CN102507381B - Colloid bismuth pectin compound and quality control method of pharmaceutical compositions thereof - Google Patents
Colloid bismuth pectin compound and quality control method of pharmaceutical compositions thereof Download PDFInfo
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Abstract
The invention relates to a colloid bismuth pectin compound and a quality control method of pharmaceutical compositions of the colloid bismuth pectin compound, and specifically provides a colloid bismuth pectin compound, new quality control indexes of pharmaceutical compositions of the colloid bismuth pectin compound and a detection method of the colloid bismuth pectin compound and the pharmaceutical compositions of the colloid bismuth. In the prior art, the quality of products having poor efficacy can not be well controlled because the efficacy-related indexes are not controlled strictly in the existing quality control methods of colloid bismuth pectin and pharmaceuticals thereof. Based on the existing quality control methods of colloid bismuth pectin and pharmaceuticals thereof, the following detection items and indexes are added: intrinsic viscosity, gel property, uniformity and galacturonic acid content. The invention can effectively ensure clinical efficacy of products, make the product quality standards more scientific, reasonable and controllable, and has great significance in quality control of the colloid bismuth pectin and the pharmaceutical preparation of colloid bismuth pectin.
Description
Technical field
The present invention relates to the quality determining method of colloidal bismmth pectin and its pharmaceutical composition, specifically, is to provide colloid
Pectin bismuth compound and its newly-increased quality control index of pharmaceutical composition and its detection method.Belong to drug world.
Background technology
The Couoidal bismuth pectin capsules clinically applied at present and its crude drug colloidal bismmth pectin proper mass standard are by the product
Product research and develop people Medicine Inst. of Datong City and Dalian Weimin Pharmaceutical Co., Ltd. (pharmaceutical factory of former institute of materia medica of Datong District)
Yu Xuemin researcher presides over and drafts.Quality standard first be Ministry of Public Health tentative standard, after switch to formal ministry standard, after record into
, version in 2010 in 2005 in 2000《Chinese Pharmacopoeia》.The standard began to use so far up to 18 years as long as from 1993, should
Standard has played certain effect in the target level of product quality is controlled.With colloidal bismmth pectin and its preparation manufacturer not
Constantly expansion and the technological progress of drug standard and the method for inspection of disconnected increase, yield and sales volume, the standard is to controlling in product
Have that inaccurate, science, level be not low, lacuna is more at quality (index relevant with clinical efficacy) aspect, poor controllability etc. it is scarce
Fall into.
Colloidal bismuth pectin compound is to replace inorganic acid radical (nitroxylic acid root, meta-aluminic acid with biomacromolecule pectin acid group
Root), small molecular organic acid root (secondary citric acid radical) and the new bismuth salt compounds that formed, its distinguishing feature and technological progress exist
Adhere in colloid property and with the high selectivity of the pathogenic bacterium helicobacter pylori (Hp) for being damaged gastrointestinal mucosa and gastrointestinal disease
Effect.The power of this selective attachment effect is with such compound to being damaged the protective effect of gastrointestinal mucosa and killing the work of Hp
With being proportionate, i.e. this selective attachment effect is stronger, to being damaged gastrointestinal mucosa protective effect and stronger to Hp killing actions,
More be conducive to eradicating Hp, be more conducive to the healing of gastroenteritic ulcer and the elimination of inflammation, after more advantageously reducing gastrointestinal disease healing
Relapse rate.The high selectivity adhesive attraction of the compound depends not only on bismuth ion, and is also dependent upon to a great extent
The ratio of acid group in connection, bismuth ion content and pectic acid radical content determines its colloid property and glues with impaired damage gastrointestinal
The high selectivity adhesive attraction of film, Hp.Existing colloidal bismmth pectin and its quality determining method in, proper mass standard [contains
It is fixed to measure] assay of bismuth pectin molecule cationic bismuth is only carried out under item, assay is not carried out to acid group pectin acid group
(referring to《Chinese Pharmacopoeia》Two P852-P853 of version in 2010).
The content of the invention
To overcome existing colloidal bismmth pectin and its preparation (i.e. pharmaceutical composition) quality control index and detection method
Deficiency, improves method of quality control level, is the safely, effectively offer guarantee of product clinical application, and the present invention provides one kind more
For effective colloidal bismmth pectin and its quality control index and detection method of preparation.
