed in Europe, China and the United states in 2007, 2011 and 2013 respectively, and the dosage form only needs to be taken once every day, so that the medication of patients is more convenient, and the drug compliance of the patients is improved.
CN1301157A discloses a largeOral formulations of a macrolide compound, wherein the macrolide compound is released in a delayed manner; an extended release formulation comprising a composition in solid solution, wherein the macrolide compound is present in an amorphous state in a solid matrix. This sustained-release preparation of a macrolide compound, wherein the time (T) required for dissolution of the macrolide compound to 63.2% of the maximum amount63.2％) The above data were measured in accordance with dissolution test No.2 (Paddle method, 50rpm) of Japanese pharmacopoeia 13 th edition for 0.7 to 15 hours, using a 0.005% hydroxypropyl cellulose aqueous solution adjusted to pH 4.5. This patent document also specifically discloses an extended release formulation comprising a solid dispersion composition characterized by: (1) tacrolimus or a hydrate thereof exists in a mixture of hypromellose and ethylcellulose, wherein the weight ratio of hypromellose and ethylcellulose to tacrolimus is 0.2: 1-0.4: 1 and 0.1: 1-5: 1, respectively, (2) lactose is contained as an excipient, and (3) the particle size of the solid dispersion composition is equal to or less than 250 μm. .
CN105687161A discloses a tacrolimus sustained-release pellet and a preparation method thereof, comprising a drug-containing pellet and a coating layer, wherein the coating layer coats the drug-containing pellet, and the drug-containing pellet comprises: 5mg of tacrolimus, 70mg of blank pill core, 120-220mg of filling agent, 25-125mg of lubricant and 5-50mg of adhesive, wherein the coating layer comprises: 35-175mg of Eudragit NE30D and 5-52mg of talcum powder, and the preparation method comprises the following steps: preparing materials; mixing; preparing an adhesive; making into pills; preparing a coating agent; coating; filling; aluminum plastic and finished products.
CN1301157A discloses a sustained release preparation of tacrolimus, which is a sustained release pharmaceutical composition in the form of capsule and tablet. The sustained-release pharmaceutical composition comprises tacrolimus, ethyl cellulose, hydrophilic high molecular materials such as hydroxypropyl methylcellulose, povidone and the like, water-soluble diluents such as lactose, mannitol and the like, and a lubricant. Also relates to a preparation method and a quality determination method of the sustained-release pharmaceutical composition. The tacrolimus slow-release pharmaceutical composition has excellent preparation quality and performance and efficient release property.
The sustained release mechanism of the tacrolimus sustained release preparation described in the above patent application and, for example, the tacrolimus sustained release capsule commercially available under the trade name of ASTAGRAF XL is to form a solid dispersion of a drug in a water-insoluble high molecular substance, ethyl cellulose, thereby delaying the release of the drug by the water-insoluble high molecular substance.
The self-microemulsion composition forms microemulsion in gastrointestinal tract, the medicine exists in the fine oil drops and is rapidly distributed in the whole gastrointestinal tract, the medicine is distributed between oil and water, the dissolution of the water-insoluble medicine is greatly improved by depending on the huge surface area of the fine oil drops, and the bioavailability is improved. The self-microemulsion composition has been proved to be capable of improving the stability of the drug in blood circulation, prolonging the duration of action of the drug, and in addition, delivering the drug to specific cells and tissues due to its uniform particle size and particle size distribution. The self-microemulsion composition has small particle size, can prevent the microemulsion from aggregating into a cluster, can penetrate into a pathological change part, changes the distribution of the medicament, improves the curative effect of the medicament and reduces side effects.
Therefore, it is desirable to provide a simple, reliable tacrolimus formulation that reduces drug absorption differences among individuals.
Disclosure of Invention
The invention aims to provide a tacrolimus self-microemulsion composition and a preparation method thereof, which are used for improving the bioavailability of tacrolimus, relieving adverse reactions of tacrolimus and simultaneously reducing the problem of drug absorption difference of different individuals.
In order to solve the technical problems, the invention adopts the following technical scheme:
in one aspect, the invention provides a tacrolimus self-microemulsion composition, which consists of the following components: tacrolimus, an oil phase, a surfactant, a cosurfactant, an organic acid and an antioxidant.
Further, the mass ratio of the tacrolimus, the oil phase, the surfactant, the cosurfactant, the organic acid and the antioxidant in the self-microemulsion composition is 1: 2-80: 10-300: 10-150: 0.1-20: 0.1-10. Further, the mass percent of the tacrolimus in the self-microemulsion composition is 0.1-1%, and further the mass percent of the tacrolimus is 0.1%, 0.2%, 0.4%, 0.6%, 0.8% and 1%. Further, the mass percentage of the oil phase in the self-microemulsion composition is 5-30%, and further, the mass percentage of the oil phase is 5%, 10%, 15%, 20%, 21.27%, 25% and 30%. Further, the mass percentage of the surfactant in the self-microemulsion composition is 10% to 90%, and further, the mass percentage of the surfactant is 10%, 20%, 25%, 30%, 40%, 44.11%, 45%, 50%, 55%, 60%, 65%, 70%, 80%, or 90%. Further, the mass percentage of the cosurfactant in the self-microemulsion composition is 5-50%, and further, the mass percentage of the cosurfactant is 5%, 10%, 15%, 20%, 25%, 30%, 32.64%, 32.65%, 35%, 40%, 45% or 50%. Further, the mass percentage of the organic acid in the self-microemulsion composition is 0.1-10%, and further, the mass percentage of the organic acid is 0.1%, 0.2%, 0.5%, 0.9%, 1%, 2%, 5%, 6%, 8%, or 10%. Further, the mass percent of the antioxidant in the self-microemulsion composition is 0.1-10%, and further, the mass percent of the antioxidant is 0.1%, 0.2%, 0.4%, 0.5%, 0.9%, 1%, 2%, 5%, 6%, 8% or 10%. Further, the mass ratio of the tacrolimus, the oil phase, the surfactant, the cosurfactant, the organic acid and the antioxidant in the self-microemulsion composition is 1: 10-50: 50-150: 50-100: 1-5.
