CN101554376A - High-bioavailability rapamycin composition and preparation method thereof - Google Patents
High-bioavailability rapamycin composition and preparation method thereof Download PDFInfo
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- CN101554376A CN101554376A CNA2009101404020A CN200910140402A CN101554376A CN 101554376 A CN101554376 A CN 101554376A CN A2009101404020 A CNA2009101404020 A CN A2009101404020A CN 200910140402 A CN200910140402 A CN 200910140402A CN 101554376 A CN101554376 A CN 101554376A
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Abstract
The invention relates to a high-bioavailability rapamycin composition and a preparation method thereof. The drug release of the solid drug composition in a gastrointestinal tract has pH sensitivity. The high dispersivity of the drug in a carrier can obviously increase the absorption of rapamycin in the gastrointestinal tract or improve other properties of the drug, thereby obviously improving bioavailability, being capable of lowering administration dosage, namely reducing the usage of the raw materials in the preparation, and further saving the production cost greatly. The rapamycin composition can be processed into various oral solid dosage forms and has simple preparation process.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of rapamycin composition and preparation method of high bioavailability.The drug release of this solid composite medicament in gastrointestinal tract has pH sensitivity, and this solid composite medicament can significantly increase rapamycin absorbs or improve medicine at gastrointestinal other performance.
Background technology
(Rapamycin RAPA), has another name called sirolimus (sirolimus) to rapamycin, is a kind of new and effective macrolide immunosuppressants.It is a kind of triolefin macrolide antibiotic with Hangzhoupro fungus effect that the fermentation of streptomyces filamentous bacteria produces.Vezina in 1975 and Sehgal separate from the soil on Canadian RapaNul island and gain the name.It has immunosuppressive action reports such as Martel in 1977.In October, 1999 drugs approved by FDA listing.Rapamycin is a white crystalline solid, molecular formula C
51H
79NO
13, molecular weight 914.2, fusing point 183-185 ℃, lipotropy is soluble in organic solvents such as methanol, ethanol, acetone, dichloromethane and chloroform, and is atomic water-soluble.Because the water-insoluble of rapamycin influences it at the gastrointestinal absorbance, causes the bioavailability of oral liquid and tablet all very low, only is 14%-17%.Improve bioavailability, can reduce dosage, promptly reduced the consumption of raw material in the preparation, can save production cost greatly.The raw material production of rapamycin need be by loaded down with trivial details step and the purification process that ferments for a long time, and cost of material is quite high, at present the about 150,000 dollars/kg of price on the international market.So the price of rapamycin preparation is subjected to the influence of the price of raw material and consumption very big, the oral liquid of import (Rapamune) price about 400 dollars/bottle (60mL), homemade (should glad can) want also that (50mg: the 50mL/ bottle), long-term prescription is great burden for the patient about 1900 yuans.In addition, the dosage form of at present domestic and international thunder pareira element mainly contains oral liquid and tablet.The rapamycin oral liquid that has gone on the market needs to change into Emulsion with water and milk before taking, and wherein contains exhibiting high surface activating agent and cosurfactant, and long-term frequent oral administration may cause gastrointestinal tract mucous damage.
It is a kind of innovation that nanotechnology is applied to increase the drug oral absorption, and has a good application prospect.Aspect the oral administration nanometer medicine, and up to the present, the FDA approved four nanocrystal technical products (medicine itself is prepared into nanoparticle, and refabrication becomes conventional oral solid formulation) by the research of ELAN company.Oral administration nanometer grain preparation just under study for action is also a lot.Studies show that nanotechnology promotes medicine to absorb at gastrointestinal and has tangible effect for the dissolubility that increases medicine.
Nanotechnology can increase the absorption of medicine, and possible principle has the following aspects: 1) owing to the nanoparticle high degree of dispersion, surface area is huge, helps increasing biomembranous time of contact of medicine and absorption site and contact area; 2) nanoparticle high degree of dispersion, surface area is huge, may directly increase the dissolubility of medicine; 3) nanoparticle has special surface property (as bioadhesive, electrical etc.), and the holdup time in the microvillus of small intestinal can prolong greatly; Therefore 4) nanoparticle can enter cell by mechanism such as endocytosis, and is different with the transmembrane transport mechanism of general medicine, may increase medicine to biomembranous permeability, when drug resistance especially occurring or special barrier being arranged; 5) nanoparticle has significant protective effect to unsettled medicine, can prevent the destruction of acid or alkali environment and various enzyme systems in the gastrointestinal tract; 6) carrier material also may prevent the gathering of some drug molecules, and drug molecule is present in the carrier with high dispersion state; 7) physicochemical property of nanoparticle scalable medicine discharges as regulating medicine, and this also has the absorption that is beneficial to medicine.The result of above comprehensive function can obviously improve the absorption and the bioavailability of medicine.
Though nanoparticle has practical application, still face some major issues at present.Comprise alternative medicinal carrier material more limited (for drug-carrying nanometer particle), the industrialization more complicated of preparation method, the long-time stability of nanoparticle have to be solved, and the safety issue of macromolecular material and surfactant etc. has to be evaluated, preparation cost is higher, or the like.
