CN103550158B - Emodin solid dispersion, drug-containing pellet core, colonic targeted micropill, and applications of three - Google Patents
Emodin solid dispersion, drug-containing pellet core, colonic targeted micropill, and applications of three Download PDFInfo
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Abstract
The invention relates to emodin solid dispersion, a drug-containing pellet core, a colonic targeted micropill, and applications of the three. The emodin solid dispersion is prepared from emodin and a carrier material, wherein the carrier material is one or several selected from poloxamer 188, poloxamer 407, Kollidon 12 PF, Kollidon VA 64, Kollicoat IR or Soluplus, and the weight ratio of emodin to the carrier material is 1:2-1:15. The drug-containing pellet core and the colonic targeted micropill both contain the emodin solid dispersion. The emodin solid dispersion is substantially improved in solubility of indissolvable drug emodin; and the targeted micropill helps to realize colonic positioning release in vivo/vitro of emodin, and has substantial protective effect on intestinal barrier of a rat severe acute pancreatitis pancreatitis model.
Description
Technical field
The present invention relates to pharmaceutics technical field, specifically, is a kind of emodin solid dispersion and colon-targeted pellets and preparation method thereof.
Background technology
Acute pancreatitis is the serious disease that a kind of state of an illness is heavy, complication is many, medical expense is high, prognosis is dangerous, there is no desirable remedy measures so far.Severe Acute Pancreatitis SAP (severe acute pancreatitis, SAP) is because of its normal and multiple Organ Failure (MSOF), and case fatality rate reaches 10% ~ 30%, and the case fatality rate of Operation treatment can reach 80%.How preventing and treating MSOF is the major issue that must solve in SAP treatment.Gut barrier function obstacle, secondary intestinal microbial population and Endotoxin Translocation are the important steps of trigger systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS) and MSOF.
The traditional Chinese medical science think pancreatitis pathogenesis for wet to accumulate, blood stasis, internal organs hold one's breath stagnant etc.Chinese medicine Radix Et Rhizoma Rhei can play the effect of dredging intestines, clearing heat secreting bile, has been widely used in the treatment of acute pancreatitis, and achieves certain clinical efficacy.But Radix Et Rhizoma Rhei is easily absorbed decomposition at upper digestive tract, poor stability, oral administration is difficult to concentrate in target site---colon, thus the performance affecting its drug effect.The mode of conventional coloclysis administration clinically solves this problem at present.But after coloclysis administration, Radix Et Rhizoma Rhei is large in colon skewness, individual variation, uses inconvenience, patient's poor compliance, and traditional Radix Et Rhizoma Rhei needs fried, and preparation inconvenience, dose is not easily grasped, and causes the workload of healthcare givers large simultaneously.If Radix Et Rhizoma Rhei can be made oral colon targeting preparation, not only facilitate clinical administration, it also can be avoided to destroy and the adverse effect of liver first-pass effect at upper gastrointestinal tract, thus improve curative effect, facilitate patient medication.
Emodin is the principle active component of Chinese herb rhubarb, and its pharmacological action and Radix Et Rhizoma Rhei have many similarities.Emodin chemistry 1,3,8-trihydroxy-6 tectoquinone by name, molecular weight is 270.23, and its chemical constitution belongs to hydroxy anthraquinones, is specially:
.There are some researches show, emodin all has very strong inhibitory action to pancreas kallikrein, trypsin, pancreatic lipase, IC
50be respectively 31.5,40.5 and 46.5 μ g/mL.Zoopery shows, and emodin and EEN therapeutic alliance are the effective ways recovering function of intestinal canal, suppress SAP to develop.After Effects of Emodin pancreatitis, pancreatic tissue transforming growth factor is expressed and is obviously strengthened, and peak moves forward, and pancreas gross protein, DNA synthetic obviously increase, and participates in regeneration and the reparation of pancreatic tissue.But the poor solubility of emodin, the dissolubility in water is only 1.98 μ g/mL, and the dissolubility in artificial colonic fluid is 4.68 μ g/mL, greatly affects the performance of oral drug effect.Therefore improve the dissolubility of emodin, strengthen its targeting, the treatment for Severe Acute Pancreatitis SAP is significant.
Chinese periodical " Chinese herbal medicine " the 42nd volume the 3rd phase, the paper " preparation of emodin solid dispersion and dissolution determination thereof " published in March, 2011, polyvinylpyrrolidone (PVP K30) and Polyethylene Glycol (PEG 8000) is selected to be carrier, emodin solid dispersion is prepared with solvent method, when experiment confirms that the mass ratio of emodin and PVP is 1:4, the solid dispersion made 45min cumulative leaching rate in simulated intestinal fluid is 70%, dissolubility at 37 DEG C is 107.3 μ g/mL, improves the dissolubility of emodin.The paper " preparation of pH dependence-time lag type emodin colon-specific pellets and tablets in vitro research " that Chinese periodical " Chinese herbal medicine " 10 periodicals in 2011 go out, centrifugal granulating seed-coating machine is adopted to prepare medicine carrying micropill with powder bed area method, and rely on skin (Eudragit FS 30D) by coating time lag internal layer (Eudragit RL 30D) successively and pH and prepare pH dependence-time lag type emodin colon-specific pellets, find that it has obvious conlon targeting characteristic.