Technical solution of the present invention is as follows：
The invention provides the quality determining method of a kind of colloidal bismuth pectin compound and its pharmaceutical composition, its feature exists
In including being determined as follows more than arbitrary or both：Intrinsic viscosity, gelling, uniformity or galacturonic acid content.
Wherein, the quality determining method of colloidal bismuth pectin compound described above and its pharmaceutical composition, its feature exists
It is in the assay method of described intrinsic viscosity：Colloidal bismmth pectin or its pharmaceutical composition is finely ground, weigh and be placed in right amount container
In, constant volume scale is added water to, shake up, according to《Chinese Pharmacopoeia》The 3rd method in the two annex VI G viscosimetries of version in 2010
It is measured.
Wherein, the quality determining method of colloidal bismuth pectin compound described above and its pharmaceutical composition, its feature exists
It is in the assay method of described gelling：Colloidal bismmth pectin or its pharmaceutical composition is finely ground, weigh and be placed in right amount in container,
Plus appropriate amount of water is mixed, shaking is made into after rubber cement, adds hydrochloric acid, forms gel.
Wherein, the quality determining method of colloidal bismuth pectin compound described above and its pharmaceutical composition, its feature exists
It is in the assay method of described uniformity：Residue on sieve and siftage that colloidal bismmth pectin crosses 200 mesh standard sieves are weighed, is pressed respectively
According to《Chinese Pharmacopoeia》Method determines bi content under two colloidal bismmth pectin [assay] items of version in 2010.
Wherein, the quality determining method of colloidal bismuth pectin compound described above and its pharmaceutical composition, its feature exists
It is in the assay method of described galacturonic acid content：According to《Chinese Pharmacopoeia》Two pectin [assay] items of version in 2010
Lower method is determined, and measures V1(initial titration value) and V2(saponification titration value) and (total titer), per 1ml sodium hydroxide titrations
Galacturonic acid of the liquid (0.1mol/L) equivalent to 19.414mg.
Preferably, the quality determining method of colloidal bismuth pectin compound described above and its pharmaceutical composition, wherein institute
The pharmaceutical composition stated is selected from capsule, tablet, granule etc..
Preferably, the quality determining method of colloidal bismuth pectin compound described above and its pharmaceutical composition, its feature
The quality determining method of the colloidal bismuth pectin compound described in being includes intrinsic viscosity, gelling, uniformity and galacturonic acid
Acid content is determined, and：
Intrinsic viscosity is to be not less than 125；
Gelling be in rubber cement add hydrochloric acid formed do not flow, be not dehydrated, without fracture, bubble-free gel；
Uniformity was that the bi content of the residue on sieve of 200 mesh standard sieves and siftage should be 14-16%, and its difference
Cannot be greater than 1.0%；
Galacturonic acid content must not be less than 60% of the drying sample after isopropanol washing.
Preferably, the quality determining method of colloidal bismuth pectin compound described above and its pharmaceutical composition, its feature
The quality determining method of the Couoidal bismuth pectin capsules agent described in being includes that intrinsic viscosity, gelling and galacturonic acid content are surveyed
It is fixed, and：
Intrinsic viscosity is to be not less than 125；
Gelling be in rubber cement add hydrochloric acid formed do not flow, be not dehydrated, without fracture, bubble-free gel；
Galacturonic acid content is the 90.0-110.0% that the galacturonic acid content of every capsule should be labelled amount.
