CN101991552A - Tacrolimus sustained-release preparation and preparation method - Google Patents
Tacrolimus sustained-release preparation and preparation method Download PDFInfo
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- CN101991552A CN101991552A CN2010105727372A CN201010572737A CN101991552A CN 101991552 A CN101991552 A CN 101991552A CN 2010105727372 A CN2010105727372 A CN 2010105727372A CN 201010572737 A CN201010572737 A CN 201010572737A CN 101991552 A CN101991552 A CN 101991552A
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Abstract
The invention provides a tacrolimus sustained-release preparation and a preparation method thereof. The solubility of the sustained-release preparation can be remarkably improved by adopting solid disperse technology or cyclodextrin inclusion technology or a solubilizing method of adding one or more surfactants and the like into a micronized medicament, so that the bioavailability of the medicament can be improved; and a matrix type sustained-release preparation can be prepared by adding one or more matrix materials and other auxiliary materials, or a membrane-controlled or osmotic pump sustained-release preparation can be prepared by coating the sustained-release material, so that the tacrolimus sustained-release preparation has better solubility and dissolution degree, high bioavailability, sustained-release effect, and easily obtained raw materials, can maintain stable blood concentration and can reduce the incidence of untoward effect; and the preparation process is simple and practicable, has high yield and low cost, can realize industrial production, and have remarkable economical benefit.
Description
The applying date of original application: on JIUYUE 25th, 2009
Application number: 200910307752.1
Invention and created name: tacrolimus sustained-release preparation and preparation method thereof
Technical field
The invention belongs to drug world, more specifically relate to a kind of tacrolimus sustained-release preparation and preparation method thereof.
Background technology
Tacrolimus (Tacrolimus, FK506) be a kind of novel potent immunosuppressant, its immunosuppressive action is 10-100 a times of ciclosporin A, be mainly used in the immunological rejection of control organ transplantation postoperative clinically, especially as a line medication of liver, renal transplantation, in 14 country's listings such as Japan, the U.S., evident in efficacy.Although the tacrolimus untoward reaction is few than ciclosporin, but the tacrolimus therapeutic index is very narrow, individual variation is bigger, still have some serious adverse effects clinically, wherein most importantly nephrotoxicity, neurotoxicity, hypertension, diabetes etc., and incidence rate is higher, has limited its clinical practice to a certain extent.Studies show that the untoward reaction of tacrolimus is mainly excessive with taking dose or blood drug level is higher relevant.
Tacrolimus be Japanese scholar in 1984 building the novel immunosuppressant of from soil fungi, extracting in the rolling land district of a kind of Macrolide, by one and half ketone groups, α, β diketone base and 23 rings are formed, its molecular formula is C
44H
69NO
12H
2O, molecular weight are 822.5.Be white in color under the room temperature crystallization or crystalline powder, water insoluble, dissolubility 1-2 μ gml in the water
-1, be dissolved in methanol, ethanol, acetone, chloroform, ethyl acetate, slightly be dissolved in hexane, petroleum ether.Be the lipophilic hydrophobicity, its fusing point is 127-129 ℃.
Its chemical constitution is as follows:
The structural formula of tacrolimus
Its mechanism of action is to suppress lymphocyte activation by the activity that suppresses the relevant cell factor transcription factor.Tacrolimus is combined into FK506-FKBP12 with receptor protein FKBP12 earlier after entering cell, and this complex combines with the calcineurin high-affinity and suppresses its activity, finally suppresses transcribing of IL-2, blocking-up Ca
2+The activated channel of dependent cell, cell thereby be suppressed, thus bring into play powerful immunosuppressive action.
At present, this drug main two aspects that will have problems:
1. typical insoluble drug, oral administration biaavailability is low
Tacrolimus belongs to the strong-hydrophobicity chemical compound because its oil-soluble and water solublity are all very poor.When tacrolimus adopts traditional adjuvant and traditional handicraft to prepare ordinary preparation, oral after, shortcoming such as the medication amount that enters blood flow may be seldom, and dissolution rate often is difficult to prediction, and bioavailability is very low.At present, the oral formulations that gone on the market is mainly capsule.But it is an ordinary preparation, for improving its solubility property, can not keep stable blood concentration, can not effectively reduce the untoward reaction that causes because of blood drug level is too high.
2. therapeutic index is very narrow, and individual variation is bigger, and untoward reaction is more obvious
Under the normal condition, when blood drug level at 5-20 ngmL
-1The time tacrolimus safe and effective, surpass 20 ngmL
-1Then probably produce the dose dependent untoward reaction.
Therefore, though behind the tacrolimus multi-dose oral half-life reach 43 h, in view of its treatment window narrow problem, it is prepared into sustained-release preparation has certain science.
Summary of the invention
The purpose of this invention is to provide a kind of tacrolimus sustained-release preparation and preparation method thereof, the tacrolimus using dosage that solves the art methods preparation is wayward, dissolution rate often is difficult to prediction, shortcomings such as shortcoming such as bioavailability is very low, wherein the middle physical ability of tacrolimus increases the dissolubility of medicine, this tacrolimus sustained-release preparation has good slow controlled-release effect, thereby keep stable blood concentration, reduce adverse reaction rate, improve clinical drug safety, and raw material is easy to get preparation technology's simple possible, productive rate height, cost is low, can realize large-scale industrialization production, have remarkable economic efficiency.
Tacrolimus sustained-release preparation of the present invention is: described tacrolimus sustained-release preparation contains the tacrolimus solid dispersion that water-soluble material is the high-dissolvability of carrier; According to mass fraction: 1 part of tacrolimus; 1～500 part of water-solubility carrier material; Described water-solubility carrier material is polyvinylpyrrolidone, hydroxypropyl emthylcellulose, polyethylene glycols, poloxamer, Myrj 45, polyoxyethylene aliphatic alcohol ether, polyethylene glycol fatty acid glyceride, the mixture of one or more in saccharide or the organic acid.
Of the present inventionly contain the preparation method of tacrolimus sustained-release preparation of tacrolimus solid dispersion that water-soluble material is the high-dissolvability of carrier, it is characterized in that: adopt solid dispersion technology to prepare the tacrolimus intermediate of high-dissolvability earlier, adding framework material and other adjuvants are made matrix type tacrolimus slow releasing preparation in the tacrolimus intermediate for preparing; Perhaps adopt slow controlled-release material to carry out coating and make film controlling type tacrolimus slow releasing preparation, perhaps adopt penetration material to be prepared into osmotic pump type tacrolimus controlled release preparation.
Tacrolimus sustained-release preparation of the present invention: described tacrolimus sustained-release preparation contains with the cyclodextrin derivative tacrolimus clathrate of the high-dissolvability that is carrier; According to mass fraction: 1 part of tacrolimus; 1～500 part of cyclodextrin derivative; Described cyclodextrin derivative is one or more the mixture in alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, methyl-beta-schardinger dextrin-, HP-, dihydroxypropyl-beta-schardinger dextrin-, hydroxyethyl-, single succinyl-DM-, maleoyl-dimethyl-beta cyclodextrin, carboxymethyl cyclodextrin or the sulfoalkyl cyclodextrin.