These particular problems according to the nanotechnology existence, the present invention adopts new thinking, developed a kind of rapamycin composition and preparation method with nanometer skeleton sustained release function, be intended to improve the oral administration biaavailability of rapamycin, simplify simultaneously preparation technology as far as possible, increase stability, improve safety, reduce cost.
Summary of the invention
The objective of the invention is rapamycin composition that discloses a kind of high bioavailability and preparation method thereof, be about to the active component rapamycin and mix, can be prepared into various oral solid formulations with nanometer skeleton carrier, pH Sensitive Polymer Materials and other pharmaceutic adjuvants.
It consists of rapamycin compositions of the present invention, nanometer skeleton carrier, pH Sensitive Polymer Materials and pharmaceutic adjuvant.
Rapamycin composition of the present invention, its prescription is composed as follows:
Rapamycin 0.01-99.0%
PH Sensitive Polymer Materials 1-99.9%
Nanometer skeleton carrier 1-99.9%
Other pharmaceutic adjuvants 0-20%
Preferred prescription is composed as follows:
Rapamycin 0.1-70%
PH Sensitive Polymer Materials 5-90%
Nanometer skeleton carrier 5-80%
Other pharmaceutic adjuvants 0-20%
Most preferred prescription is composed as follows:
Rapamycin 0.5-60%
PH Sensitive Polymer Materials 10-80%
Nanometer skeleton carrier 10-60%
Other pharmaceutic adjuvants 0-20%
Rapamycin composition of the present invention, prepare in order to the below method: after rapamycin, pH Sensitive Polymer Materials are dissolved in appropriate solvent, mix with the nanometer skeleton carrier, and absorption is on the skeleton carrier surface, the reuse proper method removes and desolvates, form the solid nano particle of a kind of rapamycin and the common coating of pH Sensitive Polymer Materials, be that rapamycin and pH Sensitive Polymer Materials wrap in nanoparticle surface, this particle and pharmaceutic adjuvant mix, and can be prepared into pharmaceutical preparations composition according to the galenic pharmacy routine techniques.
The present invention also can add other coating composition in above preparation process, with carrier band more the multiple medicines thing, improve the surface property of nanoparticle or help finishing smoothly of coating process etc.
The preparation method of rapamycin composition of the present invention, rapamycin, pH Sensitive Polymer Materials and other pharmaceutic adjuvants can be dissolved in organic solvent, water or their mixed solvent together or respectively, together or respectively with nanometer framework material mix homogeneously (the medicinal solid powder can directly add), drying.Available conventional method is pulverized after the dried if necessary.
When enteric material adopts aqueous dispersion, organic solution or commercially available liquid coatings prescription, can or disperse medicine or other material dissolves wherein to mix with the nanometer framework material again.
In the preparation method of the present invention, hybrid mode is selected from stirring, rotates, soaks into, grinds, sieves, pulverizes, even matter, ultrasonic or their combination.
In the preparation method of the present invention, drying mode is selected from vacuum drying, heat drying, spray drying, lyophilization, fluidized drying, infrared drying, microwave drying or their combination.
Rapamycin composition of the present invention can further be processed, and is prepared into oral solid pharmaceutical formulation.Described oral solid pharmaceutical formulation is selected from tablet, hard capsule, soft capsule, granule, powder, electuary, drop pill or micropill.
The present invention preferably fills a prescription and forms and the solid composite preparation method is listed in the embodiment of the invention.
PH Sensitive Polymer Materials of the present invention, it is so-called enteric solubility macromolecular material, be selected from: enteric solubility acrylic resin, hypromellose phthalate ester (HPMCP), cellulose acetate phthalate ester (CAP), Hydroxypropyl Methyl Cellulose Phthalate (HPMCAS), polyvinyl alcohol acetic acid phthalic acid ester (PVAP), cellulose acetate benzenetricarboxylic acid ester (CAT), 1,2,4-benzenetricarboxylic acid hydroxypropyl emthylcellulose (HPMCT), succinic acid cellulose acetate (CAS), Lac or their mixture.Above-mentioned enteric material comprises solid, aqueous dispersion, organic solution or commercially available coated formula.It can dissolve in specific pH environment, does not generally dissolve in sour environment, is dissolving near under the neutral condition.Different material dissolves pH differences can be chosen suitable dissolving pH by the mode that different materials share.
Nanometer skeleton carrier of the present invention is selected from: silicon dioxide, calcium silicates, aluminium-magnesium silicate (also claiming Magnesiumaluminumsilicate), Montmorillonitum, Bentonite, kaolin (also claiming Kaolin), magnesium trisilicate, magnesium silicate, activated carbon, attapulgite, saponite, Pulvis Talci, calcium sulfate, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, hydroxyapatite or their mixture, preferably silicon dioxide.Above-mentioned nanometer skeleton carrier can be anhydride, hydrate or contains not commensurability water of crystallization, can be colloid powder or the microgranule with nanoaperture.
