CN101537184A - Composition containing water-insoluble high-activity drug and preparation method thereof - Google Patents
Composition containing water-insoluble high-activity drug and preparation method thereof Download PDFInfo
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- CN101537184A CN101537184A CN200910098087A CN200910098087A CN101537184A CN 101537184 A CN101537184 A CN 101537184A CN 200910098087 A CN200910098087 A CN 200910098087A CN 200910098087 A CN200910098087 A CN 200910098087A CN 101537184 A CN101537184 A CN 101537184A
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- 239000003814 drug Substances 0.000 title claims abstract description 55
- 229940079593 drug Drugs 0.000 title claims abstract description 43
- 230000000694 effects Effects 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 239000007962 solid dispersion Substances 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 12
- 239000000945 filler Substances 0.000 claims abstract description 10
- 239000008188 pellet Substances 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 239000007787 solid Substances 0.000 claims abstract description 7
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 claims description 35
- 239000002775 capsule Substances 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 claims description 21
- 239000012530 fluid Substances 0.000 claims description 16
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- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 3
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Images
Abstract
The invention discloses a composition containing a water-insoluble high-activity drug and a preparation method thereof. The water-insoluble high-activity drug is dissolved in an organic solvent containing a solid dispersion carrier, evenly sprayed on the surface of filler or blank pellets by adopting a fluidized bed and dried. The invention realizes the one-step completion of preparing the solid dispersion of the water-insoluble high-activity drug, pelleting and drying, has simple and convenient process, and no dust pollution, and effectively avoids the adverse influence of the high-activity drug on the health of production staff. The granules prepared by the method has even granularity, and good liquidity and compression formability, and can be further prepared into oral solid preparation. The composition prepared by the method has good drug dissolvability, and high oral absorption and bioavailability.
Description
Technical field
The present invention relates to medical technical field, specifically described a kind of composition and method of making the same of moisture insoluble high-activity drug.
Technical background
The molten high-activity drug of shipwreck is meant that in water dissolubility is very little and medicine that its biological activity is very high.Dissolubility is a kind of physical property of medicine, and the 1g medicine can not dissolve fully in 10000ml water and then be poorly water soluble drugs.The biological activity of high-activity drug is very high, and low dose just can produce very strong pharmacological action.
For example, tacrolimus (English name: Tacrolimus), also claim FK506, about 1～2 μ g/ml of the dissolubility in water, oral dose 0.1～0.3mg/kg/ days.Tacrolimus is a kind of macrolide antibiotics with strong immunosuppressive activity, and clinical practice is in the rejection and the autoimmune disease of organ transplantation postoperative, and its effect is renderd a service stronger 10～100 times than ciclosporin.
The solid preparation physical and chemical stability is good, manufacturing cost is lower, take and easy to carry, occupies higher ratio in pharmaceutical preparation.For poorly water soluble drugs, the principal element that how much will become influence, limit drug absorption of the speed of its dissolution rate and stripping quantity.Usually poorly water soluble drugs is made solid dispersion, medicine is dispersed in the carrier of ease of solubility, with molecule or ionic species to improve its absorption and bioavailability.Yet, need in traditional solid dispersion preparation process dried solid dispersion is pulverized, can produce bigger dust.High-activity drug just can produce very strong active force when low dose, for example tacrolimus has strong inhibitive ability of immunity, and the dust that produces in the crushing process is to producers' health and unfavorable.At present on commercial production, generally adopt a large amount of fund inputs to acquire protective device and facility comes strengthen labour protection.Therefore the technology of preparation process efficiently of being badly in need of a kind of environmental protection solves the dust pollution question in the production process, and reduces production costs.
Traditional fluid bed marumerization is mix homogeneously under fluidized state with drug powder and various adjuvant, sprays into binding agent then and granulates, and next step operation, no dust pollution are delivered in dry back discharging.Yet poorly water soluble drugs adopts traditional fluid bed marumerization preparation, and its dissolution can't reach requirement, causes bioavailability poor.High-activity drug is low because of its taking dose, needs to add a large amount of adjuvants and makes suitable dosage form.When the ratio of medicine and adjuvant comparatively during great disparity, it is inhomogeneous to adopt traditional fluid bed preparation method to be easy to cause mixing.Therefore need remedy above-mentioned deficiency in conjunction with new Technology.
Summary of the invention
The objective of the invention is to overcome the dust pollution that the molten high-activity drug of shipwreck produces in the prior art in commercial production, a kind of environmental protection is provided, be fit to the compositions of the moisture insoluble high-activity drug of industrialization.