As one of specific embodiments of the present invention, described colloidal bismuth pectin compound and its quality of pharmaceutical composition
Detection method, it is characterised in that：
The assay method of the intrinsic viscosity be according to《Chinese Pharmacopoeia》The two annex VI G viscosimetries of version in 2010
In the 3rd method be measured, specially：Precision weighs the colloidal bismmth pectin or Couoidal bismuth pectin capsules content by 200 mesh sieves
Thing 50mg is placed in 100ml volumetric flasks, is added water and is settled to scale, is shaken up, and is filtered with No. 3 sintered glass funnels, discards just filtrate,
Take subsequent filtrate 10ml to load in the ball B of Ubbelohde viscometer that is clean, being dried, viscometer is perpendicularly fixed at into water bath with thermostatic control (water-bath
Temperature is 75 ± 0.05 DEG C) in, and make the liquid level of water-bath higher than ball C, after placing 15 minutes, the mouth of pipe 1,3 is respectively connect into a latex tubing,
The sebific duct of the mouth of pipe 3 is clamped, is evacuated from the mouth of pipe 1, the liquid level for making need testing solution is slowly increasing to the middle part of ball C, first open pipes
Mouthfuls 3, then the open mouth of pipe 1, need testing solution whereabouts naturally in pipe is made, tested oneself alignment m with stopwatch accurate recording liquid level1Drop to
Determine line m2The delivery time at place, twice, twice measured value difference must not exceed 0.1 second replication, take meansigma methodss twice
For the delivery time (T) of need testing solution；The purified water that No. 3 sintered glass funnels of learning from else's experience are filtered, same operation, replication 2
Secondary, twice measured value should be identical, is the delivery time (T of purified water0)；Estimated performance viscosity number ([η])：
Wherein c for test solution concentration, g/ml；
The assay method of the gelling is：Colloidal bismmth pectin or Couoidal bismuth pectin capsules content is finely ground, weigh
0.75g is placed in 50ml color comparison tubes, plus appropriate amount of water is mixed, and adds water to constant volume scale, and shaking is made into after rubber cement, addition hydrochloric acid (1 →
2) 4 drop, strength shake after stand, formation do not flow, be not dehydrated, without fracture, bubble-free gel；
The assay method of the uniformity is：Take colloidal bismmth pectin appropriate, cross 200 mesh standard sieves, weigh same amount of sieve
Excess and siftage, respectively according to《Chinese Pharmacopoeia》Method determines bismuth under two colloidal bismmth pectin [assay] items of version in 2010
Content；
The assay method of the galacturonic acid content is：Take colloidal bismmth pectin or Couoidal bismuth pectin capsules content
5.0g, it is accurately weighed, in putting beaker, plus 5ml concentrated hydrochloric acid and 100ml60% isopropanols, stirring 10 minutes, the mixture passes through one
Buchner funnel (capacity 60ml) vacuum filtration of dry known weight, wherein the filter paper (known weight) of two-layer constant weight is put into,
Filtering residue 6 times, each 15ml, till continuation is washed till filtrate without chloride ion with 60% isopropanol are washed with hydrochloric acid-isopropanol mixed liquor
(being dropped to without white precipitate with 1% silver nitrate test solution), then add isopropanol 20ml washings, residue to be dried 3-4 hours at 105 DEG C, put
It is cold, weigh；Precision weighs 1/10 weight for being dried residue, in putting 250ml conical flasks, plus ethanol 2ml moistenings, plus carbon dioxide removal
Distilled water 100m, shakes to whole dissolvings, plus instructions phenolphthalein solution 5 drips, and is titrated to sodium hydroxide titration liquid (0.1mol/L) micro-
Redness, it is V to consume volumetric solution volume1(initial titration value)；Repeated hydrogenation sodium oxide volumetric solution (0.5mol/L) 20.0ml, acutely shakes
After shaking 5 minutes, place 15 minutes, plus HCI liquid (0.5mol/L) 20.0ml, shake to red disappearance, then add phenolphthalein to indicate
Liquid 3 drips, and continues acutely shaking, and with sodium hydroxide titration liquid (0.1mol/L) faint pink endpoint is titrated to, and record volume is V2(soap
Change titration value)；Sodium hydroxide titration liquid (0.1mol/L) (i.e. total titer=initial titration value V of total titer per 1ml1+ soap
Change titration value V2) galacturonic acid equivalent to 19.414mg.
1. intrinsic viscosity
Use《Chinese Pharmacopoeia》The 3rd method in the viscosimetry that version in 2010 specifies determines viscosity, and then calculates spy
Property viscosity number.
1.1 assay method
Precision is weighed and is placed in 100ml volumetric flasks by the colloidal bismmth pectin 50mg of 200 mesh sieves, is added water and is settled to scale,
Shake up, filtered with No. 3 sintered glass funnels, discard just filtrate, take subsequent filtrate 10ml and load Ubbelohde viscometer that is clean, being dried
(see《Chinese Pharmacopoeia》The 3rd subtraction unit in the two annex VI G viscosimetries of version in 2010) ball B in, viscometer is hung down
In being directly fixed on water bath with thermostatic control (bath temperature is 75 ± 0.05 DEG C), and the liquid level of water-bath is made higher than ball C, after placing 15 minutes,
The mouth of pipe 1,3 is respectively connect into a latex tubing, the sebific duct of the mouth of pipe 3 is clamped, is evacuated from the mouth of pipe 1, the liquid level for making need testing solution slowly rises
Up to the middle part of ball C, first opens the mouth of pipe 3, then the open mouth of pipe 1, makes need testing solution fall naturally in pipe, is accurately remembered with stopwatch
Record liquid level is tested oneself alignment m1Drop to measure line m2The delivery time at place, twice, twice measured value difference must not exceed replication
0.1 second, take delivery time (T) of the meansigma methodss twice for need testing solution.The purification that No. 3 sintered glass funnels of learning from else's experience are filtered
Water, same operation, replication 2 times, twice measured value should be identical, is the delivery time (T of purified water0).Estimated performance is viscosity number：
C for test solution concentration, g/ml.
