CN104352540B - It is a kind of to treat hydrogel matrix type sustained release tablets of coronary disease and angina pectoris and preparation method thereof - Google Patents
It is a kind of to treat hydrogel matrix type sustained release tablets of coronary disease and angina pectoris and preparation method thereof Download PDFInfo
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Abstract
The invention provides a kind of hydrogel matrix type sustained release tablets for treating coronary disease and angina pectoris, it is prepared from by the supplementary material of following percentage compositions：Tribulus fruit extract 10%~40%, hydrophilic gel matrix material 10%~40%, filler 30%~65%, lubricant 0.5%~2%；Present invention also offers the preparation method of the sustained release tablets.In vitro test shows that continued smooth discharges in sustained release preparation 12h, and a kind of new selection is provided for prevention, treatment coronary disease and angina pectoris disease.Compared with conventional tablet, take number of times, dosage and be reduced；The compliance of patient medication is enhanced simultaneously, is improved the bioavilability of medicine, is enhanced curative effect of the puncturevine furostanol saponins to coronary disease and angina pectoris.
Description
Technical field
The present invention relates to a kind of hydrogel matrix type sustained release tablets for treating coronary disease and angina pectoris.
Background technology
Improve with living standard, aging population and morbidity rejuvenation, the cardiovascular and cerebrovascular incidence of disease increases year by year, it has also become
Endanger the second largest disease of human health.Angina pectoris is as caused by myocardium ischemia, anoxic, with ictal pectoralgia or chest
Discomfort is main performance, and wherein coronary disease and angina pectoris accounts for 90%.At present treatment angina pectoris be mainly nitrate, nitrous acid ester,
Beta-blocker, calcium antagonist etc., but all there is larger toxic side effect in it, and be generally the product taken stopgap measures, unsuitable long-term taking.
Puncture vine is zygophyllaceae puncture vine platymiscium, the effects such as with flat liver solution strongly fragrant, promoting blood circulation by removing wind, expelling phlegm and arresting coughing, is clinically used for
Headache, dizziness, tracheitis, hypertension etc. are treated, particularly using more in the component for the treatment of cardiovascular and cerebrovascular disease.Modern medicine
Reason and clinical research confirmation, saponin component are the bases that puncture vine treats cardiovascular and cerebrovascular disease.Total saponins of tribulus constituents, which have, to be changed
The blood circulation of mercy brain, the effect for reducing blood viscosity, the disease such as the caused obstruction of qi in the chest, coronary heart diseases and angina pectoris, uncomfortable in chest is hindered for painstaking effort numbness.
For many years, preferably, its usage is medication 3 times, every time 2~3 daily to curative effect for Xinnaoshutong tablet clinical practice.
Puncturevine furostanol saponins class treatment coronary disease and angina pectoris needs frequent drug administration, clinical practice inconvenience, therefore one kind is made
Lasting medicine is stable, the sustained release preparation of good patient compliance seems particularly necessary.
The content of the invention
It is an object of the invention to provide a kind of sustained release tablets and preparation method for treating coronary disease and angina pectoris.
The invention provides a kind of hydrogel matrix type sustained release tablets for treating coronary disease and angina pectoris, it is by following percentages
The supplementary material of content is prepared from：
Tribulus fruit extract 10%~40%, hydrophilic gel matrix material 10%~40%, filler 30%~65%, lubrication
Agent 0.5%~2%；
Wherein, in the tribulus fruit extract content of furostanol saponin more than 50%；
Described hydrophilic gel matrix material be chitosan, galactolipin mannitol glycan, sodium alginate, carbomer,
HPMCE15LV、HPMCK4M、HPMCK15M、HPMCK100MOne or more kinds of mixing；
Described filler is one kind or two in starch, dextrin, mannitol, microcrystalline cellulose, lactose, pregelatinized starch
Plant the mixing of the above；
Described lubricant is one or more kinds of mixing in magnesium stearate, talcum powder, superfine silica gel powder.
It is further preferred that described hydrophilic gel matrix material is HPMCK4M、HPMCK15M、HPMCK100MIn one kind or
Two or more mixing；Described filler is more than one or both of microcrystalline cellulose, lactose, pregelatinized starch mixed
Close；Described lubricant is magnesium stearate.
Mixed it is further preferred that described filler is microcrystalline cellulose and lactose：Microcrystalline cellulose is used with lactose
Amount is than being (5%~65%)：(10%~60%).
It is further preferred that it is prepared from by the supplementary material of following weight percentage：
Tribulus fruit extract 29%, sustained-release matrix material HPMCK15M20%, microcrystalline cellulose 35.5%, lactose 15%, firmly
Fatty acid magnesium 0.5%.
