Summary of the invention
The purpose of this invention is to provide a kind of 'Huachan ' essence coated micropills that overcomes the shortcoming and defect of existing cinobufacin sheet, oral liquid and injection.
For achieving the above object, the invention provides a kind of coated micropill that is used for the treatment of tumor, hepatitis B, it is characterized in that being prepared from by following components by part by weight:
Cinobufacin extract powder 40-50, diluent 30-40, binding agent 0.5-5, coating material, plasticizer, opacifier or antiplastering aid total amount 1-10.
The particle diameter of described coated micropill is 0.5-2.5mm, and the particle diameter of micropill is followed successively by 05.-1mm, and 0.5-0.7mm, 0.5-0.6mm are good.
Described diluent is at least a among lactose, mannitol, starch, dextrin, Icing Sugar, the microcrystalline Cellulose MCC.
Described binding agent is wherein at least a of water, alcoholic acid aqueous solution, starch slurry, methylcellulose MC, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose CMC-Na, polyvinylpyrrolidone PVP.
Described coating solution is formed the alcoholic solution of the mixture that comprises coating material, plasticizer, opacifier or antiplastering aid, and wherein coating material, plasticizer, opacifier or antiplastering aid weight part ratio are:
Coating material 0.9-8, plasticizer>0-5, opacifier or antiplastering aid>0-3 get coating material, plasticizer, opacifier or antiplastering aid and add the ethanol of 60-100% percetage by weight to 80-120ml.
Wherein at least a of described enteric-coating material cellulose acetate-phthalate CAP, phthalic acid hydroxypropyl methylcellulose HPMCP, hydroxypropyl methylcellulose acetic acid succinate HPMCAS, acrylic resin.
Described acrylic resin is number wherein at least a of acrylic resin L30D-55, acrylic resin S100, acrylic resin L100, acrylic resin II number, acrylic resin III.
Described gastric solubleness coating material is ethyl cellulose EC, cellulose acetate CA a kind of 2-5 weight portion and Polyethylene Glycol PEG, the hydroxypropyl methylcellulose HPMC formed coating material of a kind of 0.2-5 weight portion wherein wherein.
Described plasticizer is wherein at least a of glycerol, propylene glycol, Polyethylene Glycol PEG, Oleum Ricini, triethyl citrate, triglycerin acetate, diethyl phthalate.
Described opacifier is a titanium dioxide.
Described antiplastering aid is Pulvis Talci or magnesium stearate.
A kind of method for preparing coated micropill comprises the steps:
With cinobufacin extract powder, mixing diluents evenly after, add binding agent and place in the extruder, extrudate places spheronizator, behind the round as a ball one-tenth micropill, place fluid bed, temperature 40-60 ℃ condition following drying time of 0.5-4 hour, spray again with coating solution, make coated micropill.
The another kind of method for preparing coated micropill comprises the steps:
With cinobufacin extract powder, mixing diluents evenly after, add binding agent system soft material, cross the 15-20 mesh sieve and granulate, place coating pan, behind the round as a ball one-tenth micropill, the blowing hot-air drying is 0.5-4 hour under temperature 40-60 ℃ condition, sprays with coating solution again, makes coated micropill.
The method that another prepares coated micropill comprises the steps:
Cinobufacin extract powder, diluent are placed centrifugal-fluid bed, with 0.5-2.5m
3/ min blasts air-flow, and mix homogeneously sprays into the solution of binding agent then, makes the micropill of particle size range at 0.5-2.5mm, and gained micropill in ebullated bed under 40-60 ℃ of condition hot air drying 0.5-4 hour sprays into coating solution again, makes coated micropill.
Described binding agent is the aqueous solution or the alcoholic solution of the aqueous solution of the aqueous solution of water, ethanol water, starch slurry, methylcellulose or alcoholic solution, sodium carboxymethyl cellulose or alcoholic solution, polyvinylpyrrolidone.
The described alcoholic solution concentration that is weight percentage is the 60-90% alcoholic solution.
