CN107260708A - A kind of dual-release preparation of Betahistine or its salt and preparation method thereof - Google Patents
A kind of dual-release preparation of Betahistine or its salt and preparation method thereof Download PDFInfo
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- CN107260708A CN107260708A CN201610215770.7A CN201610215770A CN107260708A CN 107260708 A CN107260708 A CN 107260708A CN 201610215770 A CN201610215770 A CN 201610215770A CN 107260708 A CN107260708 A CN 107260708A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
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Abstract
The invention discloses the dual-release preparation of a kind of Betahistine or its salt, it is characterised in that it is made up of common pastille quick releasing formulation and sustained release preparation two parts, and the proportion that wherein immediate release section contains main ingredient Betahistine or its salt with slow-released part is 1:1~1:10, preferably 1:2~1:6；Total effective dose of Betahistine or its salt in the dual-release preparation is to be calculated as 1~64mg, preferably 2~40mg with Betahistine；The invention belongs to pharmaceutical preparations technology field.The Betahistine of steady effective blood drug concentration or the dual-release preparation of its salt and preparation method thereof can be persistently maintained again it is an object of the invention to provide a kind of good patient compliance, Small side effects, energy quick acting.The dual-release preparation reduces the medicining times of patient, reduces adverse reaction, improves patient compliance.
Description
Technical field
The invention belongs to art of pharmaceutical industry, and in particular to the present invention relates to a kind of Betahistine or its salt pref, especially
It is to be related to a kind of Betahistine or the dual-release preparation of its salt and preparation method thereof, it is characterised in that this dual-release preparation is by common
Pastille quick releasing formulation and sustained release preparation two parts composition, wherein immediate release section contain main ingredient Betahistine or its salt with slow-released part
Weight ratio be 1:1~1:10, preferably 1:2~1:6；Total effective dose of Betahistine and its salt in the dual-release preparation
1 ~ 64mg, preferably 2 ~ 40mg are calculated as with Betahistine.
Background technology
Betahistine, English name is：Betahistine, chemical name is：N- methyl -2- pyridine ethylamines, molecular formula
For：C8H12N2, molecular weight is：136, molecular structural formula is：
Wherein the physicochemical property of Betahistine Hydrochloride is white crystals or crystalline powder powder, and wettability is strong, is highly soluble in water
With dichloromethane, chloroform and ethanol are soluble in；It is atomic to be dissolved in ether；The physicochemical property of Betahistine Mesylate be white crystals or
Crystalline powder, wettability is strong, is highly soluble in water, is insoluble or poorly soluble in isopropanol.Biopharmaceutics Classification is BCS I class medicines
Thing, i.e. high-dissolvability high osmosis medicine.Betahistine mesylate tablet is succeeded in developing by Japanese Eisai Co., Ltd earliest, and 1969
Year in Japanese Initial Public Offering 6mg specifications, listing 12mg specifications in 1978, its be used to treating Meniere's disease, Mei Er syndromes,
The adjoint dizziness of the diseases such as vertigo and dizzy sense.
The specification that Betahistine Hydrochloride piece is listed at home is 4mg/ pieces, 5mg/ pieces；The indication ratified at home is：It is main to use
In Andre Meynier syndrome, vascular headache and cerebral arteriovenous malformation, and available for treatment acute ischemic cerebrovascular disease, such as brain blood
Bolt, cerebral embolism, transient cerebral ischemia etc.；It is also effective to caused by hypertension orthostatic dizziness, tinnitus etc..
Betahistine is Histamine agents thing.1. there is the effect of expansion capillary, microcirculation, expansion of cerebral vascular, the heart can be improved
Blood vessel, particularly has obvious dilating effect to vertebra bottom arterial system, dramatically increases the heart, brain and surrounding loop CBF.②
There are relexation, increase cochlea and vestibular CBF to the precapillary sphincter of inner ear, so as to eliminate auditory vertigo, ear
Ring and ear close sense；Capillary permeability can also be increased, promote the absorption of extracellular fluid, inner ear lymphedema is eliminated.3. can be right
The contracting blood vessel function and reduction angiosthenia of anti-catecholamine, and there is the platelet aggregation for suppressing the clotting of plasma and ADP inductions to act on,
Rats in vitro thrombosis time can be extended；Also slight diuresis.It is oral easily to absorb, in liver through extensive metabolism, turn
2 kinds of metabolins are turned to, the peak time of its metabolin is 3 ~ 5 hours, most medicines are arranged with metabolite form from urine in 3 days
Let out.
Commercially available betahistine mesylate tablet be conventional tablet, usage and dosage for generally adult one time 1 ~ 2（Betahistine Mesylate
One 6 ~ 12mg of secondary amounts）, 3 times a day, (maximum daily dose must not exceed 36mg).Commercially available Betahistine Hydrochloride is ordinary tablet, is used
Method consumption is daily 2 ~ 4 times, 1 ~ 2 every time, every 4mg or 5mg (maximum daily dose must not exceed 48mg).Betahistine
Or its salt is oral rear rapid by intestinal absorption, biological half-life is shorter (3 ~ 4h), and action time is short, needs medicining times many, in addition
Ordinary tablet peak plasma concentrations fluctuation degree is big, is also easy to produce adverse reaction.In view of there is deficiency above in ordinary tablet, in order to reduce medication
Number of times, improves patient medication compliance, and retains the rapid-action advantage of Betahistine, my company developed Betahistine or
The dual-release preparation of its salt.