Wherein, the preparation method of described tribulus fruit extract is：Puncture vine is taken to add water to cook extraction, Aqueous extracts are dense using normal pressure
Contracting method is concentrated；Plus ethanol makes decoction alcohol content be 60%, refrigeration；Reclaim ethanol, upper macroporous absorbent resin elution；Eluent is passed through back
Receive after ethanol, 50~80 DEG C of dryings, produce tribulus fruit extract under normal pressure.
It is further preferred that puncturevine furostanol saponins extraction and purification process：Extraction process be 10 times amount water, extract 3 times, every time
1.5h.Aqueous extracts are concentrated into crude drug concentration 1.05g/mL or so using normal pressure concentration method, plus ethanol makes decoction alcohol content be 60%,
4 DEG C of refrigeration 12h.Ethanol is reclaimed to 0.4g/mL mass concentration loading, D101 large pore resin absorption column resins blade diameter length ratio is 1:8,
4BV water is eluted with 2mL/min flow velocitys, is eluted respectively with the ethanol of 5BV 50%, 70% ethanol with 2BV/h.The recovered second of eluent
After alcohol, 50~80 DEG C of dryings under normal pressure, gained extraction purification thing determines its content by bulk drug content assaying method.
Present invention also offers a kind of preparation method for preparing described sustained release tablets, it comprises the following steps：
(1) supplementary material is weighed by recipe ratio；
(2) and after other auxiliary materials and mixings, pelletizing press sheet or direct tablet compressing technique.
Wherein, the pressure limit of tabletting is 45~55N after granulation.
Sustained release tablets prepared by the present invention show that continued smooth discharges in sustained release preparation 12h by vitro test, to prevent,
Treat coronary disease and angina pectoris disease and provide a kind of new selection.Compared with conventional tablet, take number of times, dosage and be reduced；
The compliance of patient medication is enhanced simultaneously, is improved the bioavilability of medicine, is enhanced puncturevine furostanol saponins to coronary heart disease
Anginal curative effect.
The present invention is based on commercially available same veriety Xinnaoshutong tablet, using puncture vine simple as raw material, is used after water extract-alcohol precipitation
Its active ingredient of D101 purification with macroreticular resin.Active ingredient puncturevine furostanol saponins content of the present invention be 50% with
On.Secondly, the present invention relates to it is a kind of can effective anginal hydrogel matrix type sustained release tablets of prevention and treatment of coronary heart disease preparation method,
The preparation method is simple and easy to apply, meet the requirement of industrialized production.
Brief description of the drawings
Influence of Fig. 1 difference framework materials to dissolution of sustained-release tablets
Influences of the HPMCK15M of Fig. 2 different amounts to dissolution of sustained-release tablets
Influence of Fig. 3 difference fillers to dissolution of sustained-release tablets
Influence of Fig. 4 lactose consumption to dissolution of sustained-release tablets
Influence of Fig. 5 difference lubricants to dissolution of sustained-release tablets
Influence of Fig. 6 difference preparation methods to dissolution of sustained-release tablets
Influence of Fig. 7 pressure to dissolution of sustained-release tablets
Fig. 8 response surface figures
Fig. 9 contour maps
Figure 10 sustained-release tablets investigate result
Figure 11 sucting wet curves are drawn
Figure 12 critical relative moistures
Figure 13 critical relative moistures
Embodiment
Main material and instrument
Material：Tribulus fruit extract, hydroxypropyl methyl cellulose, lactose, microcrystalline cellulose, magnesium stearate
Instrument：The intelligent dissolving-out tester of TU-1810 ultraviolet-uisible spectrophotometers, ZRS-8G, ZP-5 rotary tablet machines.