The preparation method of tacrolimus sustained-release preparation of tacrolimus clathrate that contains with the cyclodextrin derivative high-dissolvability that is carrier of the present invention, it is characterized in that: adopt cyclodextrin inclusion technique to prepare the tacrolimus intermediate of high-dissolvability earlier, adding framework material and other adjuvants are made matrix type tacrolimus slow releasing preparation in the tacrolimus intermediate for preparing; Perhaps adopt slow-release material to carry out coating and make film controlling type tacrolimus slow releasing preparation, perhaps adopt penetration material to be prepared into osmotic pump type tacrolimus controlled release preparation.
Tacrolimus sustained-release preparation of the present invention: described tacrolimus sustained-release preparation contains the pharmaceutical composition of tacrolimus and surfactant composition; According to mass fraction: 1 part of tacrolimus; 1～500 part in surfactant; Described surfactant is one or more a mixture of sodium lauryl sulphate, dodecyl sodium sulfate, carboxylic acid sodium, alkyl sodium sulfate ester, dioctyl sodium sulphosuccinate or sodium lauryl sulfate, macrogol ester, polyvinylether, poloxamer, Myrj 45 or polyoxyethylene aliphatic alcohol ether apoplexy due to endogenous wind.
The preparation method that contains the tacrolimus sustained-release preparation of the pharmaceutical composition that tacrolimus and surfactant form of the present invention: will add the tacrolimus intermediate that surfactant prepares high-dissolvability behind the tacrolimus micronization earlier, and in the tacrolimus intermediate for preparing, add framework material and other adjuvants are made matrix type tacrolimus slow releasing preparation; Perhaps adopt slow controlled-release material to carry out coating and make film controlling type tacrolimus slow releasing preparation, perhaps adopt penetration material to be prepared into osmotic pump type tacrolimus controlled release preparation.
Remarkable advantage of the present invention is:
(1) the present invention has overcome tacrolimus poorly water-soluble in the past, problems such as the treatment window is narrow, adopt solid dispersion technology or cyclodextrin inclusion technique or will add one or more solubilization methods such as surfactant behind the drug micronization, significantly improve its dissolubility, thereby improve its bioavailability, solved the slow controlled release problem of insoluble drug tacrolimus, adopt the slow release control technology then, on the basis of the high-dissolvability tacrolimus intermediate that makes, add conventional slow controlled-release material, make preparation of the present invention have slow controlled-release effect, thereby keep stable blood concentration, reduce adverse reaction rate, improve clinical drug safety, and raw material is easy to get preparation technology's simple possible, productive rate height, cost is low, can realize large-scale industrialization production, have remarkable economic efficiency.
(2) preferred cyclodextrin inclusion technique of the present invention is as the solubilization method of tacrolimus.Wherein, (HP-β-CD) solubilization to tacrolimus obviously is better than other cyclodextrin derivative to HP-.With HP-β-CD is example, specifically inquires into the solubilization of cyclodextrin derivative to tacrolimus.The result shows, tacrolimus is had significant solubilization to HP-β-CD and along with the increase of HP-β-CD concentration, the dissolubility of medicine increases.In the time of 25 ℃, 5 %HP-β-CD can make the dissolubility of tacrolimus in water increase 2.10 times; 50 %HP-β-CD can make the dissolubility of tacrolimus in water increase 81.03 times.Along with the rising of temperature, the dissolubility of medicine also increases thereupon.When HP-β-CD mass concentration is 50 %, the dissolubility of tacrolimus is respectively 167.74,180.88 and 205.60 μ gml when 25 ℃, 37 ℃ and 50 ℃
-1Tacrolimus-HP-(dissolubility (as table 1) of HP-β-CD).When HP-β-CD mass concentration less than 30 %, during greater than 5 %, the effect that prepared cyclodextrin clathrate redissolves is better, and the dissolubility of tacrolimus can satisfy the requirement of preparation.Feature of the present invention is, adopts HP-to prepare the tacrolimus cyclodextrin clathrate, and its concentration range is 5～30 %.
The dissolubility of table 1 tacrolimus in variable concentrations HP-β-CD aqueous solution
Description of drawings
Fig. 1 is the releasing curve diagram of embodiment 1 tacrolimus hydrogel matrix tablet.
Fig. 2 is the releasing curve diagram of embodiment 2 tacrolimus film controlling type slow releasing tablet.
Fig. 3 is the releasing curve diagram of embodiment 3 tacrolimus osmotic pump tablets.
Fig. 4 is the capsular releasing curve diagrams of embodiment 4 tacrolimus slow release.
Fig. 5 is the capsular releasing curve diagrams of embodiment 5 tacrolimus slow release.
Fig. 6 is embodiment 1 tacrolimus hydrogel matrix tablet and the average blood drug level-time plot of commercially available capsule.
The specific embodiment
Preparation contains with the water-soluble material tacrolimus sustained-release preparation of the tacrolimus solid dispersion that is carrier:
Contain water-soluble material and be the tacrolimus sustained-release preparation manufacture method of tacrolimus solid dispersion of the high-dissolvability of carrier: adopt solid dispersion technology to prepare the tacrolimus intermediate of high-dissolvability earlier, in the tacrolimus intermediate for preparing, add framework material and other adjuvants are made matrix type tacrolimus slow releasing preparation; Perhaps adopt slow-release material to carry out coating and make film controlling type tacrolimus slow releasing preparation, perhaps adopt penetration material to be prepared into osmotic pump type tacrolimus controlled release preparation.
Described matrix type tacrolimus slow releasing preparation:
(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of described preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 1～500 part in water-soluble material carrier; The preparation of employing solid dispersion technology, described solid dispersion technology is solvent method, fusion method or solvent-fusion method: tacrolimus is dissolved in adequate amount of ethanol, water-soluble material carrier after the adding fusion, mix homogeneously, stir, pour out cooling rapidly, boulton process or freeze-drying are prepared into the tacrolimus intermediate of high-dissolvability;
(2) add lubricant at the tacrolimus intermediate for preparing and grind, after sieving, add framework material and other adjuvant mix homogeneously, adopt direct powder compression, dry granulation tabletting, wet granule compression tablet to obtain slow-release tablet; Perhaps, encapsulated after centrifugal granulation, fluidized bed coating prepare slow controlled release micro pill by extruding spheronization, perhaps directly it is prepared into slow releasing preparation; According to mass fraction: 1 part of tacrolimus; 1～500 part of water-solubility carrier material; 0.5～300 part of lubricant, 5～2000 parts of framework materials; 0～2000 part of other adjuvant; Described framework material is a hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, methylcellulose, vinyl acetate copolymer, sodium alginate, xanthan gum, sodium carboxymethyl cellulose, poly(ethylene oxide), methacrylic acid copolymer, maleic anhydride-methyl ethylene ether copolymer, carbomer, polyvinylpyrrolidone, ethyl cellulose, cellulose acetate, methacrylate, polyoxyethylene, polyvinyl alcohol, Rikemal B 200, glyceryl monostearate, octadecanol, hexadecanol, stearic acid, the mixture of one or more in Brazil wax or the Cera Flava; Described other adjuvant is diluent or binding agent.