But further research and development dissolubility better emodin solid dispersion and the better emodin colon-targeted pellets of locating effect are still very necessary.
Summary of the invention
The object of the invention is for deficiency of the prior art, a kind of emodin solid dispersion is provided.
Of the present invention again one object be provide a kind of containing pill core.
Another object of the present invention provides a kind of emodin colon-targeted pellets.
4th object of the present invention is, provides above-mentioned emodin solid dispersion, purposes containing pill core, emodin colon-targeted pellets.
For realizing above-mentioned first object, the technical scheme that the present invention takes is:
A kind of emodin solid dispersion, be made up of emodin and carrier material, described carrier material is selected from one or more in PLURONICS F87, poloxamer188, polyvinylpyrrolidone (Kollidon 12 PF), copolyvidone (Kollidon VA64), Polyethylene Glycol/polyvinyl alcohol graft copolymerized copolymer (Kollicoat IR) or Soluplus, and described emodin and the weight ratio of carrier material are 1:2 ~ 1:15.
The preferred copolyvidone of described carrier material (Kollidon VA64).
Described emodin and the preferred 1:2 ~ 1:5 of the weight ratio of carrier material.
Described emodin solid dispersion adopts hot-melt extruded legal system standby, and its preparation process is: take emodin and carrier material mixes, and puts in hot-melt extruded equipment, under suitable temperature, speed conditions, fusing is extruded, cooling, pulverize, cross 60 ~ 120 mesh sieves, to obtain final product.Wherein hot melting temperature is 50 ~ 250 DEG C, and screw speed is 15 ~ 100rpm.
For realizing above-mentioned second object, the technical scheme that the present invention takes is:
A kind of containing pill core, it adds mixing diluents by as above arbitrary described emodin solid dispersion, then add that wetting agent or adhesive prepare.
Particularly, take emodin solid dispersion and appropriate diluent, mix homogeneously, add appropriate wetting agent or adhesive, soft material processed, wet feed extruding sieve, strip wet feed cut off round as a ball, be drying to obtain containing pill core.Described wetting agent or the consumption of adhesive are appropriate, and all there are relation its consumption and ambient humidity and operating time, and those skilled in the art can determine according to traditional drug formulations method.
Described emodin and the preferred 1:0.5 ~ 1:12 of the weight ratio of diluent.
Described diluent, wetting agent and adhesive can adopt galenic pharmacy conventional thinner, wetting agent and adhesive.Described diluent can select one or more in microcrystalline Cellulose pH101, microcrystalline Cellulose pH102, microcrystalline Cellulose pH103, microcrystalline Cellulose pH301, microcrystalline Cellulose pH302, microcrystalline Cellulose pH303, lactose, chitosan, starch, DI-CALCIUM PHOSPHATE, wherein preferably microcrystalline cellulose pH101 and lactose used in combination, the preferred 3:7 ~ 7:3 of the two weight ratio; Described wetting agent can select water, 30% ~ 80% ethanol; Described adhesive can select 3% ~ 5% polyvinylpyrrolidone, 2% ~ 5% hydroxypropyl methylcellulose, 1% ~ 2% sodium carboxymethyl cellulose, 2% ~ 7% hydroxypropyl cellulose etc.
For realizing above-mentioned 3rd object, the technical scheme that the present invention takes is:
A kind of emodin colon-targeted pellets, it is prepared by one or more coatings superscribed in time lag layer, pH Dependent Layer, enzyme contact layer containing pill core as above.
Particularly, adopt fluidized bed coating, time lag layer or pH Dependent Layer or enzyme contact layer or above-mentioned two or more clothing layers any will be superscribed containing pill core.If micropill wraps up two or more clothing layers, its order of the chromosomal packing is: first wrap up time lag layer, then wrap up enzyme contact layer, finally wraps up pH Dependent Layer.
Described coating can be 8.5% ~ 35% with containing the percentage by weight of pill core, and preferably 10% ~ 35%.
Described time lag layer comprises time lag material, porogen, plasticizer, antitackiness agent.Wherein time lag material can select hydroxypropyl emthylcellulose (HPMC), ethyl cellulose (EC), cellulose acetate (AC), Eudragit RL 30D etc.Porogen can select low-viscosity HPMC or PVP K30.Plasticizer can adopt triethyl citrate (TEC), and consumption is 2% ~ 15% of micropill gross weight, and wherein preferably 10%.Antitackiness agent can adopt Pulvis Talci, and consumption is 10% ~ 50% of micropill gross weight, and wherein preferably 50%.