Embodiment 1
Take tribulus fruit extract 7.54g, HPMCK4M5.2g, microcrystalline cellulose 9.23g, lactose 3.9g, are well mixed, with 3%
PVPK3075% ethanol solution is pelletized in right amount, is dried under the conditions of 50~80 DEG C, No. four sieve whole grains, adds magnesium stearate
0.13g, suppresses 100, produces.(hardness 45N)
Embodiment 2
Take tribulus fruit extract 7.54g, HPMCK15M5.2g, microcrystalline cellulose 9.23g, lactose 3.9g, are well mixed, with 3%
PVPK3075% ethanol solution is pelletized in right amount, is dried under the conditions of 50~80 DEG C, No. four sieve whole grains, adds magnesium stearate
0.13g, suppresses 100, produces.(hardness 45N)
Embodiment 3
Take tribulus fruit extract 7.54g, HPMCK100M5.2g, microcrystalline cellulose 9.23g, lactose 3.9g, are well mixed, with 3%
PVPK3075% ethanol solution is pelletized in right amount, is dried under the conditions of 50~80 DEG C, No. four sieve whole grains, adds magnesium stearate
0.13g, suppresses 100, produces.(hardness 45N)
Embodiment 4
Take tribulus fruit extract 7.54g, HPMCK15M5.2g, microcrystalline cellulose 13.13g, are well mixed, with 3%
PVPK3075% ethanol solution is pelletized in right amount, is dried under the conditions of 50~80 DEG C, No. four sieve whole grains, adds magnesium stearate
0.13g, suppresses 100, produces.(hardness 45N)
Embodiment 5
Take tribulus fruit extract 7.54g, HPMCK15M5.2g, lactose 13.13g, are well mixed, use 3%PVPK3075% ethanol
Solution is pelletized in right amount, is dried under the conditions of 50~80 DEG C, No. four sieve whole grains, is added magnesium stearate 0.13g, is suppressed 100,
Produce.(hardness 45N)
Embodiment 6
Take tribulus fruit extract 7.54g, HPMCK15M5.2g, microcrystalline cellulose 9.23g, lactose 3.9g, are well mixed, with 3%
PVPK3075% ethanol solution is pelletized in right amount, is dried under the conditions of 50~80 DEG C, No. four sieve whole grains, adds magnesium stearate
0.13g, suppresses 100, produces.(hardness 45N)
Embodiment 7
Take tribulus fruit extract 7.54g, HPMCK15M5.2g, microcrystalline cellulose 9.23g, lactose 3.9g, are well mixed, with 3%
PVPK3075% ethanol solution is pelletized in right amount, is dried under the conditions of 50~80 DEG C, No. four sieve whole grains, adds talcum powder
0.13g, suppresses 100, produces.(hardness 45N)
Embodiment 8
Take tribulus fruit extract 7.54g, HPMCK15M5.2g, microcrystalline cellulose 9.23g, lactose 3.9g are well mixed, with 3%
PVPK3075% ethanol solution is pelletized in right amount, is dried under the conditions of 50~80 DEG C, No. four sieve whole grains, adds superfine silica gel powder
0.13g, suppresses 100, produces.(hardness 45N)
Detection method：
Drug release determination method
Reference《Pharmacopoeia of People's Republic of China》Second annex XC the second method (slurry processes of version in 2010：Small-radius curve track) device,
Self-control sustained release tablets are fitted into stripping rotor using 200mL water as dissolution medium, rotating speed 50r/min, 37 ± 0.5 DEG C of temperature regularly takes
Sample 10mL miillpore filters are filtered, while adding Isothermal release medium 10mL.Precision draws subsequent filtrate in right amount, adds 5mL improvement pair
Dimethylaminobenzaldehyde solution, 58 DEG C of ± 2 DEG C of insulation 2h, takes out, 2min is placed in ice-water bath, taking-up puts room temperature and places 5min,
It is cooled to room temperature.Sample solution is replaced with methanol, the solution that same treatment is obtained makees blank.According to AAS (B of annex V),
Trap is determined at 515nm wavelength.Precision draws cobalt chloride solution, and blank is made with water, determines and absorbs at 515nm wavelength
Degree, calculates the every burst size in different time.
To evaluate the release in vitro behavior of self-control sustained release tablets, 2h Accumulation dissolutions are drafted tired for 10%~30%, 6h~10h
Product release is that to be not less than 90% be criterion of acceptability to 30%~80%, 12h Accumulation dissolutions.
Content assaying method：Puncture vine is the bulk drug of the sustained release tablets, is purchased from the natural pharmaceutcal corporation, Ltd in Sichuan Cologne, batch
Number：131001a.Reference《Drug Standard of Ministry of Public Health of the Peoples Republic of China》Traditional Chinese medicine historical preparation (the 16th)：Xinnao Shutong
Capsule.Set up puncturevine furostanol saponins content assaying method as follows：Cobalt chloride 0.6g is weighed, the constant volume that is dissolved in water is in 25mL volumetric flasks
In, shake up, be used as reference substance solution.Precision draws solution to be measured in right amount, adds 5mL improvement paradime thylaminobenzaldehyde solution
(paradime thylaminobenzaldehyde 0.5g, plus methanol 50mL, hydrochloric acid 17mL, produce), 58 ± 2 DEG C of insulation 2h, takes out, is put in ice-water bath
2min is put, takes out, 5min is placed at room temperature, room temperature is cooled to.Sample solution is replaced with methanol, the solution that same treatment is obtained is made
Blank.According to AAS (B of annex V), trap is determined at 515nm wavelength.Precision draws cobalt chloride solution, is made with water
Blank determines trap at 515nm wavelength, calculates.