Described film controlling type tacrolimus slow releasing preparation:
(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of described preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 1～500 part of water-solubility carrier material; The preparation of employing solid dispersion technology, described solid dispersion technology is solvent method, fusion method or solvent-fusion method: tacrolimus is dissolved in adequate amount of ethanol, water-soluble material carrier after the adding fusion, mix homogeneously, stir, pour out cooling rapidly, spray drying method or freeze-drying are prepared into the tacrolimus intermediate of high-dissolvability;
(2) add lubricant in the tacrolimus intermediate for preparing and grind, after sieving,, adopt direct powder compression, dry granulation tabletting or wet granule compression tablet to prepare the pastille label with the adjuvant mix homogeneously; Perhaps prepare the medicine carrying micropill by extruding spheronization, centrifugal granulation or fluidized bed coating; Perhaps the tacrolimus intermediate for preparing directly is dissolved in the mixed solution of water or alcohol, prepares the medicine carrying micropill by fluidized bed coating; According to mass fraction: 1 part of tacrolimus; 1～500 part of water-solubility carrier material; 0.5～300 part of lubricant, 0～5000 part of adjuvant; Described adjuvant is one or more the mixture in binding agent, diluent, antiplastering aid, defoamer, antistatic additive, coloring agent or the lucifuge agent;
(3) adopt the coating filmogen to carry out coating, film controlling type tacrolimus slow releasing preparation, coating 1 %～50 % that increase weight; Described coating filmogen is one or more a mixture of cellulose acetate, cellulose acetate-phthalate, ethyl cellulose and aqueous dispersion thereof, ethylene-vinyl acetate copolymer, crylic acid resin and aqueous dispersion thereof, silicone elastomer, polyvinylpyrrolidone, crosslinked alginate or Polyethylene Glycol apoplexy due to endogenous wind; Described coating filmogen accounts for 0.1 %～50 % of coating solution gross weight; Described coating solvent is one or more the mixture in acetone, ethanol, isopropyl alcohol, dichloromethane or the chloroform.
Described osmotic pump type tacrolimus sustained-release preparation:
(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of described preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 1～500 part of water-solubility carrier material; The preparation of employing solid dispersion technology, described solid dispersion technology is solvent method, fusion method or solvent-fusion method: tacrolimus is dissolved in adequate amount of ethanol, water-soluble material carrier after the adding fusion, mix homogeneously, stir, pour out cooling rapidly, boulton process or freeze-drying are prepared into the tacrolimus intermediate of high-dissolvability;
(2) add lubricant in the tacrolimus intermediate for preparing and grind, after sieving,, adopt direct powder compression, dry granulation tabletting, wet granule compression tablet to prepare the pastille label with osmo active substance, short osmopolymer and other adjuvant mix homogeneously; According to mass fraction: 1 part of tacrolimus; 1～500 part in water-soluble material carrier; 0.5～300 part of lubricant, 1～2000 part of osmo active substance, 1～2000 part of short osmopolymer, 0～2000 part of other adjuvant; Described osmotic pressure active substance is one or more the mixture in low molecule saccharide, sodium chloride, potassium chloride, potassium sulfate, sodium sulfate, magnesium sulfate, magnesium chloride, carbamide, sodium hydrogen phosphate or the sodium carbonate; Described short osmopolymer is one or more the mixture in polyoxyethylene, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, hydroxypropyl emthylcellulose, carbomer, cross-linking sodium carboxymethyl cellulose or the polyvinylpyrrolidone; Described other adjuvants are binding agent or diluent;
(3) adopt coating material to carry out coating, coating 1 %～50 % that increase weight make a call to 0.6～1.0 mm small delivery aperture in tablet surface at last, promptly get osmotic pump type tacrolimus controlled release preparation; Described coating material is semipermeable membrane material, adjuvant and coating solvent; Described semipermeable membrane material is one or more the mixture in cellulose acetate, ethyl cellulose, methylcellulose, acrylic resin, cellulose acetate phthalate ester, hydroxypropyl methylcellulose phthalate ester, polyvinyl alcohol, polrvinyl chloride, polyethylene or Merlon and the ethylene-vinyl acetate copolymer; Described adjuvant is one or more the mixture in binding agent, plasticizer, porogen, antiplastering aid, defoamer, antistatic additive, coloring agent or the lucifuge agent; Described coating solvent is one or more the mixture in acetone, ethanol, isopropyl alcohol, dichloromethane or the chloroform; Described semipermeable membrane material accounts for 0.1 %～50 % of coating solution gross weight, and described adjuvant accounts for 0～50 % of coating solution gross weight.
Preparation contains with the cyclodextrin derivative tacrolimus sustained-release preparation of the tacrolimus clathrate that is carrier:
Contain cyclodextrin derivative and be the tacrolimus sustained-release preparation manufacture method of tacrolimus clathrate of the high-dissolvability of carrier: adopt cyclodextrin inclusion technique to prepare the tacrolimus intermediate of high-dissolvability earlier, in the tacrolimus intermediate for preparing, add framework material and other adjuvants are made matrix type tacrolimus slow releasing preparation; Perhaps adopt slow-release material to carry out coating and make film controlling type tacrolimus slow releasing preparation, perhaps adopt penetration material to be prepared into osmotic pump type tacrolimus controlled release preparation.
Described matrix type tacrolimus slow releasing preparation:
(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of described preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 1～500 part of cyclodextrin derivative; The preparation of employing cyclodextrin inclusion technique, described cyclodextrin inclusion technique is paddling process, microwave method or supercritical ultrasonics technology: tacrolimus and cyclodextrin derivative are dissolved in adequate amount of ethanol, sonic oscillation 5～60min, Rotary Evaporators is 20～60 ℃ of solvent evaporated, and boulton process or freeze-drying are prepared into the tacrolimus intermediate of high-dissolvability;
(2) the tacrolimus intermediate for preparing is ground, after sieving, add framework material and other adjuvant mix homogeneously, adopt direct powder compression, dry granulation tabletting, wet granule compression tablet to obtain slow releasing tablet; Perhaps by extruding spheronization, centrifugal granulation, encapsulated after fluidized bed coating prepares slow-release micro-pill, perhaps directly it is prepared into slow releasing preparation; According to mass fraction: 1 part of tacrolimus; 1～500 part of cyclodextrin derivative; 5～2000 parts of framework materials; 0～2000 part of other adjuvant; Described framework material is a hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, methylcellulose, vinyl acetate copolymer, sodium alginate, xanthan gum, sodium carboxymethyl cellulose, poly(ethylene oxide), methacrylic acid copolymer, maleic anhydride-methyl ethylene ether copolymer, carbomer, polyvinylpyrrolidone, ethyl cellulose, cellulose acetate, methacrylate, polyoxyethylene, polyvinyl alcohol, Rikemal B 200, glyceryl monostearate, octadecanol, hexadecanol, stearic acid, the mixture of one or more in Brazil wax or the Cera Flava; Described other adjuvant is diluent or binding agent.