Further, the antioxidant is selected from one or two of tert-butyl p-hydroxyanisole BHA, butylated hydroxytoluene BHT and vitamin E (dl-alpha-tocopherol).
Further, the organic acid is selected from one of citric acid, tartaric acid, oxalic acid and malic acid.
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 acid glyceride with the chain length between 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 monoglyceride or diester (Capmul MCM), coconut oil C8/C10 propylene glycol diester (Captex 200), coconut oil C8/C10 triglyceride (Captex 355), coconut oil aminopropyl betaine, purified acetylated monoglyceride (Miglyol 812), purified sunflower oil monoglyceride, polyglycolized laurate, glyceryl monooleate, oleoyl polyoxyethylene glyceride, monolinolein, triglyceride, polyglycolized oleate, polyglycolized linoleate, polyglycolized caprylic capric glyceride, polyoxyethylene oleate, polyoxyethylene linoleate, palm oil, cottonseed oil, coix seed oil, castor oil, hydrogenated castor oil, coconut oil C8/C10 monoglyceride (Capmul MCM), coconut oil C8/C10 propylene glycol diester (Capacity), coconut oil C8/C10 triglyceride, purified medium chain monoglyceride (Miglyol 812), purified sunflower oil monoglyceride, polyethylene glycol laurate, glyceryl monoolein the form, glyceryl monolinoleate, polyethylene glycol oleate, polyethylene glycol linoleate, polyethylene glycol caprylic acid, polyethylene glycol linoleate, polyethylene glycol caprylic acid, or polyethylene glycol caprylic acid, or polyethylene glycol capryl, Camellia glyceride, almond oil oleic acid PEG-6 glyceride, corn oil linoleic acid PEG-6 glyceride, and olein: propylene glycol (90:10 vol/vol), egg yolk lecithin, soybean lecithin, dioleoyl lecithin, dilauroyl lecithin, dimyristoyl lecithin, dipalmitoyl lecithin, distearoyl lecithin, cephalin, creatinine, inositol phospholipid, lysophospholipid, phosphatidic acid, phosphatidylglycerol, stearoyl/palmitoyl/oleoyl phosphatidylcholine, stearoyl/palmitoyl/oleoyl phosphatidylethanolamine, phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol and phosphatidylinositol, distearoyl phosphatidylethanolamine, oleoyl phosphatidylcholine, hexanoic acid, octanoic acid, oleic acid, vitamin E, stearic acid, isopropyl laurate, isopropyl palmitate, isopropyl myristate, propylene glycol monolaurate, propylene glycol monocaprylate, sorbitol oleate, sodium stearate, sodium myristate, sodium monolaurate, sodium oleate, sodium stearate, sodium oleate, sodium stearate, sodium oleate, sodium stearate, Ethyl orthosilicate, ethyl myristate, ethyl oleate (abbreviated as EO in some embodiments), ethyl linoleate, or at least two of them.
Further, the oil phase is selected from one or at least two of sunflower oil (such as refined sunflower oil), soybean oil, oleic acid, castor oil, glyceryl monolinoleate, glyceryl oleoyl polyoxyethylene, glyceryl monooleate, Medium Chain Triglyceride (MCT), caprylic acid, ethyl oleate, isopropyl myristate, propylene glycol monolaurate, and ethyl oleate. Wherein the oil phase is selected from glycerol monolinoleate, glycerol monooleate, oleoyl polyoxyethylene glyceride, a mixed oil phase of glycerol monooleate and oleoyl polyoxyethylene glyceride (the mass ratio of the two is 1-2: 1), a mixed oil phase of ethyl oleate, isopropyl myristate, caprylic acid, oleic acid and medium chain triglyceride (the mass ratio of the two is 1-9: 1-9, further 8:2 or 6:4), a mixed oil phase of glycerol monooleate and caprylic acid (the mass ratio of the two is 1-9: 1-9, further 4:1), oleic acid and glycerol monolinoleate (the mass ratio of the two is 1-9: 1-9, further 1:4), ethyl oleate and glycerol monolinoleate (the mass ratio of the two is 1-9: 1-9, further 1:3), isopropyl myristate and glycerol monolinoleate (the mass ratio of the two is 1-9: 1-9, further one or at least two of 1: 1).
Further, the surfactant is selected from the group consisting of nonionic, anionic, cationic and zwitterionic surfactants.