Prescription and the preparation technology screening of the sustained release tablets of embodiment 9
First, the screening of auxiliary material
1. influence of the different framework materials to dissolution of sustained-release tablets
The present invention ensure to take puncturevine furostanol saponins day total amount it is constant in the case of, daily clothes twice, one at a time.It is general
Puncturevine furostanol saponins are 15mg/ pieces in logical tablet recipe, every 0.26g, each taking 3, day dose 6.Sustained release tablets every contain
Puncturevine furostanol saponins are 45mg.
In the case of the auxiliary proportions constant of medicine, drug powder is directly added to different model HPMC, pelletized, tabletting, measure is released
Degree of putting, the results are shown in Table 1.With the time (h) for abscissa, release (%) is ordinate, draws the drug release profiles of sustained release tablets, sees figure
1。
The screening of the different framework materials of table 1
It can be seen that HPMCK4M、HPMCK15M、HPMCK100MSustained release tablets prepared by sustained-release matrix material are in 2h without phenomenon of burst release
Occur.From drug release profiles, HPMCK4M、HPMCK15MDrug release is steady and slow release effect is more excellent, therefore present invention selection HPMCK15M
Make sustained-release matrix material.
2. influences of the HPMC of different amounts to Dissolution of Sustained Release Tablet
In the case of the auxiliary proportions constant of medicine, drug powder is directly added to different amounts of HPMCK15M, granulation, tabletting, measure
Release, the results are shown in Table 2.With the time (h) for abscissa, release (%) is ordinate, draws the drug release profiles of sustained release tablets, sees
Fig. 2.
The HPMC of table 2K15MThe screening of consumption
It can be seen that HPMCK15MWhen consumption is 10%, there is phenomenon of burst release to produce and almost without slow release effect；When HPMC consumptions are more than
When 20%, the trend for then keeping almost unchanged first drops with the increase of HPMC consumptions in preparation.Therefore HPMC of the present inventionK15MWith
Amount selection 20%.
3. influence of the different fillers to Dissolution of Sustained Release Tablet
Certain auxiliary material need to be selected as filler for the ease of granulation, shaping.The present invention with microcrystalline cellulose, lactose,
Pregelatinized starch adds the same amount of filler of variety classes as filler, and granulation, tabletting determines release, the results are shown in Table
3.With the time (h) for abscissa, release (%) is ordinate, draws the drug release profiles of sustained release tablets, sees Fig. 3.
The screening of the filler of table 3
As a result show：Microcrystalline cellulose, lactose are more excellent.Present invention selection microcrystalline cellulose, lactose make filler.
4. filler ratio is screened
Understand from the above, auxiliary material selects HPMCK15M, microcrystalline cellulose, lactose.It is determined that after supplementary product kind, investigating
Influence of the filler ratio to Dissolution of Sustained Release Tablet, the results are shown in Table 4.With the time (h) for abscissa, release (%) is ordinate,
The drug release profiles of sustained release tablets are drawn, Fig. 4 is seen.
The filler loading of table 4 is screened
When lactose consumption is 15%, microcrystalline cellulose adjusts larger to accumulation dissolution during piece weight, therefore present invention selection lactose
Consumption is 15%, is adjusted with microcrystalline cellulose to piece weight.
5. the screening of lubricant species and consumption
Influence of the different lubricants to insoluble drug release is investigated, respectively with magnesium stearate, superfine silica gel powder, talcum powder, crystallite is fine
The plain three kinds of lubricants of dimension account for piece and weigh 0.5%, and microcrystalline cellulose adjusts tablet quality to 260mg, prepares sustained release tablets, determines release
Degree, the results are shown in Table 5.With the time (h) for abscissa, release (%) is ordinate, draws the drug release profiles of sustained release tablets, sees Fig. 5.
The screening of the lubricant species of table 5
As seen from the figure, the release of lubricant species and consumption to medicine does not make significant difference.But 0.5% magnesium stearate is used as profit
During lubrication prescription tabletting, punching is not sticked and obtained sustained release tablets are smooth compared with other surfaces, is relatively beneficial to insoluble drug release compared to other.Therefore selection
0.5% magnesium stearate is used as lubricant.
2nd, influence of the technological factor to insoluble drug release
1. the selection of granulation solvent
Water, 70% ethanol, 3%PVP are used respectivelyK3075% ethanol solution, 2%PVPK30Ethanol solution is pelletized, tabletting,
Granulation situation is observed, 6 are the results are shown in Table.
The selection of the granulation solvent of table 6
As a result show：3%PVPK30The granulation of 75% ethanol solution is easy, therefore present invention selection 3%PVPK3075% ethanol is molten
Liquid is used as granulation solvent.
