CN102836237B - YANG invigorating also five controlled slow-release preparations and preparation method thereof of a kind of entirety release - Google Patents
YANG invigorating also five controlled slow-release preparations and preparation method thereof of a kind of entirety release Download PDFInfo
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Abstract
The invention provides a kind of preparation method that can make YANG invigorating also overall controlled release of five controlled slow-release preparation multicomponents.This controlled slow-release preparation utilizes osmotic pressure, film controlled release principle makes various types of controlled slow-release preparation.Adopt YANG invigorating also five full formula extractions add starch, dextrin, high molecular weight water soluble polymer and height and ooze the adjuvants such as thing and make label, the insoluble polymer solution of outside containing porogen carries out coating, and punching obtains osmotic pump tablet; Macromolecular material and porogen is adopted to obtain microporous membrane coated tablet; Adopt the obtained control of film controlled-release material slow-release micro-pill, microsphere, small pieces, or load the obtained hard capsule of hard capsule case.The present invention also provides a kind of YANG invigorating also five controlled slow-release preparations of entirety release obtained by the method for the present invention, and it can accomplish multicomponent overall controlled release drug, the action time of energy prolong drug, reduces administration number of times, improves the compliance of clinical patient medication.
Description
Technical field
The invention belongs to medical art, relate to a kind of controlled slow-release preparation of Chinese medicine compound, overall controlled slow-release preparation of multicomponent medicine particularly relating to classics recipe BUYANG HUANWU TANG prescription and preparation method thereof.
Background technology
BUYANG HUANWU TANG head is loaded in Qing Dynasty's Wang Qingren errors in Medicine Corrected, full side is by Radix Astragali 60g, Radix Angelicae Sinensis 9g, Rhizoma Chuanxiong 6g, Radix Paeoniae Rubra 9g, Semen Persicae 9g, Flos Carthami 9g, Pheretima 9g forms, there is QI invigorating, the function of dredging collateral, research afterwards shows that it is at antithrombotic further, defying age, anti-brain bolt blood, antilipemic and immunity moderation function aspects have the effect of prevention and therapy, particularly ischemia apoplexy (cerebral infarction) acute attack stage and apoplexy early stage and convalescent period all can play good preventive and therapeutic action, and the total control guideline half-life that the party composes is 7 hours, the most patients that is suitable for take medicine more difficult, be suitable for being prepared into controlled slow-release preparation, prolong drug action time, reduce patient's medicining times, better can comply with clinical demand, there is great clinical application meaning and market value.
In prior art based on YANG invigorating also five sides, carry out adding and subtracting simply or multi-flavor medical material, the research of developing new pharmacologically active and clinical practice is more, based on traditional BUYANG HUANWU TANG agent, improving dosage form is carried out to it, as capsule, soft capsule, injection, fast-dissolved embolism-eliminating pulvis etc.Be mention BUYANG HUANWU TANG slow release formulation in the Chinese patent of 200710020874.3 at application number, but in application documents, do not provide any technical scheme realizing this dosage form.
In fact, the controlled slow-release preparation of preparation Chinese medicine compound still has many problems to need to solve, and preparation the controlled slow-release preparation of the synchronous controlled release of Multiple components can more need to overcome many technical barriers, and the complexity of its appraisement system also needs to be explored further.
At present, single composition controlled slow-release preparation technology of preparing is day by day ripe, although the research of Chinese medicine controlled slow-release preparation gets more and more, its research is still still in the starting stage, and the depth of investigation is inadequate.Clean up not yet completely with the Chinese medicine compound controlled slow-release preparation technology of preparing problem that concerns because the Chinese medicine ingredients mechanism of action, total amount pharmacokinetics, total amount controlled slow-release preparation technique core technology, total amount quality evaluation system, Chinese crude drug steady quality etc. are a series of, the Chinese medicine controlled slow-release preparation of real maturation listing is less, major part is single component variety, the control slow release release formulation embodying Chinese medicine compound medication more without.