1.2 measurement result
It is measured by the colloidal bismmth pectin sample to different bi contents and galacturonic acid content, measurement result is as follows
Table.
| Sample number into spectrum | Bi content (%) | Galacturonic acid content (%) | C(8ml) | [η] |
| 1 | 15 | 60 | 0.1 | 147 |
| 2 | 15 | 60 | 0.1 | 151 |
| 3 | 15 | 60 | 0.1 | 154 |
| 4 | ＜ 14 | ＞ 65 | 0.1 | 121 |
| 5 | ＜ 14 | ＞ 65 | 0.1 | 118 |
| 6 | ＜ 14 | ＞ 65 | 0.1 | 120 |
| 7 | ＞ 16 | ＜ 55 | 0.1 | 109 |
| 8 | ＞ 16 | ＜ 55 | 0.1 | 104 |
| 9 | ＞ 16 | ＜ 55 | 0.1 | 97 |
As can be seen from the above table：When bi content 15%, galacturonic acid content 60%, intrinsic viscosity highest is 147-
154；When bi content is less than 14%, and galacturonic acid content is more than 65%, intrinsic viscosity is 118-121；When bi content is more than
16%, when galacturonic acid content is less than 55%, intrinsic viscosity is 97-109, worst.
2. gelling
Gelling under [discriminating] item, appropriate hydrochloric acid is added in colloidal bismmth pectin, forms the gel for not flowing and not being dehydrated,
Jing test of many times determines that the gelling test has specificity.
2.1 assay method
Colloidal bismmth pectin or Couoidal bismuth pectin capsules content is finely ground, weigh 0.75g and be placed in 50ml color comparison tubes, add water
It is appropriate to mix, constant volume scale is added water to, shaking is made into after rubber cement, adds the drop of hydrochloric acid (1 → 2) 4, strength to stand after shaking, and is formed
Do not flow, be not dehydrated, without fracture, bubble-free gel.
2.2 measurement result
Colloidal bismmth pectin and Couoidal bismuth pectin capsules sample respectively to 3 different batches is measured, and measurement result is such as
Following table.
| Sample number into spectrum | Sampling amount (g) | Acid adding amount (drop) | Gel is formed after standing |
| Raw material 1 | 0.7529 | 4 | Do not flow, be not dehydrated, without fracture, bubble-free |
| Raw material 2 | 0.7508 | 4 | Do not flow, be not dehydrated, without fracture, bubble-free |
| Raw material 3 | 0.7537 | 4 | Do not flow, be not dehydrated, without fracture, bubble-free |
| Capsule 1 | 0.7598 | 4 | Do not flow, be not dehydrated, without fracture, bubble-free |
| Capsule 2 | 0.7577 | 4 | Do not flow, be not dehydrated, without fracture, bubble-free |
| Capsule 3 | 0.7587 | 4 | Do not flow, be not dehydrated, without fracture, bubble-free |
3. uniformity
According to《Chinese Pharmacopoeia》Method is determined under two P853 colloidal bismmth pectin [assay] items of version in 2010.
3.1 assay method
Take colloidal bismmth pectin appropriate, cross 200 mesh standard sieves, weigh same amount of residue on sieve and siftage, respectively according to《China
Pharmacopeia》Method determines bi content under two P853 colloidal bismmth pectin [assay] items of version in 2010.
3.2 measurement results such as following table.
| Sample number into spectrum | Residue on sieve bi content (%) | Siftage bi content (%) | Bi content difference (%) |
| 1 | 15.34 | 15.29 | ＜ 1.0 |
| 2 | 14.87 | 14.96 | ＜ 1.0 |
| 3 | 14.98 | 14.73 | ＜ 1.0 |
| 4 | 15.61 | 15.73 | ＜ 1.0 |
| 5 | 15.29 | 15.32 | ＜ 1.0 |
| 6 | 14.69 | 14.57 | ＜ 1.0 |
The bi content of 6 different batches samples, residue on sieve and siftage in the range of 14.0-16.0%, and both
Difference be less than 1.0%.