2. the screening of preparation technology
Direct tablet compressing：Take tribulus fruit extract 7.54g, HPMCK15M5.2g, microcrystalline cellulose 9.23g, lactose 3.9g, it is stearic
Sour magnesium 0.13g, is well mixed direct tablet compressing, suppresses 100, produces.(hardness 45N)
Tabletting after granulation：Take tribulus fruit extract 7.54g, HPMCK15M5.2g, microcrystalline cellulose 9.23g, lactose 3.9g, are mixed
Close uniform, use 3%PVPK3075% ethanol solution is pelletized in right amount, is dried under the conditions of 50~80 DEG C, No. four sieve whole grains, plus
Enter magnesium stearate 0.13g, suppress 100, produce.
Sustained release tablets obtained by direct compression method, granulating tabletting process, determine release, the results are shown in Table 7.It is horizontal stroke with the time (h)
Coordinate, release (%) is ordinate, draws the drug release profiles of sustained release tablets, sees Fig. 6.
The screening of the preparation technology of table 7
Using the sustained release tablets that full powder direct compression method is made, 2h is interior without phenomenon of burst release.Direct powder compression and granulation are pressed
Piece method does not make significant difference to the release of sustained release tablets.Consider big production and labour protection, prepared by selection pelletizing press sheet technique should
Sustained release tablets.The present invention moulding process be：Drug powder adds microcrystalline cellulose, lactose, HPMCK15M, use 3%PVPK3075%
Ethanol solution is pelletized, 60 DEG C~65 DEG C dryings, No. four sieve whole grains, is added magnesium stearate, is mixed tabletting, produce.
3. influence of the tablet hardness to release
Take tribulus fruit extract 7.54g, HPMCK15M5.2g, microcrystalline cellulose 9.23g, lactose 3.9g, are well mixed, and use
3%PVPK3075% ethanol solution is pelletized in right amount, is dried under the conditions of 50~80 DEG C, No. four sieve whole grains, adds magnesium stearate
0.13g, sustained release tablets are prepared using different pressures, determine sustained release tablets hardness, control hardness is respectively 45,55,65N, determine made
The release of sustained release tablets, the results are shown in Table 8.With the time (h) for abscissa, release (%) is ordinate, draws releasing for sustained release tablets
Medicine curve, is shown in Fig. 7.
Influence of the pressure of table 8 to dissolution of sustained-release tablets
The hardness of tablet is moderate when pressure limit is 45~55N.
Present invention sustained release piece preparation method uses wet granulation process, comprises the following steps that：Take a certain amount of medicine with it is appropriate auxiliary
Expect mixing → addition suitable amount of adhesive softwood → granulation → wet granular in 60 DEG C of dry 30min → No. 4 sieve whole grain → addition profits
Lubrication prescription mixing → tabletting.
3rd, the formulation optimization of sustained release tablets
Central Composite design-effect surface method is to apply a kind of more optimization method.Central complex design method can be investigated respectively
Interaction between factor, carrying out the experiment of fewer number just can obtain substantial amounts of information.Effect surface method is to shadow by effect value
The factor of sound makees surface chart, so as to directly read the method in optimal factor region, has the advantages that directly perceived, accurate.The two combination collection
Mathematics and statistical method are in integrally making experimental result more science reliable.
On the basis of single factor exploration, designed using Central Composite-effect surface method to influence insoluble drug release it is main because
Element, i.e. HPMCK15MConsumption (X1) and lactose consumption (X2) level optimization of 2 factor 5 is carried out, totally 13 kinds of prescription compages, each prescription is kept
Medicine, magnesium stearate content are respectively the 29% of piece weight, 0.5%, and prepare sustained release with microcrystalline cellulose adjustment sheet weight to 260mg
Piece, Accumulation dissolution of each prescription in 2h, 6h, 10h, 12h is determined according to " drug release determination method ".The factor of Central Composite design
With water-glass 9, test arrangement is shown in Table 10.
The factor level of the Central Composite of table 9 design
The test arrangement of the Central Composite of table 10 design
To control the release of early, middle, late stage, using comprehensive scoring method, choose each prescription 2,6,12h totally 3 points
Accumulation dissolution is as evaluation index, and release standard is respectively 2h 10%~30%, 6h 30%~70%, and 12h is not less than
90%, comprehensive grading is carried out with the difference of the measured value of corresponding points release and standard value and for effect value, each time point
Weight factor is 1.Comprehensive grading value (Y) calculation formula is：Y=| P2-20|+|P6-50|+|P12-90|
Result of the test is shown in Table 11.In formula, P2、P6、P12Respectively 2,6,12h Accumulation dissolution (%), comprehensive grading value
Small person is optimal when minimum to be excellent.