Described film controlling type tacrolimus slow releasing preparation:
(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of described preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 1～500 part of cyclodextrin derivative; The preparation of employing cyclodextrin inclusion technique, described cyclodextrin inclusion technique is paddling process, microwave method or supercritical ultrasonics technology: tacrolimus and cyclodextrin derivative are dissolved in adequate amount of ethanol, sonic oscillation 5～60min, Rotary Evaporators is 20～60 ℃ of solvent evaporated, and boulton process or freeze-drying are prepared into the tacrolimus intermediate of high-dissolvability;
(2) the tacrolimus intermediate for preparing is ground, after sieving,, adopt direct powder compression, dry granulation tabletting or wet granule compression tablet to prepare the pastille label with the adjuvant mix homogeneously; Perhaps prepare the medicine carrying micropill by extruding spheronization, centrifugal granulation or fluidized bed coating; Perhaps the tacrolimus intermediate for preparing directly is dissolved in the mixed solution of water or alcohol, prepares the medicine carrying micropill by fluidized bed coating; According to mass fraction: 1 part of tacrolimus; 1～500 part of cyclodextrin derivative; 0～5000 part of adjuvant; Described adjuvant is one or more the mixture in binding agent, antiplastering aid, defoamer, antistatic additive, coloring agent or the lucifuge agent;
(3) adopt the coating filmogen to carry out coating, film controlling type tacrolimus slow releasing preparation, coating 1 %～50 % that increase weight; Described coating filmogen is one or more a mixture of cellulose acetate, cellulose acetate-phthalate, ethyl cellulose and aqueous dispersion thereof, ethylene-vinyl acetate copolymer, crylic acid resin and aqueous dispersion thereof, silicone elastomer, polyvinylpyrrolidone, crosslinked alginate or Polyethylene Glycol apoplexy due to endogenous wind; Described coating filmogen accounts for 0.1 %～50 % of coating solution gross weight; Described coating solvent is one or more the mixture in acetone, ethanol, isopropyl alcohol, dichloromethane or the chloroform.
Described osmotic pump type tacrolimus controlled release preparation:
(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of described preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 1～500 part of cyclodextrin derivative; The preparation of employing cyclodextrin inclusion technique, described cyclodextrin inclusion technique is paddling process, microwave method or supercritical ultrasonics technology: tacrolimus and cyclodextrin derivative are dissolved in adequate amount of ethanol, sonic oscillation 5～60 min, Rotary Evaporators is 20～60 ℃ of solvent evaporated, and boulton process or freeze-drying are prepared into the tacrolimus intermediate of high-dissolvability;
(2) the tacrolimus intermediate for preparing is ground, after sieving,, adopt direct powder compression, dry granulation tabletting, wet granule compression tablet to prepare the pastille label with osmo active substance, short osmopolymer and other adjuvant mix homogeneously; According to mass fraction: 1 part of tacrolimus; 1～500 part of cyclodextrin derivative; 1～2000 part of osmo active substance, 1～2000 part of short osmopolymer, 0～2000 part of other adjuvant; Described osmotic pressure active substance is one or more the mixture in low molecule saccharide, sodium chloride, potassium chloride, potassium sulfate, sodium sulfate, magnesium sulfate, magnesium chloride, carbamide, sodium hydrogen phosphate or the sodium carbonate; Described short osmopolymer is one or more the mixture in polyoxyethylene, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, hydroxypropyl emthylcellulose, carbomer, cross-linking sodium carboxymethyl cellulose or the polyvinylpyrrolidone; Described other adjuvants are binding agent or diluent;
(3) adopt coating material to carry out coating, coating 1 %～50 % that increase weight make a call to 0.6～1.0 mm small delivery aperture in tablet surface at last, promptly get osmotic pump type tacrolimus controlled release preparation; Described coating material is semipermeable membrane material, adjuvant and coating solvent; Described semipermeable membrane material is one or more the mixture in cellulose acetate, ethyl cellulose, methylcellulose, acrylic resin, cellulose acetate phthalate ester, hydroxypropyl methylcellulose phthalate ester, polyvinyl alcohol, polrvinyl chloride, polyethylene or Merlon and the ethylene-vinyl acetate copolymer; Described adjuvant is one or more the mixture in binding agent, plasticizer, porogen, antiplastering aid, defoamer, antistatic additive, coloring agent or the lucifuge agent; Described coating solvent is one or more the mixture in acetone, ethanol, isopropyl alcohol, dichloromethane or the chloroform; Described semipermeable membrane material accounts for 0.1 %～50 % of coating solution gross weight, and described adjuvant accounts for 0～50 % of coating solution gross weight.
The tacrolimus sustained-release preparation of the pharmaceutical composition that preparation tacrolimus and surfactant are formed:
The preparation method that contains the tacrolimus sustained-release preparation of the pharmaceutical composition that tacrolimus and surfactant form: will add the tacrolimus intermediate that surfactant prepares high-dissolvability behind the tacrolimus micronization earlier, and in the tacrolimus intermediate for preparing, add framework material and other adjuvants are made matrix type tacrolimus slow releasing preparation; Perhaps adopt slow controlled-release material to carry out coating and make film controlling type tacrolimus slow releasing preparation, perhaps adopt penetration material to be prepared into osmotic pump type tacrolimus controlled release preparation.
Described matrix type tacrolimus slow releasing preparation:
(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of described preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 1～500 part in surfactant; Adopt the equivalent method of progressively increasing: tacrolimus is dissolved in adequate amount of ethanol, adds the surfactant mix homogeneously, be prepared into the tacrolimus intermediate of high-dissolvability;
(2) tacrolimus for preparing is added framework material and other adjuvant mix homogeneously, adopt direct compression, obtain slow releasing tablet with dry granulation tabletting, wet granule compression tablet; Perhaps by extruding spheronization, centrifugal granulation, encapsulated after fluidized bed coating prepares slow-release micro-pill, perhaps directly it is prepared into slow releasing preparation; According to mass fraction: 1 part of tacrolimus; 1～500 part in surfactant; 5～2000 parts of framework materials; 0～2000 part of other adjuvant; Described framework material is a hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, methylcellulose, vinyl acetate copolymer, sodium alginate, xanthan gum, sodium carboxymethyl cellulose, poly(ethylene oxide), methacrylic acid copolymer, maleic anhydride-methyl ethylene ether copolymer, carbomer, polyvinylpyrrolidone, ethyl cellulose, cellulose acetate, methacrylate, polyoxyethylene, polyvinyl alcohol, Rikemal B 200, glyceryl monostearate, octadecanol, hexadecanol, stearic acid, the mixture of one or more in Brazil wax or the Cera Flava; Described other adjuvant is diluent or binding agent.