The invention provides a kind of compositions of moisture insoluble high-activity drug, it can prepare by following method: molten high-activity drug of shipwreck and solid dispersion carrier are dissolved in the organic solvent, adopt fluid bed to make it be sprayed on filler or celphere surface equably, and dry.
Wherein said solid dispersion carrier is one or more in cellulose derivative, surfactant or the high molecular polymer; Wherein cellulose derivative is selected from one or more in hypromellose (HPMC), hyprolose (HPC), methylcellulose (MC) or the ethyl cellulose (EC); Surfactant is poloxamer (Poloxamer), one or more in sodium lauryl sulphate (Sodium Lauryl Sulfate) or the polyoxyethylene stearic acid ester (Polyoxyethylene Stearates); High molecular polymer is one or more in Polyethylene Glycol (PEG), polyvidone (PVP), polyacrylic resin (Eudragit), polyvinyl alcohol (PVA) or the polyoxyethylene (Polyethylene Oxide).Wherein the preferred cellulose derivant is as solid dispersion, particularly hypromellose (HPMC).
Wherein said organic solvent is one or more in methanol, ethanol, acetone, chloroform, dichloromethane, ethyl acetate or the ether.
Wherein said filler is one or more in lactose, starch, sucrose, mannitol or the maltose; Blank micropellets is one or more in cane sugar type medicinal core pellet, starch type medicinal core pellet or the microcrystalline Cellulose type medicinal core pellet, and particle diameter is 20～80 orders.
Wherein the part by weight of molten high-activity drug of shipwreck and solid dispersion carrier is 1: 0.5～1: 10, and medicine layer gain in weight is 0.1%～20%.
The molten high-activity drug of shipwreck all can be with this prepared preparation, such as tacrolimus, letrozole, Anastrozole, lenalidomide, cisapride, teniposide or etoposide etc.
The compositions of the moisture insoluble high-activity drug for preparing, can add acceptable diluent on the pharmacopedics, disintegrating agent, binding agent, lubricant, correctives etc., preparation process routinely, further making oral solid formulation and be used for clinically, and serves as preferred with capsule, tablet or dry suspension.
The present invention also provides a kind of preparation to contain the insoluble high-activity drug method for compositions, its method is: molten high-activity drug of shipwreck and solid dispersion carrier are dissolved in the organic solvent, adopt fluid bed to make it be sprayed on filler or celphere surface equably, and dry.In particular, its preparation method is:
The molten high-activity drug of shipwreck and solid dispersion carrier with the ratio of 1: 0.5～1: 10 weight ratio, are dissolved in an amount of organic solvent;
Said mixture is sprayed on filler or celphere surface in the fluid bed equably, and medicine layer gain in weight is 0.1%～20%;
Directly discharging behind the fluid bed inner drying.
Wherein said solid dispersion carrier is one or more in cellulose derivative, surfactant or the high molecular polymer; Wherein cellulose derivative is selected from one or more in hypromellose (HPMC), hyprolose (HPC), methylcellulose (MC) or the ethyl cellulose (EC); Surfactant is poloxamer (Poloxamer), one or more in sodium lauryl sulphate (Sodium Lauryl Sulfate) or the polyoxyethylene stearic acid ester (Polyoxyethylene Stearates); High molecular polymer is one or more in Polyethylene Glycol (PEG), polyvidone (PVP), polyacrylic resin (Eudragit), polyvinyl alcohol (PVA) or the polyoxyethylene (Polyethylene Oxide).Wherein the preferred cellulose derivant is as solid dispersion, particularly hypromellose (HPMC).
Wherein said organic solvent is one or more in methanol, ethanol, acetone, chloroform, dichloromethane, ethyl acetate or the ether.
Wherein said filler is one or more in lactose, starch, sucrose, mannitol or the maltose; Blank micropellets is one or more in cane sugar type medicinal core pellet, starch type medicinal core pellet or the microcrystalline Cellulose type medicinal core pellet, and particle diameter is 20～80 orders.
The molten high-activity drug of shipwreck all can be with this prepared preparation, such as tacrolimus, letrozole, Anastrozole, lenalidomide, cisapride, teniposide or etoposide etc.
The compositions of the moisture insoluble high-activity drug for preparing, can add acceptable diluent on the pharmacopedics, disintegrating agent, binding agent, lubricant, correctives etc., preparation process routinely, further making oral solid formulation and be used for clinically, and serves as preferred with capsule, tablet or dry suspension.