Preparation cinobufacin extract powder is the method preparation of all knowing with those skilled in the art, for example:
Dry maxima skin is cleaned, decocted with water secondary, 45 minutes for the first time, 30 minutes for the second time, collecting decoction filtered, it is 1.1~1.2 that filtrate is concentrated into relative density, and the temperature that relative density is measured is 80 ℃, is cooled to 40 ℃, adding ethanol makes and contains alcohol amount and reach 60%, stir evenly, left standstill 24 hours, get supernatant and reclaim ethanol to there not being the alcohol flavor, adding ethanol makes and contains alcohol amount and reach 85%, stir evenly, left standstill 48 hours, filter, reclaim ethanol to there not being the alcohol flavor, under 80 ℃ of conditions, be condensed into the thick paste that relative density is 1.3-1.6,, pulverize again through the low-temperature reduced-pressure drying, cross 100 mesh sieves, promptly get (Chinese medicine ministry standard WS3-B-2687-97 the 14th).
Coated micropill of the present invention is the spherical shape solid dosage forms of particle diameter between 0.5-2.5mm, divides gastric solubleness coated micropill and enteric coated-pellet, has good fluidity, and medicine stability is good, and can cover the cinobufacin disagreeable taste, promotes the preparation exterior quality; Utilize the coated micropill size of preparation method preparation provided by the invention even, stripping absorbs fast, bioavailability height, instant effect, good looking appearance, preparation technology is simple, and production cost is low, can be loaded on hard capsule or packed, be convenient to store, transport, be convenient to patient again and take, carry.
The only disintegrate in intestinal of enteric-coating material that the inventor filters out from numerous coating materials through a large amount of tests, can avoid the zest of medicine to gastric mucosa, wherein preferred acrylic resin L30D-55, acrylic resin S100, acrylic resin L100, acrylic resin II number, acrylic resin III number, can be in intestinal disintegrate fast, and unexpectedly, the curative effect of cinobufacin also is greatly improved; The gastric solubleness coated micropill extensively distributes equably at gastric, and is wide with the contact area of gastric mucosa, overcome the local irritation of tablet to stomach.The influence of unable to take food things such as the transhipment in gastrointestinal tract, absorption and gastric emptying absorbs rapid-actionly, and infiltration rate is even, and bioavailability among individuals difference is little.
Clinical research confirmation, coated micropill of the present invention, this medicine in the treatment, diseases such as late tumor, chronic hepatitis B have significant curative effect.
The specific embodiment
Other has except the explanation, and the preparation method of cinobufacin extract powder is as follows among the embodiment:
Dry maxima skin is cleaned, decocted with water secondary, 45 minutes for the first time, 30 minutes for the second time, collecting decoction filtered, it is 1.1~1.2 that filtrate is concentrated into relative density, and the temperature that relative density is measured is 80 ℃, is cooled to 40 ℃, adding ethanol makes and contains alcohol amount and reach 60%, stir evenly, left standstill 24 hours, get supernatant and reclaim ethanol to there not being the alcohol flavor, adding ethanol makes and contains alcohol amount and reach 85%, stir evenly, left standstill 48 hours, filter, reclaim ethanol to there not being the alcohol flavor, under 80 ℃ of conditions, be condensed into the thick paste that relative density is 1.3-1.6,, pulverize again through the low-temperature reduced-pressure drying, cross 100 mesh sieves, promptly get (Chinese medicine ministry standard WS3-B-2687-97 the 14th).
Embodiment 1
Enteric coated micropill prescription (inventorys of 200 capsules):
Cinobufacin extract powder 45g
Dextrin 40g
Water 5g
Coating solution: following each component is prepared into the 100ml alcoholic solution
Phthalic acid hydroxypropyl methylcellulose HPMCP 6g triethyl citrate 0.6g
Titanium dioxide 0.49g
Behind above-mentioned 3 kinds of component mix homogeneously, adding weight percent concentration is 70% ethanol, makes the 100ml coating solution.