Further, the surfactant is selected from the group consisting of egg yolk lecithin, soybean lecithin, dioleoyl lecithin, dilauroyl lecithin, dimyristoyl lecithin, dipalmitoyl lecithin, distearoyl lecithin, cephalin, creatinine, inositol phospholipid, lysophospholipid, phosphatidic acid, phosphatidylglycerol, stearoyl/palmitoyl/oleoyl phosphatidylcholine, stearoyl/palmitoyl/oleoyl phosphatidylethanolamine, phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol and phosphatidylinositol, distearoyl phosphatidylethanolamine, oleoyl phosphatidylcholine, dimyristoyl phosphatidylethanolamine, dipalmitoyl phosphatidylethanolamine, distearoyl phosphatidylethanolamine, dimyristoyl phosphatidylserine, acetylated monoglyceride, sorbitan fatty acid ester, and mixtures thereof, Polyethylene glycol glyceryl amygdala oleate, coconut oil C8/C10 polyethylene glycol glycerides, polyoxyethylene lauryl stearate, polyethylene glycol 100 vitamin E succinate, polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene castor oil (Cremophor EL35), polyoxyethylene hydrogenated castor oil (Cremophor RH 40), polyoxyethylene polyoxypropylene copolymer (e.g., poloxamers 188 and 407), polyoxyethylene glycerides, polyoxyethylene sorbitan trioleate, polyoxyethylene glycerol trioleate, polyoxyethylene sorbitan fatty acid esters, sodium octyl succinate, calcium octyl succinate, potassium octyl succinate, sodium lauryl sulfate, dipalmitoyl phosphatidic acid, ethoxylated castor oil, mannitol oleate polyoxyethylene ether, polyethylene glycol glycerides, oleoyl polyoxyethylene glycerides, polyethylene glycol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, and the like, Polyethylene glycol fatty acid ester, polyethylene glycol-15 hydroxystearate (Solutol), polyethylene glycol-8-glyceryl caprylate/caprate, lauric acid polyethylene glycol-32 glyceride, lauroyl polyethylene glycol-32 glyceride, caprylic/capric acid polyethylene glycol glyceride, sorbitan sesquioleate, polysorbates (such as polysorbate 20 and polysorbate 80), water-soluble natural vitamin E, span 80, Tween 80, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), caprylic acid, sodium caprylate, bile acid and its salt, ursodeoxycholic acid, sodium cholate, sodium taurocholate, sodium glycocholate, N-hexadecyl-N, N-dimethyl-3-ammonia (amonio) -1-propane sulfonate, palmitoyl lysophosphatidyl-L-serine, Lysophospholipids (e.g. 1-acyl-SN-glycerol-3-phosphate of ethanolamine, choline, serine or threonine), N-alkyl-N, N-dimethylamino-1-propanesulfonate, 3-cholamide-1-propyldimethylamino-1-propanesulfonate, dodecyl-phosphorylcholine, myristoyl-lysophosphatidylcholine, egg lysolecithin, propylene glycol monolaurate, hexadecyl-trimethylammonium bromide, hexadecyl-pyridinium chloride, polyethylene oxide/polypropylene oxide block copolymers (Pluronics/Tetronics, Triton X-100, dodecyl beta-D-glucopyranoside), sodium taurodihydrofusinate, oleic acid, acylcarnitines, lysine, arginine, or the like, One or at least two of histidine and lysine.
Further, the surfactant is one or at least two selected from polyoxyethylene castor oil (Cremophor EL35, EL35), polyoxyethylene hydrogenated castor oil (Cremophor RH 40), lauroyl macrogol-32 glyceride, caprylic/capric macrogol glyceride (Labrasol), oleoyl polyoxyethylene glyceride, macrogol glyceride, polysorbate (such as polysorbate 20, polysorbate 80), and propylene glycol monolaurate. Further, the surfactant is selected from one or at least two of polyoxyethylene hydrogenated castor oil (Cremophor RH 40), oleoyl polyoxyethylene glyceride, polyoxyethylene castor oil, lauric acid polyethylene glycol-32 glyceride, caprylic/capric polyethylene glycol glyceride, a mixed surfactant of polyoxyethylene hydrogenated castor oil (Cremophor RH 40) and oleoyl polyoxyethylene glyceride (the mass ratio of the two is 1-9: 1, and further 4-5: 1), a mixed surfactant of caprylic/capric polyethylene glycol glyceride and polyoxyethylene hydrogenated castor oil (the mass ratio of the two is 1-9: 1, and further 2-3: 1), and a mixed surfactant of polysorbate 80 and RH40 (3: 1).
Further, the cosurfactant is selected from one or more of medium/short chain alcohol and ether. Further, the cosurfactant is selected from ethanol, propylene glycol, isopropanol, N-butanol, polyethylene glycol (molecular weight range of 100Da-10kDa, 300Da-2000Da, or 400Da-1000Da) such as polyethylene glycol 200-600 (such as PEG400, polyethylene glycol 600), polyethylene glycol vitamin E succinate, propylene carbonate, tetrahydrofurfuryl alcohol, ethylene glycol furfuryl alcohol, glycerol furfurol, dimethyl isosorbide, dimethyl acetamide, N-methyl pyrrolidone, one or at least two of diethylene glycol monoethyl ether (Transcutol or Transcutol P or Transcutol HP or TP), ethylene glycol monoethyl ether, docosahexaenoic acid, cholesterol, azone, glycerol, ethyl acetate, polyoxyethylene, polyethylene glycol caprylate/capric acid glyceride, propylene carbonate, glyceryl monostearate, glyceryl distearate and polyglycerol-6-dioleate.