Other pharmaceutic adjuvants can be selected from has bioadhesion, adjustment release speed or improve the medicinal materials of mobility of particle, as bioadhesive material, plasticizer, porogen, medicinal solid powder or their mixture, wherein said bioadhesive material is selected from chitosan, chitosan derivatives is (as the Pegylation chitosan, the carboxy methylation chitosan), chitin, alginic acid and sodium salt, xanthan gum, pectin and calcium pectinate, hyaluronic acid and sodium salt, agar, gelatin, glucosan, Carbopol, CMC, CMC, HPMC, HPC, HEC, MC, PVP or their mixture.The consumption of described bioadhesive polymer (weight %) accounts for the 0.0-20.0% of final rapamycin composition weight; Wherein said plasticizer is selected from glycerol, propylene glycol, Polyethylene Glycol, triethyl citrate, glycerol triacetate, acetyl monoglyceride, phthalic acid ester, ethyl sebacate, Oleum Ricini or their mixture, and described plasticizer dosage (weight %) accounts for the 0.0-20.0% of final rapamycin composition weight; Wherein said porogen is selected from PEG, propylene glycol, isopropyl alcohol, glycerol, lactose, glucose, sucrose, mannitol, sorbitol, sodium chloride or their mixture, and the consumption of porogen (weight %) accounts for the 0.0-20.0% of final rapamycin composition weight; The wherein said material that improves mobility of particle is selected from Pulvis Talci, magnesium stearate, calcium stearate, zinc stearate, stearic acid, micropowder silica gel, solid-state PEG, Bentonite or their mixture, and the consumption of fluidizer (weight %) accounts for the 0.0-20.0% of final rapamycin composition weight.
Prepare rapamycin composition with the present invention, and carried out the research of dissolution and rat bioavailability, result of study is found, this new structure can obviously increase the oral back of rat bioavailability of medicament, behind nano-silica surface absorption medicine and enteric solubility macromolecular material, external stripping has tangible pH sensitivity.
One of characteristics of the present invention are to have adopted rapamycin and the pH Sensitive Polymer Materials structure of coating inertia nanometer framework material simultaneously, are different from existing document or patented technology.
Two of characteristics of the present invention are to have realized the effect that nanotechnology brings with straightforward procedure.Because nanometer framework material particle is very little, and the tool loose structure, so surface area is huge, this helps increasing its bioadhesive, its holdup time in gastrointestinal tract is prolonged, can increase biomembranous time of contact of carrier band medicine and absorption site and contact area thus; Because nanometer framework material particle high degree of dispersion, surface area is huge, can increase the dissolubility of rapamycin.These all are very beneficial for medicine and absorb at gastrointestinal.
Three of characteristics of the present invention are the regulation and control that realized medicine-releasing performance with simple method.When selecting the pH Sensitive Polymer Materials for use, the drug coating nanoparticle of the present invention's preparation can produce enteric or slow controlled-release effect.The problem that nanotechnology often runs into is the selection of material, and the medicinal materials that can be used for preparing nanoparticle is few, and catabolite also has safety issue.One of advantage of the present invention shows, the adjuvant that compositions is used comprises that nano material (as silica sol) all is medicinal specification, is galenic pharmacy adjuvant commonly used.Silica sol can oral absorption yet, and safety is very good.
Another subject matter that nanotechnology is used is the general more complicated of preparation method, needs several days time sometimes as the pulverizing of Nano medication, and very high to equipment requirements.The liquid (mainly being water) that generally needs significant volume during the polymer manufacture nanoparticle is as decentralized photo, and is concentrated, dry then, needs for a long time and special equipment, and cost is very high; If make liquid preparation, then volume is big, and packing, use are all inconvenient, and stability is bad.Two of advantage of the present invention shows that the preparation method that compositions adopted is very simple.As silica sol has been nanoparticle, does not need preparation; Behind dissolution with solvents medicine and the macromolecular material, the most only need the moistening nano material, so consumption seldom; Can use organic solvent to fat-soluble medicine, drying is very fast; To water soluble drug available water/ORGANIC SOLVENT MIXTURES or water, because consumption seldom, drying is also than being easier to.
The main difficult point that administration nano-drug administration system is used is exactly stability, particularly physical stability problem.Because surface area is huge, nanoparticle is typical thermodynamic unstable system, and aggregation tendency is very strong, and secular physical stability is a difficult problem always.Three of advantage of the present invention shows that compositions mainly exists with solid form, and this stability to nanoparticle (comprising physical stability) is highly beneficial.
Owing to above these reasons, the solid composite medicament of the present invention's preparation can obtain the characteristics that nanotechnology brings under lower cost, and this is the 4th advantage of the present invention.
The present invention also carries out coating with medicine and pH Sensitive Polymer Materials with the silica sol particle as the nanometer framework material, can add other coating composition when needing, and has obtained the oral rapamycin composition of a kind of high bioavailability.
Description of drawings
The release of Fig. 1 rapamycin composition of the present invention in acid medium (pH 1.0) and neutral medium (pH 7.4)
Fig. 2 rapamycin composition x-ray diffraction pattern of the present invention
Fig. 3 rapamycin composition of the present invention and microemulsion formulation are in the comparison of the intravital oral absorption situation of rat
The specific embodiment
By the following examples, further specify the present invention, but not as limitation of the present invention.