The advantage of Betahistine or its salt dual-release preparation is 1）Betahistine or its salt dual-release preparation have developed its advantage,
Improve the deficiency of common formulations, because it is made up of immediate release section and slow-released part, the Betahistine in oral rear immediate release section is fast
It is instant go out, reach effective blood drug concentration, quick acting；Slow-released part then slowly discharges, and can keep in a long time effective, flat
Steady blood concentration, makes drug effect maintain 12 ~ 24 hours as long as；2）Pharmaceutical release time is obviously prolonged, therefore reduces medication
Number of times, improves patient's compliance.
The content of the invention
It is an object of the present invention to provide the rapid long-acting dual-release preparation of a kind of Betahistine or its salt, to reduce
The day medicining times of patients with vertigo, improve patient medication compliance, and retain the quick medicine advantage that works.
Another object of the present invention is to a kind of preparation method for the dual-release preparation for providing Betahistine or its salt.
The Betahistine of the present invention or the dual-release preparation of its salt, it is characterised in that the dual-release preparation is by common pastille quick-release system
Agent and sustained release preparation two parts composition.
Dual-release preparation of Betahistine of the present invention or itself or its salt and preparation method thereof, it is characterised in that described double to release
It is 1 that the immediate release section and slow-released part for putting preparation, which contain main ingredient Betahistine or the proportion of its salt,:1~1:10, preferably 1:2~1:
6；Total effective dose of Betahistine and its salt in dual-release preparation is calculated as 1 ~ 64mg, preferably 2 ~ 40mg with Betahistine；
While Betahistine is with its original shape or with mesylate, dimethanesulfonate, hydrochloride, dihydrochloride, lemon in the dual-release preparation
The shape of the pharmaceutical salts such as lemon hydrochlorate, phthalate, succinate, maleate, tartrate, malonate or fumarate
Formula is used, and preferably dimethanesulfonate, the form of dihydrochloride are used.
Dual-release preparation of Betahistine of the present invention or itself or its salt and preparation method thereof, it is characterised in that prepare respectively
The immediate-release granules or micropill or piece of Betahistine or its salt, and Betahistine or its salt slow-releasing granules or micropill or piece, press
Ratio mixing pack or encapsulated or pressure double-layer tablets, to reach that two-phase discharges, and reach that quick acting can persistently remain steady again
The purpose of effective blood drug concentration.
Dual-release preparation of Betahistine of the present invention or itself or its salt and preparation method thereof, it is characterised in that immediate release section
Betahistine containing main ingredient or its salt and disintegrant, diluent, adhesive, lubricant and/or capsule core material, damp-proof layer coating material；
Slow-released part Betahistine containing main ingredient or its salt, slow-release material, diluent, adhesive, lubricant and/or capsule core material, sustained release bag
Clothing material, damp-proof layer coating material.
The dual-release preparation of Betahistine or its salt of the present invention, it is characterised in that described slow-release material is selected from slow-release material
Selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium alginate, sodium carboxymethylcellulose, PVP, copolyvidone, polyethylene
Alcohol, carbopol, POLYPROPYLENE GLYCOL, ethyl cellulose, hydroxyethyl cellulose, polyacrylic resin are birdsed of the same feather flock together compound, stearic acid, Brazil
One kind in palm wax, glycerin monostearate, octadecanol, beeswax, xanthans, shellac, guar gum, pectin, chitosan or
More than one mixture.
The dual-release preparation of Betahistine or its salt of the present invention, it is characterised in that described diluent is selected from microcrystalline cellulose
One or more in element, mannitol, starch, Icing Sugar, pregelatinized starch, lactose, calcium sulfate, calcium phosphate, calcium monohydrogen phosphate
Mixture.
The dual-release preparation of Betahistine and its salt of the present invention, it is characterised in that described disintegrant is selected from crosslinked polyethylene
One kind in pyrrolidones, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, starch, Ac-Di-Sol or one
Plant the mixture of the above.
The dual-release preparation of Betahistine or its salt of the present invention, it is characterised in that described adhesive is selected from PVP, is total to
PVP, hydroxypropyl methylcellulose, hydroxypropyl cellulose, starch, CMS are received, ethyl cellulose, polyacrylic resin class
One or more kinds of mixtures in polymer.
The dual-release preparation of Betahistine or its salt of the present invention, it is characterised in that described lubricant agent is selected from stearic acid
Hang magnesium, stearic acid, calcium stearate, hard fumaric acid sodium, superfine silica gel powder, talcum powder, the moon one kind in alcohol magnesium sulfate or it is a kind of with
On mixture.
The dual-release preparation of Betahistine or its salt of the present invention, it is characterised in that the capsule core material includes diluent, glued
Mixture, disintegrant, wetting agent；Diluent is sucrose, starch, microcrystalline cellulose, lactose, the one or more of beta-schardinger dextrin
Mixture；Adhesive is that described adhesive is syrup, starch slurry, polyvinylpyrrolidone, polyvinyl alcohol, cellulose derivative
（Hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, sodium carboxymethylcellulose）One or more kinds of mixing
Thing；Disintegrant is starch, sodium carboxymethyl starch, Ac-Di-Sol, low-substituted hydroxypropyl cellulose, PVPP
One or more kinds of mixtures；Wetting agent is water, one or more kinds of mixtures of ethanol.