Further, the co-surfactant is selected from: one or at least two of ethanol, propylene glycol, isopropanol, diethylene glycol monoethyl ether, polyethylene glycol 400, glycerol and polyethylene glycol 600. Further, the cosurfactant is one or at least two selected from propylene glycol, glycerol, polyethanol 400 and diethylene glycol monoethyl ether.
Further, the particle size of the microemulsion formed by dispersing the self-microemulsion composition into an aqueous medium is less than 500 nm. Further, the particle size of the microemulsion formed by dispersing the self-microemulsion composition into an aqueous medium is less than 300 nm. Further, the particle size of the microemulsion formed by dispersing the self-microemulsion composition into an aqueous medium is less than 200 nm. Further, the particle size of the microemulsion formed by dispersing the self-microemulsion composition into an aqueous medium is less than 100 nm. Further, the particle size of the microemulsion formed by dispersing the self-microemulsion composition into an aqueous medium is less than 50 nm. Further, the particle size of the microemulsion formed by dispersing the self-microemulsion composition into an aqueous medium is less than 30 nm. Further, the particle size of the microemulsion formed from the microemulsion composition dispersed into an aqueous medium is less than 500nm, 450nm, 400nm, 350nm, 300nm, 250nm, 200nm, 150nm, 100nm, 90nm, 80nm, 60nm, 55nm, 53nm, 52nm, 51.5nm, 51nm, 50.5nm, 50nm, 49.5nm, 49nm, 48nm, 47nm, 46nm, 45nm, 43nm, 42nm, 40nm, 35nm, 30nm, 25nm, 20nm, 15nm, 10nm, or even less. Furthermore, the particle size of the microemulsion formed by dispersing the self-microemulsion composition into an aqueous medium is 5-500 nm or 5-400 nm or 5-300 nm or 5-200 nm or 5-100 nm or 5-60 nm or 5-30 nm.
The preparation of the invention is prepared by mixing and dissolving the component materials, and the mixing and dissolving mode can be various, such as: micro-jetting, stirring, shaking and the like, and aims to improve the stability of the self-microemulsion composition and reduce the particle size of the nano-emulsion dispersed in an aqueous medium.
Further, the active ingredient of tacrolimus may include crystalline or amorphous forms, salts, anhydrates or hydrates, solvates, prodrugs, metabolites, etc. of tacrolimus, all of which may be used in the formulations of the present invention.
Further, the tacrolimus self-microemulsion composition consists of the following components: tacrolimus, an oil phase, a surfactant, a cosurfactant, an organic acid and an antioxidant;
the self-microemulsion composition comprises tacrolimus, an oil phase, a surfactant, a cosurfactant, an organic acid and an antioxidant in a mass ratio of 1: 10-50: 50-150: 50-100: 1-5.
Further, the antioxidant is selected from vitamin E.
Further, the organic acid is selected from citric acid.
By adding the organic acid and the antioxidant, the stability of the self-microemulsion composition is obviously enhanced, no precipitate is formed after long-term stability, and the emulsification time is short so as to quickly dissolve out the tacrolimus.
Further, the oil phase is selected from: one or two of oleoyl polyoxyethylene glyceride and glyceryl monooleate. The oil phase is selected from one of mixed oil phases of glyceryl monooleate and oleoyl polyoxyethylene glyceride (the mass ratio of the two is 1-5: 1) and glyceryl monooleate.
Further, the surfactant is selected from one or two of polyoxyethylene hydrogenated castor oil (Cremophor RH 40) and oleoyl polyoxyethylene glyceride.
Further, the surfactant is one or at least two selected from polyoxyethylene hydrogenated castor oil (Cremophor RH 40), polyoxyethylene hydrogenated castor oil (Cremophor RH 40) and a mixed surfactant of oleoyl polyoxyethylene glyceride (the mass ratio of the two is 1-9: 1, and further 4-5: 1).
In the embodiment of the invention, the oleoyl polyoxyethylene glyceride can be used as both the oil phase and the surfactant. By adopting the mixed oil phase and the mixed emulsifier, the nano-emulsion particles emulsified by the self-microemulsion composition prepared by the invention are below 500nm, even less than 100nm, and basically can be stabilized near 30nm, so that the dissolution rate of the self-microemulsion composition is greatly improved, and the bioavailability is improved. By adopting the mixed oil phase and the mixed emulsifier and adding the organic acid and the antioxidant, the shelf life of the tacrolimus is effectively prolonged, the adverse reaction of the tacrolimus is reduced, and the drug absorption difference of different individuals is reduced.
Further, the cosurfactant is selected from propylene glycol, PEG600 or diethylene glycol monoethyl ether. The auxiliary emulsifier adopted in the embodiment of the invention can accelerate the emulsification of the self-microemulsion composition, improve the dissolution rate and is not easy to degrade subsequently prepared capsule coats.