Embodiment 1: the preparation of rapamycin composition
Take by weighing 1g Eudragit S100, fully disperse, be dissolved in an amount of dehydrated alcohol, form uniform solution, take by weighing the 0.2g rapamycin, be dissolved in the above-mentioned solution; Get 1.0g Aerosil 200 and above-mentioned solution mixing, liquid is fully adsorbed; The container that fills said mixture is placed vacuum desiccator, and removal of solvent under reduced pressure forms white blocks of solid.Take out, pulverize, sieve, promptly.
Embodiment 2: the preparation of rapamycin composition
Take by weighing 0.9g Eudragit S100, fully disperse, be dissolved in the dehydrated alcohol, form uniform solution, take by weighing the 0.3g rapamycin, be dissolved in this solution; Get 0.9g Aerosil 300 powders and above-mentioned solution mixing, liquid is fully adsorbed; The container that fills this mixture is placed vacuum desiccator, and removal of solvent under reduced pressure forms white blocks of solid.Take out, pulverize, sieve, promptly.
Embodiment 3: the preparation of rapamycin composition
Take by weighing 140mg Eudragit S100, fully disperse, be dissolved in the dehydrated alcohol, form uniform solution, take by weighing the 20mg rapamycin, be dissolved in this solution; Get 120mg Cab-O-Sil H5 and above-mentioned solution mixing, liquid is fully adsorbed; The container that fills this mixture is placed vacuum desiccator, and removal of solvent under reduced pressure forms white blocks of solid.Take out, pulverize, sieve, promptly.
Embodiment 4: the preparation of rapamycin composition
Take by weighing 100mg hypromellose phthalate ester (HP-55), fully disperse, be dissolved in the acetone, form uniform solution, take by weighing the 20mg rapamycin, be dissolved in this solution; Get 120mg Wacker HDK T40 and above-mentioned solution mixing, liquid is fully adsorbed; The container that fills this mixture is placed vacuum desiccator, and removal of solvent under reduced pressure forms white blocks of solid.Take out, pulverize, sieve, promptly.
Embodiment 5: the preparation of rapamycin composition
Take by weighing 100mg hypromellose phthalate ester (HP-55), fully disperse, be dissolved in the acetone, form uniform solution, take by weighing the 20mg rapamycin, be dissolved in this solution; Get 120mg Wacker HDK T30 and above-mentioned solution mixing, liquid is fully adsorbed; The container that fills this mixture is placed vacuum desiccator, and removal of solvent under reduced pressure forms white blocks of solid.Take out, pulverize, sieve, promptly.
Embodiment 6: the preparation of rapamycin composition
Take by weighing 80mg Eudragit S100, fully disperse, be dissolved in acetone and the alcohol mixture, form uniform solution, take by weighing the 20mg rapamycin, be dissolved in this solution; Get 100mg Aerosil 380 and above-mentioned solution mixing, liquid is fully adsorbed; The container that fills this mixture is placed vacuum desiccator, and removal of solvent under reduced pressure forms white blocks of solid.Take out, pulverize, sieve, promptly.
Embodiment 7: the preparation of rapamycin composition
Take by weighing 80mg cellulose acetate phthalate ester (CAP), fully disperse, be dissolved in the alcoholic solution, form uniform solution, take by weighing the 20mg rapamycin, be dissolved in this solution; Get 100mg Cab-O-Sil HM-5 and above-mentioned solution mixing, liquid is fully adsorbed; This mixture spray drying except that desolvating, is formed white powder.Take out, sieve, promptly.
Embodiment 7: the preparation of rapamycin composition
Take by weighing 80mg cellulose acetate phthalate ester (CAP), fully disperse, be dissolved in the alcoholic solution, form uniform solution, take by weighing the 20mg rapamycin, be dissolved in this solution; Get 100mg Sylysia 320 and above-mentioned solution mixing, liquid is fully adsorbed; This mixture spray drying except that desolvating, is formed white powder.Take out, sieve, promptly.
Embodiment 8: the preparation of rapamycin composition
Take by weighing 80mg cellulose acetate phthalate ester (CAP), fully disperse, be dissolved in the alcoholic solution, form uniform solution, take by weighing the 20mg rapamycin, be dissolved in this solution; Get 100mg Cab-O-Sil M-5 and above-mentioned solution mixing, liquid is fully adsorbed; This mixture spray drying except that desolvating, is formed white powder.Take out, sieve, promptly.
Embodiment 9: the preparation of rapamycin composition
Take by weighing 90mg Eudragit S100, fully disperse, be dissolved in the alcoholic solution, form uniform solution, take by weighing the 20mg rapamycin, be dissolved in this solution; Get 110mg Wacker HDK N20 and above-mentioned solution mixing, liquid is fully adsorbed; This mixture is carried out vacuum drying, remove and desolvate, form white blocks of solid.Take out, pulverize, sieve, promptly.