Chinese medicine many genus polypharmacy is the mutual compatibility of Multiple components, multiaction, multipath, Mutiple Targets, multi-level comprehensive function result, and its curative effect is formed when effect coefficient jointly determined by the pharmacokinetic parameter of each composition, medicine.The effect coefficient of right each composition is determined by its physicochemical property, is certain value, without the need to controlled, therefore will prepare the controlled slow-release preparation that the former side of Chinese medicine compound Cheng Hefu requires, then tackle the pharmacokinetic parameter of each composition and medicine constituent ratio and carry out entirety and control.Pharmacokinetic parameter divides configuration and input parameter, controlled slow-release preparation can only change input parameter, namely absorption equilibrium constant, and Chinese medicine compound multicomponent pharmacokinetic parameter is because of mutual compatibility, its configuration all becomes with input parameter, therefore the concentration ratio of all compositions in pharmacokinetic parameter and body is stablized to only have the strict ratio controlling each ingredient just can guarantee, its group effect could be stablized controlled, therefore the synchronous release controlling all compositions of Chinese medicine compound as how preparation technique entirety is the key core technology that Chinese medicine compound control is delayed preparation and prepared, by vast medicament scientist is attracted attention.Obviously only simply apply mechanically that single composition is precisely controlled to be developed Chinese medicine compound multicomponent controlled slow-release preparation with evaluation model and will there are serious problems.
Therefore, for Chinese medicine compound is made controlled slow-release preparation, its guiding theory is: overall controlled (multicomponent is synchronously with the form controlled release of stable total amount constituent ratio), synchronous corrosion (medicine and adjuvant dissolve release simultaneously) and the random complementary stripping of many particles (the random release simultaneously of many releases particle, produce complementary, general synchronization).
Current oligomict control slow release method mainly contains: 1. reservoir formula; 2. monoblock type; 3. peplos monoblock type; 4. formula in bio-degradable polymer is dispersed in; 5. multicenter is with time control sustained-release delivery systems.Existing sustained release in TCM major part is used single composition medicine control slow release technology of preparing and is prepared from the market, mostly be oral controlled slow-release preparation, main dosage form has matrix tablet, film controlling type slow releasing tablet, multilayer tablet, gastric endocopy, bioadhesive tablet, microcapsule, microsphere, slow releasing capsule, transdermal drug delivery system, slow-release micro-pill, bagged steeping drug, osmotic pump tablet etc., these preparations and technology of preparing are not necessarily applicable to the preparation of Chinese medicine compound controlled slow-release preparation.
Make multicomponent by the controlled release of similar constituent ratio timing, then necessarily require this drug-supplying system can control the overall medicine drug release behavior of Chinese medicine compound, that is the solution after Chinese medicine (compound recipe) chip medicine dissolution can be controlled with the stable form release of total amount constituent ratio, therefore reservoir fenestra control volume type drug delivery system is more satisfactory, as osmotic pump type, microporous membrane drug-supplying system;
When adopting overall skeleton administration, as medicine and substrate can simultaneously by outside to inside one piece of corrosions (solution), then medicine also can embody the multicomponent synchronous overall controlled release of Chinese medicine compound, but substrate needs water-soluble high-molecular material more, and inconvenience realizes slow controlled release target; As adopted the skeleton drug-supplying system of entirety not corrosion, each composition spreads stripping from framework material, and because the diffusion coefficient of each composition is different, also difficult identical with the constituent ratio that former side's decoction requires, therefore the overall controllability of medicine is poor.So technology is not desirable Chinese medicine compound multicomponent control Atrigel;
, film controlled-release administrating system skeleton for not corrosion also can adopt multicenter administering mode to realize the target of overall release, as preparations such as micropill, microsphere, microcapsule, small pieces, due to multicenter stripping simultaneously, solvent easily enters centers for making of pharmaceutical preparations, the inequality of single stripping particle center compositions stripping can be made up, the requirement controlled while that integral macroscopic meeting, similarity is high.
Therefore, suitable Chinese medicine compound controlled slow-release preparation and technology of preparing mainly contain: 1. osmotic pump type controlled-release administrating system; 2. fenestra controlled-release administrating system; 3. slow-release micro-pill, microsphere, microcapsule and small pieces are controlled; 4. floating in stomach is detained controlled-release administrating system etc.
Summary of the invention
In order to solve the problem of prior art, the arduousness practice of the present inventor through the several years is groped, after the feature of the current single composition controlled slow-release preparation preparation of systematic analysis " parameter is exclusive, precisely controlled, focuses on and modifies input pharmacokinetic parameters "; The preparation of Chinese medicine compound multicomponent controlled slow-release preparation propose after should follow the thinking of " overall controlled; synchronous corrosion; the random stripping of many particles is complementary ", just sum up after have passed through many experiments failure and success with founded YANG invigorating also five controlled slow-release preparations prepare Principles and measurements, propose with the multicomponent control slow release technology of preparing of the overall controlled or random complementary stripping of many particles of minimum drug delivery unit.