Further, the particle size of the microemulsion formed by dispersing the self-microemulsion composition into an aqueous medium is less than 50 nm. Further, the particle size of the microemulsion formed by dispersing the self-microemulsion composition into an aqueous medium is less than 30 nm. Further, the self-microemulsion composition forms a microemulsion having a particle size of less than 30nm, 25nm, 20nm, 15nm, 10nm, or even less when dispersed in an aqueous medium. Further, the particle size of the microemulsion formed by dispersing the self-microemulsion composition into an aqueous medium is 5-60 nm or 5-30 nm.
In one aspect, the invention provides a dosage form, the obtained self-microemulsion composition is filled into soft or hard capsules, and an absorbent can also be added to prepare solid self-emulsifying tablets, pills, powder, granules and the like.
Further, the self-microemulsion composition is a capsule, and comprises a self-microemulsion composition and a capsule shell, wherein the self-microemulsion composition is described in the invention; the capsule shell is made of hard capsule or soft capsule materials. The capsule shell is a hard capsule and/or soft capsule material well known in the art, such as a gelatin hard capsule or a gelatin soft capsule, and can be commercially obtained or prepared, and is not particularly limited herein.
The invention adopts self-microemulsifying technology to prepare the self-microemulsifying soft capsule, can quickly form microemulsion after being taken, and greatly improves the dissolution rate of the medicament and the permeability of gastrointestinal mucosa, thereby improving the bioavailability of the medicament and reducing adverse reactions.
On the other hand, the invention provides a preparation method of a tacrolimus self-microemulsion composition, which comprises the following specific processes:
the method comprises the following steps: dissolving organic acid in cosurfactant to form a first mixture;
step two: dissolving an antioxidant in an oil phase to form a mixture II;
step three: dissolving tacrolimus in the first mixture to form a third mixture;
step four: adding a surfactant to the third mixture to form a fourth mixture;
step five: and dissolving the second mixture in the fourth mixture to form a uniform and transparent self-microemulsion composition.
According to the invention, the mixture I, the mixture III and the mixture IV formed in the preparation process are uniformly mixed one by one, so that the phenomenon of turbidity is avoided, and partial substances are not dissolved, and uniform dispersion can be rapidly realized; then the mixture II is dispersed in the mixture IV, so that the preparation of the uniform and transparent self-microemulsion composition can be realized; the preparation method of the invention can reduce the emulsification time, improve the dissolution rate and dissolution rate of the medicine and improve the bioavailability of the medicine.
Further, the specific steps of forming the first mixture are as follows: dissolving organic acid in a cosurfactant at 37 ℃, carrying out ultrasonic mixing under the condition of keeping out of the sun, and carrying out mechanical stirring at the speed of 100-400 rpm.
Further, the specific steps of forming the second mixture are as follows: dissolving the antioxidant in the oil phase at 37 ℃, carrying out ultrasonic mixing under the condition of keeping out of the sun, and carrying out mechanical stirring at the speed of 100-400 rpm.
Further, the concrete steps of the formation of the mixture III are as follows: dissolving tacrolimus in the first mixture at 37 ℃, and carrying out ultrasonic mixing under the condition of keeping out of the sun, and carrying out mechanical stirring at the speed of 100-400 rpm.
Further, the specific steps of forming the mixture four are as follows: and adding a surfactant into the mixture III, performing ultrasonic mixing at 37 ℃ in a dark condition, and performing mechanical stirring at the speed of 100-400 rpm.
Further, the specific steps of forming the uniform transparent self-microemulsion composition are as follows: and dissolving the second mixture in the fourth mixture at 37 ℃, ultrasonically mixing under the condition of keeping out of the sun, and mechanically stirring at the speed of 100-400 rpm.
After the self-microemulsion composition prepared by the invention enters the gastrointestinal tract by oral administration, the self-microemulsion composition can be self-microemulsified into O/W nanoemulsion when meeting the gastrointestinal fluid, drug molecules are wrapped in a carrier, the formed O/W nanoemulsion is smaller than 500nm and even smaller than 100nm and is kept at about 30nm, so that the drug can be rapidly distributed in the whole gastrointestinal tract, the drug can be more easily and directly contacted with small intestinal epithelial cells, the absorption of the drug through small intestinal mucosal epithelial cells can be promoted through the actions of pinocytosis or endocytosis and the like, the dissolution process of the drug is not a rate-limiting step of in vivo absorption any more, the solubility and the dissolution rate of tacrolimus in the gastrointestinal fluid are obviously improved, the oral absorption rate and the bioavailability of the drug are increased, the permeability is improved, the gastrointestinal tract reaction is reduced, and the adverse reaction is reduced; the self-microemulsion composition forms a nano-emulsion after emulsification, so that transmembrane absorption of the drug is promoted, and meanwhile, tacrolimus is wrapped by a blank microemulsion carrier, so that slow release of the drug is realized, the drug release speed is stable, overlarge fluctuation of blood concentration can be prevented, the curative effect of the drug is improved, and adverse reactions are reduced.
Tacrolimus is prepared into a self-microemulsion composition, and after oral administration, the tacrolimus is contacted with gastrointestinal tract liquid and immediately self-emulsified into nano-emulsion, and the nano-scale particle size can increase the total surface area so as to enhance the dissolution rate of the medicament, thereby promoting the dispersion, dissolution and stable absorption of the medicament and further improving the bioavailability of an individual. Meanwhile, the medicine can be released stably and slowly, so that serious adverse reaction of a digestive system caused by overhigh blood medicine concentration after taking the medicine can be avoided, the influence caused by unqualified dissolution can also be avoided, the adverse reaction is obviously reduced, and the curative effect is improved. Significantly improves bioavailability, reduces the number of dosage units administered daily, alleviates or eliminates the need to take the drug while eating, provides more freedom to the recipient, and can significantly improve patient acceptance and/or compliance.