Embodiment 10: the preparation of rapamycin composition
The aqueous dispersion (Sureteric) of weighing polyvinyl alcohol acetic acid phthalic acid ester (PVAP) an amount of (containing PVAP100mg) takes by weighing the 5mg rapamycin, is dissolved in this solution; Get the aqueous solution a small amount of (chitosan-containing 10mg) of 0.5% chitosan, add mixing in the above-mentioned solution; Get 120mg Neusilin US2 and above-mentioned solution mixing, liquid is fully adsorbed; This mixture spray drying except that desolvating, is formed white powder.Take out, sieve, promptly.
Embodiment 11: the preparation of rapamycin composition
Take by weighing Eudragit L 30D-55 (aqueous dispersion) an amount of (containing solid polymer 100mg), take by weighing the 10mg rapamycin, be dissolved in this solution; Get the aqueous solution a small amount of (chitosan-containing 10mg) of 0.5% chitosan, add mixing in the above-mentioned solution; Get 120mg Aerosil 380 and above-mentioned solution mixing, liquid is fully adsorbed; This mixture spray drying except that desolvating, is formed white powder.Take out, sieve, promptly.
Embodiment 12: the preparation of rapamycin composition
Take by weighing 100mg Eudragit S100, fully disperse, be dissolved in the acetone, form uniform solution, take by weighing the 20mg rapamycin, be dissolved in this solution; Get 100mg Aerosil 380 and above-mentioned solution mixing, liquid is fully adsorbed; The container that fills this mixture is placed vacuum desiccator, and removal of solvent under reduced pressure forms white blocks of solid.Take out, pulverize, sieve, promptly.
Embodiment 13: the preparation of rapamycin composition
Take by weighing 100mg Eudragit S100, fully disperse, be dissolved in the dehydrated alcohol, form uniform solution, take by weighing the 20mg rapamycin, be dissolved in this solution; Get 100mg Aerosil 300 and above-mentioned solution mixing, liquid is fully adsorbed; The container that fills this mixture is placed vacuum desiccator, and removal of solvent under reduced pressure forms white blocks of solid.Take out, pulverize, sieve, promptly.
Embodiment 14: the preparation of rapamycin composition
Take by weighing 100mg hypromellose phthalate ester (HP-55), fully disperse, be dissolved in the acetone, form uniform solution, take by weighing the 20mg rapamycin, be dissolved in this solution; Get 110mg Aerosil 300 and above-mentioned solution mixing, liquid is fully adsorbed; The container that fills this mixture is placed vacuum desiccator, and removal of solvent under reduced pressure forms solid mass.Take out, pulverize, sieve, promptly.
Embodiment 15: the preparation of rapamycin composition
Take by weighing 100mg hypromellose phthalate ester (HP-55), fully disperse, be dissolved in the acetone, form uniform solution, take by weighing the 30mg rapamycin, be dissolved in this solution; Get 110mg Wacker HDK N20 and above-mentioned solution mixing, liquid is fully adsorbed; The container that fills this mixture is placed vacuum desiccator, and removal of solvent under reduced pressure forms solid mass.Take out, pulverize, sieve, promptly.
Embodiment 16: the preparation of rapamycin composition
Take by weighing the 100mg Hydroxypropyl Methyl Cellulose Phthalate, fully disperse, be dissolved in the acetone, form uniform solution, take by weighing the 20mg rapamycin, be dissolved in this solution; Get 120mg Wacker HDK T30 and above-mentioned solution mixing, liquid is fully adsorbed; The container that fills this mixture is placed vacuum desiccator, and removal of solvent under reduced pressure forms solid mass.Take out, pulverize, sieve, promptly.
Embodiment 17: the preparation of rapamycin composition
Take by weighing the 500mg Hydroxypropyl Methyl Cellulose Phthalate, fully disperse, be dissolved in the acetone, form uniform solution, take by weighing the 100mg rapamycin, be dissolved in the chloroform, mix two kinds of solution; Get 3000mg Wacker HDKT40 and above-mentioned solution mixing, liquid is fully adsorbed; The container that fills this mixture is placed vacuum desiccator, and removal of solvent under reduced pressure forms solid mass.Take out, pulverize, sieve, promptly.
Embodiment 18: the preparation of rapamycin composition
Take by weighing 60mg Eudragit L100, fully disperse, be dissolved in the dehydrated alcohol, form uniform solution, take by weighing the 60mg rapamycin, dissolve in the above-mentioned solution; Get 150mg Aerosil 300 and above-mentioned solution mixing, liquid is fully adsorbed; The container that fills this mixture is placed vacuum desiccator, and removal of solvent under reduced pressure forms solid mass.Take out, pulverize, sieve, promptly.
Embodiment 20: the preparation of rapamycin composition
Take by weighing 100mg Eudragit S100, fully disperse, be dissolved in acetone/dehydrated alcohol mixed solvent, form uniform solution, take by weighing the 200mg rapamycin, be dissolved in the above-mentioned solution; Get 120mg Aerosil 380 and above-mentioned solution mixing, liquid is fully adsorbed; The container that fills this mixture is placed vacuum desiccator, and removal of solvent under reduced pressure forms solid mass.Take out, pulverize, sieve, promptly.