The dual-release preparation of Betahistine or its salt of the present invention, it is characterised in that the damp-proof layer coating material includes film
Filmogen and additive, forming thin film material are carbohydrate, polyethylene glycol, polyvinyl alcohol, hydroxypropyl cellulose, Methyl cellulose
Element, ethyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose or the one or more kinds of of Opadry film-coating product mix
Compound, additive includes plasticizer, opacifier, colouring agent, antiplastering aid, antistatic agent；Wherein plasticizer be glycerine, propane diols,
Polyethylene glycol, rutgers（DMP）, diethyl phthalate（DEP）, dibatyl phithalate（DBP）, SA two
Butyl ester（DBS）, glycerol triacetate（GTA）, triethyl citrate（TEC）, ATBC（TBC）, acetyl citrate
Triethyl, citroflex A-4（TBAC）, castor oil one or more kinds of mixtures；Opacifier is titanium dioxide
Titanium；Colouring agent is iron oxide；Antitack agent include magnesium stearate, talcum powder, glycerin monostearate it is one or more kinds of
Mixture.
The dual-release preparation of Betahistine or its salt of the present invention, it is characterised in that the sustained-release coating layer includes sustained-release coating layer
Polymer, plasticizer, pore-foaming agent, opacifier, antiplastering aid, the polymer include polyacrylic resin section bar material, acetate fiber
Element, ethyl cellulose, Surelease (Sulisi) aqueous dispersion, Aquacoat aqueous dispersions it is one or more kinds of molten
Liquid or dispersion liquid；The plasticizer is glycerine, propane diols, polyethylene glycol, rutgers（DMP）, phthalic acid diethyl
Ester（DEP）, dibatyl phithalate（DBP）, SA dibutyl ester（DBS）, glycerol triacetate（GTA）, triethyl citrate
（TEC）, ATBC（TBC）, CitroflexA-2, citroflex A-4（TBAC）, castor oil
One or more kinds of mixtures；The pore-foaming agent be PEG classes, PVP, HPMC, HPC, sucrose it is one or more kinds of
Mixture；The opacifier is titanium dioxide；Colouring agent is iron oxide；Antitack agent is that magnesium stearate, talcum powder, monostearate are sweet
One or more kinds of mixtures of grease.
The dual-release preparation of Betahistine or its salt of the present invention, it is characterised in that include following preparation process：
A) preparation of immediate release section
The bulk drug of Betahistine or its salt was crushed into 80 mesh sieves, it is standby；Weigh the raw material, disintegrant, dilution of recipe quantity
Agent, is well mixed, addition suitable amount of adhesive solution, progress wet granulation, the wet whole grain of 20 mesh sieves, 60 DEG C of drying, 18 mesh sieve whole grains,
Calculated yield, adds lubricant, and mixing is prepared into immediate-release granules；
Or Betahistine or the mixing of its salt and capsule core material are prepared into load pill core, then active medicine piller is prevented again
Damp film coating, is made fast release micropill；
Or first prepare blank capsule core, then medicine accommodation layer piller, Ran Houzai will be made in Betahistine or the medicine-feeding of its salt to blank capsule core
Medicine-feeding piller is subjected to moisture-proof film coating, fast release micropill is made；
B) preparation of slow-released part
The bulk drug of Betahistine or its salt will be crushed 80 mesh sieves, it is standby；Weigh the bulk drug of recipe quantity, slow-release material,
Diluent, is well mixed, and adds suitable amount of adhesive solution, carries out wet granulation, and 20 mesh sieve whole grains, 60 DEG C of drying, 18 mesh sieves are whole
Grain, calculated yield adds lubricant, and mixing is standby to be prepared into slow-releasing granules；
Or Betahistine or its salt and capsule core material, slow-release material are mixed and be prepared into carried medicine sustained-release capsule core, dry, rear choose is advised
Determine the micropill of scope, carry out moisture-proof film coating again on the basis of this micropill, check character and release, qualified rear i.e. sustained release
Micropill；
Or taking fast release micropill to be placed in fluid bed, regulation fluid bed parameter is to suitable, by the sustained-release coating layer liquid configured with compacted
Dynamic pump adds spray chamber atomization by spray gun and is coated, and coating is dried after terminating, and the micropill of prescribed limit is chosen, in the base of this micropill
Moisture-proof film coating is carried out on plinth again, character and release, qualified rear i.e. sustained release pellet is checked；
Or first prepare blank capsule core, then medicine accommodation layer piller, Ran Houzai will be made in Betahistine or the medicine-feeding of its salt to blank capsule core
Medicine-feeding piller is placed in fluid bed, regulation fluid bed parameter leads to the sustained-release coating layer liquid peristaltic pump configured to suitable
Cross spray gun and add spray chamber atomization coating, coating is dried after terminating, and chooses the micropill of prescribed limit, on the basis of this micropill again
Progress moisture-proof film coating, coating is dried after terminating, and the micropill for choosing prescribed limit checks character and release, qualified rear i.e. slow
Release micropill；
C) mixed-forming
Particle a) and b) prepared is mixed in proportion, it is directly encapsulated, produce double release capsules；
Or particle made from a) is added to the side hopper for putting Double layer pellet equipment, start tablet press machine, adjustment sheet weight and hardness；Again
Particle made from b) is added to the opposite side hopper for putting Double layer pellet equipment, adjustment sheet weight and hardness, is continuously suppressed, produced
Double-layer sustained release tablets；
Or mix in proportion micropill a) and b) prepared, it is directly encapsulated, produce two-phase sustained-release micro-pill capsules；
Or particle a) and b) prepared is pressed into small pieces respectively filling in capsule, release capsule in pairs；
d）Packaging
Using aluminium-plastic bubble plate packing（PTP）The packaging of overcoat Medicinal composite film bag.