Described film controlling type tacrolimus slow releasing preparation:
(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of described preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 1～500 part in surfactant; Adopt the equivalent method of progressively increasing: tacrolimus is dissolved in adequate amount of ethanol, adds the surfactant mix homogeneously, be prepared into the tacrolimus intermediate of high-dissolvability;
(2), adopt direct powder compression, dry granulation tabletting or wet granule compression tablet to prepare the pastille label with the tacrolimus intermediate and the adjuvant mix homogeneously that prepare; Perhaps prepare the medicine carrying micropill by extruding spheronization, centrifugal granulation or fluidized bed coating; Perhaps the tacrolimus intermediate for preparing directly is dissolved in the mixed solution of water or alcohol, prepares the medicine carrying micropill by fluidized bed coating; According to mass fraction: 1 part of tacrolimus; 1～500 part in surfactant; 0～2000 part of adjuvant; Described adjuvant is one or more the mixture in binding agent, plasticizer, porogen, antiplastering aid, defoamer, antistatic additive, coloring agent or the lucifuge agent;
(3) adopt the coating filmogen to carry out coating, film controlling type tacrolimus slow releasing preparation, coating 1 %～50 % that increase weight; Described coating filmogen is one or more a mixture of cellulose acetate, cellulose acetate-phthalate, ethyl cellulose and aqueous dispersion thereof, ethylene-vinyl acetate copolymer, crylic acid resin and aqueous dispersion thereof, silicone elastomer, polyvinylpyrrolidone, crosslinked alginate or Polyethylene Glycol apoplexy due to endogenous wind; Described coating filmogen accounts for 0.1 %～50 % of coating solution gross weight; Described coating solvent is one or more the mixture in acetone, ethanol, isopropyl alcohol, dichloromethane or the chloroform.
Described osmotic pump type tacrolimus controlled release preparation:
(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of described preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 1～500 part in surfactant; Adopt the equivalent method of progressively increasing: tacrolimus is dissolved in adequate amount of ethanol, adds the surfactant mix homogeneously, be prepared into the tacrolimus intermediate of high-dissolvability;
(2) with the tacrolimus intermediate and osmo active substance, short osmopolymer and other adjuvant mix homogeneously that prepare, adopt direct powder compression, dry granulation tabletting, wet granule compression tablet to prepare the pastille label; According to mass fraction: 1 part of tacrolimus; 1～500 part in surfactant; 1～2000 part of osmo active substance, 1～2000 part of short osmopolymer, 0～2000 part of other adjuvant; Described osmotic pressure active substance is one or more the mixture in low molecule saccharide, sodium chloride, potassium chloride, potassium sulfate, sodium sulfate, magnesium sulfate, magnesium chloride, carbamide, sodium hydrogen phosphate or the sodium carbonate; Described short osmopolymer is one or more the mixture in polyoxyethylene, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, hydroxypropyl emthylcellulose, carbomer, cross-linking sodium carboxymethyl cellulose or the polyvinylpyrrolidone; Described other adjuvants are binding agent or diluent;
(3) adopt coating material to carry out coating, coating 1 %～50 % that increase weight make a call to 0.6～1.0 mm small delivery aperture in tablet surface at last, promptly get osmotic pump type tacrolimus controlled release preparation; Described coating material is semipermeable membrane material, adjuvant and coating solvent; Described semipermeable membrane material is one or more the mixture in cellulose acetate, ethyl cellulose, methylcellulose, acrylic resin, cellulose acetate phthalate ester, hydroxypropyl methylcellulose phthalate ester, polyvinyl alcohol, polrvinyl chloride, polyethylene or Merlon and the ethylene-vinyl acetate copolymer; Described adjuvant is one or more the mixture in binding agent, plasticizer, porogen, antiplastering aid, defoamer, antistatic additive, coloring agent or the lucifuge agent; Described coating solvent is 0.1 %～50 % that one or more the described semipermeable membrane material of mixture in acetone, ethanol, isopropyl alcohol, dichloromethane or the chloroform accounts for the coating solution gross weight, and described adjuvant accounts for 0～50 % of coating solution gross weight.
Tacrolimus sustained-release preparation of the present invention is prepared into various conventional forms, be used for oral, as hydrogel matrix tablet, waxiness class matrix tablet, insoluble matrix tablet, slow-releasing granules, intra-gastric floating tablet, bioadhesive tablet and skeleton micropill, microporous membrane controlled release tablet, film controlled release tablet, film controlled release micro pill, film controlled release granule, oral sustained release, controlled release tablet, wherein these tablets are matrix tablet, Entogastric lingering sheet, film controlled release tablet, osmotic pump tablet or the like.
By " 2005 editions two appendix XD first methods of Chinese pharmacopoeia adopt the device of dissolution method (appendix XC first method), get tacrolimus slow release sheet, are dissolution medium with 500 ml aqueous solutions, rotating speed is that per minute 100 changes, respectively at 1,2,4,6,8,10,12 h get solution 5ml, add the distilled water of uniform temp, equal volume simultaneously, institute's sample thief filters immediately, get subsequent filtrate and adopt high performance liquid chromatography to measure, it is an amount of to get reference substance, calculates release by external standard method.
The representational embodiment of preparation of the present invention is provided below, and these embodiment only are used to illustrate the present invention, and protection domain are not caused restriction.
Embodiment
The preparation of embodiment 1 tacrolimus hydrogel matrix tablet
Preparation technology:
With tacrolimus and HP-with an amount of anhydrous alcohol solution after, in Ultrasound Instrument, behind ultrasonic 20 min, it is transferred to the Rotary Evaporators solvent evaporated, temperature is 30-40 ℃, precipitate places 24 h in the 25-40 ℃ of vacuum drying oven, takes out, and grinds, after crossing 80 mesh sieves, with hydroxypropyl emthylcellulose K4M, microcrystalline Cellulose, lactose, magnesium stearate, adopt the equivalent method mix homogeneously that progressively increases, behind the direct powder compression, the coloured moisture-proof film clothing of bag one deck, promptly.
By " 2005 editions two appendix XD first methods of Chinese pharmacopoeia adopt the device of dissolution method (appendix XC first method), get tacrolimus slow release sheet, are dissolution medium with 500 ml aqueous solutions, rotating speed is that per minute 100 changes, respectively at 1,2,4,6,8,10,12 h get solution 5ml, add the distilled water of uniform temp, equal volume simultaneously, institute's sample thief filters immediately, get subsequent filtrate and adopt high performance liquid chromatography to measure, it is an amount of to get reference substance, calculates release by external standard method.
The preparation of embodiment 2 tacrolimus film controlling type slow releasing tablet
Preparation technology:
Tacrolimus is dissolved in the adequate amount of ethanol solution, after treating that polyethylene glycol 6000 is heated to fusion in 60-70 ℃ of water-bath, mixing, vigorous stirring also is poured over fused mass and forms thin layer on the corrosion resistant plate, makes it to be cooled to rapidly solid, again this solid is positioned over 24 h in the 25-40 ℃ of vacuum drying oven, take out, add a small amount of micropowder silica gel and grind (micropowder silica gel can reduce the loss of solid dispersion in process of lapping as lubricant), after crossing 80 mesh sieves, with the lactose mix homogeneously, it is an amount of to add 1% polyoxyethylene ketopyrrolidine aqueous solution, the system soft material, granulate, drying is sieved, granulate, add the magnesium stearate mix homogeneously, tabletting.Carry out coating with above-mentioned coating material, control its release by gain in weight.