Embodiment 21: the preparation of rapamycin composition
Take by weighing 50mg Eudragit S100, fully disperse, be dissolved in the 10ml dehydrated alcohol, form uniform solution, take by weighing the luxuriant and rich with fragrance nobert of 200mg, be dissolved in this solution; Get 50mg Aerosil 200 and add in these solution, airtight infiltration, stirring or ultrasonic etc. are fully adsorbed liquid; The container that fills this mixture is placed vacuum desiccator, and removal of solvent under reduced pressure forms white blocks of solid.Take out, pulverize, sieve, promptly.
Embodiment 22: the preparation of rapamycin composition
Take by weighing 100mg EudragitL100-55, fully disperse, be dissolved in the 10ml dehydrated alcohol, form uniform solution, take by weighing the 100mg rapamycin, be dissolved in this solution; Get 200mg Sylysia 350 and add in these solution, airtight infiltration, stirring or ultrasonic etc. are fully adsorbed liquid; The container that fills this mixture is placed vacuum desiccator, and removal of solvent under reduced pressure forms white blocks of solid.Take out, pulverize, sieve back gained white powder and concentration are 10% chitosan aqueous solution mix homogeneously, get product after the spray drying.
Embodiment 23 contains the hard capsule of rapamycin composition
Solid composite among the embodiment 1 to embodiment 22 is packed in the hard gelatin capsule, seal, carry out the quality examination of capsule, promptly.
Embodiment 24 contains the hard capsule of rapamycin composition
Add adjuvant commonly used such as lactose, polyvinylpolypyrrolidone, Pulvis Talci etc. in the solid composite in embodiment 1 to embodiment 22, behind the mix homogeneously, mixture is packed in the hard gelatin capsule, seal.Carry out the quality examination of capsule, promptly.
Add HPMC in the solid composite in embodiment 1 to embodiment 22, behind the mix homogeneously, mixture is packed in the hard gelatin capsule, seal.Carry out the quality examination of capsule, promptly.
Embodiment 26 contains the hard capsule of rapamycin composition
Add HPMC in the solid composite in embodiment 1 to embodiment 22, and adjuvant commonly used such as lactose, polyvinylpolypyrrolidone, Pulvis Talci etc., behind the mix homogeneously, mixture is packed in the hard gelatin capsule, seal.Carry out the quality examination of capsule, promptly.
Embodiment 27 contains the tablet of rapamycin composition
Add adjuvant lactose commonly used, polyvinylpolypyrrolidone, microcrystalline Cellulose, Pulvis Talci etc. in the solid composite in embodiment 1 to embodiment 22, behind the mix homogeneously, direct compression carries out the quality examination of tablet, promptly.
Embodiment 28 contains the tablet of rapamycin composition
Add adjuvant lactose commonly used, HPMC, polyvinylpolypyrrolidone, microcrystalline Cellulose, Pulvis Talci etc. in the solid composite in embodiment 1 to embodiment 22, behind the mix homogeneously, direct compression carries out the quality examination of tablet, promptly.
Embodiment 29 contains the tablet of rapamycin composition
Add lactose, polyvinylpolypyrrolidone, microcrystalline Cellulose etc. in the solid composite in embodiment 1 to embodiment 22, behind the mix homogeneously, granulate, after the drying, add Pulvis Talci with 10%PVP solution, mix homogeneously, tabletting carries out the quality examination of tablet, promptly.
Add lactose, HPMC, polyvinylpolypyrrolidone, microcrystalline Cellulose etc. in the solid composite in embodiment 1 to embodiment 22, behind the mix homogeneously, granulate with 10%PVP solution, after the drying, add Pulvis Talci, mix homogeneously, tabletting carries out the quality examination of tablet, promptly.
The dissolution in vitro of embodiment 31 rapamycin solid composites of the present invention is measured
1, sample preparation
Take by weighing 90mg Eudragit L100-55, fully disperse, be dissolved in an amount of dehydrated alcohol, form uniform solution, take by weighing the 30mg rapamycin, be dissolved in the above-mentioned solution; Get 90mg Aerosil 200 and above-mentioned solution mixing, liquid is fully adsorbed; The container that fills said mixture is placed vacuum desiccator, and removal of solvent under reduced pressure forms white blocks of solid.Take out, pulverize, sieve, promptly get rapamycin solid composite R.A.E (L100-55).
2, assay method
Release medium: the pH7.4 aqueous solution 50ml that contains 0.4%SDS is as neutral medium, and the pH1.0 aqueous solution 50ml that contains 0.4%SDS is as acid medium
Release conditions: 37 ℃, constant temperature vibration, rotating speed 100rpm
Sample time and method: respectively at 5min, 10min, 20min, 30min, 1h, 3h, 5h sampling, each 0.5ml, and use the 0.2um membrane filtration, replenish release medium 0.5ml simultaneously
Detection method: the HPLC method is measured
(1) release under the acid condition
The result is that medicine did not almost discharge in 5 hours.