Betahistine of the present invention or its salt dual-release preparation, it is characterised in that because Betahistine or its salt are small dimension
Preparation, to ensure the uniformity of dosage units of preparation, the blend step of immediate-release granules is as follows：1）Recipe quantity Betahistine or its salt, collapse
Solution agent is put in medicinal low density polyethylene (LDPE) compound membrane bag with 1/10 recipe quantity diluent, by hand shaking mixing 5 minutes；2）By 3/10
Recipe quantity diluent and 1 step material of mixing are placed in efficient wet granulator, and it is 15Hz to set stirring motor frequency, stirs 5 points
Clock；3）Remaining 6/10 recipe quantity diluent same rotational speed is added to continue to mix 15 minutes.
Betahistine of the present invention or its salt dual-release preparation, it is characterised in that because Betahistine or its salt hygroscopicity are strong,
To ensure the smooth production and product quality of this product, the humiture of production environment can be controlled in 25 DEG C, relative humidity is not higher than
50%, intermediate product moisture is controlled 1 ~ 3%.In addition, when the reduction this product preparation intermediate products that to try one's best are aerial exposed
Between.
Betahistine of the present invention or its salt dual-release preparation, it is characterised in that to reduce the influence of humidity, using plastic-aluminum
Blister package（PTP）The packaging of overcoat Medicinal composite film bag, aluminum-plastic blister material is polyvinyl chloride（PVC）Stiff sheet and Key works Drug packing
With aluminium foil, Medicinal composite film bag material is polyester/aluminium/polyethylene composite film（PET/AL/PE）.
The positive beneficial effect of the present invention：
（1）The Betahistine or its salt dual-release preparation of the present invention；Said preparation is using the prescription after optimization, vitro release experiment
Show, its release performance stable uniform, batch between release relative standard deviation be less than 3%, its therapeutic effect with each taking phase
The ordinary preparation of same specification quite, can stability contorting plasma drug level peak value, the side effect that reduction medicine is brought, raising medicine
Bioavilability, improve patient medication compliance.
（2）The Betahistine or its salt dual-release preparation of the present invention, moistureproof isolation coat is carried out to preparation, while controlling intermediate
The measure such as moisture, the humidity of production environment, additional moistureproof packaging material prevent the strong hygroscopicity of Betahistine, it is ensured that dual-release preparation
Stability；Investigated through accelerated test in stability study, property stability, dissolution, relevant material are controllable in 6 months
In the range of, while testing the investigation under the conditions of high temperature, high humidity and strong illumination through influence factor in stability study, performance is good
It is good.
（3）The present invention can prepare 2 ~ 40mg different sizes（In terms of Betahistine）Betahistine or its salt dual-release preparation,
The need for adapting to different crowd.
（4）Pharmacokinetic studies show that immediate release section is in short-term in the Betahistine or its salt dual-release preparation body of the present invention
Interior to produce release, plasma drug level reaches first peak value；Sustained release release afterwards maintains effective plasma level drug concentration model
Within enclosing.Internal pharmacokinetic shows that the bioavilability of said preparation and ordinary preparation is equivalent, will not produce because of part
Slow releasing function and the problem of reduce bioavilability, its pair of releasing theory reduces blood plasma drug concentration peak value, reduces and produces
The possibility of side effect, it is daily only to take once, improve the compliance of patient medication.
Embodiment
Done with reference to specific embodiment and further implement explanation.