Described pH Dependent Layer comprises pH sensitive material, plasticizer, antitackiness agent.Wherein pH sensitive material can select Eudragit S 100, Eudragit III or Eudragit FS 30D.Plasticizer can adopt triethyl citrate (TEC), and consumption is 2% ~ 15% of micropill gross weight, and wherein preferably 10%.Antitackiness agent can adopt Pulvis Talci, and consumption is 10% ~ 50% of micropill gross weight, and wherein preferably 50%.
Described enzyme contact layer comprises enzyme and touches material, wetting agent.Wherein enzyme touches the optional nitrogen compound of choosing spouse of material, amylose, glucosan, pectin or guar gum, and use amount is 1% ~ 10% of micropill gross weight, and preferably 4%.Wetting agent can select HPMC, and use amount is 5% ~ 20% of micropill gross weight, and preferably 15%.Enzyme touches material and the preferred 2:1 ~ 1:10 of wetting agent weight ratio.
For realizing above-mentioned 4th object, the technical scheme that the present invention takes is:
As above arbitrary described emodin solid dispersion, as above containing pill core, the as above arbitrary described flavin colon-targeted pellets purposes in preparation treatment Severe Acute Pancreatitis SAP medicine.
It should be noted that, the preparation method and the fluidized bed coating that more than contain pill core prepare targeted micropill, and the consumption of its concrete steps and pharmaceutical carrier is this area routine operation.
The invention has the advantages that:
1, a kind of emodin solid dispersion is provided, which employs specific carrier material, confirm that emodin dissolubility significantly improves through solubility experiment, and be significantly better than emodin solid dispersion of the prior art, as Chinese periodical " Chinese herbal medicine " the 42nd volume the 3rd phase, polyvinylpyrrolidone (PVP K30) is selected, the emodin solid dispersion prepared with solvent method disclosed in the paper " preparation of emodin solid dispersion and dissolution determination thereof " published in March, 2011;
2, provide a kind of comprise emodin solid dispersion of the present invention containing pill core, should possess containing pill core the advantage that emodin dissolubility is high, bioavailability is high equally;
3, a kind of emodin colon-targeted pellets comprising emodin solid dispersion of the present invention is provided; in extracorporeal releasing experiment, Internal pharmacokinetics experiment and body, pharmacodynamic experiment result confirms; it all can realize conlon targeting release in vivo and in vitro; emodin bioavailability can be improved; to severe acute pancreatitis in rats model gut barrier, there is significant protective effect, therefore can be used for effectively treating Severe Acute Pancreatitis SAP.
Accompanying drawing explanation
Accompanying drawing 1 is emodin colon-targeted pellets In-vitro release curves.
Accompanying drawing 2 is Drug-time curve (n=6) in Oral Rhubarb element colon-targeted pellets rat body.
Detailed description of the invention
Below in conjunction with accompanying drawing, detailed description of the invention provided by the invention is elaborated.
embodiment 1 emodin is containing the preparation () of pill core
Emodin 10g
Carrier material: copolyvidone (Kollidon VA64) 20g
Diluent: microcrystalline Cellulose pH101 70g
Adhesive: 5% hydroxypropyl cellulose (HPC) 20mL
By above-mentioned weight, take emodin and copolyvidone (Kollidon VA64), mix homogeneously, is placed in hot-melt extruded equipment, design temperature is about 160 DEG C, screw speed 30 rpm, and fusing is extruded, after cooling, pulverize, cross 60 mesh sieves, obtain emodin solid dispersion.Mixed homogeneously with microcrystalline Cellulose pH101 by emodin solid dispersion, then add adhesive 5% HPC, mediate evenly, soft material processed, be screened into slice, shearing rounding in spheronizator through extruder extruding, 50 DEG C of drying 3 h, obtain emodin pastille micropill.
embodiment 2 emodin is containing the preparation (two) of pill core
Emodin 10g
Carrier material: Soluplus 30g
Diluent: microcrystalline Cellulose pH101 30g, lactose 30g
Wetting agent: water 15mL
By above-mentioned weight, take emodin and Soluplus, mix homogeneously, be placed in hot-melt extruded equipment, design temperature is about 130 DEG C, screw speed 40 rpm, and fusing is extruded, and after cooling, pulverizes, crosses 60 mesh sieves, obtain emodin solid dispersion.Mixed homogeneously with microcrystalline Cellulose pH101, lactose by emodin solid dispersion, add suitable quantity of water, mediate evenly, soft material processed, be screened into slice, shearing rounding in spheronizator through extruder extruding, 50 DEG C of drying 3 h, obtain emodin pastille micropill.
embodiment 3 emodin is containing the preparation (three) of pill core
Emodin 10g
Carrier material: Polyethylene Glycol/polyvinyl alcohol graft copolymerized copolymer (Kollicoat IR) 40g
Diluent: chitosan 30g
Wetting agent: 30% ethanol 15mL
By above-mentioned weight, take emodin and Polyethylene Glycol/polyvinyl alcohol graft copolymerized copolymer (Kollicoat IR), mix homogeneously, is placed in hot-melt extruded equipment, and design temperature is about 170 DEG C, screw speed 50 rpm, fusing is extruded, and after cooling, pulverizes, cross 60 mesh sieves, obtain emodin solid dispersion.Mixed homogeneously with chitosan by emodin solid dispersion, add 30% ethanol, mediate evenly, soft material processed, be screened into slice, shearing rounding in spheronizator through extruder extruding, 50 DEG C of drying 3 h, obtain pastille micropill.