(2) release under the neutrallty condition
Result's medicine in the time of 20 minutes has just discharged about 85%.
The result shows that the rapamycin composition that the present invention prepares has good pH sensitivity when release in vitro, in sour environment, discharge hardly, and under neutrallty condition very fast release medicine.This specific character helps medicine and keeps stable under one's belt, and discharges rapidly in main absorption site small intestinal.
Embodiment 32 rapamycin composition character of the present invention are checked
Four kinds of material powder such as RAPA crude drug, A200 and Eudragit (L100-55) physical mixture, RAPA and A200 and Eudragit (L100-55) physical mixture, rapamycin solid composite R.A.EL100-55 are carried out X-ray powder diffraction analysis (Rigaku/max2500 type, Japan), and the comparative observation medicine crystal in each sample, have a situation.The characteristic X-ray collection of illustrative plates of sample as shown in Figure 2.The result shows, can observe the crystalline characteristic X-ray diffraction maximum of tangible RAPA raw material in the physical mixture that RAPA and A200 and E (L100-55) are formed, then not observe RAPA crystal diffraction peak in the X ray diffracting spectrum of rapamycin solid composite R.A.EL100-55.The result shows that RAPA may be in amorphous state in nanometer skeleton carrier system or drug molecule effectively is wrapped in carrier material inside.
The oral absorption of embodiment 33 rapamycin compositions of the present invention
Experiment purpose: (Rapamune) is reference with commercially available rapamycin, estimates rapamycin solid composite R.A.EL100-55 of the present invention in the intravital oral absorption situation of rat
Laboratory animal: male SD rat, body weight 250g,
The experiment grouping: animal is divided into 2 groups.Give respectively rapamycin solid composite R.A.EL100-55 (RAPA: A200: E (L100-55)=1: 3: 3, w/w) and commercially available rapamycin (Rapamune).
Administration and sampling: fasting is 12 hours before the test, freely drinks water.Irritate stomach respectively in 9:00-10:00am and give rapamycin composition (being prepared into suspension with preceding water, dosage 20mg/kg) and Rapamune microemulsion solution (dosage 5mg/kg).Respectively at getting blood 0.6ml through the eye socket rear vein beard in 0.25,0.5,1.0,2.0,3.0,4.0,6.0,8.0,12.0 and 24.0 hour after the administration, place the dry EP pipe of 1% anticoagulant heparin, chilled storage.Administration allows rat freely to drink water after 4 hours.
Sample treatment: adopt Waters OASIS HLB solid phase extraction column to handle blood sample, high efficient liquid phase analysis method detects.
The experimental result explanation, rapamycin solid composite R.A.EL100-55 (RAPA: A200: the E (L100-55)=1: 3: 3 of the present invention's preparation, w/w) be better than Rapamune in the intravital oral absorption situation of rat and compare, relative bioavailability is 266.05%.
Claims (10)
1, a kind of rapamycin composition of high bioavailability is characterized in that, its prescription is composed as follows:
Rapamycin 0.01-99.0%
PH Sensitive Polymer Materials 1-99.9%
Nanometer skeleton carrier 1-99.9%
Other pharmaceutic adjuvants 0-20%.
2, the rapamycin composition of claim 1 is characterized in that,
Rapamycin 0.1-70%
PH Sensitive Polymer Materials 5-90%
Nanometer skeleton carrier 5-80%
Other pharmaceutic adjuvants 0-20%.
3, the rapamycin composition of claim 2 is characterized in that,
Rapamycin 0.5-60%
PH Sensitive Polymer Materials 10-80%
Nanometer skeleton carrier 10-60%
Other pharmaceutic adjuvants 0-20%.
4, the rapamycin composition of claim 1, it is characterized in that, described nanometer skeleton carrier is selected from: silicon dioxide, calcium silicates, aluminium-magnesium silicate, Montmorillonitum, Bentonite, kaolin, magnesium trisilicate, magnesium silicate, activated carbon, attapulgite, saponite, Pulvis Talci, calcium sulfate, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, hydroxyapatite or their mixture, silica sol preferably, above-mentioned nanometer skeleton carrier can be anhydride, hydrate or contain not commensurability water of crystallization, can be colloid powder or microgranule with nanoaperture, described enteric solubility macromolecular material is selected from: the enteric solubility acrylic resin, the hypromellose phthalate ester, the cellulose acetate phthalate ester, Hydroxypropyl Methyl Cellulose Phthalate, polyvinyl alcohol acetic acid phthalic acid ester, cellulose acetate benzenetricarboxylic acid ester, 1,2,4-benzenetricarboxylic acid hydroxypropyl emthylcellulose, the succinic acid cellulose acetate, Lac or their mixture, above-mentioned enteric material comprises solid, aqueous dispersion, organic solution or commercially available coated formula, other pharmaceutic adjuvants can be selected from has bioadhesion, adjustment release speed or improve the medicinal materials of mobility of particle, as bioadhesive material, plasticizer, porogen, medicinal solid powder or their mixture, wherein said bioadhesive material is selected from chitosan, chitosan derivatives, chitin, alginic acid and sodium salt, xanthan gum, pectin and calcium pectinate, hyaluronic acid and sodium salt, agar, gelatin, glucosan, Carbopol, CMC, CMC, HPMC, HPC, HEC, MC, PVP or their mixture, the consumption of described bioadhesive polymer accounts for the 0.0-20.0% of final rapamycin composition weight; Wherein said plasticizer is selected from glycerol, propylene glycol, Polyethylene Glycol, triethyl citrate, glycerol triacetate, acetyl monoglyceride, phthalic acid ester, ethyl sebacate, Oleum Ricini or their mixture, and described plasticizer dosage accounts for the 0.0-20.0% of final rapamycin composition weight; Wherein said porogen is selected from PEG, propylene glycol, isopropyl alcohol, glycerol, lactose, glucose, sucrose, mannitol, sorbitol, sodium chloride or their mixture, and the consumption of porogen accounts for the 0.0-20.0% of final rapamycin composition weight; The wherein said material that improves mobility of particle is selected from Pulvis Talci, magnesium stearate, calcium stearate, zinc stearate, stearic acid, micropowder silica gel, solid-state PEG, Bentonite or their mixture, and the consumption of fluidizer accounts for the 0.0-20.0% of final rapamycin composition weight.