The compositions of the molten high-activity drug of shipwreck provided by the invention, according to " Chinese Pharmacopoeia 2005 editions " regulation, be not less than 70% at 45 minutes dissolutions, study on the stability (40 ℃, relative humidity 75%), after six months, outward appearance, content, dissolution have no significant change.
The present invention combines solid dispersions technique and fluidization advantage separately, the slightly water-soluble high-activity drug is made the form of solid dispersion, save the pulverizing process of solid dispersion preparation, replace with the fluid bed marumerization, thereby efficiently solve molten high-activity drug dissolution of shipwreck and dust two large problems.Compositions dissolution height, the processability of the molten high-activity drug of shipwreck of the present invention's preparation are good, and no dust pollution has significantly reduced the adverse effect of high-activity drug to producers' health in process of production.And preparation method technology is easy.
The composition medicine dissolution of the present invention's preparation is good, oral absorption and bioavailability height, and processability is good, can further make oral solid formulations such as capsule, tablet, dry suspension.
Description of drawings
Accompanying drawing 1: utilize the FK506 capsule of technical solution of the present invention preparation and the external stripping curve of reference substance (Prograf)
The FK506 capsule of accompanying drawing 2:22 name experimenter single oral technical solution of the present invention preparation and the average blood drug level of reference substance (Prograf) through the time curve
The specific embodiment
Following examples only are of the present invention further specifying, and should not be construed as limitation of the present invention.
Embodiment 1: the capsule, the tablet that with FK506 are active ingredient
FK506 1g
HPMC 1g
Lactose 63g
FK506 is dissolved in the 10mL ethanol, adds HPMC and fully disperse, add the 15mL dichloromethane and make its dissolving.Above-mentioned solution is sprayed at lactose granule surface in the fluid bed equably, blast pressure 0.1MPa, hydrojet speed 1mL/min, hydrojet pressure 0.05MPa, the medicine-feeding after drying 5min discharging that finishes.
The compositions that makes can be added 66.5g starch, 7g cross-linking sodium carboxymethyl cellulose and 1.5g magnesium stearate, be filled in capsule behind the mix homogeneously No. 4, make the capsule that labelled amount is 1mg, promptly sample 1.
The compositions that makes can be added 160g amylum pregelatinisatum, 60g microcrystalline Cellulose, 14g cross-linking sodium carboxymethyl cellulose and 1g magnesium stearate, be pressed into tablet behind the mix homogeneously, the heavy 300mg of sheet, labelled amount is 1mg.
Embodiment 2: the capsule, tablet, the dry suspension that with FK506 are active ingredient
FK506 1g
PVP 0.5g
HPMC 1.5g
Sucrose ball core 62g
FK506 is dissolved in the 12mL methanol, adds PVP and fully dissolve, add HPMC again and fully disperse, add the 18mL chloroform and make its dissolving.Above-mentioned solution is sprayed at sucrose ball wicking surface in the fluid bed equably, blast pressure 0.15MPa, hydrojet speed 1mL/min, hydrojet pressure 0.05MPa, the medicine-feeding after drying 5min discharging that finishes.
The compositions that makes can be added the 75g celphere, be filled in capsule behind the mix homogeneously No. 4, make the capsule that labelled amount is 1mg, promptly sample 2.
The compositions that makes can be added the 235g celphere, be pressed into tablet behind the mix homogeneously, the heavy 300mg of sheet, labelled amount is 1mg.
The compositions that makes can be added the 75g celphere, 6g sodium alginate and 0.5g strawberry essence are distributed into dry suspension behind the mix homogeneously, and labelled amount is 1mg.
Embodiment 3: the capsule, tablet, the dry suspension that with FK506 are active ingredient
FK506 1g
HPC 5g
Eudragit 2g
Microcrystalline Cellulose ball core 57g
FK506 is dissolved in the 25mL ethanol, adds HPC and Eudragit and fully dissolve.Above-mentioned solution is sprayed at microcrystalline Cellulose ball wicking surface in the fluid bed equably, blast pressure 0.15MPa, hydrojet speed 1mL/min, hydrojet pressure 0.05MPa, the medicine-feeding after drying 5min discharging that finishes.
The compositions that makes can be added the 75g celphere, be filled in capsule behind the mix homogeneously No. 4, make the capsule that labelled amount is 1mg, promptly sample 3.