Embodiment 1
Preparation method：
A) preparation of immediate release section
1）By Betahistine Mesylate, stearic acid respectively with vibration be sieved through 80 mesh, microcrystalline cellulose, low-substituted hydroxypropyl cellulose,
Silica, talcum powder are sieved through 60 mesh with vibration respectively, take Betahistine Mesylate to detect moisture, standby； 2）Prepare bonding
Agent：Weigh hydroxypropyl cellulose appropriate, 5% hydroxypropyl cellulose solution is configured to purified water, it is standby；3）Mixing：Mix 1 step：
Recipe quantity Betahistine Mesylate, low-substituted hydroxypropyl cellulose first are put into medicinal low-density with 1/10 recipe quantity microcrystalline cellulose to gather
In ethene compound membrane bag, shaking mixing 5 minutes by hand；Mix 2 steps：By 1 step material of 3/10 recipe quantity microcrystalline cellulose and mixing
It is placed in efficient wet granulator, it is 15Hz to set stirring motor frequency, is stirred 5 minutes；Mix 3 steps：Add at remaining 6/10
Side's amount microcrystalline cellulose same rotational speed continues to mix 15 minutes.Detect intermediate products uniformity of dosage units；4）Wet granulation：Set high
2 revolutions per seconds of wet granulator stirring frequency is imitated, 5 revolutions per seconds of pelletizing frequency opens efficient wet granulator, at the uniform velocity adds 5% hydroxypropyl
Cellulose solution, adds and continues to stir 4 minutes after adhesive, set 4 revolutions per seconds of stirring frequency, 8 revolutions per seconds of pelletizing frequency is made
Grain, Granulation time 1.5 ~ 3 minutes, discharging；5）Dry：Wet granular puts forced air drying in 60 DEG C of baking ovens, and control particle water content exists
1%~3%；6）Whole grain：Dry particl is with 18 mesh whole grains；7）It is total mixed by whole good Betahistine Mesylate dry particle and recipe quantity two
Silica, talcum powder, stearic acid, are added to three-dimensional motion mixing, mix 10 minutes, be well mixed, produce Betahistine quick-release
Particle；
B) preparation of slow-released part
1）By Betahistine Mesylate, stearic acid respectively with vibration be sieved through 80 mesh, microcrystalline cellulose, low-substituted hydroxypropyl cellulose,
Silica, talcum powder are sieved through 60 mesh with vibration respectively, take Betahistine Mesylate to detect moisture, standby； 2）Prepare bonding
Agent：Weigh hydroxypropyl cellulose appropriate, 5% hydroxypropyl cellulose ethanol solution is configured to second alcohol and water, it is standby；3）Mixing：It is mixed
Close 1 step：First medicinal low density polyethylene (LDPE) compound membrane bag is put by recipe quantity Betahistine Mesylate, with recipe quantity microcrystalline cellulose
In, shaking mixing 5 minutes by hand；Mix 2 steps：Recipe quantity hydroxypropyl cellulose K4M and K15M are mixed into 1 step material to be placed in efficiently
In wet granulator, it is 15Hz to set stirring motor frequency, is stirred 5 minutes； 4）Wet granulation：Efficient wet granulator is set
2 revolutions per seconds of stirring frequency, 5 revolutions per seconds of pelletizing frequency opens efficient wet granulator, at the uniform velocity adds 5% hydroxypropyl cellulose ethanol molten
Liquid, adds and continues to stir 4 minutes after adhesive, set 4 revolutions per seconds of stirring frequency, 8 revolutions per seconds of pelletizing frequency is pelletized, during granulation
Between 1.5 ~ 3 minutes, discharging；5）Dry：Wet granular puts forced air drying in 60 DEG C of baking ovens, and control particle water content is 1% ~ 3%；6）It is whole
Grain：Dry particl is with 18 mesh whole grains；7）It is total mixed by whole good Betahistine Mesylate dry particle and recipe quantity silica, talcum
Powder, stearic acid, are added to three-dimensional motion mixing, mix 10 minutes, be well mixed, produce Betahistine slow-releasing granules；
C) mixed-forming
Particle a) and b) prepared is mixed in proportion, it is directly encapsulated, produce double release capsules；
Or particle made from a) is added to the side hopper for putting Double layer pellet equipment, start tablet press machine, adjustment sheet weight and hardness；Again
Particle made from b) is added to the opposite side hopper for putting Double layer pellet equipment, adjustment sheet weight and hardness, is continuously suppressed, produced
Double-layer sustained release tablets；
d）Packaging
Using aluminium-plastic bubble plate packing（PTP）The packaging of overcoat Medicinal composite film bag.
Embodiment 2
Preparation method：
A) preparation of pill core is carried
Betahistine or its salt are mixed with microcrystalline cellulose and made, 2% hydroxypropyl cellulose solution, softwood processed, extruded machine is added
Sieve plate（Aperture is 0.9 ~ 1.0mm）It is extruded into fine strip shape, puts in spheronizator, regulation rotating speed and round as a ball time, makes particle completely round as a ball,
Micropill is taken out in 40 DEG C of dry 12h, the micropill of 20 ~ 40 mesh is obtained after screening, the uniformity and water content inspection, qualified rear conduct is carried out
Carry pill core standby；
B) preparation of fast release micropill
Medicine fine pellet core will be carried to be put into fluid bed, regulation EAT to 45 DEG C, the m of intake about 703*h-1, by Opadry bag
Clothing liquid peristaltic pump first adds spray chamber atomization with 1.5ml/min flow velocity by way of the spray of bottom and is coated, atomizing pressure 1.6bar,
Feed flow speed is gradually stepped up to 5ml/min, until coating solution bag is complete.Taken out after coating and put 40 DEG C of dry 12h in baking oven, chosen
Cross the piller of 18 ~ 40 mesh sieves, check character and release, it is qualified after produce fast release micropill；
C) preparation of sustained release pellet
Medicine fine pellet core will be carried to be put into fluid bed, regulation EAT to 45 DEG C, the m of intake about 703*h-1, by Sulisi bag
Clothing liquid peristaltic pump first adds spray chamber atomization with 1.5ml/min flow velocity by way of the spray of bottom and is coated, atomizing pressure 2bar, by
Feed flow speed is gradually improved to 5ml/min, until coating solution bag is complete.Taken out after coating and put 40 DEG C of dry 12h in baking oven, chosen
The piller of 18 ~ 40 mesh sieves, checks character and release, it is qualified after, then sustained release pellet is put into fluid bed, carries out Opadry
Moistureproof coating, produces sustained release pellet；
D) mixed-forming
Fast release micropill and sustained release pellet are pressed 5：13 weight ratio is packed into capsule respectively, produces the double release capsules of Betahistine；
E) pack
Using aluminium-plastic bubble plate packing（PTP）The packaging of overcoat Medicinal composite film bag.