5, the preparation method of the rapamycin composition of claim 1, it is characterized in that,, be dissolved in together or respectively in organic solvent, water or their mixed solvent rapamycin, pH Sensitive Polymer Materials, other pharmaceutic adjuvants, together or respectively with nanometer framework material mix homogeneously, drying.
6, the preparation method of claim 5 is characterized in that, described solvent is organic solvent, water and composition thereof.Wherein organic solvent is selected from ethanol, acetone, dichloromethane, chloroform, methyl acetate, ethyl acetate or their mixture.Preferably ethanol, acetone or their mixture.
7, the preparation method of claim 5 is characterized in that, when enteric material adopts aqueous dispersion, organic solution or commercially available liquid coatings prescription, can or disperse medicine or other material dissolves wherein to mix with the nanometer framework material again.
8, the preparation method of claim 5, it is characterized in that, mix be selected from stirrings, rotate, soak into, grind, sieve, pulverize, spare matter, ultrasonic or their combination, drying is selected from vacuum drying, heat drying, spray drying, lyophilization, fluidized drying, infrared drying, microwave drying or their combination.
9, the preparation method of claim 5 is characterized in that, comprises the step of further making tablet, hard capsule, soft capsule, granule, powder, electuary, drop pill or pellet preparations.
10, the preparation method of claim 5 is characterized in that, takes by weighing 0.9g Eudragit S100, fully disperses, is dissolved in the dehydrated alcohol, forms uniform solution, takes by weighing the 0.3g rapamycin, is dissolved in this solution; Get 0.9g Aerosil 300 powders and above-mentioned solution mixing, liquid is fully adsorbed; The container that fills this mixture is placed vacuum desiccator, and removal of solvent under reduced pressure forms white blocks of solid.Take out, pulverize, sieve, promptly.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102961345A (en) * | 2012-11-20 | 2013-03-13 | 桂林电子科技大学 | Method for preparing rapamycin/magnetic carboxymethyl chitosan nano drug-loaded microspheres |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5536729A (en) * | 1993-09-30 | 1996-07-16 | American Home Products Corporation | Rapamycin formulations for oral administration |
| CN1883474A (en) * | 2005-06-22 | 2006-12-27 | 华北制药集团新药研究开发有限责任公司 | A composition containing macrolide compound and porous water insoluble hydrophilic carrier |
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| CN102961345A (en) * | 2012-11-20 | 2013-03-13 | 桂林电子科技大学 | Method for preparing rapamycin/magnetic carboxymethyl chitosan nano drug-loaded microspheres |
| CN102961345B (en) * | 2012-11-20 | 2014-05-21 | 桂林电子科技大学 | Method for preparing rapamycin/magnetic carboxymethyl chitosan nano drug-loaded microspheres |
| CN103933069B (en) * | 2014-05-09 | 2016-10-26 | 山东司邦得制药有限公司 | A kind of Fufang Anfenwanan capsules and preparation method thereof |
| CN106176614A (en) * | 2016-08-31 | 2016-12-07 | 佛山市弘泰药物研发有限公司 | A kind of everolimus nanoparticle, preparation and preparation method thereof |
| CN109939238A (en) * | 2019-04-10 | 2019-06-28 | 大连理工大学 | Hyaluronic acid decorated load medicine composite nano materials and preparation method thereof |
| CN109939238B (en) * | 2019-04-10 | 2021-09-24 | 大连理工大学 | Hyaluronic acid modified drug-loaded composite nano material and preparation method thereof |
| CN112516148A (en) * | 2020-04-10 | 2021-03-19 | 北京德立福瑞医药科技有限公司 | Meloxicam solid pharmaceutical composition and preparation method thereof |
| CN112516148B (en) * | 2020-04-10 | 2022-04-26 | 北京德立福瑞医药科技有限公司 | Meloxicam solid pharmaceutical composition and preparation method thereof |
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