Drawings
FIG. 1 comparative graph of the dissolution rates of tacrolimus self-microemulsion composition and reference formulation in water
FIG. 2 graph comparing the dissolution rates of tacrolimus from microemulsion compositions and reference formulations in phosphate buffer (pH6.8)
FIG. 3 is a comparison of the pharmacokinetics of Pulexant (solid Dispersion) according to example 1 of the invention and a reference formulation.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. These examples are intended to illustrate the invention and are not intended to limit the scope of the invention.
Test one: the preparation process of the self-emulsifying preparation is as follows:
the method comprises the following steps: dissolving organic acid in a cosurfactant at 37 ℃, carrying out ultrasonic mixing under the condition of keeping out of the sun, and carrying out mechanical stirring at the speed of 100-400 rpm to form a first mixture;
step two: dissolving an antioxidant in an oil phase at 37 ℃, carrying out ultrasonic mixing under a dark condition, and carrying out mechanical stirring at a speed of 100-400 rpm to form a mixture II;
step three: dissolving tacrolimus in the first mixture at 37 ℃, carrying out ultrasonic mixing under a dark condition, and carrying out mechanical stirring at a speed of 100-400 rpm to form a third mixture;
step four: adding a surfactant into the mixture III, performing ultrasonic mixing at 37 ℃ in a dark condition, and performing mechanical stirring at the speed of 100-400 rpm to form a mixture IV;
step five: and dissolving the mixture II in the mixture IV at 37 ℃, ultrasonically mixing under a dark condition, mechanically stirring at a speed of 100-400 rpm to form a uniform and transparent self-microemulsion composition, uniformly stirring, fully dissolving and filling the self-microemulsion composition into soft capsules.
And (2) test II: determination of microemulsion size
The particle size of the tacrolimus formulations prepared in the examples was tested.
The prepared tacrolimus self-microemulsion preparation is diluted by 100 times by using an aqueous medium with pH6.8 and then is measured by using a nanometer particle size analyzer. At least three tests were performed per sample to ensure the accuracy of the results.
Example 1
The prescription is as follows: tacrolimus: 1 mg;
the total mass of the SMEDDS carrier is 200 mg: 23.4mg of glyceryl monooleate, 20mg of oleyl polyoxyethylene glyceride, 90mg of RH40, 66.6mg of diethylene glycol monoethyl ether;
organic acid: 2mg citric acid
Antioxidant: 1mg vitamin E.
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 tacrolimus preparation is 20.54 nm.
Example 2
The prescription is as follows: tacrolimus: 1 mg;
the total mass of the SMEDDS carrier is 200 mg: 10mg of glycerol monooleate, 50mg of oleoyl polyoxyethylene glyceride, 90mg of RH40, 50mg of diethylene glycol monoethyl ether;
organic acid: 5mg citric acid
Antioxidant: 5mg vitamin E.
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 tacrolimus preparation is 25.82 nm.
Example 3
The prescription is as follows: tacrolimus: 1 mg;
the total mass of the SMEDDS carrier is 200 mg: 10mg of glycerol monooleate, 40mg of oleoyl polyoxyethylene glyceride, 50mg of RH40, 100mg of diethylene glycol monoethyl ether;
organic acid: 1mg citric acid
Antioxidant: 3mg vitamin E.
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 tacrolimus preparation is 20.14 nm.
Example 4
The prescription is as follows: tacrolimus: 1 mg;
the total mass of the SMEDDS carrier is 200 mg: 40mg of glycerol monooleate, 10mg of oleoyl polyoxyethylene glyceride, 90mg of RH40, 60mg of diethylene glycol monoethyl ether;
organic acid: 4mg citric acid
Antioxidant: 3mg vitamin E.
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 tacrolimus preparation is 28.82 nm.
Example 5
The prescription is as follows: tacrolimus: 1 mg;
the total mass of the SMEDDS carrier is 200 mg: 15mg of glycerol monooleate, 10mg of oleoyl polyoxyethylene glyceride, 150mg of RH40, 25mg of diethylene glycol monoethyl ether;
organic acid: 2mg citric acid
Antioxidant: 1mg vitamin E.
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 tacrolimus preparation is 21.02 nm.
Example 6
The prescription is as follows: tacrolimus: 1 mg;
the total mass of the SMEDDS carrier is 200 mg: 11.7mg of glyceryl monooleate, 15mg of oleyl polyoxyethylene glyceride, 104mg of RH40, 69.3mg of diethylene glycol monoethyl ether;
organic acid: 3mg citric acid
Antioxidant: 2mg vitamin E.
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 tacrolimus preparation is 23.29 nm.
Example 7
The prescription is as follows: tacrolimus: 1 mg;
the total mass of the SMEDDS carrier is 200 mg: 23.4mg of glycerol monooleate, 20mg of oleoyl polyoxyethylene glyceride, 90mg of RH40, 66.6mg of propylene glycol;
organic acid: 2mg citric acid
Antioxidant: 1mg vitamin E.