Embodiment 3
Preparation method：
A) preparation of pill core is carried
Betahistine or its salt are added into 2% hydroxypropyl cellulose solution, stirs, is fully dissolved into medicine layer solution, will be micro-
The micro- core of crystalline cellulose blank is put into fluid bed, and regulation EAT adjusts the m of intake about 60 to 45 DEG C3*h-1, will configure
Medicine layer coating solution with peristaltic pump by way of the spray of bottom with 2ml/min flow velocity add to spray chamber be atomized, atomizing pressure
1.0bar, it is complete to medicine layer liquid bag, 40 DEG C of dry 12h in convection oven are placed after terminating, the micropill of 20 ~ 40 mesh is obtained after screening,
The uniformity and water content inspection are carried out, it is qualified rear standby as pill core is carried；
B) preparation of fast release micropill
Medicine fine pellet core will be carried to be put into fluid bed, regulation EAT to 45 DEG C, the m of intake about 603*h-1, by Opadry bag
Clothing liquid peristaltic pump first adds spray chamber atomization with 1.5ml/min flow velocity by way of the spray of bottom and is coated, atomizing pressure 2bar, by
Feed flow speed is gradually improved to 5ml/min, until coating solution bag is complete.Taken out after coating and put 40 DEG C of dry 12h in baking oven, chosen
The piller of 18 ~ 40 mesh sieves, checks character and release, it is qualified after produce fast release micropill；
C) preparation of sustained release pellet
Talcum powder is added to the water, homogenized with refiner.This suspension is poured into Utech NE30D before use.Stirring mixing is equal
It is even, through 40 mesh sieves, Utech NE30D coating solution；Medicine fine pellet core will be carried to be put into fluid bed, adjusted into wind-warm syndrome
Degree is to 38 DEG C, intake about 60m3*h-1, then elder generation is added with 1.5ml/min flow velocity by way of the spray of bottom by coating solution peristaltic pump
Enter spray chamber atomization coating, atomizing pressure 2bar gradually steps up feed flow speed to 7ml/min, until coating solution bag is complete.After coating
40 DEG C of dry 12h in baking oven are put in taking-up, choose the piller of 18 ~ 40 mesh sieves, check character and release, it is qualified after, then will
Sustained release pellet is put into fluid bed, by EAT to 38 DEG C, intake about 60m3*h-1, mode is sprayed with 1.5ml/min stream in bottom
Speed adds spray chamber atomization and is coated, and atomizing pressure 2bar carries out Opadry moistureproof coating, produces sustained release pellet；
D) mixed-forming
Fast release micropill and sustained release pellet are pressed 5：13 weight ratio is packed into capsule respectively, produces the double release capsules of Betahistine；
E) pack
Using aluminium-plastic bubble plate packing（PTP）The packaging of overcoat Medicinal composite film bag.
Embodiment 4：Release is tested
The sample of Example 1,2,3, according to drug release determination method（Chinese Pharmacopoeia four 0,931 second methods of version in 2015）, with water
900ml is dissolution medium, and rotating speed is 50 turns per minute, is operated in accordance with the law, through 15,30,60,120,240,360,480,720 minutes
When, solution 5ml is taken, is filtered with 0.45um miillpore filters, takes subsequent filtrate as need testing solution.Separately take Betahistine Mesylate pair
It is accurately weighed according to product about 17mg, put in 100ml measuring bottles, be dissolved in water and be diluted to scale, measure 2ml, put 50ml ［ 12mg：
25ml ］ in measuring bottle, scale is diluted with water to, reference substance solution is used as.According to the chromatographic condition under assay, precision measures confession
Test sample solution and each 20ul of reference substance solution, are injected separately into liquid chromatograph, by external standard method with calculated by peak area go out every or
Stripping quantity.Test result indicates that：The Betahistine dual-release preparation release meets the requirements 1 hour release 15-45%, 4 small
When 50-70%, 8 hours be more than 85% release requirement.
The releasing result that experiment measures dual-release preparation made from embodiment 1-3 is shown in Table 1：
Table 1：0 day release result of the embodiment sample in water（%）
Embodiment 5：Stability test
The sample and reference preparation-Betahistine of difference Example, by adding for chemicals stability study technological guidance's principle
Speed experiment, influence factor experiment, its stripping curve, the change about material are detected by quality standard.As a result show that the product has
There is good stability.
Table 2：Influence factor result collects
Table 3：The release result that Samples EXAMPLE sample is tested in influence factor after June accelerates（%）
Table 4：The release result that embodiment sample is tested in influence factor（%）
Table 5：The release result that embodiment sample is tested in influence factor（%）
Claims (10)
1. dual-release preparation of a kind of Betahistine or its salt and preparation method thereof, it is characterised in that described dual-release preparation by
Common pastille quick releasing formulation and sustained release preparation two parts composition.
2. dual-release preparation of Betahistine or its salt and preparation method thereof according to claims 1, it is characterised in that institute
It is Betahistine original shape or its mesylate, dimethanesulfonate, hydrochloride, dihydrochloride, citric acid to state Betahistine or its salt
The pharmaceutical salts such as salt, phthalate, succinate, maleate, tartrate, malonate or fumarate, are preferably used
The dimethanesulfonate and dihydrochloride of Betahistine prepares this dual-release preparation.