Above-mentioned preparation can direct compression, carries out coating with slow-release material, obtains common sustained release coating sheet.Also can adopt extrude spheronization and prepare micropill after, carry out coating, slow-release micro-pill, directly incapsulate.The concrete release of the slow-release micro-pill of preparation is: 91.3 %.
The preparation of embodiment 3 tacrolimus osmotic pump tablets
Preparation technology:
With tacrolimus and HP-with an amount of anhydrous alcohol solution after, in Ultrasound Instrument behind ultrasonic 20 min, it is transferred to the Rotary Evaporators solvent evaporated, and temperature is 30-40 ℃, and precipitate places 24 h in the 25-40 ℃ of vacuum drying oven, take out, grind, excessively behind 80 mesh sieves, with polyoxyethylene, sodium chloride, magnesium stearate, adopt the equivalent method mix homogeneously that progressively increases, tabletting.Carry out coating with above-mentioned coating material, on coated tablet, make a call to an aperture (0.6-1 mm) then.Obtain osmotic pump tablet.More than the concrete release of Zhi Bei osmotic pump tablet is: 90.6 %.
The capsular preparation of embodiment 4 tacrolimus slow release
Preparation technology:
With tacrolimus and kollidon K30 with an amount of anhydrous alcohol solution after, it is transferred to the Rotary Evaporators solvent evaporated, temperature is 40-70 ℃, precipitate places 24h in the 25-40 ℃ of vacuum drying oven, takes out, and grinds, after crossing 80 mesh sieves, with lactose, microcrystalline Cellulose, adopt the equivalent method mix homogeneously that progressively increases, extrude spheronization and prepare the medicine carrying micropill.Also can adopt centrifugal granulation to prepare the medicine carrying micropill.The above-mentioned coating material of reuse carries out coating, controls its release by gain in weight.Promptly get slow-release micro-pill, directly incapsulate.
The capsular preparation of embodiment 5 tacrolimus slow release
Preparation technology:
It is an amount of that microcrystalline Cellulose is added binding agent, and the system soft material adopts and extrudes spheronization, preparation celphere (or directly adopting commercially available celphere); With tacrolimus with an amount of dissolve with ethanol after, add in the aqueous solution that contains poloxamer 188, stir, adopt fluidized bed coating, medicinal liquid is sprayed on the celphere surface, preparation medicine carrying micropill; After the drying, the above-mentioned coating material of reuse carries out coating, controls its release by gain in weight.Promptly get slow-release micro-pill, directly incapsulate.More than the concrete release of Zhi Bei slow-release micro-pill is: 90.3 %.
The preparation of embodiment 6 tacrolimus hydrogel matrix tablets
Preparation technology:
Tacrolimus is dissolved in the adequate amount of ethanol solution, treat polyoxyethylene-40-stearate, hydroxypropyl emthylcellulose E5, pool falls husky nurse 188 or polyethylene glycol 6000 be heated to fusion in 60-70 ℃ of water-bath after, mixing, vigorous stirring also is poured over fused mass and forms thin layer on the corrosion resistant plate, make it to be cooled to rapidly solid, again this solid is positioned over 24 h in the 25-40 ℃ of vacuum drying oven, take out, (micropowder silica gel or Pulvis Talci are as lubricant to add the grinding of a small amount of micropowder silica gel or Pulvis Talci, can reduce the loss of solid dispersion in process of lapping), after crossing 80 mesh sieves, adopt equivalent method mix homogeneously that progressively increases with other adjuvants in the prescription, behind the direct powder compression, the coloured moisture-proof film clothing of bag one deck, promptly.More than the concrete release of Zhi Bei tablet is: 95.2 %.
The preparation of embodiment 7 tacrolimus hydrogel matrix tablets
Preparation technology: with embodiment 6.More than the concrete release of Zhi Bei tablet is: 94.9 %.
The preparation of embodiment 8 tacrolimus film controlling type slow releasing tablet
Preparation technology:
Tacrolimus is dissolved in the adequate amount of ethanol solution, treat poloxamer 188, polyoxyethylene stearate (40) ester, dodecyl sodium sulfate or macrogol ester are heated to fusion in 60-70 ℃ of water-bath after, mixing, vigorous stirring also is poured over fused mass and forms thin layer on the corrosion resistant plate, make it to be cooled to rapidly solid, again this solid is positioned over 24 h in the 25-40 ℃ of vacuum drying oven, take out, add a small amount of micropowder silica gel or Pulvis Talci and grind (micropowder silica gel or Pulvis Talci can reduce the loss of solid dispersion in process of lapping as lubricant), after crossing 80 mesh sieves, with lactose, microcrystalline Cellulose or starch mix homogeneously add 1 % polyoxyethylene ketopyrrolidine, hydroxypropyl emthylcellulose water or alcoholic solution are an amount of, the system soft material, granulate, drying is sieved, granulate, add the magnesium stearate mix homogeneously, tabletting.Carry out coating with above-mentioned coating material, control its release by gain in weight.
Above-mentioned preparation can direct compression, carries out coating with slow-release material, obtains common sustained release coating sheet.Also can adopt extrude spheronization and prepare micropill after, carry out coating, slow-release micro-pill, directly incapsulate.More than the concrete release of Zhi Bei tablet is: 91.9 %.
The preparation of embodiment 9 tacrolimus film controlling type slow releasing tablet
Preparation technology: with embodiment 8.More than the concrete release of Zhi Bei tablet is: 95.3 %.
The preparation of embodiment 10 tacrolimus osmotic pump tablets
Preparation technology:
With tacrolimus and methyl-beta-schardinger dextrin-, HP-, dihydroxypropyl-beta-schardinger dextrin-, hydroxyethyl-or sulfoalkyl cyclodextrin with an amount of anhydrous alcohol solution after, in Ultrasound Instrument behind ultrasonic 20 min, it is transferred to the Rotary Evaporators solvent evaporated, temperature is 30-40 ℃, and precipitate places 24 h in the 25-40 ℃ of vacuum drying oven, takes out, grind, after crossing 80 mesh sieves, adopt equivalent method mix homogeneously that progressively increases, tabletting with other adjuvants of recipe quantity.Carry out coating with above-mentioned coating material, on coated tablet, make a call to an aperture (0.6-1 mm) then.Obtain osmotic pump tablet.More than the concrete release of Zhi Bei tablet is: 90.9 %.
The preparation of embodiment 11 tacrolimus osmotic pump tablets
Preparation technology: the concrete release of the tablet for preparing more than 10 with embodiment is: 92.6 %.