Therefore, the object of the present invention is to provide a kind of preparation method of YANG invigorating also five controlled slow-release preparations of entirety release, this preparation method comprises the steps:
Medical material mixes by following proportioning by A, the Radix Astragali 60 parts, Radix Angelicae Sinensis 9 parts, Rhizoma Chuanxiong 6 parts, Radix Paeoniae Rubra 9 parts, 9 parts, Semen Persicae, 9 parts, Flos Carthami, Pheretima 9 parts;
Above-mentioned medical material water or organic solvent or its mixture extract as Extraction solvent by B, then filter, obtain filtrate;
C is by after step B gained concentrating filter liquor, and precipitate with ethanol or centrifugalize, obtain supernatant, and concentrate drying obtains extractum;
D adds pharmaceutically acceptable adjuvant in step C gained extractum, and then tabletting or make micropill of granulating, obtains label or ball core;
The coating solution of E preparation containing slow releasing agent, porogen, the consumption of this slow releasing agent is 0.5% ~ 15% of described extractum weight; The consumption of this porogen is 0% ~ 2% of extractum weight; Then this coating solution is sprayed onto described label or ball wicking surface, described art for coating condition is: coating temperature 20 ~ 60 DEG C, coating solution flow velocity 10 ~ 80ml/min, until the weight of tablet, micropill or microsphere increases by 0.1% ~ 20%.
Further, this preparation method also comprises the steps:
F respectively punches in the above-mentioned upper and lower surface of coated tablet symmetry the hole that footpath is 0.1 ~ 2.0mm.
Further, after the tablet obtaining coating or micropill, can also comprise the steps:
The tablet of coating or micropill are loaded obtained YANG invigorating also the five kinds of stiffness in infant capsule controlled slow-release preparation in hard capsule softgel shell.
Preferably, the extracting factor of described step B is: Extraction solvent selects water or 10 ~ 90% ethanol-water solutions, and Extraction solvent consumption is 3-20 times of medical material weight; Extraction time is 1-5 time, and extraction time is 0.5 ~ 3 hour.
Preferably, the alcohol precipitation process condition of described step C is: concentration of alcohol 80 ~ 100%; Ethanol consumption is 2 ~ 10 times of extracting liquid volume; 4 ~ 48 hours precipitate with ethanol time.
Preferably, preparation method according to claim 1, is characterized in that, the process conditions of the centrifugalize of described step C are: rotating speed is 1000 ~ 5000rpm, and centrifugation time is 5 ~ 30min.
Preferably, the pharmaceutically acceptable adjuvant of described D step comprises the combination being selected from and being made up of starch, pregelatinized Starch, dextrin, lactose, sodium chloride, calcium carbonate, calcium hydrogen phosphate, calcium sulfate, sucrose, mannitol, sorbitol, microcrystalline Cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, magnesium stearate, Pulvis Talci, Polyethylene Glycol.
Preferably, the slow releasing agent of described E step is selected from the combination be made up of cellulose acetate, ethyl cellulose, ethylene-vinyl acetate copolymer, polyacrylic acid resin; Described porogen is selected from by the also combination that forms of five extract water-soluble substanceses of Polyethylene Glycol, polyvinyl pyrrolidone, sodium lauryl sulphate, mannitol, lactose, glucose, fructose, carbamide, sucrose, sodium chloride, sodium bicarbonate, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, polysorbate 20, Eudragit L or YANG invigorating.
Preferably, the molecular weight of described Polyethylene Glycol is 400-20000.
The present invention also provides a kind of YANG invigorating also five controlled slow-release preparations of entirety release, and it is prepared from by said method.
Further, the YANG invigorating of this entirety release also five controlled slow-release preparations is tablet, micropill, microsphere or capsule, and it can In Vitro Dissolution synchronous release in proportion in 0.5 ~ 10 hour, and the similarity of its finger printing is 0.5 ~ 1; Said preparation can reach the control slow release effect of more than 12 hours in vivo.
Compare with preparation method in the past, advantage of the present invention at least comprises:
1) controlled slow-release preparation obtained meets overall controlled, the drug release behavior of synchronous release or the random complementary release of many particles;
2) prepare the controlled slow-release preparation that BUYANG HUANWU TANG becomes synchronous release first, improve the compliance of clinical patient medication.
3) adopt first with multicomponent drug delivery unit as preparation technology of preparing is to realize the overall controlled target of multicomponent;
4) adopt first with the random complementary stripping in many particles center as preparation technology of preparing is to realize the target of the synchronous stripping of multicomponent.
5) adopt multicomponent fingerprint similarity as the evaluation methodology of the overall controlled stripping of controlled slow-release preparation, to YANG invigorating also five controlled slow-release preparations evaluate.