3. dual-release preparation of Betahistine or its salt and preparation method thereof according to claims 1, it is characterised in that speed
It is 1 to release the proportion for containing main ingredient Betahistine or its salt with slow-released part in part:1~1:10, preferably 1:2~1:6；Double release systems
Total effective dose of Betahistine or its salt is calculated as 1 ~ 64mg, preferably 2 ~ 40mg with Betahistine in agent.
4. dual-release preparation of Betahistine or its salt and preparation method thereof according to claims 1, it is characterised in that point
Do not prepare Betahistine or the immediate-release granules or micropill or piece of its salt, and Betahistine or its salt slow-releasing granules or micropill or
Piece, mixing pack or encapsulated or pressure double-layer tablets, to reach that two-phase discharges, and reach that quick acting can be tieed up persistently again in proportion
The purpose of fair steady effective blood drug concentration.
5. dual-release preparation of Betahistine or its salt and preparation method thereof according to claims 1, it is characterised in that speed
Release part Betahistine containing main ingredient or its salt and disintegrant, diluent, adhesive, lubricant and/or capsule core material, moistureproof isolation
Layer coating material；Slow-released part Betahistine containing main ingredient or its salt, slow-release material, diluent, adhesive, lubricant and/or capsule core
Material, sustained release coating layer material, moistureproof spacer layer coating material.
6. dual-release preparation of Betahistine or its salt and preparation method thereof according to claims 1, it is characterised in that institute
The slow-release material stated is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium alginate, sodium carboxymethylcellulose, PVP, copolymerization
Dimension ketone, polyvinyl alcohol, carbopol, POLYPROPYLENE GLYCOL, ethyl cellulose, hydroxyethyl cellulose, polyacrylic resin birds of the same feather flock together compound,
Stearic acid, Brazil wax, glycerin monostearate, octadecanol, beeswax, xanthans, shellac, guar gum, pectin, chitosan
In one or more kinds of mixtures；
Described diluent is selected from microcrystalline cellulose, mannitol, starch, Icing Sugar, pregelatinized starch, lactose, calcium sulfate, phosphoric acid
One or more kinds of mixtures in calcium, calcium monohydrogen phosphate；
Described disintegrant be selected from PVPP, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, starch,
One or more kinds of mixtures in Ac-Di-Sol；
Described adhesive is selected from PVP, copolyvidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, starch, CMS
Receive, one or more kinds of mixtures that ethyl cellulose, polyacrylic resin are birdsed of the same feather flock together in compound；
Described lubricant agent be selected from magnesium stearate, stearic acid, calcium stearate, hard fumaric acid sodium, superfine silica gel powder, talcum powder,
The moon hangs one or more kinds of mixtures in alcohol magnesium sulfate；
The capsule core material includes diluent, adhesive, disintegrant, wetting agent；Diluent be sucrose, starch, microcrystalline cellulose,
One or more kinds of mixtures of lactose, beta-schardinger dextrin；Adhesive is syrup, starch slurry, polyvinylpyrrolidone, poly- second
Enol, cellulose derivative（Hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, sodium carboxymethylcellulose）One kind
Or more than one mixture；Disintegrant is starch, sodium carboxymethyl starch, Ac-Di-Sol, low substituted hydroxy-propyl
One or more kinds of mixtures of cellulose, PVPP；Wetting agent is water, the one or more kinds of of ethanol mix
Compound；
The moistureproof spacer layer coating material includes forming thin film material and additive, and forming thin film material is carbohydrate, poly- second two
Alcohol, polyvinyl alcohol, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose or Europe
Bar is for one or more kinds of mixtures of moisture-proof film clothing product, and additive includes plasticizer, opacifier, colouring agent, anti-
Stick, antistatic agent；Wherein plasticizer is glycerine, propane diols, polyethylene glycol, rutgers（DMP）, phthalic acid two
Ethyl ester（DEP）, dibatyl phithalate（DBP）, SA dibutyl ester（DBS）, glycerol triacetate（GTA）, lemon triethylenetetraminehexaacetic acid
Ester（TEC）, ATBC（TBC）, CitroflexA-2, citroflex A-4（TBAC）, castor oil
One or more kinds of mixtures；Opacifier is titanium dioxide；Colouring agent is iron oxide；Antitack agent include magnesium stearate,
One or more kinds of mixtures of talcum powder, glycerin monostearate；
The sustained-release coating layer includes sustained-release coating layer polymer, plasticizer, pore-foaming agent, opacifier, antiplastering aid, the polymer bag
Include polyacrylic resin section bar material, cellulose acetate, ethyl cellulose, Surelease (Sulisi) aqueous dispersion, Aquacoat
One or more kinds of solution or dispersion liquid of aqueous dispersion；The plasticizer is glycerine, propane diols, polyethylene glycol, benzene two
Formic acid dimethyl ester（DMP）, diethyl phthalate（DEP）, dibatyl phithalate（DBP）, SA dibutyl ester（DBS）, it is sweet
Oily triacetate（GTA）, triethyl citrate（TEC）, ATBC（TBC）, CitroflexA-2, acetyl group
ATBC（TBAC）, castor oil one or more kinds of mixtures；The pore-foaming agent be PEG classes, PVP, HPMC,
HPC, sucrose one or more kinds of mixtures；The opacifier is titanium dioxide；Colouring agent is iron oxide；Antitack agent is
Magnesium stearate, talcum powder, one or more kinds of mixtures of glycerin monostearate.