4. galacturonic acid content is determined
Galacturonic acid is the monomer after the degraded of pectin acid group, and bronsted lowry acids and bases bronsted lowry can break the glycosidic bond of connection galacturonic acid
Split so as to which galacturonic acid monomers are changed into from galacturonic acid polymer.According to《Chinese Pharmacopoeia》Two P1203- of version in 2010
Method is determined under P1204 pectin [assay] item.
4.1 assay method
Colloidal bismmth pectin 5.0g is taken, it is accurately weighed, in putting beaker, plus 5ml concentrated hydrochloric acid and 100ml60% isopropanols, stirring
10 minutes, buchner funnel (capacity 60ml) vacuum filtration that the mixture passes through a known weight being dried, wherein being put into two-layer
The filter paper (known weight) of constant weight, filtering residue 6 times is washed with hydrochloric acid-isopropanol mixed liquor, and 60% isopropanol is used in each 15ml, continuation
(with the isopropanol of different manufacturers, the number of times difference of washing till filtrate is washed till without chloride ion；Nothing is dropped to 1% silver nitrate test solution
White precipitate), then add isopropanol 20ml washings, residue to be dried 3-4 hours at 105 DEG C, let cool, weigh.
Precision weighs 1/10 weight for being dried residue, in putting 250ml conical flasks, plus ethanol 2ml moistenings, plus carbon dioxide removal
Distilled water 100m, shakes to whole dissolvings, plus instructions phenolphthalein solution 5 drips, and is titrated to sodium hydroxide titration liquid (0.1mol/L) micro-
Redness, it is V to consume volumetric solution volume1(initial titration value).Repeated hydrogenation sodium oxide volumetric solution (0.5mol/L) 20.0ml, acutely shakes
After shaking 5 minutes, place 15 minutes, plus HCI liquid (0.5mol/L) 20.0ml, shake to red disappearance, then add phenolphthalein to indicate
Liquid 3 drips, and continues acutely shaking, and with sodium hydroxide titration liquid (0.1mol/L) faint pink endpoint is titrated to, and record volume is V2(soap
Change titration value).Sodium hydroxide titration liquid (0.1mol/L) (i.e. total titer=initial titration value V of total titer per 1ml1+ soap
Change titration value V2) galacturonic acid equivalent to 19.414mg.
4.1.1 specificity test
Colloidal bismmth pectin is the salt compounds formed by pectin (Poly Gal A Galacturonan) and trivalent bismuth ion, in order to examine
Examine the specificity of content assaying method, foundation《Chemicalses Quality Control Analysis method validation technological guidance's principle (one)》It is exclusive
Property the assay of money 3 principle, i.e., for main constituent assay can add impurity or adjuvant in test sample, investigate and determine knot
Whether fruit disturbs, and with not plus impurity and adjuvant test sample comparative measurements result.The galacturonic acid content of colloidal bismmth pectin
Assay method, has used for reference the galacturonic acid content assay method of pectin, and colloidal bismmth pectin is colloid fruit with the difference of pectin
There is trivalent metal bismuth ion in glue bismuth, be whether the presence for investigating trivalent bismuth ion has an impact to determining galacturonic acid, adopt
Trivalent metal bismuth (Bi is added in colloidal bismmth pectin2O3) method tested, if had an impact, the addition measured is not
The sample size of commensurability trivalent metal bismuth has error；If without impact, error then should be in the range of methodological precision, can be true
The presence for determining trivalent metal bismuth is noiseless to the content of galacturonic acid in measure colloidal bismmth pectin, and the method is to determining colloid fruit
Galacturonic acid content in glue bismuth has preferable specificity.
4.1.1.1 precision weighs colloidal bismmth pectin (lot number：20080101) 5.0g, surveys totally according to method under " 4.1 " item by five parts
The content for obtaining galacturonic acid is 2.2032g.
4.1.1.2 precision weighs colloidal bismmth pectin (lot number：20080105) 5.0g, is separately added into Bi by totally five parts2O3
0.25g, 0.5g, 0.75g, 1.00g, 1.25g, the content for measuring galacturonic acid according to method under " 4.1 " item is 2.2012g.Point
Bi is not added2O3Measurement result after 0.25g, 0.5g, 0.75g, 1.00g, 1.25g with do not add Bi2O3Measurement result without
Significant difference, in the range of precision allowable error.