And the method is suitable for and comprises the preparation such as osmotic pumps, fenestra controlled release preparation and film controlled release small pieces, micropill, microsphere, the release of microcapsule many particles.Comprehensively above-mentioned, the present invention has not only cleaned up single composition controlled slow-release preparation theoretically and multicomponent controlled slow-release preparation prepares theoretical boundary line, and searched out the drug release hole scope (membrane aperture produced with the porogen of 0.01% ~ 2% extractum weight) of the controlled drug delivery unit needs of satisfied entirety, solve an international difficult problem for the synchronous overall controlled release of multicomponent.
Accompanying drawing explanation
The finger printing of Fig. 1 YANG invigorating also preferred embodiment of five controlled slow-release preparations.
Drawing reference numeral illustrates:
S1 ~ S10 is respectively the finger printing of different time points sampling in 0.5,1.5,3,4,5,6,7,8,9,10 hour; S11 be composition complete molten time sampling finger printing.
Detailed description of the invention
The preparation method of the YANG invigorating that the object of the invention is to propose a kind of entirety release also five controlled slow-release preparations, the overall controlled slow releasing of Multiple components in compound recipe can be made by the method, embody the mutual compatibility of Multiple components, Mutiple Targets, multi-level comprehensive function effect, meet the feature of middle medical drugs.
Entirety release of the present invention refers to multi-medicament components in certain proportion synchronous release within a certain period of time.Controlled slow-release preparation of the present invention can drug release hole be control slow release means, as osmotic pumps, is zero-order release, namely reaches controlled-release effect when the quality that the quality of medicine is dissolved much larger than saturated concentration; Be one-level release when the concentration of medicine is less than its saturated concentration, namely reach slow release effect.The another kind of controlled slow-release preparation of the present invention take fenestra as small pieces or the micropill of controlling slow release means, relevant with porogen, when porogen large usage quantity, produces the control slow release effect of osmotic pumps; When porogen is less of when not having, then embody based on the controlled control slow release effect of diffusion coefficient.
Slow releasing agent of the present invention includes but not limited to cellulose acetate, ethyl cellulose, ethylene-vinyl acetate copolymer, polyacrylic acid resin; Porogen of the present invention includes but not limited to Polyethylene Glycol, polyvinyl pyrrolidone, sodium chloride, sucrose, mannitol, sodium lauryl sulphate, lactose, glucose, fructose, lactose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, carbamide.Porogen of the present invention includes but not limited to Polyethylene Glycol, polyvinyl pyrrolidone, sodium lauryl sulphate, mannitol, lactose, glucose, fructose, carbamide, sucrose, sodium chloride, sodium bicarbonate, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, polysorbate 20, Eudragit L or YANG invigorating also five extract water-soluble substanceses.
Below coordinating accompanying drawing and the preferred embodiments of the present invention, setting forth the technological means that the present invention takes for reaching predetermined goal of the invention further.
The preparation of embodiment 1 YANG invigorating also five full formula extractions 1
Get Radix Astragali 60g.Radix Angelicae Sinensis 9g, Rhizoma Chuanxiong 6g, Radix Paeoniae Rubra 9g, Semen Persicae 9g, Flos Carthami 9g, Pheretima 9g, carry out extracting about 2 hours with 8 times amount distilled water, filter, filtering residue adds 8 times amount distilled water second extraction about 1 hour again, filters, merge twice filtrate, concentrate and obtain YANG invigorating also five full side's extracting solution, adopt 95% ethanol precipitate with ethanol, transition, filters, and filtrate concentrates, reclaim ethanol, obtain YANG invigorating also five full side's prescription fluid extracts, dry YANG invigorating also five full formula extractions 1.
The preparation of embodiment 2 YANG invigorating also five full formula extractions 2
Get Radix Astragali 6kg.Radix Angelicae Sinensis 0.9kg, Rhizoma Chuanxiong 0.6kg, Radix Paeoniae Rubra 0.9kg, Semen Persicae 0.9kg, Flos Carthami 0.9kg, Pheretima 0.9kg, carry out extracting about 3 hours with 20 times amount distilled water, filter, filtering residue adds 15 times amount distilled water second extraction about 2 hours again, filters, filtering residue adds 10 times amount distilled water again and extracts about 1 hour for three times, merge three filtrates, concentrate and obtain YANG invigorating also five full side's extracting solution, adopt 80% ethanol precipitate with ethanol, centrifugalize, supernatant is concentrating under reduced pressure at about 60 DEG C, then at 70 ~ 75 DEG C oven drying, obtain YANG invigorating also five full formula extractions 2.