7. Betahistine or its salt dual-release preparation described in claim 1-6, it is characterised in that include following preparation process：
A) preparation of immediate release section
The bulk drug of Betahistine or its salt was crushed into 80 mesh sieves, it is standby；Weigh the raw material, disintegrant, dilution of recipe quantity
Agent, is well mixed, addition suitable amount of adhesive solution, progress wet granulation, the wet whole grain of 20 mesh sieves, 60 DEG C of drying, 18 mesh sieve whole grains,
Calculated yield, adds lubricant, and mixing is prepared into immediate-release granules；
Or Betahistine or the mixing of its salt and capsule core material are prepared into load pill core, then active medicine piller is prevented again
Damp film coating, is made fast release micropill；
Or first prepare blank capsule core, then medicine accommodation layer piller, Ran Houzai will be made in Betahistine or the medicine-feeding of its salt to blank capsule core
Medicine-feeding piller is subjected to moisture-proof film coating, fast release micropill is made；
B) preparation of slow-released part
The bulk drug of Betahistine or its salt was crushed into 80 mesh sieves, it is standby；Weigh the bulk drug of recipe quantity, it is slow-release material, dilute
Agent is released, is well mixed, addition suitable amount of adhesive solution, progress wet granulation, 20 mesh sieve whole grains, 60 DEG C of drying, 18 mesh sieve whole grains,
Calculated yield, adds lubricant, and mixing is standby to be prepared into slow-releasing granules；
Or Betahistine or its salt and capsule core material, slow-release material are mixed and be prepared into carried medicine sustained-release capsule core, dry, rear choose is advised
Determine the micropill of scope, carry out moisture-proof film coating again on the basis of this micropill, check character and release, qualified rear i.e. sustained release
Micropill；
Or taking fast release micropill to be placed in fluid bed, regulation fluid bed parameter is to suitable, by the sustained-release coating layer liquid configured with compacted
Dynamic pump adds spray chamber atomization by spray gun and is coated, and coating is dried after terminating, and the micropill of prescribed limit is chosen, in the base of this micropill
Moisture-proof film coating is carried out on plinth again, character and release, qualified rear i.e. sustained release pellet is checked；
Or first prepare blank capsule core, then medicine accommodation layer piller, Ran Houzai will be made in Betahistine or the medicine-feeding of its salt to blank capsule core
Medicine-feeding piller is placed in fluid bed, regulation fluid bed parameter leads to the sustained-release coating layer liquid peristaltic pump configured to suitable
Cross spray gun and add spray chamber atomization coating, coating is dried after terminating, takes the micropill of prescribed limit, enter again on the basis of this micropill
Row moisture-proof film coating, coating is dry after terminating, and the micropill for choosing prescribed limit checks character and release, qualified rear i.e. sustained release
Micropill；
C) mixed-forming
Particle a) and b) prepared is mixed in proportion, it is directly encapsulated, produce double release capsules；
Or particle made from a) is added to the side hopper for putting Double layer pellet equipment, start tablet press machine, adjustment sheet weight and hardness；Again
Particle made from b) is added to the opposite side hopper for putting Double layer pellet equipment, adjustment sheet weight and hardness, is continuously suppressed, produced
Double-layer sustained release tablets；
Or mix in proportion micropill a) and b) prepared, it is directly encapsulated, produce double sustained-release micro-pill capsules；
Or particle a) and b) prepared is pressed into small pieces respectively filling in capsule, release capsule in pairs；
d）Packaging
Using aluminium-plastic bubble plate packing（PTP）The packaging of overcoat Medicinal composite film bag.
8. the preparation method of the dual-release preparation described in claim 6, it is characterised in that because Betahistine or its salt are small rule
Lattice preparation, to ensure the uniformity of dosage units of preparation, the blend step of immediate-release granules is as follows：1）Recipe quantity Betahistine or its salt,
Disintegrant and 1/10 recipe quantity diluent are put in medicinal low density polyethylene (LDPE) compound membrane bag, by hand shaking mixing 5 minutes；2）By 3/
10 recipe quantity diluents and 1）Step material is placed in efficient wet granulator, is set stirring motor frequency, is stirred；3）Add
Remaining 6/10 recipe quantity diluent same rotational speed continues well mixed.
9. the preparation method of the dual-release preparation described in claim 6, it is characterised in that because Betahistine or its salt hygroscopicity are strong,
To ensure the smooth production and product quality of this product, the humiture of production environment can be controlled in 25 DEG C, relative humidity is not higher than
50%, intermediate product moisture is controlled in 1 ~ 3% scope；In addition, it is aerial sudden and violent to reduce this product preparation intermediate products as far as possible
The dew time.
10. dual-release preparation of Betahistine or its salt according to claims 6 and preparation method thereof, it is characterised in that
To reduce the influence of humidity, using aluminium-plastic bubble plate packing（PTP）The packaging of overcoat Medicinal composite film bag；Aluminum-plastic blister material is poly-
Vinyl chloride（PVC）Stiff sheet and Key works Drug packing aluminium foil, Medicinal composite film bag material is polyester/aluminium/polyethylene composite film（PET/
AL/PE）.
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| CN201610215770.7A CN107260708A (en) | 2016-04-09 | 2016-04-09 | A kind of dual-release preparation of Betahistine or its salt and preparation method thereof |
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Cited By (1)
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| CN110368369A (en) * | 2019-08-30 | 2019-10-25 | 广州新济药业科技有限公司 | Calcium complement agent and preparation method thereof |
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