The capsular preparation of embodiment 12 tacrolimus slow release
Preparation technology:
Microcrystalline Cellulose, lactose, starch or dextrin adding binding agent is an amount of, and the system soft material adopts and extrudes spheronization, preparation celphere (or directly adopting commercially available celphere); With tacrolimus with an amount of dissolve with ethanol after, add in the aqueous solution that contains poloxamer 188, polyoxyethylene stearate (40) ester, dodecyl sodium sulfate or hydroxypropyl emthylcellulose, stir, adopt fluidized bed coating, medicinal liquid is sprayed on the celphere surface, preparation medicine carrying micropill; After the drying, the above-mentioned coating material of reuse carries out coating, controls its release by gain in weight.Promptly get slow-release micro-pill, directly incapsulate.More than the concrete release of Zhi Bei tablet is: 94.8 %.
The capsular preparation of embodiment 13 tacrolimus slow release
Preparation technology:
With tacrolimus and HP-, single succinyl-DM-, dihydroxypropyl-beta-schardinger dextrin-or hydroxyethyl-with an amount of anhydrous alcohol solution after, it is transferred to the Rotary Evaporators solvent evaporated, temperature is 40-70 ℃, precipitate places 24 h in the 25-40 ℃ of vacuum drying oven, take out, grind, excessively behind 80 mesh sieves, adopt equivalent method mix homogeneously that progressively increases with other adjuvants in the prescription, extrude spheronization and prepare the medicine carrying micropill.Also can adopt centrifugal granulation to prepare the medicine carrying micropill.The above-mentioned coating material of reuse carries out coating, controls its release by gain in weight.Promptly get slow-release micro-pill, directly incapsulate.More than the concrete release of Zhi Bei tablet is: 94.6 %.
Pharmacokinetics experiment in the tacrolimus sustained-release preparation Beagle dog body:
The present invention is contrast with commercially available tacrolimus capsule, tacrolimus hydrogel matrix tablet (embodiment 1) relative bioavailability and pharmacokinetic studies have been carried out, adopt micropartical enzyme linked immunosorbent assay (microparticle enzyme immuno assay, MEIA) measure, and the slow releasing tablet quality has been carried out interior evaluating by indexs such as pharmacokinetic parameters that blood drug level-the time feedback information obtains and inside and outside dependencys.
Experimental program is as follows:
1. be subjected to test preparation and reference preparation: being subjected to test preparation is tacrolimus hydrogel matrix tablet (embodiment 1,1 mg sheet
-1, T), reference preparation is commercially available capsule (1 a mg grain
-1, R).
2. laboratory animal: 6 healthy adult Beagle dogs, must not take other medicines at test the last fortnight and duration of test, test fasting 12 h unifiedly behind administration 4 h advance the low fat standard meal.
3. medication and sampling time: 6 Beagle dogs are divided into two groups at random, and embedding let the acupuncture needle remain at a certain point in the forelimb small saphenous vein.Adopt single-dose binary cycle cross-over experiment design, swallowable capsule and hydrogel matrix tablet, be two weeks blanking time.Fasting 12h before the test, the unified drinking water that gives behind the 4h that takes medicine.Get blank blood before taking medicine, take medicine the back commercially available capsule in 0.25,0.5,0.45,1.0,1.5,2,3,4,6,8,10,12,14,18,24,48 h; Hydrogel matrix tablet is in 1,2, and 3,4,6,8,10,12,14,18,20,22,24,36,48,72 h take a blood sample 2 ml respectively in anticoagulant tube, hide standbyly in 4 ℃ of refrigerator and cooled, measure in 7 days and finish.
Average blood drug level-the time graph of Beagle dog oral test preparation and reference preparation is seen Fig. 6.Non-compartment model pharmacokinetic parameters sees Table 2.
The pharmacokinetic parameters of the non-compartment model of table 2
The result shows, compares with commercially available capsule, and embodiment 1 hydrogel matrix tablet,
C Max Reduce,
T Max Prolong, have good slow controlled-release effect.Adopt the relatively bioequivalence of the two of method of analysis of variance, two-one sided test and (1-2 α) confidence interval method, show two preparation bioequivalences.Carry out regression analysis with absorbing percent in the body of embodiment 1 hydrogel matrix tablet with external release percent of corresponding time, show the inside and outside dependency well (
r=0.9828), can be by situation in the release in vitro curve prediction body.
Claims (4)
1. tacrolimus sustained-release preparation, it is characterized in that: described tacrolimus sustained-release preparation contains the tacrolimus solid dispersion that water-soluble material is the high-dissolvability of carrier; Wherein the mass ratio of tacrolimus and carrier is 1: 1～1: 500; Described carrier material is polyvinylpyrrolidone, hydroxypropyl emthylcellulose, polyethylene glycols, poloxamer, Myrj 45, polyoxyethylene aliphatic alcohol ether, polyethylene glycol fatty acid glyceride, the mixture of one or more in saccharide or the organic acid.
2. the preparation method of a tacrolimus sustained-release preparation as claimed in claim 1, it is characterized in that: adopt solid dispersion technology to prepare the tacrolimus intermediate of high-dissolvability earlier, adding framework material and other adjuvants are made matrix type tacrolimus slow releasing preparation in the tacrolimus intermediate for preparing; Perhaps adopt slow controlled-release material to carry out coating and make film controlling type tacrolimus slow releasing preparation, perhaps adopt penetration material to be prepared into osmotic pump type tacrolimus controlled release preparation.