The preparation of embodiment 3 YANG invigorating also five full formula extractions 3
Medical material takes by following proportioning: the Radix Astragali 60 parts, Radix Angelicae Sinensis 9 parts, Rhizoma Chuanxiong 6 parts, Radix Paeoniae Rubra 9 parts, 9 parts, Semen Persicae, 9 parts, Flos Carthami, Pheretima 9 parts.Then extract about 2 hours with 15 times amount 50% alcoholic solution, filter, filtering residue adds 8 times amount 50% alcoholic solution second extraction about 1.5 hours again, filter, filtering residue adds 3 times amount 50% ethanol again and extracts about 1 hour for three times, merge three filtrates, at 60 DEG C, vacuum concentration obtains YANG invigorating also five full side's extracting solution, and the relative density of this extracting solution is 1.1 ~ 1.3; Then use the dehydrated alcohol sedimentation method, about 48 hours, then at 60 DEG C concentrating under reduced pressure, then vacuum drying at 70 ~ 75 DEG C, obtain YANG invigorating also five full formula extractions 3.
The preparation of embodiment 4 YANG invigorating also five full formula extractions 4
Get Radix Astragali 120g.Radix Angelicae Sinensis 18g, Rhizoma Chuanxiong 12g, Radix Paeoniae Rubra 18g, Semen Persicae 18g, Flos Carthami 18g, Pheretima 18g, add medical material 8 times amount 10% ethanol and decoct extraction one hour, filter, filtering residue adds medical material 8 times amount 10% ethanol again and decocts extraction one hour, filter, merge secondary filtrate, be concentrated into 260ml, alcohol settling is added in concentrated solution, add ethanol 390ml first, make alcohol content about 60%, be precipitated to substantially without newly precipitating generation, filter, filtrate adds a certain amount of ethanol again makes alcohol content reach about 85%, precipitate about 24 hours, filter, filter cake 100ml ethanol carries out drip washing, be incorporated in filtrate, ethanol is reclaimed with Rotary Evaporators, and it is concentrated that fluid extract is about 45g to extracting solution, obtain extract 4.
The preparation of embodiment 5 YANG invigorating also five control slow releasing tablet labels
Get said extracted thing and be about 90g, add 46g starch, 12g dextrin, mixing, 70 DEG C of aeration-drying lower than about 8% to water content, obtains dry extract and is about 112g, pulverizes extractum and crosses 40 mesh sieves, pack for subsequent use.
Get the YANG invigorating also five full presciption medicine powder prepared, add sodium chloride 5-10g, microcrystalline Cellulose 7-12g, suitably grinding makes mix homogeneously, spray into appropriate 95% ethanol, 10 mesh sieves are granulated, and are placed in drying baker after 60 DEG C of aeration-drying 1.5h, 14 mesh sieve granulate, fine powder content is made to be no more than 20%, add the magnesium stearate of 1% ~ 2% as fluidizer, mixing, tabletting obtains label.
The preparation of embodiment 6 YANG invigorating also five osmotic pump controlled slow-release tablets
Take 25 ~ 35g cellulose acetate, be dissolved in the acetone of 1L, obtain the acetone soln that concentration is the cellulose acetate of 25 ~ 35g/L, the PEG4000 adding cellulose acetate quality 2% ~ 20%, as porogen, obtains coating solution; Get the label suppressed, coating is carried out by above-mentioned coating solution even spraying to label, the method of coating be any in prior art can implementation method, until sheet heavily increases by 3%, then respectively punch in the upper and lower surface symmetry of coated tablet the hole that footpath is 600 microns respectively, obtain YANG invigorating also five osmotic pump controlled slow-release tablets.
The preparation of the YANG invigorating also five osmotic pump controlled slow-release tablets of embodiment 7 entirety release
Get the YANG invigorating also five full side's extractum medicated powder prepared, add sucrose 5-10g, microcrystalline Cellulose 7-12g, suitably grinding makes mix homogeneously, spray into 95% ethanol, 10 mesh sieves are granulated, and are placed in drying baker after 60 DEG C of aeration-drying 1.5h, 14 mesh sieve granulate, fine powder content is made to be no more than 20%, add the magnesium stearate of 1% ~ 2% as fluidizer, mixing, tabletting obtains label.
Prepare the acetone soln of the cellulose acetate of about 25-35g/L, the PEG6000 adding cellulose acetate quality 2% ~ 20%, as porogen, gets compressed cores, spray coating, beat diameter in the tablet both sides of coating respectively and be about 0.6mm aperture, obtained YANG invigorating is five osmotic pump controlled slow-release tablets also.