The compositions that makes can be added the 235g celphere, be pressed into tablet behind the mix homogeneously, the heavy 300mg of sheet, labelled amount is 1mg.
The compositions that makes can be added the 75g celphere, but 4g arabic gum, 2g tragakanta and 0.5g essence are distributed into dry suspension behind the mix homogeneously, labelled amount is 1mg.
Embodiment 4: the capsule, the tablet that with the letrozole are active ingredient
Letrozole 2.5g
PEG400 8g
Starch 69.5g
Letrozole is dissolved in the 5mL acetone, adds the abundant mixing of PEG400.Above-mentioned solution is sprayed at starch surface in the fluid bed equably, blast pressure 0.1MPa, hydrojet speed 1mL/min, hydrojet pressure 0.05MPa, the medicine-feeding after drying 5min discharging that finishes.
The compositions that makes can be added 51.5g starch, 7g cross-linking sodium carboxymethyl cellulose and 1.5g magnesium stearate, be filled in capsule behind the mix homogeneously No. 4, make the capsule that labelled amount is 2.5mg.
The compositions that makes can be added 145g amylum pregelatinisatum, 60g microcrystalline Cellulose, 14g cross-linking sodium carboxymethyl cellulose and 1g magnesium stearate, be pressed into tablet behind the mix homogeneously, the heavy 300mg of sheet, labelled amount is 2.5mg.
Embodiment 5: the capsule, tablet, the dry suspension that with the Anastrozole are active ingredient
Anastrozole 1g
Poloxamer 3.5g
Starch ball core 60.5g
Anastrozole is dissolved in the 20mL ethanol, adds poloxamer and make its dissolving.Above-mentioned solution is sprayed at starch ball wicking surface in the fluid bed equably, blast pressure 0.15MPa, hydrojet speed 1mL/min, hydrojet pressure 0.05MPa, the medicine-feeding after drying 5min discharging that finishes.
The compositions that makes can be added the 75g celphere, be filled in capsule behind the mix homogeneously No. 4, make the capsule that labelled amount is 1mg.
The compositions that makes can be added the 235g celphere, be pressed into tablet behind the mix homogeneously, the heavy 300mg of sheet, labelled amount is 1mg.
The compositions that makes can be added the 75g celphere, 6g sodium alginate and 0.5g strawberry essence are distributed into dry suspension behind the mix homogeneously, and labelled amount is 1mg.
Embodiment 6: the capsule, the tablet that with the lenalidomide are active ingredient
Lenalidomide 2.5g
PVP 2g
Eudragit 3g
Lactose 57.5g
Lenalidomide is dissolved in the 25mL ethanol, adds PVP and Eudragit and make its dissolving.Above-mentioned solution is sprayed at lactose surface in the fluid bed equably, blast pressure 0.1MPa, hydrojet speed 1mL/min, hydrojet pressure 0.05MPa, the medicine-feeding after drying 5min discharging that finishes.
The compositions that makes can be added 4g cross-linking sodium carboxymethyl cellulose and 1g magnesium stearate, be filled in capsule behind the mix homogeneously No. 4, make the capsule that labelled amount is 5mg.
The compositions that makes can be added 47g amylum pregelatinisatum, 30g microcrystalline Cellulose, 7g cross-linking sodium carboxymethyl cellulose and 1g magnesium stearate, be pressed into tablet behind the mix homogeneously, the heavy 300mg of sheet, labelled amount is 5mg.
Experimental example 7: external dissolution test
" second method in 2005 editions appendix XC of Chinese pharmacopoeia dissolution method, oar method, dissolution medium: contain 0.005% hydroxypropyl cellulose (HPC), pH value 4.5,900mL, rotating speed 50 commentaries on classics/min, 37.0 ℃ ± 0.5 ℃ of temperature are adopted in this test.Respectively at 15min, 30min, 45min, 60min takes a sample when 90min and 120min, measures concentration and calculates the accumulation dissolution.
Concentration adopts high effective liquid chromatography for measuring, and chromatographic column is a filler with octyl silane group silica gel; 0.1% phosphate aqueous solution: acetonitrile (40: 60) is a mobile phase; Flow velocity 1.0mL/min; Sample size 100 μ L; 50 ℃ of column temperatures; Detect wavelength 210nm.
The contrast medicine is Prograf (Prograf) 1mg capsule (lot number 1D5152A), and Japanese rattan pool company (Fujisawa) produces.