Preparation technology: with cinobufacin extract powder, diluent dextrin mix homogeneously; Mixture system soft material with binding agent water and cinobufacin extract powder, dextrin, place in the extruder, be squeezed into cylindrical strip extrudate, place spheronizator then, behind the round as a ball one-tenth micropill, place fluid bed, in 0.5 hour following drying time of condition of 50 ℃ of temperature, spray again with coating solution, make coated micropill, be loaded in the capsulae vacuus after the drying.The particle diameter of coated micropill is 0.5-2.5mm.
Embodiment 2
Enteric coated micropill prescription (inventorys of 200 capsules):
Cinobufacin 40g
Mannitol: lactose (1: 1 weight ratio) mixture 40g
Hydroxypropyl methylcellulose 0.6g
Coating solution: following each component is prepared into the 100ml alcoholic solution
Hydroxypropyl methylcellulose acetic acid succinate HPMCAS 4g
Triethyl citrate 0.4g
Pulvis Talci 3g
Behind above-mentioned 3 kinds of component mix homogeneously, adding weight percent concentration is 65% ethanol, makes the 100ml coating solution.
Preparation technology: after will getting cinobufacin extract powder, mannitol and lactose mix homogeneously, it is 10% the aqueous solution and the mixture system soft material of cinobufacin extract powder, mannitol and lactose that the binding agent hydroxypropyl methylcellulose is prepared into percentage by weight, crossing 18 mesh sieves granulates, place coating pan, behind the round as a ball one-tenth micropill, 4 hours drying times of blowing hot-air under 40 ℃ of conditions of temperature, spray again with coating solution, make coated micropill, be loaded in the capsulae vacuus.The particle diameter of coated micropill is 0.5-1.0mm.
Embodiment 3
Enteric coated micropill prescription (inventorys of 200 capsules):
Cinobufacin 42g
Icing Sugar: starch (1: 2 weight ratio) mixture 32g
Methylcellulose 0.8g
Coating solution: following each component is prepared into the 100ml alcoholic solution
Acrylic resin L100 5g
Triglycerin acetate 0.5g
Magnesium stearate 2g
Behind above-mentioned 3 kinds of component mix homogeneously, adding weight percent concentration is 85% ethanol, makes the 100ml coating solution.
Preparation technology: after will getting cinobufacin extract powder, Icing Sugar and starch mix homogeneously, it is 10% the aqueous solution and the mixture system soft material of cinobufacin extract powder, Icing Sugar and starch that the binding agent methylcellulose is prepared into percentage by weight, crossing 15 mesh sieves granulates, place coating pan, behind the round as a ball one-tenth micropill, 0.5 hour drying time of blowing hot-air under 60 ℃ of conditions of temperature, spray again with coating solution, make coated micropill, be loaded in the capsulae vacuus.The particle diameter of coated micropill is 0.5-0.7mm.
Embodiment 4
Enteric coated micropill prescription (inventorys of 200 capsules):
Cinobufacin 48g
Microcrystalline Cellulose: lactose (4: 1 weight ratios) mixture 38g
Starch slurry starch 0.5g adds water 10g
Coating solution: following each component is prepared into the 100ml alcoholic solution
Acrylic resin L30D-55 2g
Glycerol 0.2g
Pulvis Talci 2g
Behind above-mentioned 3 kinds of component mix homogeneously, adding weight percent concentration is 90% ethanol, makes the 100ml coating solution.
Preparation technology: after will getting cinobufacin extract powder, microcrystalline Cellulose and lactose mix homogeneously, with starch slurry system soft material, crossing 20 mesh sieves granulates, place coating pan, behind the round as a ball one-tenth micropill, 2 hours drying times of blowing hot-air under 50 ℃ of conditions of temperature, spray again with coating solution, make coated micropill, be loaded in the capsulae vacuus.The particle diameter of coated micropill is 0.5-0.6mm; The weight percent concentration of starch slurry is 10%.