embodiment 4 emodin is containing the preparation (four) of pill core
Emodin 10g
Carrier material: polyvinylpyrrolidone (Kollidon 12 PF) 50g
Diluent: microcrystalline Cellulose pH301 40g
Wetting agent: 50% ethanol 20mL
By above-mentioned weight, take emodin and polyvinylpyrrolidone (Kollidon 12 PF), mix homogeneously, is placed in hot-melt extruded equipment, design temperature is about 110 DEG C, screw speed 35 rpm, and fusing is extruded, after cooling, pulverize, cross 60 mesh sieves, obtain emodin solid dispersion.Mixed homogeneously with microcrystalline Cellulose pH301 by emodin solid dispersion, add 50% ethanol, mediate evenly, soft material processed, be screened into slice, shearing rounding in spheronizator through extruder extruding, 50 DEG C of drying 3 h, obtain pastille micropill.
embodiment 5 emodin is containing the preparation (five) of pill core
Emodin 10g
Carrier material: copolyvidone (Kollidon VA64) 150g
Diluent: microcrystalline Cellulose pH102 120g
Adhesive: 5% PVPK30 mL
By above-mentioned weight, take emodin and copolyvidone (Kollidon VA64), mix homogeneously, is placed in hot-melt extruded equipment, design temperature is about 160 DEG C, screw speed 30 rpm, and fusing is extruded, after cooling, pulverize, cross 60 mesh sieves, obtain emodin solid dispersion.Emodin solid dispersion is mixed homogeneously with microcrystalline Cellulose pH102, then adds adhesive 5% polyvinylpyrrolidone, mediate evenly, soft material processed, is screened into slice, shearing rounding in spheronizator through extruder extruding, 50 DEG C of drying 3 h, obtain emodin pastille micropill.
embodiment 6 emodin is containing the preparation (six) of pill core
Emodin 10g
Carrier material: copolyvidone (Kollidon VA64) 50g
Diluent: poloxamer188 50g, PLURONICS F87 50g
Adhesive: 4% hydroxypropyl methylcellulose 20mL
By above-mentioned weight, take emodin and copolyvidone (Kollidon VA64), mix homogeneously, is placed in hot-melt extruded equipment, design temperature is about 160 DEG C, screw speed 30 rpm, and fusing is extruded, after cooling, pulverize, cross 60 mesh sieves, obtain emodin solid dispersion.Emodin solid dispersion is mixed homogeneously with poloxamer188 and PLURONICS F87, then adds adhesive 4% hydroxypropyl methylcellulose, mediate evenly, soft material processed, is screened into slice, shearing rounding in spheronizator through extruder extruding, 50 DEG C of drying 3 h, obtain emodin pastille micropill.
embodiment 7 emodin is containing the preparation (seven) of pill core
Emodin 10g
Carrier material: Soluplus 30g, polyvinylpyrrolidone (Kollidon 12 PF) 10g
Diluent: microcrystalline Cellulose pH101 30g, lactose 70g
Wetting agent: water 20mL
By above-mentioned weight, take emodin, Soluplus and polyvinylpyrrolidone (Kollidon 12 PF), mix homogeneously, is placed in hot-melt extruded equipment, and design temperature is about 130 DEG C, screw speed 40 rpm, fusing is extruded, and after cooling, pulverizes, cross 60 mesh sieves, obtain emodin solid dispersion.Mixed homogeneously with microcrystalline Cellulose pH101 and lactose by emodin solid dispersion, add suitable quantity of water, mediate evenly, soft material processed, be screened into slice, shearing rounding in spheronizator through extruder extruding, 50 DEG C of drying 3 h, obtain emodin pastille micropill.
embodiment 8 emodin is containing the preparation (eight) of pill core
Emodin 10g
Carrier material: Polyethylene Glycol/polyvinyl alcohol graft copolymerized copolymer (Kollicoat IR) 60g
Diluent: microcrystalline Cellulose pH101 3.5g, lactose 1.5g
Wetting agent: 80% ethanol 15mL
By above-mentioned weight, take emodin, Polyethylene Glycol/polyvinyl alcohol graft copolymerized copolymer (Kollicoat IR), mix homogeneously, is placed in hot-melt extruded equipment, and design temperature is about 130 DEG C, screw speed 40 rpm, fusing is extruded, and after cooling, pulverizes, cross 60 mesh sieves, obtain emodin solid dispersion.Mixed homogeneously with microcrystalline Cellulose pH101 and lactose by emodin solid dispersion, add suitable quantity of water, mediate evenly, soft material processed, be screened into slice, shearing rounding in spheronizator through extruder extruding, 50 DEG C of drying 3 h, obtain emodin pastille micropill.