3. according to the preparation method of the tacrolimus sustained-release preparation described in the claim 2, it is characterized in that:
Described preparation matrix type tacrolimus slow releasing preparation:
(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of described preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 1～500 part in water-soluble material carrier; The preparation of employing solid dispersion technology, described solid dispersion technology is solvent method, fusion method or solvent-fusion method: tacrolimus is dissolved in adequate amount of ethanol, water-soluble material carrier after the adding fusion, mix homogeneously, stir, pour out cooling rapidly, boulton process or freeze-drying are prepared into the tacrolimus intermediate of high-dissolvability;
(2) add lubricant at the tacrolimus intermediate for preparing and grind, the back of sieving adds framework material and other adjuvant mix homogeneously, adopts direct powder compression, dry granulation tabletting, wet granule compression tablet to obtain slow-release tablet; Perhaps, encapsulated after centrifugal granulation, fluidized bed coating prepare slow controlled release micro pill by extruding spheronization, perhaps directly it is prepared into slow releasing preparation; According to mass fraction: 1 part of tacrolimus; 1～500 part in water-soluble material carrier; 0.5～300 part of lubricant, 5～2000 parts of framework materials; 0～2000 part of other adjuvant; Described framework material is a hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, methylcellulose, vinyl acetate copolymer, sodium alginate, xanthan gum, sodium carboxymethyl cellulose, poly(ethylene oxide), methacrylic acid copolymer, maleic anhydride-methyl ethylene ether copolymer, carbomer, polyvinylpyrrolidone, ethyl cellulose, cellulose acetate, methacrylate, polyoxyethylene, polyvinyl alcohol, Rikemal B 200, glyceryl monostearate, octadecanol, hexadecanol, stearic acid, the mixture of one or more in Brazil wax or the Cera Flava; Described other adjuvant is diluent or binding agent;
Described film controlling type tacrolimus slow releasing preparation:
(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of described preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 1～500 part in water-soluble material carrier; The preparation of employing solid dispersion technology, described solid dispersion technology is solvent method, fusion method or solvent-fusion method: tacrolimus is dissolved in adequate amount of ethanol, water-soluble material carrier after the adding fusion, mix homogeneously, stir, pour out cooling rapidly, spray drying method or freeze-drying are prepared into the tacrolimus intermediate of high-dissolvability;
(2) add lubricant in the tacrolimus intermediate for preparing and grind, after sieving,, adopt direct powder compression, dry granulation tabletting or wet granule compression tablet to prepare the pastille label with the adjuvant mix homogeneously; Perhaps prepare the medicine carrying micropill by extruding spheronization, centrifugal granulation or fluidized bed coating; Perhaps the tacrolimus intermediate for preparing directly is dissolved in the mixed solution of water or alcohol, prepares the medicine carrying micropill by fluidized bed coating; According to mass fraction: 1 part of tacrolimus; 1～500 part in water-soluble material carrier; 0.5～300 part of lubricant, 0～5000 part of adjuvant; Described adjuvant is one or more the mixture in binding agent, diluent, antiplastering aid, defoamer, antistatic additive, coloring agent or the lucifuge agent;
(3) adopt the coating filmogen to carry out coating, film controlling type tacrolimus slow releasing preparation, coating 1 %～50 % that increase weight; Described coating filmogen is one or more a mixture of cellulose acetate, cellulose acetate-phthalate, ethyl cellulose and aqueous dispersion thereof, ethylene-vinyl acetate copolymer, crylic acid resin and aqueous dispersion thereof, silicone elastomer, polyvinylpyrrolidone, crosslinked alginate or Polyethylene Glycol apoplexy due to endogenous wind; Described coating filmogen accounts for 0.1 %～50 % of coating solution gross weight; Described coating solvent is one or more the mixture in acetone, ethanol, isopropyl alcohol, dichloromethane or the chloroform;
Described osmotic pump type tacrolimus controlled release preparation:
(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of described preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 1～500 part in water-soluble material carrier; The preparation of employing solid dispersion technology, described solid dispersion technology is solvent method, fusion method or solvent-fusion method: tacrolimus is dissolved in adequate amount of ethanol, water-soluble material carrier after the adding fusion, mix homogeneously, stir, pour out cooling rapidly, boulton process or freeze-drying are prepared into the tacrolimus intermediate of high-dissolvability;
(2) add lubricant in the tacrolimus intermediate for preparing and grind, after sieving,, adopt direct powder compression, dry granulation tabletting, wet granule compression tablet to prepare the pastille label with osmo active substance, short osmopolymer and other adjuvant mix homogeneously; According to mass fraction: 1 part of tacrolimus; 1～500 part in water-soluble material carrier; 0.5～300 part of lubricant, 1～2000 part of osmo active substance, 1～2000 part of short osmopolymer, 0～2000 part of other adjuvant; Described osmotic pressure active substance is one or more the mixture in low molecule saccharide, sodium chloride, potassium chloride, potassium sulfate, sodium sulfate, magnesium sulfate, magnesium chloride, carbamide, sodium hydrogen phosphate or the sodium carbonate; Described short osmopolymer is one or more the mixture in polyoxyethylene, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, hydroxypropyl emthylcellulose, carbomer, cross-linking sodium carboxymethyl cellulose or the polyvinylpyrrolidone; Described other adjuvants are binding agent or diluent;
(3) adopt coating material to carry out coating, coating 1 %～50 % that increase weight make a call to 0.6～1.0 mm small delivery aperture in tablet surface at last, promptly get osmotic pump type tacrolimus controlled release preparation; Described coating material is semipermeable membrane material, adjuvant and coating solvent; Described semipermeable membrane material is one or more the mixture in cellulose acetate, ethyl cellulose, methylcellulose, acrylic resin, cellulose acetate phthalate ester, hydroxypropyl methylcellulose phthalate ester, polyvinyl alcohol, polrvinyl chloride, polyethylene or Merlon and the ethylene-vinyl acetate copolymer; Described adjuvant is one or more the mixture in binding agent, plasticizer, porogen, antiplastering aid, defoamer, antistatic additive, coloring agent or the lucifuge agent; Described coating solvent is one or more the mixture in acetone, ethanol, isopropyl alcohol, dichloromethane or the chloroform; Described semipermeable membrane material accounts for 0.1 %～50 % of coating solution gross weight, and described adjuvant accounts for 0～50 % of coating solution gross weight.
4. the tacrolimus sustained-release preparation of tacrolimus sustained-release preparation according to claim 1 or claim 2 or 3 described preparation method preparations, it is characterized in that: described tacrolimus sustained-release preparation is prepared into various conventional forms.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103432099A (en) * | 2013-08-13 | 2013-12-11 | 江苏正大清江制药有限公司 | Tacrolimus slow-releasing capsule and preparation method thereof |
| CN104069071A (en) * | 2014-06-25 | 2014-10-01 | 江苏大学 | Silibinin slow release micropill with double layers of coatings and preparation method of silibinin slow release micropill |
| CN105769786A (en) * | 2014-12-24 | 2016-07-20 | 上海星泰医药科技有限公司 | Mirabegron sustained release tablet and preparation method thereof |
| CN106309395A (en) * | 2016-09-22 | 2017-01-11 | 沈阳药科大学 | Tacrolimus sustained-release tablets and preparation method thereof |
| CN106880617A (en) * | 2015-12-14 | 2017-06-23 | 山东新时代药业有限公司 | A kind of tacrolimus capsules |
| CN117860977A (en) * | 2024-03-08 | 2024-04-12 | 中国科学院宁波材料技术与工程研究所 | Biodegradable antibacterial material and preparation method and application thereof |
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2009
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103432099A (en) * | 2013-08-13 | 2013-12-11 | 江苏正大清江制药有限公司 | Tacrolimus slow-releasing capsule and preparation method thereof |
| CN104069071A (en) * | 2014-06-25 | 2014-10-01 | 江苏大学 | Silibinin slow release micropill with double layers of coatings and preparation method of silibinin slow release micropill |
| CN105769786A (en) * | 2014-12-24 | 2016-07-20 | 上海星泰医药科技有限公司 | Mirabegron sustained release tablet and preparation method thereof |
| CN106880617A (en) * | 2015-12-14 | 2017-06-23 | 山东新时代药业有限公司 | A kind of tacrolimus capsules |
| CN106880617B (en) * | 2015-12-14 | 2021-08-31 | 山东新时代药业有限公司 | Tacrolimus capsule |
| CN106309395A (en) * | 2016-09-22 | 2017-01-11 | 沈阳药科大学 | Tacrolimus sustained-release tablets and preparation method thereof |
| CN106309395B (en) * | 2016-09-22 | 2019-09-20 | 沈阳药科大学 | A kind of tacrolimus sustained release piece and preparation method thereof |
| CN117860977A (en) * | 2024-03-08 | 2024-04-12 | 中国科学院宁波材料技术与工程研究所 | Biodegradable antibacterial material and preparation method and application thereof |
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