The preparation of the YANG invigorating also five osmotic pump controlled slow-release tablets of embodiment 8 entirety release
Get the YANG invigorating also five full side's extractum medicated powder prepared, add mannitol 5-10g, microcrystalline Cellulose 7-12g, suitably grinding makes mix homogeneously, spray into appropriate 95% ethanol, 10 mesh sieves are granulated, and are placed in drying baker after 60 DEG C of aeration-drying 1.5h, 14 mesh sieve granulate, fine powder content is made to be no more than 20%, add the magnesium stearate of 1% ~ 2% as fluidizer, mixing, tabletting obtains label.
Prepare the acetone soln of the cellulose acetate of about 25-35g/L, the PEG2000 adding cellulose acetate quality 2% ~ 20%, as porogen, gets compressed cores, spray coating, beat diameter in the tablet both sides of coating respectively and be about 0.6mm aperture, obtained YANG invigorating is five osmotic pump controlled slow-release tablets also.
The preparation of the YANG invigorating also five osmotic pump controlled slow-release tablets of embodiment 9 entirety release
Get the YANG invigorating also five full side's extractum medicated powder prepared, add sodium chloride 5-10g, hydroxypropyl emthylcellulose 7-12g, suitably grinding makes mix homogeneously, spray into appropriate 95% ethanol, 10 mesh sieves are granulated, and are placed in drying baker after 60 DEG C of aeration-drying 1.5h, 14 mesh sieve granulate, fine powder content is made to be no more than 20%, add the magnesium stearate of 1% ~ 2% as fluidizer, mixing, tabletting obtains label.
Prepare the acetone soln of the cellulose acetate of about 25-35g/L, the PEG6000 adding cellulose acetate quality 2% ~ 20%, as porogen, gets compressed cores, spray coating, beat diameter in the tablet both sides of coating respectively and be about 0.6mm aperture, obtained YANG invigorating is five osmotic pump controlled slow-release tablets also.
The preparation of the YANG invigorating also five microporous membrane control sustained release coating tablets of embodiment 10 entirety release
Get the YANG invigorating also five full side's extractum medicated powder prepared, spray into appropriate 95% ethanol, granulate, 60 DEG C of aeration-dryings, granulate, control fine powder content to make to meet tabletting requirement, add the magnesium stearate of 1% ~ 2%, mixing, namely tabletting obtains Buyanghuanwupian core, with cellulose acetate, ethyl cellulose, ethylene-vinyl acetate copolymer, polyacrylic acid resin is as coating membrane material, the PEG class accounting for coating membrane quality of materials 2% ~ 20% is added in coating solution, PVP, PVA, sodium lauryl sulphate, lactose or a small amount of YANG invigorating be the water-soluble substances such as five extracts also, namely YANG invigorating also five microporous membrane control sustained release coating tablets are obtained to label coating.
The preparation of the YANG invigorating also five film-controlled slow-release small pieces of embodiment 11 entirety release
Get the YANG invigorating also five full side's extractum medicated powder prepared, add 3-6g sodium chloride, 4-8g hydroxypropyl emthylcellulose, suitably grinding makes mix homogeneously, spray into 95% ethanol, 16 mesh sieves are granulated, and are placed in drying baker after 60 DEG C of aeration-drying 1.5h, 20 mesh sieve granulate, fine powder content is made to be no more than 20%, add the magnesium stearate of 1% ~ 2% as fluidizer, mixing, is pressed into the little label of diameter 4mm.
The acetone soln of preparation 25-35g/L cellulose acetate, add the PEG4000 of cellulose acetate quality 2% ~ 20%, polysorbate 20 or Eudragit L as porogen, get the little label fluidized coating of part, separately get the little label of part, carry out fluidized coating with the acetone soln of Eudragit RL 100 and Eudragit RS 100, obtained YANG invigorating is five film controlled release fertilizer small pieces also.
The preparation of the YANG invigorating also five film-controlled slow-release micropills of embodiment 12 entirety release
Get the YANG invigorating also five full side's extractum medicated powder prepared, add 3-6g sodium chloride, 4-8g hydroxypropyl emthylcellulose, suitable grinding makes mix homogeneously, with 40 order sucrose particles for core, with the syrup containing ethanol for binding agent, under rolling, be sprinkled into 100 order fine drug powders, make diameter be 1.4mm containing pill core, dry.