embodiment 9 emodin is containing the preparation (nine) of pill core
Emodin 10g
Carrier material: copolyvidone (Kollidon VA64) 20g
Diluent: microcrystalline Cellulose pH103 20g, microcrystalline Cellulose pH302 20g, starch 20g, DI-CALCIUM PHOSPHATE 10g;
Adhesive: 2% sodium carboxymethyl cellulose 20mL
By above-mentioned weight, take emodin and copolyvidone (Kollidon VA64), mix homogeneously, is placed in hot-melt extruded equipment, design temperature is about 160 DEG C, screw speed 30 rpm, and fusing is extruded, after cooling, pulverize, cross 60 mesh sieves, obtain emodin solid dispersion.Emodin solid dispersion is mixed homogeneously with microcrystalline Cellulose pH103, microcrystalline Cellulose pH302, starch, DI-CALCIUM PHOSPHATE, add adhesive 2% sodium carboxymethyl cellulose again, mediate evenly, soft material processed, slice is screened into through extruder extruding, shearing rounding in spheronizator, 50 DEG C of drying 3 h, obtain emodin pastille micropill.
comparative example 1 emodin contrasts (one) containing the preparation of pill core
Emodin 10g
Carrier material: copolyvidone (Kollidon VA64) 19g
Diluent: microcrystalline Cellulose pH101 70g
Adhesive: 5% hydroxypropyl cellulose (HPC) 20mL
By above-mentioned weight, take emodin and copolyvidone (Kollidon VA64), mix homogeneously, is placed in hot-melt extruded equipment, design temperature is about 160 DEG C, screw speed 30 rpm, and fusing is extruded, after cooling, pulverize, cross 60 mesh sieves, obtain emodin solid dispersion.Mixed homogeneously with microcrystalline Cellulose pH101 by emodin solid dispersion, then add adhesive 5% HPC, mediate evenly, soft material processed, be screened into slice, shearing rounding in spheronizator through extruder extruding, 50 DEG C of drying 3 h, obtain emodin pastille micropill.
comparative example 2 emodin contrasts (two) containing the preparation of pill core
Emodin 10g
Carrier material: copolyvidone (Kollidon VA64) 155g
Diluent: microcrystalline Cellulose pH102 120g
Adhesive: 5% PVPK30 mL
By above-mentioned weight, take emodin and copolyvidone (Kollidon VA64), mix homogeneously, is placed in hot-melt extruded equipment, design temperature is about 160 DEG C, screw speed 30 rpm, and fusing is extruded, after cooling, pulverize, cross 60 mesh sieves, obtain emodin solid dispersion.Emodin solid dispersion is mixed homogeneously with microcrystalline Cellulose pH102, then adds adhesive 5% polyvinylpyrrolidone, mediate evenly, soft material processed, is screened into slice, shearing rounding in spheronizator through extruder extruding, 50 DEG C of drying 3 h, obtain emodin pastille micropill.
embodiment 10 pH dependent form emodin colon-targeted pellets preparation (one)
Containing pill core 100g
Eudragit FS 30D 5g
Triethyl citrate (TEC) 0.5g
Pulvis Talci 3g
90% ethanol 200mL
By above-mentioned weight, take Eudragit FS 30D and triethyl citrate (TEC), Pulvis Talci, be dissolved in 90% ethanol, stir, 80 eye mesh screens filter, and obtain coating solution.The pill core that contains of arbitrary for embodiment 1-9 preparation is placed in fluid bed, preheating 5 about min, adjustment atomizing pressure is 1.5Pa, fluidized pressure is 1.0Pa, temperature of charge be 36 DEG C and constant flow pump rotating speed is 8rad/min, coating, drying, obtains pH dependent form emodin colon-targeted pellets.
embodiment 11 pH dependent form emodin colon-targeted pellets preparation (two)
Containing pill core 100g
Eudragit S 100 10g
Triethyl citrate (TEC) 1g
Pulvis Talci 5g
80% ethanol 200mL
By above-mentioned weight, take Eudragit S 100 and triethyl citrate (TEC), Pulvis Talci, be dissolved in 80% ethanol, stir, 80 eye mesh screens filter, and obtain coating solution.The pill core that contains of arbitrary for embodiment 1-9 preparation is placed in fluid bed, preheating 5 about min, adjustment atomizing pressure is 1.0Pa, fluidized pressure is 0.5Pa, temperature of charge be 37 DEG C and constant flow pump rotating speed is 10rad/min, coating, drying, obtains pH dependent form emodin colon-targeted pellets.