The experimental test result of table 11
Data in table 11 are handled with SAS softwares, are index to HPMC using comprehensive grading valueK15MConsumption, lactose
Each level of consumption carries out multiple linear regression, and fit equation is:
Y=102.48973-8.1712X1-1.15934X2-0.018725X1X2+0.19503X1 2+0.046064X2 2(R2=
0.9974)
Statistic analysis result is shown in Table 12.
The statistic analysis result of table 12
P-Probability level
As shown in Table 12, X1、X2Coefficient be negative, illustrate HPMCK15MConsumption (X1) and lactose consumption (X2) to release
The influence of degree is in the same direction, and comprehensive grading value reduces during both consumption increases, i.e. the measured value of each point is differed with standard value
Minimum, wherein HPMCK15MConsumption (X1) influence be more than lactose consumption (X2) influence.The results of analysis of variance shows, factor X1's
P<0.0001, illustrate HPMCK15MConsumption has pole to significantly affect release；Factor X2P<0.05, illustrate lactose consumption to releasing
Degree of putting has a significant impact；The two interaction item X1X2P<0.0001, illustrating the interaction change of two factors has notable shadow to release
Ring.
With STAT Software on Drawing HPMCK15MConsumption (X1) and lactose consumption (X2) to theoretical release comprehensive grading value institute
Prediction effect surface figure, the contour map of work, are shown in Fig. 8, Fig. 9.
Predictability checking
Predicted according to fit equation, work as HPMCK15MConsumption (X1) it is 20%, lactose consumption (X2) be 15% when, comprehensive grading
Value has minimum value 3.76.
Being predicted property of fit equation is verified, chooses and is a little surveyed in optimal region.According to fit equation, when
HPMCK15MTheoretical amount is 20%, when lactose consumption is 15%, and comprehensive grading value Y is 3.76, and preparing 3 batches according to the prescription delays
Piece is released, release is determined, the results are shown in Table 13.
The statistic analysis result of table 13
As a result show, the release of sustained release tablets prepared by the prescription optimized according to central complex design method meets standard, should
Fit equation is predictive good.Work as HPMCK15M, lactose is respectively accounted for when piece weighs 20%, 15% is best prescription.
4th, sustained release tablets quality evaluation
1. sustained release tablets of the present invention are brown, gas is micro-, mildly bitter flavor.
2. tablet weight variation inspection
Sustained release tablets 20 are taken, accurately weighed gross weight calculates average piece weight；Accurately weighed each sheet weight is distinguished again, as a result
It is shown in Table 14.According to version in 2010《Chinese Pharmacopoeia》Two annex I ruless of preparations regulations：Average piece weight or designation card weight 0.30g with
Lower person, limit test of weight variation is ± 7.5%；It must not be more than 2 beyond limit test of weight variation, and must not have 1 overrun 1
Times.Sustained release tablets designation card weight of the present invention is 0.26g, then it is 0.2405g~0.2795g to allow piece weight scope.
The tablet weight variation inspection of table 14
Tablet weight variation inspection result：Per sheet weight without departing from permission piece weight scope.Meet regulation.
3. friability is determined
Take 25 accurately weighed (m of sustained release tablets1), it is put into friability instrument, is taken out after 100 turns of rotation, observes the change of outward appearance,
Accurately weighed (m2), calculate weightless (%).As a result：M1=6.57g, m2=6.521g, weightless (%)=0.75%.Weightless (%)
＜ 0.8%, meets regulation.
4. sustained release tablets assay and development of methodology
Every batch takes preparation sustained release tablets 10, accurately weighed, calculates average piece weight, is crushed to smalls, accurately weighed about suitable
In the powder of 1 sheet weight, it is placed in small beaker plus 10mL pure water, magnetic stirrer 6h, transfer constant volume is in 25mL volumetric flasks
In, 0.45um filtering with microporous membrane is determined the content of puncturevine furostanol saponins in the sustained release tablets by bulk drug method.
4.1 auxiliary material blank Interference Detections
Precision weighs the auxiliary material of sustained-release tablet recipe ratio, adds in 10mL volumetric flasks, uses water constant volume, take 1mL to be diluted with water
10 times, filtering, color developing detection.As a result show and noiseless is determined to predominant amount.
The preparation of 4.2 standard curves and the range of linearity are investigated
Furostanol saponin standard curve：Precision weighs cobalt chloride 0.9251g, and the constant volume that is dissolved in water shakes up in 25mL volumetric flasks
It is used as mother liquor (i.e. 37.004mg/mL).Precision draws this liquid 2,3,4,5,6mL mother liquors, and constant volume is diluted with water respectively and holds in 10mL
It is standby in measuring bottle.Its suction is determined at ultraviolet specrophotometer λ=515nm with mother liquor, above-mentioned dilution, water (blank) respectively
Shading value.Using absorbance A as ordinate, cobalt chloride concentration C (mg/mL) draws standard curve, obtains the side of recurrence as abscissa
Journey is Y=0.0195X (r=0.9988).As a result show, in the range of 7.4008~37.004mg/mL, absorbance is in concentration
Good linear relation.