The preparation Eudragit RL 100 of 5 ~ 30% equivalent and the isopropyl alcohol of Eudragit RS 100: acetone (60:40) solution, the PEG adding polymer quality 2% ~ 20% makes coating solution, to micropill fluidized coating, make the micropill that diameter is 1.5mm, or load obtained YANG invigorating also five film-controlled slow-release pellet preparations in hard capsule.
The preparation of YANG invigorating also five slow releasing capsule of embodiment 13 entirety release
The YANG invigorating entirety of embodiment 11,12 gained discharged also five control eluting patches or micropill or its mixture loads 0#, 1# or 2# capsule, obtains the YANG invigorating also five control slow releasing capsule of overall release.
The test of embodiment 14 In Vitro Dissolution and fingerprint similarity thereof measure
Measure its release by the 2nd method in Chinese Pharmacopoeia 2010 editions two annex dissolution methods, respectively 0.5,1.5,3,4,5,6,7,8,9,10h time measure its release, the results are shown in Table 1.
The release (%) of table 1 preferred embodiment of the present invention In Vitro Dissolution test.
From table 1, the YANG invigorating of above each preferred embodiment also five controlled slow-release preparations reached the object delaying to discharge in 10 hours.
With the hydrochloric acid solution of 0.1mol/L for dissolution medium, rotating speed is 100r/min, temperature 37.0 DEG C, in accordance with the law operation and respectively 0.5,1.5,3,4,5,6,7,8,9,10h time and composition complete molten time sample respectively, every sub-sampling 5mL, supplement the isopyknic dissolution medium of isothermal simultaneously, filter and obtain testing sample.Adopt similarity evaluation to carry out similarity evaluation, high-efficient liquid phase chromatogram is shown in Fig. 1, and chromatographic condition is: C18 post, with acetonitrile and 1% acetic acid water for eluent gradient eluting; UV determined wavelength is 264nm, and the similarity evaluation of preferred embodiment of the present invention In Vitro Dissolution test finger printing the results are shown in Table 2.
The similarity of table 2 preferred embodiment of the present invention In Vitro Dissolution test finger printing
From table 2, the fingerprint similarity of each preferred embodiment In Vitro Dissolution test of the present invention, between 0.5 ~ 1, meets the requirement of overall release in proportion, substantially achieves the effect of many composition point synchronous release.
The above is only the preferred embodiments of the present invention, not any pro forma restriction is done to the present invention, although the present invention discloses as above with preferred embodiment, but and be not used to limit the present invention, any those skilled in the art, not departing from the scope of technical solution of the present invention, make a little change when the technology contents of above-mentioned announcement can be utilized or be modified to the Equivalent embodiments of equivalent variations, in every case be the content not departing from technical solution of the present invention, according to any simple modification that technical spirit of the present invention is done above embodiment, equivalent variations and modification, all still belong in the scope of technical solution of the present invention.
Claims (9)
1. the preparation method of the YANG invigorating of an overall release also five controlled slow-release preparations, it is characterized in that, carry out multicomponent entirety by minimum drug delivery unit controlled, the drug release hole of described drug delivery unit is the membrane aperture produced with the porogen of 0.01% ~ 2% extractum weight, comprises the steps:
Medical material mixes by following proportioning by A, the Radix Astragali 60 parts, Radix Angelicae Sinensis 9 parts, Rhizoma Chuanxiong 6 parts, Radix Paeoniae Rubra 9 parts, 9 parts, Semen Persicae, 9 parts, Flos Carthami, Pheretima 9 parts;
Above-mentioned medical material water or ethanol or its mixture extract as Extraction solvent by B, then filter, obtain filtrate;
C is by after step B gained concentrating filter liquor, and precipitate with ethanol or centrifugalize, obtain supernatant, and concentrate drying obtains extractum;
D adds pharmaceutically acceptable adjuvant in step C gained extractum, and then tabletting or make micropill of granulating, obtains label or ball core;
The coating solution of E preparation containing slow releasing agent, porogen, the consumption of this slow releasing agent is 0.5% ~ 15% of described extractum weight; The consumption of this porogen is 0.01% ~ 2% of described extractum weight; Then this coating solution is sprayed onto described label or ball wicking surface, obtains tablet or micropill, described art for coating condition is: coating temperature 20 ~ 60 DEG C, coating solution flow velocity 10 ~ 80ml/min, until the weight of this tablet or micropill increases by 0.1% ~ 20%;
Wherein, the pharmaceutically acceptable adjuvant of described D step comprises the combination being selected from and being made up of starch, pregelatinized Starch, dextrin, lactose, sodium chloride, calcium carbonate, calcium hydrogen phosphate, calcium sulfate, sucrose, mannitol, sorbitol, microcrystalline Cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, magnesium stearate, Pulvis Talci, Polyethylene Glycol;
Described porogen comprises and being selected from by the also combination that forms of five extract water-soluble substanceses of Polyethylene Glycol, polyvinyl pyrrolidone, sodium lauryl sulphate, mannitol, lactose, glucose, fructose, carbamide, sucrose, sodium chloride, sodium bicarbonate, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, polysorbate 20, Eudragit L, YANG invigorating.