The external stripping curve of sample 1, sample 2, sample 3 and Prograf is seen accompanying drawing 1, sample 1 (band lineae trapezoidea) and the external stripping curve similar factors F of Prograf (band triangle line)
2=58.7; Sample 2 (band square line) and the external stripping curve similar factors of Prograf F
2=59.3; Sample 3 (band rice molded lines) and the external stripping curve similar factors of Prograf F
2=55.1.
Accompanying drawing and data declaration, consistent with the capsular stripping of tacrolimus of technical scheme preparation provided by the invention with Prograf.
Experimental example 8: bioequivalence test
Adopt open at random, own control, divide 2 stage trial design.All experimenters are divided into 2 groups at random, every group 11, every experimenter is divided into 2 stages and takes medicine, 14 days at least at interval per stage, each experimenter will divide for 2 stages took following any test medication at random: tacrolimus capsule (sample 1), Prograf (Prograf) 1mg capsule (lot number 1D5152A), Japanese rattan pool company (Fujisawa) produces.
Each stage of taking medicine is observed 72 hours obtaining plasma concentration curve, the test article (sample 1) of 22 experimenter's single oral 5mg amounts or the average blood drug level of reference substance (Prograf) through the time curve see Fig. 2.
The average pharmacokinetic parameter of test article of 22 experimenter's single oral 5mg amounts (sample 1, band square line) or reference substance (Prograf, band triangle line) sees the following form.
| Parameter | Test article | Reference substance |
| AUC 0-inf±SD(h*ng/mL) | 437.017±239.3502 | 394.944±186.3394 |
| AUC 0-t±SD(h*ng/mL) | 366.996±191.2464 | 330.274±143.4726 |
| C max±SD(ng/mL) | 49.41±22.21 | 41.30±19.63 |
| T max±SD(h) | 1.20±0.40 | 1.70±0.77 |
| T 1/2±SD(h) | 31.00±11.36 | 31.43±9.04 |
AUC, Cmax after to number conversion statistical results show both have bioequivalence, the average relative bioavailability of test article is calculated as 114.125 ± 50.137% with AUCinf; The average relative bioavailability of test article is calculated as 114.754 ± 48.690% with AUCt.Interpret sample 1 is consistent with the bioavailability of Prograf.
Claims (10)
1, a kind of compositions of moisture insoluble high-activity drug is characterized in that molten high-activity drug of shipwreck and solid dispersion carrier are dissolved in the organic solvent, adopts fluid bed to make it be sprayed on filler or celphere surface equably, and dry.
2, by the described compositions of claim 1, it is characterized in that described solid dispersion carrier is one or more in cellulose derivative, surfactant or the high molecular polymer; Organic solvent is one or more in methanol, ethanol, acetone, chloroform, dichloromethane, ethyl acetate or the ether; Filler is one or more in lactose, starch, sucrose, mannitol or the maltose; Blank micropellets is one or more in cane sugar type medicinal core pellet, starch type medicinal core pellet or the microcrystalline Cellulose type medicinal core pellet, and particle diameter is 20～80 orders.
3, by the described compositions of claim 2, it is characterized in that described cellulose derivative is one or more in hypromellose, hyprolose, methylcellulose or the ethyl cellulose.
4, by the described compositions of claim 2, it is characterized in that described surfactant is one or more in poloxamer, sodium lauryl sulphate or the polyoxyethylene stearic acid ester.
5, by the described compositions of claim 2, it is characterized in that described high molecular polymer is one or more in Polyethylene Glycol, polyvidone, polyacrylic resin, polyvinyl alcohol or the polyoxyethylene.
6,, it is characterized in that the molten high-activity drug of described shipwreck is a kind of in tacrolimus, letrozole, Anastrozole, lenalidomide, cisapride, teniposide or the etoposide by the described compositions of claim 1.
7, by the described compositions of claim 1, it is characterized in that the part by weight 1: 0.5～1: 10 of molten high-activity drug of described shipwreck and solid dispersion carrier, medicine layer gain in weight is 0.1%～20%.
8,, it is characterized in that described compositions can further make oral solid formulation by the described compositions of claim 1.
9, by the described compositions of claim 1, it is characterized in that described oral solid formulation is capsule, tablet or dry suspension.
10, a kind of preparation compositions method as claimed in claim 1 is characterized in that molten high-activity drug of shipwreck and solid dispersion carrier are dissolved in the organic solvent, adopts fluid bed to make it be sprayed on filler or celphere surface equably, and dry.
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