prepared by embodiment 12 enzymatic type emodin colon-targeted pellets
Containing pill core 100g
Pectin 10g
HPMC 30g
Water 200mL
By above-mentioned weight, take HPMC, soluble in water, then pectin is added to HPMC solution, stir, 80 eye mesh screens filter, and obtain coating solution.The pill core that contains of arbitrary for embodiment 1-9 preparation is placed in fluid bed, preheating 5 about min, adjustment atomizing pressure is 2.0Pa, fluidized pressure is 1.5Pa, temperature of charge be 38 DEG C and constant flow pump rotating speed is 12rad/min, dry, obtains enzymatic type emodin colon-targeted pellets.
prepared by embodiment 13 time lag type emodin colon-targeted pellets
Containing pill core 100g
Eudragit RL 30D 5 g
PVP K30 3g
Triethyl citrate (TEC) 0.5g
Pulvis Talci 2.5g
Water 200mL
By above-mentioned weight, take Eudragit RL 30D, PVP K30, TEC, Pulvis Talci, be placed in water, stir, 80 eye mesh screens filter, and obtain coating solution.The pill core that contains of arbitrary for embodiment 1-9 preparation is placed in fluid bed, preheating 5 about min, adjustment atomizing pressure is 1.0Pa, fluidized pressure is 0.5Pa, temperature of charge be 37 DEG C and constant flow pump rotating speed is 10rad/min, coating, drying, obtains time lag type emodin colon-targeted pellets.
embodiment 14 time lag is prepared in conjunction with pH dependent form emodin colon-targeted pellets
Containing pill core 100g
Eudragit RL 30D 5g
PVP K30 3g
Eudragit S 100 10g
Triethyl citrate (TEC) 1.5g
Pulvis Talci 5g
Water 300mL
By above-mentioned weight, take Eudragit RL 30D, PVP K30, TEC, Pulvis Talci, be placed in water, stir, 80 eye mesh screens filter, and obtain time lag coating solution.The pill core that contains of arbitrary for embodiment 1-9 preparation is placed in fluid bed, preheating 5 about min, regulates atomizing pressure, fluidized pressure, temperature of charge and constant flow pump rotating speed, coating, dry, obtain bag time lag clothing micropill.Take Eudragit S 100, TEC, Pulvis Talci again, be placed in water, stirring and dissolving, obtain pH dependent form coating solution.Bag time lag clothing micropill is placed in fluid bed, preheating 5 about min, adjustment atomizing pressure is 2.0Pa, fluidized pressure is 1.5Pa, temperature of charge be 38 DEG C and constant flow pump rotating speed is 12rad/min, coating, drying, obtains time lag in conjunction with pH dependent form emodin colon-targeted pellets.
embodiment 15 enzyme touches to be prepared in conjunction with pH dependent form emodin colon-targeted pellets
Containing pill core 100g
Pectin 4g
HPMC 15g
Eudragit S 100 10g
Triethyl citrate (TEC) 1g
Pulvis Talci 5g
90% ethanol 200mL
Water 100mL
By above-mentioned weight, take HPMC, soluble in water, then pectin is added to HPMC solution, stir, 80 eye mesh screens filter, and obtain enzyme and touch coating solution.The pill core that contains of arbitrary for embodiment 1-9 preparation is placed in fluid bed, preheating 5 about min, regulates atomizing pressure, fluidized pressure, temperature of charge and constant flow pump rotating speed, coating, dry, obtain bag enzyme and touch clothing micropill.Take Eudragit S 100, TEC, Pulvis Talci again, be placed in 90% ethanol, stir, 80 eye mesh screens filter, and obtain pH dependent form coating solution.Bag enzyme is touched clothing micropill and is placed in fluid bed, preheating 5 about min, adjustment atomizing pressure is 2.0Pa, fluidized pressure is 1.5Pa, temperature of charge be 38 DEG C and constant flow pump rotating speed is 12rad/min, coating, drying, obtains enzyme and touches in conjunction with pH dependent form emodin colon-targeted pellets.
the solubility test of embodiment 16 emodin solid dispersion
The solid dispersion of mass ratio obtained by solid dispersion obtained during 1:4, embodiment 1-9 of excessive emodin crude drug, emodin and polyvinylpyrrolidone (PVP K30), the solid dispersion obtained by comparative example 1-2 are joined in the artificial colonic fluid of appropriate pH=7.6 respectively, under air-tight state in 25 DEG C of water-baths 100rpm vibrate 48h, drug solution is reached capacity, leave standstill after several minutes, get the supernatant and cross 0.45 μm of microporous filter membrane, get subsequent filtrate HPLC sample introduction to measure, calculate medicine dissolubility of (25 DEG C) in artificial colonic fluid.
Measurement result is in table 1: the dissolubility of emodin crude drug in artificial colonic fluid is 4.68 μ g/mL, and the dissolubility of the emodin solid dispersion that embodiment 1-9 obtains in artificial colonic fluid is all at 250 more than μ g/mL, dissolubility is significantly improved (P<0.01); Compared to the solid dispersion of mass ratio obtained by 1:4 of emodin and PVP K30, the obtained emodin solid dispersion dissolubility of embodiment of the present invention 1-9 also significantly higher (P<0.01); The emodin solid dispersion dissolubility that embodiment of the present invention 1-9 obtains and comparative example 1 are compared with comparative example 2 all significantly higher (P<0.05).