2. a preparation method as claimed in claim 1, is characterized in that, also comprises the steps:
F respectively punches in the above-mentioned upper and lower surface of coated tablet symmetry the hole that footpath is 0.1 ~ 2.0mm.
3. a preparation method as claimed in claim 1, is characterized in that, also comprises the steps:
The tablet of coating or micropill are loaded obtained YANG invigorating also the five kinds of stiffness in infant capsule controlled slow-release preparation in hard capsule softgel shell by F.
4. preparation method according to claims 1 to 3, is characterized in that, the extracting factor of described step B is: Extraction solvent selects water or 10 ~ 90% ethanol-water solutions, and Extraction solvent consumption is 3-20 times of medical material weight; Extraction time is 1-5 time, and extraction time is 0.5 ~ 3 hour.
5. preparation method according to claims 1 to 3, is characterized in that, the alcohol precipitation process condition of described step C is: concentration of alcohol 80 ~ 100%; Ethanol consumption is 2 ~ 10 times of extracting liquid volume; 4 ~ 48 hours precipitate with ethanol time.
6. preparation method according to claims 1 to 3, is characterized in that, the process conditions of the centrifugalize of described step C are: rotating speed is 1000 ~ 5000rpm, and centrifugation time is 5 ~ 30min.
7. preparation method according to claims 1 to 3, is characterized in that, the slow releasing agent of described E step is selected from the combination be made up of cellulose acetate, ethyl cellulose, ethylene-vinyl acetate copolymer, polyacrylic acid resin; Described porogen is selected from by the also combination that forms of five extract water-soluble substanceses of Polyethylene Glycol, polyvinyl pyrrolidone, sodium lauryl sulphate, mannitol, lactose, glucose, fructose, carbamide, sucrose, sodium chloride, sodium bicarbonate, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, polysorbate 20, Eudragit L or YANG invigorating.
8. preparation method according to claim 7, is characterized in that, the molecular weight of described Polyethylene Glycol is 400-20000.
9. YANG invigorating also five controlled slow-release preparations of an overall release, it is characterized in that, obtained by its preparation method according to any one of claim 1 to 8, said preparation can In Vitro Dissolution synchronous release in proportion in 0.5 ~ 10 hour, and the similarity of its finger printing is 0.5 ~ 1.
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| CN111658696A (en) * | 2020-07-31 | 2020-09-15 | 李志林 | Traditional Chinese medicine preparation for treating thrombus and preparation method thereof |
| CN115531479A (en) * | 2022-11-14 | 2022-12-30 | 河南中医药大学 | Traditional Chinese medicine composition for treating senile cerebral infarction and preparation method and application thereof |
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| CN1903267A (en) * | 2006-08-05 | 2007-01-31 | 李华林 | Traditional Chinese medicine decoction Buyang Xiaoshuan Huanwu Tang for tonifying yang and dissolving thrombus |
| CN101036705A (en) * | 2007-04-10 | 2007-09-19 | 邵旭 | Buyang huanwu gantong medicine for preventing and curing cardiovascular or cerebrovascular disease and the agent and the method for preparing the same |
| CN101856337A (en) * | 2010-05-28 | 2010-10-13 | 中国科学院上海药物研究所 | Novel penetration and controlled-release medicament delivery system and preparation method thereof |
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| CN101966203A (en) * | 2009-07-28 | 2011-02-09 | 安徽中医学院 | Study and application of release technique of effective compound group of traditional Chinese Medical prescription |
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| CN1903267A (en) * | 2006-08-05 | 2007-01-31 | 李华林 | Traditional Chinese medicine decoction Buyang Xiaoshuan Huanwu Tang for tonifying yang and dissolving thrombus |
| CN101036705A (en) * | 2007-04-10 | 2007-09-19 | 邵旭 | Buyang huanwu gantong medicine for preventing and curing cardiovascular or cerebrovascular disease and the agent and the method for preparing the same |
| CN101856337A (en) * | 2010-05-28 | 2010-10-13 | 中国科学院上海药物研究所 | Novel penetration and controlled-release medicament delivery system and preparation method thereof |
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