4.3 precision test
Cobalt chloride 0.601g is taken, constant volume is dissolved in water in 25mL volumetric flasks, shakes up, be used as reference substance solution.Will control
Product solution is determined 6 times at 515nm wavelength, records its absorbance：0.491、0.503、0.505、0.501、0.501、
0.496, its RSD value is calculated, RSD=1.03% shows that instrument precision is good.
4.4 stability test
By bulk drug assay method develop the color, respectively 0 after the completion of colour developing, 10,20,30,40,60min determine its absorbance,
Record absorbance：0.602、0.593、0.591、0.588、0.580、0.576；It is 1.59% to calculate RSD values, shows that sample is molten
It is stable in 1h after liquid colour developing.
4.5 replica test
Same 6 parts of batch sustained release tablets are taken, are developed the color by bulk drug, furostanol saponin absorbance is determined in UV detector,
Record absorbance：0.575、0.608、0.562、0.601、0.597、0.583；RSD values are 2.97%.As a result show, the method
It is repeated good.
4.6 average recoveries are tested
The average recovery of table 15 is tested
4.7 containing survey
The assay result of table 16
Set up 5. dissolution of sustained-release tablets is determined with method
The preparation of 5.1 standard curves and the range of linearity are investigated
Furostanol saponin standard curve：Precision weighs cobalt chloride 0.9258g, and the constant volume that is dissolved in water shakes up in 25mL volumetric flasks
It is used as mother liquor (i.e. 37.032mg/mL).Precision draws this liquid 2,3,4,5,6mL mother liquors, and constant volume is diluted with water respectively and holds in 10mL
It is standby in measuring bottle.Its suction is determined at ultraviolet specrophotometer λ=515nm with mother liquor, above-mentioned dilution, water (blank) respectively
Shading value.Using absorbance A as ordinate, cobalt chloride concentration C (mg/mL) draws standard curve, obtains the side of recurrence as abscissa
Journey is Y=0.0196X (r=0.9983).As a result show, in the range of 7.4064~37.032mg/mL, absorbance is in concentration
Good linear relation.
5.2 precision test
Cobalt chloride 0.611g is taken, constant volume is dissolved in water in 25mL volumetric flasks, shakes up.By reference substance solution in 515nm ripples
Strong point is determined 6 times, records its absorbance：0.497th, 0.515,0.515,0.511,0.513,0.516, its RSD value is calculated,
RSD=1.40%, shows that instrument precision is good.
5.3 recovery test
The average recovery of table 17 is tested
The investigation of 5.4 release in vitro behaviors
5.4.1 the measure of release：
Release conditions：Method：Slurry processes (small-radius curve track)；Rotating speed：50r/min；Dissolution medium：Pure water；Temperature：37±0.5℃
Each stripping rotor places 1 sustained release tablets, and after measure starts, 10mL is respectively sampled respectively at 2,6,10,12h, uses
0.45um filtering with microporous membrane, while supplementing the dissolution medium of same volume.3 batches of sustained release tablets are investigated respectively, by above-mentioned dissolution side
Method, determines release.Compared release with ordinary tablet, and models fitting, its release of preliminary examinations are carried out to release in vitro result
Mechanism.
As a result show：3 batches of self-control sustained release tablets respectively may be about 20% in 2,6,10,12h cumulative release percentage, 55%,
70%th, 90%.Compared with ordinary tablet, it has reappearance between obvious sustained releasing character, each batch preferable.
5.4.2 sustained-release tablets release models fitting
Release data of the puncture vine hydrogel matrix sustained release tablets in water are carried out to t by the model formation of table 18 (1)~(3)
Fitting, the results are shown in Table 19.
The drug release model fitting formula of table 18
It can be obtained by above-mentioned coefficient correlation, release in vitro models fitting degree of closeness is followed successively by：Zero order model>Higuchi moulds
Type>First-order model.Therefore, sustained-release tablets release of the present invention is mainly discharged with zero order model.
It is attached：
First, medicament powder quality standard
1. the medicament powder character of the present invention：Filbert, gas is fragrant, mildly bitter flavor.
2. heap density：A certain amount of medicinal powder is weighed, is added in 10mL graduated cylinders, graduated cylinder is fallen for several times from certain altitude, make powder
Body is elastic suitable, measures volume, calculates heap density, the results are shown in Table 20.