Table 1 emodin solid dispersion solubility test result
| Test sample | Dissolubility (μ g/mL) |
| Emodin crude drug | 4.68 |
| The mass ratio of emodin and PVP K30 is the solid dispersion that 1:4 obtains | 220.053 |
| The solid dispersion that embodiment 1 is obtained | 274.015 |
| The solid dispersion that embodiment 2 is obtained | 259.647 |
| The solid dispersion that embodiment 3 is obtained | 256.201 |
| The solid dispersion that embodiment 4 is obtained | 253.589 |
| The solid dispersion that embodiment 5 is obtained | 268.634 |
| The solid dispersion that embodiment 6 is obtained | 273.058 |
| The solid dispersion that embodiment 7 is obtained | 264.289 |
| The solid dispersion that embodiment 8 is obtained | 262.422 |
| The solid dispersion that embodiment 9 is obtained | 271.066 |
| The solid dispersion that comparative example 1 is obtained | 231.651 |
| The solid dispersion that comparative example 2 is obtained | 235.054 |
embodiment 17 extracorporeal releasing test
The emodin colon-targeted pellets vitro release obtained by embodiment 10-15 is measured by " Chinese Pharmacopoeia " (version two in 2010) annex XC Rotating shaker, release medium be containing 0.5% sodium lauryl sulphate pH1.0 HCL(0 ~ 2 h), pH6.8 PBS(2 ~ 5 h), containing pectase pH7.4 PBS(5 ~ 12 h), rotating speed is 100 rpm, temperature (37 ± 0.5) DEG C, simulation micropill release behavior in the gastrointestinal tract, 2 mL are sampled in different time points, 0.45 μm of filtering with microporous membrane, sample introduction analysis measures, add equality of temperature same volume release medium 2 mL simultaneously.
Measurement result shows, emodin colon-targeted pellets obtained by embodiment 10-15 does not substantially discharge in simulated gastric fluid, also a small amount of release is only had in artificial intestinal fluid, medicine burst size in 5h be less than 20%(wherein with embodiment 1 containing pill core according to the emodin colon-targeted pellets prepared by embodiment 15 method In-vitro release curves as shown in Figure 1, in figure, 3 curves represent three batches of goods respectively); And after entering artificial colonic fluid, medicine can discharge fast, therefore obtained by the present invention, the release in vitro behavior of emodin colon-targeted pellets meets segmented intestine targeted designing requirement.
embodiment 18 rat pharmacokinetics is tested
Male SD rat is divided into 3 groups at random, often organize 6, by emodin 40mg/kg dosage, gavage gives emodin colon-targeted pellets obtained by emodin raw material medicine solution, emodin solid dispersal liquid solution prepared by embodiment 1, embodiment 15 (wherein adopt containing pill core and prepared by embodiment 1) respectively.Before administration, fasting 12h, freely drinks water.Crude drug group and solid dispersion group respectively at after (0h) before administration and administration 0.083,0.25,0.5,1,1.5,2,2.5,3,4,6,8,10,12,24h; Micropill group respectively at after (0h) before administration and administration 2,3,4,4.5,5,5.5,6,6.5,7,7.5,8,9,10,12,24h gets blood about 500 μ L by orbital venous plexus, be placed in the plastic centrifuge tube scribbling heparin, the centrifugal 10min of 9000 r/min, be separated 200 μ L blood plasma, be placed in-20 DEG C of refrigerator freezings and be saved to mensuration.
Adopt HPLC-UV method to measure, assay method is as follows: chromatographic column: Alltech BDS C
18(5 μm, 250 × 4.6mm); Pre-column: SHIMADZU 10L × 4.6; Mobile phase: methanol-0.1% phosphoric acid solution (85:15); Flow velocity: 1.0 mL/min; Determined wavelength: 254 nm; Column temperature: room temperature; Sample size: 10 μ L; Interior mark: curcumin.
Accurate absorption rat plasma 100 μ L is placed in the centrifuge tube of 1.5mL, add 300 μ L methanol (being mixed with the inner mark solution that concentration is 10 μ g/mL) as protein precipitant, vortex mixed 1min, the centrifugal 15min of 12000r/min, get supernatant, with 0.22 μm of filtering with microporous membrane in internal lining pipe, sample introduction 10 μ L, HPLC analytic record peak area, calculates each time point blood drug level.
Experimental result is in table 2 and Fig. 2.Result shows: the dense peak time T of emodin average blood medicine in the blood plasma of emodin colon-targeted pellets group
maxvalue be 7.583h, compared with emodin crude drug group significant prolongation (
p<0.01).After general rat oral gavage administration, within 6 to 8 hours, arrive colon site, the T of colon-targeted pellets group
maxvalue just in time conforms to these data, illustrates that the targeting of emodin colon-targeted pellets prepared by the present invention is good, reaches expection requirement.The MRT of emodin colon-targeted pellets group
(0-t)and MRT
(0-∝)value, all much larger than crude drug group, illustrates that emodin mean residence time in rat body extends, reaches the object of emodin colon site slow releasing, continuous action in rat body.And AUC (0-t) and AUC (0-∞) value decreases, meet the requirement for the treatment of acute pancreatitis colon local action.