Embodiment 5
Enteric coated micropill prescription (inventorys of 200 capsules)
Cinobufacin 50g Icing Sugar 40g alcohol 60% percetage by weight solution 5ml
Coating solution: following each component is prepared into the 100ml alcoholic solution
Acrylic resin S100 5g
Diethyl phthalate 0.5g
Magnesium stearate 2g
Behind above-mentioned 3 kinds of component mix homogeneously, adding weight percent concentration is 60% ethanol, makes the 100ml coating solution.
Preparation technology: cinobufacin extract powder, diluent Icing Sugar are placed centrifugal-fluid bed, with 2.5m
3/ min blasts air-flow, mix homogeneously, spray into the binding agent alcoholic solution then, the percent by volume of alcoholic solution is 70%, make the micropill of particle size range at 0.5-2.5mm, the gained micropill in ebullated bed under 60 ℃ of conditions of temperature 0.5 hour hot air drying time, spray into coating solution again, make coated micropill.The particle diameter of coated micropill is 0.5-2.5mm.
Embodiment 6
Enteric coated micropill prescription (inventorys of 200 capsules)
Cinobufacin extract powder 40g
Mannitol 35g
Sodium carboxymethyl cellulose 0.5g
Coating solution: following each component is prepared into the 100ml alcoholic solution
Cellulose acetate-phthalate CAP 5g
Polyethylene glycol 6000 2.7g
Diethyl phthalate 0.3g
Pulvis Talci 2g
Behind above-mentioned 4 kinds of component mix homogeneously, add dehydrated alcohol, make the 100ml coating solution.
Preparation technology: cinobufacin extract powder, diluent Icing Sugar are placed centrifugal-fluid bed, with 2.5m
3/ min blasts air-flow, mix homogeneously, spray into the percentage by weight that is prepared into by the binding agent sodium carboxymethyl cellulose then and be 5% aqueous solution, make the micropill of particle size range at 0.5-0.6mm, the gained micropill in ebullated bed under 50 ℃ of conditions of temperature 2.5 hours hot air drying time, spray into coating solution again, make coated micropill.The particle diameter of coated micropill is 0.5-2.5mm.
Embodiment 7
Gastric solubleness micropill prescription (inventorys of 200 capsules):
Cinobufacin extract powder 50g
Microcrystalline Cellulose 30g
Polyvinylpyrrolidone 0.5g
Coating solution: following each component is prepared into the 100ml alcoholic solution
Ethyl cellulose EC 3g
Polyethylene Glycol PEG4000 3g
Diethyl phthalate 0.2g
Titanium dioxide 3g
Behind above-mentioned 4 kinds of component mix homogeneously, adding weight percent concentration is 80% ethanol, makes the 100ml coating solution.
Preparation technology: with cinobufacin extract powder, diluents microcrystalline cellulose mix homogeneously; Polyvinyl pyrrolidone is prepared into the mixture system soft material that percentage by weight is 10% alcoholic solution and cinobufacin extract powder, microcrystalline Cellulose, place in the extruder, be squeezed into cylindrical strip extrudate, place spheronizator then, behind the round as a ball one-tenth ball, place fluid bed, in 3 hours following drying times of condition of 60 ℃ of temperature, spray again with coating solution, make coated micropill, be loaded in the capsulae vacuus after the drying.The particle diameter of coated micropill is 0.5-2.5mm.
Embodiment 8
Gastric solubleness micropill prescription (inventorys of 200 capsules)
Cinobufacin 48g dextrin 35g 70% percetage by weight ethanol 7ml
Coating solution: following each component is prepared into the 100ml alcoholic solution
Cellulose acetate CA 3g
Polyethylene Glycol PEG 5g
Propylene glycol 0.5g
Magnesium stearate 0.4g
Behind above-mentioned 4 kinds of component mix homogeneously, add dehydrated alcohol, make the 100ml coating solution.
Preparation technology: cinobufacin extract powder, diluent Icing Sugar are placed centrifugal-fluid bed, with 0.5m
3/ min blasts air-flow, and mix homogeneously sprays into binding agent then, the ethanol water of percetage by weight 70% makes the micropill of particle size range at 0.5-2.5mm, the gained micropill in ebullated bed under 40 ℃ of conditions of temperature 4 hours hot air drying time, spray into coating solution again, make coated micropill.The particle diameter of coated micropill is 0.5-2.5mm.