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 tacrolimus preparation is 35.49 nm.
Example 8
The prescription is as follows: tacrolimus: 1 mg;
the total mass of the SMEDDS carrier is 200 mg: 30mg of glycerol monooleate, 20mg of oleoyl polyoxyethylene glyceride, 130mg of RH40, 20mg of propylene glycol;
organic acid: 2mg citric acid
Antioxidant: 1mg vitamin E.
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 tacrolimus preparation is 33.96 nm.
Example 9
The prescription is as follows: tacrolimus: 1 mg;
the total mass of the SMEDDS carrier is 200 mg: 30mg of glycerol monooleate, 20mg of oleoyl polyoxyethylene glyceride, 130mg of RH40, 20mg of PEG 600;
organic acid: 2mg citric acid
Antioxidant: 1mg vitamin E.
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 tacrolimus preparation is 34.12 nm.
Example 10
The prescription is as follows: tacrolimus: 1 mg;
the total mass of the SMEDDS carrier is 200 mg: 40mg glycerol monooleate, 130mg RH40, 30mg PEG 400;
organic acid: 2mg citric acid
Antioxidant: 1mg vitamin E.
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 tacrolimus preparation is 142.23 nm.
Example 11
The prescription is as follows: tacrolimus: 1 mg;
the total mass of the SMEDDS carrier is 200 mg: 30mg of glycerol monooleate, 150mg of RH40, 20mg of diethylene glycol monoethyl ether;
organic acid: 2mg citric acid
Antioxidant: 1mg vitamin E.
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 tacrolimus preparation is 303.92 nm.
Example 12
The prescription is as follows: tacrolimus: 1 mg;
the total mass of the SMEDDS carrier is 200 mg: 30mg glycerol monooleate, 150mg RH40, 20mg PEG 600;
organic acid: 2mg citric acid
Antioxidant: 1mg vitamin E.
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 tacrolimus preparation is 323.53 nm.
Test example 1 measurement of dispersibility and solubility
The tacrolimus self-microemulsion composition provided in the example and the commercially available reference preparation Proteable solid dispersion capsule are dispersed in 250mL of aqueous medium to determine the dispersibility and solubility of the drug, and whether the drug is separated out or not is observed.
The aqueous medium comprises water and a phosphate buffer (pH 6.8).
The research method comprises the following steps: usp method II (slurry method).
Dissolution apparatus: TDT-08L, aqueous medium: 250mL, 50rpm, 37 ℃.
The specific method comprises the following steps: 1g of tacrolimus self-microemulsion composition prepared in the embodiment of the invention and a commercially available reference preparation Proteable solid dispersion capsule are respectively placed in a dissolution cup for dispersion, 2mL of samples are taken at 10min, 20 min, 30min and 60min, and the samples are filtered and diluted by a 0.45-micron polypropylene filter for HPLC analysis. The results are given in the following table:
TABLE 1 dissolution (%)% of Tacrolimus self-microemulsion composition and reference formulation in water
Figure BDA0002755566540000121
Figure BDA0002755566540000131
TABLE 2 dissolution (%)% of tacrolimus from microemulsion composition and reference formulation in phosphate buffer (pH6.8)
Sampling point/min Reference formulation Example 1 Example 3 Example 9
1 0 55.7 60.4 64.1
10 22.8 90.7 93.9 97.1
20 56.7 100 100 100
30 79.5 100 100 100
60 96.7 100 100 100
As can be seen from tables 1 and 2, FIGS. 1 and 2, the inventive examples were dispersed in water (pH7.0) or phosphate buffer (pH6.8), respectively, and were substantially completely dissolved within 10min, whereas the marketed tacrolimus reference preparation was substantially completely dissolved within 60 min; the tacrolimus self-microemulsion composition has good drug dispersibility and solubility, can be completely emulsified within 0.5-2 min to form transparent slightly blue O/W type microemulsion, and has no drug precipitation at 37 ℃ for 24h, thereby being beneficial to improving the oral bioavailability of tacrolimus and reducing individual difference.
Test example 2 stability test
The present experimental example provides a stability test of the tacrolimus soft capsules provided in the examples.
After the tacrolimus soft capsules are filled into polyethylene plastic bottles, the plastic bottles are respectively placed under the conditions of refrigeration of 2-8 ℃, normal temperature of 25 +/-2 ℃, light protection (25 +/-2 ℃), high temperature (60 ℃) and illumination (4500lX, illumination at 25 ℃), lofting of 5 days, 10 days, 30 days and 2 months, the pharmaceutical composition is diluted by 100 times by using an aqueous medium with pH6.8, and a supernatant is taken to test the content of tacrolimus, and the results are shown in table 3.
Table 3:
Figure BDA0002755566540000132
Figure BDA0002755566540000141
therefore, the tacrolimus soft capsule prepared by the invention has good stability.
Test example 3
This experimental example provides pharmacokinetic testing of the inventive example 1 and the reference formulation pleclonidine (solid dispersion).
Test methods and objects:
healthy rats 16, randomly divided into 2 groups of 8, were tested for 2 cycles with 7 days of interperiod washout, and had no statistical differences in age, sex, body weight, body surface area, etc. (P > 0.05).