Table 2 emodin colon-targeted pellets rat Internal pharmacokinetics parameter (n=6, Mean ± SD)
In addition, after tested, its result all presents MRT to all emodin colon-targeted pellets prepared by embodiment 10-15
(0-t)and MRT
(0-∝)value, all much larger than crude drug group, shows the object all reaching emodin colon site slow releasing, continuous action in rat body.
embodiment 19 pharmacodynamics test
Adopt 3% Fel Bovis seu Bubali sodium sulfonate pancreatic duct injection of driving in the wrong direction to prepare rat acute pancreatitis model, through the administration of jejunum stoma pipe, complete the assessment to gut barrier function.Rat model is divided into 3 groups, often organizes 6, be respectively model control group, give octreotide as positive controls, and give the test group (wherein being prepared by embodiment 1 containing pill core employing) of emodin colon-targeted pellets obtained by embodiment 15.24h after administration, measures the indexs such as IL-1 β, IL-10, D-ALPHA-Hydroxypropionic acid, diamine oxidase, endotoxin, IL-8, and evaluate the gut barrier function protective effect of preparation acute pancreatitis in rats model, experimental result is in table 3.
Result show: 24h after administration, gives the test group of emodin colon-targeted pellets, the indices such as IL-1 β, D-ALPHA-Hydroxypropionic acid, diamine oxidase, endotoxin, IL-8 all comparatively model control group have remarkable change (
p<0.05), and compared with the positive controls giving octreotide, all without significant difference (
p>0.05), namely emodin colon-targeted pellets shows obvious gut barrier function protective effect.
Table 3 emodin colon-targeted pellets is to acute pancreatitis in rats model
Gut barrier function protective effect (n=6)
| IL-1β | IL-8 | D-ALPHA-Hydroxypropionic acid | Diamine oxidase | Endotoxin | |
| Operative control group | 229.97±132.98 | 237.04±34.50 | 521.03±32.19 | 1.98±0.21 | 287.41±10.59 |
| Test group | 84.43±22.13 | 82.63±25.43 | 496.79±8.93 | 1.59±0.11 | 259.84±35.51 |
| Octreotide matched group | 56.19±23.92 | 12.37±7.86 | 494.86±11.08 | 1.60±0.27 | 258.28±20.31 |
in addition, after tested, its result all shows obvious gut barrier function protective effect to all emodin colon-targeted pellets prepared by embodiment 10-15.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the prerequisite not departing from the inventive method; can also make some improvement and supplement, these improve and supplement and also should be considered as protection scope of the present invention.
Claims (9)
1. an emodin solid dispersion, be made up of emodin and carrier material, it is characterized in that, described carrier material is selected from one or more in polyvinylpyrrolidone Kollidon 12 PF, copolyvidone Kollidon VA64, Polyethylene Glycol/polyvinyl alcohol graft copolymerized copolymer Kollicoat IR or Soluplus, and described emodin and the weight ratio of carrier material are 1:2 ~ 1:15.
2. emodin solid dispersion according to claim 1, is characterized in that, described carrier material is copolyvidone Kollidon VA64.
3. emodin solid dispersion according to claim 2, is characterized in that, described emodin and the weight ratio of carrier material are 1:2 ~ 1:5.
4. containing a pill core, it is characterized in that, it adds mixing diluents by the arbitrary described emodin solid dispersion of claim 1-3, then add that wetting agent or adhesive prepare.
5. according to claim 4 containing pill core, it is characterized in that, described diluent is the mixture of microcrystalline Cellulose pH101 and lactose, and described microcrystalline Cellulose pH101 and the weight ratio of lactose are 3:7 ~ 7:3.
6. an emodin colon-targeted pellets, is characterized in that, it is prepared by one or more coatings superscribed in time lag layer, pH Dependent Layer, enzyme contact layer containing pill core described in claim 4 or 5.
7. emodin colon-targeted pellets according to claim 6, is characterized in that, described coating is 10% ~ 35% with the percentage by weight containing pill core.
8. emodin colon-targeted pellets according to claim 7, is characterized in that, described time lag layer comprises time lag material, porogen, plasticizer, antitackiness agent; Described pH Dependent Layer comprises pH sensitive material, plasticizer, antitackiness agent; Described enzyme contact layer comprises enzyme and touches material, wetting agent.
9. described in the arbitrary described emodin solid dispersion of claim 1-3, claim 4 or 5 containing pill core, the purposes of the arbitrary described emodin colon-targeted pellets of claim 6-8 in preparation treatment Severe Acute Pancreatitis SAP medicine.
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