Embodiment 9
Gastric solubleness micropill prescription (inventorys of 200 capsules):
Cinobufacin extract powder 40g
Mannitol 35g
Hydroxypropyl methylcellulose HPMC 0.5g
Coating solution: following each component is prepared into the 100ml alcoholic solution
Hydroxypropyl methylcellulose HPMC 5g
Ethyl cellulose EC 4g
Titanium dioxide 0.5g
Behind above-mentioned 3 kinds of component mix homogeneously, being dissolved in weight percent concentration is in 70% ethanol, makes the 100ml coating solution.
Preparation technology: with cinobufacin extract powder, diluent mannitol mix homogeneously; The binding agent hydroxypropyl methylcellulose is prepared into the mixture system soft material that percentage by weight is 5% alcoholic solution and cinobufacin extract powder, mannitol, place in the extruder, be squeezed into cylindrical strip extrudate, place spheronizator then, behind the round as a ball one-tenth ball, place fluid bed, in 4 hours following drying times of condition of 60 ℃ of temperature, spray again with coating solution, make coated micropill, be loaded in the capsulae vacuus after the drying.The particle diameter of coated micropill is 0.5-2.5mm.
Embodiment 10
Micropill prescription (inventorys of 200 capsules):
Cinobufacin extract powder 40g
Mannitol 35g
Sodium carboxymethyl cellulose 0.5g
Coating solution: following each component is prepared into the 100ml alcoholic solution
Hydroxypropyl methylcellulose HPMC 5g
Cellulose acetate CA 3.7g
Titanium dioxide 1g
Behind above-mentioned 3 kinds of component mix homogeneously, being dissolved in weight percent concentration is in 70% ethanol, makes the 20ml coating solution.
Preparation technology: with cinobufacin extract powder, diluent mannitol mix homogeneously; The binding agent sodium carboxymethyl cellulose is prepared into the mixture system soft material that percentage by weight is 10% alcoholic solution and cinobufacin extract powder, mannitol, place in the extruder, be squeezed into cylindrical strip extrudate, place spheronizator then, behind the round as a ball one-tenth ball, place fluid bed, in 4 hours following drying times of condition of 50 ℃ of temperature, spray again with coating solution, make coated micropill, be loaded in the capsulae vacuus after the drying.The particle diameter of coated micropill is 0.5-2.5mm.
Table 1 pellet capsule provided by the invention and the external disintegrate of commercially available cinobufacin sheet, stripping measurement result relatively see the following form
Inspection item | Embodiment 2 micropills | Embodiment 5 micropills | Embodiment 7 micropills | Commercially available cinobufacin sheet |
Differentiate the complete stripping required time (min) of disintegration time (min) in indoles total alkaloid contents (μ g) water | Up to specification 105 8 18 | Up to specification 106 12 15 | Up to specification 110 10 20 | Up to specificationly do not require 50 60 |
As shown in Table 1, coated micropill provided by the invention is compared with commercially available cinobufacin sheet, and disintegration time on average has only 10 minutes, and dissolution time on average has only 18 minutes fully, has shortened disintegration time and complete dissolution time greatly, and drug effect is improved.
Coated micropill prescription provided by the invention is reasonable, production technology is simple, quality standard improves comprehensively.Particularly adopted film-coated technique, made micropill weightening finish few, supplementary product consumption is little, and the film-coat layer has protection against the tide, shading, effect such as heat insulation, has improved the stability of micropill, has prolonged the storage period of medicine.Prepared 'Huachan ' essence coated micropills both can be distributed into capsule and use, and can be distributed into pouch again or be pressed into tablet for clinical practice.
Micropill has that to absorb onset rapid among the present invention, the bioavailability height, determined curative effect, untoward reaction is few, good looking appearance is stored characteristics such as easy to use, has overcome many shortcoming and defect of the existing preparation of cinobufacin fully, enrich the clinical application kind of this medicine, can satisfy the needs of medical treatment better.