The test is designed as a fasting test.
Open web test: the test was fasted for 10 hours, and administered on an empty stomach (administration was completed within 30 minutes), and administered at a rate of 10 mg/kg.
The reference preparation is pleione, and each single particle contains 1mg of tacrolimus;
the test capsules are the tacrolimus soft capsules provided by the embodiment 1 of the invention, and the single particles contain 1mg of tacrolimus.
Sampling design: collecting 2mL blood samples 30min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h and 24h after administration, centrifuging to separate plasma, and measuring the specific blood concentration of tacrolimus in the plasma by HPLC/MS/MS.
The results show that the peak time mean values of the tacrolimus soft capsule prepared in the example 1 and the reference preparation plectanol are respectively 1.5 hours and 2 hours, the peak concentration mean values are respectively 86ng/ml and 22ng/ml, compared with the reference preparation, the bioavailability of the tacrolimus soft capsule prepared in the example 1 is about 4 times that of the reference preparation, and the bioavailability is obviously improved.
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (7)

1. The tacrolimus self-microemulsion composition is characterized by consisting of the following components: tacrolimus, an oil phase, a surfactant, a cosurfactant, an organic acid and an antioxidant;
the self-microemulsion composition comprises tacrolimus, an oil phase, a surfactant, a cosurfactant, an organic acid and an antioxidant in a mass ratio of 1: 10-50: 50-150: 50-100: 1-5;
the particle size of the microemulsion formed by dispersing the self-microemulsion composition into an aqueous medium is less than 200 nm;
the antioxidant is selected from vitamin E;
the organic acid is selected from citric acid;
the cosurfactant is selected from propylene glycol, PEG600 or diethylene glycol monoethyl ether;
the oil phase is selected from: one or two of oleoyl polyoxyethylene glyceride and glyceryl monooleate;
the surfactant is one or two selected from polyoxyethylene hydrogenated castor oil and oleoyl polyoxyethylene glyceride.
2. The tacrolimus self-microemulsion composition according to claim 1, wherein the oil phase is selected from one of a mixed oil phase of glycerol monooleate and oleoyl polyoxyethylene glyceride and glycerol monooleate, and the mass ratio of the glycerol monooleate to the oleoyl polyoxyethylene glyceride is 1-5: 1.
3. The self-microemulsion composition of tacrolimus according to claim 1 wherein the surfactant is selected from one of polyoxyethylene hydrogenated castor oil, a mixed surfactant of polyoxyethylene hydrogenated castor oil and oleoyl polyoxyethylene glyceride; in the mixed surfactant of the polyoxyethylene hydrogenated castor oil and the oleoyl polyoxyethylene glyceride, the mass ratio of the polyoxyethylene hydrogenated castor oil to the oleoyl polyoxyethylene glyceride is 1-9: 1.
4. The self-microemulsion composition of tacrolimus according to claim 3 wherein the surfactant is selected from one of polyoxyethylene hydrogenated castor oil, a mixed surfactant of polyoxyethylene hydrogenated castor oil and oleoyl polyoxyethylene glyceride; in the mixed surfactant of the polyoxyethylene hydrogenated castor oil and the oleoyl polyoxyethylene glyceride, the mass ratio of the polyoxyethylene hydrogenated castor oil to the oleoyl polyoxyethylene glyceride is 4-5: 1.
5. A dosage form, wherein the self-microemulsion composition obtained in any one of claims 1 to 4 is filled into a soft or hard capsule, or an absorbent is added to the self-microemulsion composition to prepare a solid self-emulsifying tablet, pill, powder, or granule.
6. A preparation method of the tacrolimus self-microemulsion composition obtained in any one of claims 1 to 4 is characterized by comprising the following specific steps:
the method comprises the following steps: dissolving organic acid in cosurfactant to form a first mixture;
step two: dissolving an antioxidant in an oil phase to form a mixture II;
step three: dissolving tacrolimus in the first mixture to form a third mixture;
step four: adding a surfactant to the third mixture to form a fourth mixture;
step five: and dissolving the second mixture in the fourth mixture to form a uniform and transparent self-microemulsion composition.
7. The method of claim 6, wherein the step of forming the first mixture comprises: dissolving organic acid in a cosurfactant at 37 ℃, carrying out ultrasonic mixing under the condition of keeping out of the sun, and carrying out mechanical stirring at the speed of 100-400 rpm;
the specific steps for forming the second mixture are as follows: dissolving an antioxidant in an oil phase at 37 ℃, carrying out ultrasonic mixing under a dark condition, and carrying out mechanical stirring at a speed of 100-400 rpm;
the concrete steps of the formation of the mixture III are as follows: dissolving tacrolimus in the first mixture at 37 ℃, carrying out ultrasonic mixing under a dark condition, and carrying out mechanical stirring at a speed of 100-400 rpm;
the concrete steps of the formation of the mixture IV are as follows: adding a surfactant into the mixture III, performing ultrasonic mixing at 37 ℃ in a dark condition, and performing mechanical stirring at the speed of 100-400 rpm;
the specific steps of forming the homogeneous transparent self-microemulsion composition are as follows: and dissolving the second mixture in the fourth mixture at 37 ℃, ultrasonically mixing under the condition of keeping out of the sun, and mechanically stirring at the speed of 100-400 rpm.
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