The powder heap Density measurements of table 20
3. angle of repose：Powder of getting it filled is appropriate, makes to leak down in coniform from funnel, surveys its angle of repose, the results are shown in Table 21.
The angle of repose measurement result of table 21
4. sucting wet curve：Medicinal powder about 2g is weighed, it is accurately weighed, it is respectively placed in drier and is placed 5 days, surveys its weight
Change, calculates hydroscopicity (%).With the time (h) for abscissa, hydroscopicity (%) is that ordinate draws sucting wet curve, as a result sees figure
11。
As a result understand：Medicinal powder hygroscopicity is not strong.
5. critical relative moisture：Medicinal powder about 2g (totally 12 parts) is weighed, it is accurately weighed, it is respectively placed in different relative humidity
In the environment of, place 7 days, survey its weight change, the results are shown in Table 22.
The critical relative moisture of table 22 is determined
Relative humidity is mapped with medicinal powder percentage weight increase, Figure 12 is seen.
2nd, granular mass standard
1. the drug particles character of the present invention：Brown, gas are micro-, mildly bitter flavor.
2. heap density：Weigh a certain amount of particle, add in 10mL graduated cylinders, graduated cylinder is fallen for several times from certain altitude, make
Grain is elastic suitable, measures volume, calculates heap density, the results are shown in Table 23.
The granular pile density measurement result of table 23
3. angle of repose：Take particle appropriate, make to leak down in coniform from funnel, survey its angle of repose, the results are shown in Table 24.
The angle of repose measurement result of table 24
4. critical relative moisture：Particle about 2g (totally 12 parts) is weighed, it is accurately weighed, it is respectively placed in different relative humidity
In the environment of, place 7 days, survey its weight change, the results are shown in Table 25.
The critical relative moisture of table 25 is determined
Relative humidity is mapped with weight gain percentage, Figure 13 is seen.
Claims (3)
1. a kind of hydrogel matrix type sustained release tablets for treating coronary disease and angina pectoris, it is characterised in that：It is by following weight hundred
What the supplementary material of point content was prepared from：
Tribulus fruit extract 29%, sustained-release matrix material HPMCK15M20%, microcrystalline cellulose 35.5%, lactose 15%, magnesium stearate
0.5%；
The preparation method of described tribulus fruit extract is：Puncture vine is taken to add water to cook extraction, Aqueous extracts are concentrated using normal pressure concentration method；
Plus ethanol makes decoction alcohol content be 60%, refrigeration；Reclaim ethanol, upper macroporous absorbent resin elution；After the recovered ethanol of eluent,
50~80 DEG C of dryings, produce tribulus fruit extract under normal pressure.
2. a kind of preparation method of the sustained release tablets prepared described in claim 1, it comprises the following steps：
(1) supplementary material is weighed by recipe ratio；
(2) and after other auxiliary materials and mixings, pelletizing press sheet or direct tablet compressing technique.
3. preparation method according to claim 2, it is characterised in that：The pressure limit of tabletting is 45~55N after granulation.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1039595A (en) * | 1988-05-22 | 1990-02-14 | 洮南市第一制药厂 | The production technique of puncture vine total saponin |
| WO2003094944A1 (en) * | 2002-05-10 | 2003-11-20 | Indena S.P.A. | Formulations useful in the treatment of male and female impotence |
| CN101455696A (en) * | 2007-12-12 | 2009-06-17 | 西安天健医药科学研究所 | Puncturevine herb extract rich in furostanol saponin and preparation method thereof |
| CN101502540A (en) * | 2008-02-04 | 2009-08-12 | 北京凯瑞创新医药科技有限公司 | High-efficient medicament composition using aglycone as effective ingredient and preparation method thereof |
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2014
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1039595A (en) * | 1988-05-22 | 1990-02-14 | 洮南市第一制药厂 | The production technique of puncture vine total saponin |
| WO2003094944A1 (en) * | 2002-05-10 | 2003-11-20 | Indena S.P.A. | Formulations useful in the treatment of male and female impotence |
| CN101455696A (en) * | 2007-12-12 | 2009-06-17 | 西安天健医药科学研究所 | Puncturevine herb extract rich in furostanol saponin and preparation method thereof |
| CN101502540A (en) * | 2008-02-04 | 2009-08-12 | 北京凯瑞创新医药科技有限公司 | High-efficient medicament composition using aglycone as effective ingredient and preparation method thereof |
Non-Patent Citations (1)
| Title |
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| 蒺藜皂甙治疗冠心病心绞痛406例临床观察;王博文等;《中西医结合杂志》;19900430;第10卷(第2期);第85页左栏第1段 * |
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