4.1.1.3 precision weighs the Bi equivalent to bi content in 5.0g colloidal bismmth pectin2O30.85g, shines totally by five parts
The content that method measures galacturonic acid under " 4.1 " item is 0, so Bi2O3The assay result of galacturonic acid is not affected.
Therefore, 4.1.1.1-4.1.1.3 result of the tests show, trivalent metal bismuth to determining colloidal bismmth pectin in galacturonic acid content
Noiseless, the method has preferable specificity.
4.1.2 linear relationship test
Precision weighs galacturonic acid (content >=97.0%) 0.25g, 0.20g, 0.15g, 0.1g, 0.05g, shines " 4.1 "
Method is determined under, measurement result such as following table.
| Galacturonic acid (g) | 0.2501 | 0.2003 | 0.1509 | 0.1003 | 0.0509 |
| Consume sodium hydroxide (0.1mol/L) total amount (ml) | 12.59 | 10.1 | 7.5 | 5.0 | 2.6 |
Amount (g) with galacturonic acid (X) as abscissa, sodium hydroxide titration liquid (0.1mol/L) volume (ml) is vertical seat
Mark (Y), obtains linear equation y=50.32X-0.0152, and (R=0.9998) linear relationship is good.
4.1.3 scope test
According to " " it can be seen from the linear relationship tested under item, sample size is in good linear relation in the range of 1～6g to 4.1.2.
4.1.4 accuracy (response rate) test
Precision weighs the colloidal bismmth pectin (lot number of known content：20080101) nine parts of about 2g, survey according to method under " 4.1 " item
It is fixed, it is accurate respectively to add height when operation is to " precision weigh be dried 1/10 weight of residue put in 250ml conical flasks ", in, it is low heavy
The galacturonic acid of magnitude, is then continued to determine by method under " 4.1 " item, and calculating average recovery rate is 99.02%, RSD=
0.71%, n=9.Colloidal bismmth pectin recovery test measurement result such as following table.
4.1.5 precision test
4.1.5.1 replica test
Precision weighs colloidal bismmth pectin (lot number：20080102) 5g, determines totally according to method under " 4.1 " item by six parts, measures half
The meansigma methodss of lactobionic acid are 2.117467g, RSD=0.40%.
4.1.5.2 reappearance test
Laboratory 1 4.1.5.2.1 (Dalian Weimin Pharmaceutical Co., Ltd.)
Instrument and reagent
Drying baker：Model 101-1ES (light Medical Instruments factory of Beijing)
Balance：Model FA1604 (Shanghai Fang Rui Instrument Ltd.)
Isopropanol, ethanol, sodium hydroxide, hydrochloric acid, it is pure that silver nitrate is analysis
Precision weighs colloidal bismmth pectin (lot number：20080103) 5g, determines respectively totally according to method under " 4.1 " item by three parts, surveys
Determine result such as following table.
4.1.5.2.2 laboratory 2 (Medicine Inst. of Datong City analysis room)
Instrument and reagent
Drying baker：Model KWY-101-1 (Wuhan Wuchang)
Balance：Model 120WD (Japanese Shimadzu)
Accurately weighed colloidal bismmth pectin (lot number：20080103) 5g, determines totally according to method under " 4.1 " item by three parts, determines knot
Fruit such as following table.
Measurement result shows：The method is accurately and reliably.
4.1.6 the measure of sample
Precision weighs 3 batches of samples, and (lot number is respectively：20080104th, 20080105,20080106) each three parts, per part about
5g.Determine by method under " 4.1 " item, measurement result such as following table.
When determining, if with the isopropanol of different manufacturers, the number of times of washing is different, but measurement result is unaffected；With
The buchner funnel of suitable different size, in different environments, the different time, measures result unaffected.
Present invention surprisingly has found that, the newly-increased quality control checking of colloidal bismmth pectin and its pharmaceutical composition of the present invention
Project, index and detection method are on the basis of existing quality standard, by increased intrinsic viscosity, gelling, uniformity
The index determined with galacturonic acid content and method, can guarantee that product clinical efficacy, make target level of product quality more science, conjunction
Reason, it is controllable.Jing lot of experiments research show, bi content be 15 ± 2% and galacturonic acid (monomer of pectin) content be 60 ±
When 2%, the colloid property of product and to be damaged gastrointestinal mucosa, Hp selective attachment effect it is most strong, clinical efficacy is preferably also.
The physicochemical properties related to gastrointestinal mucosa and Hp high selectivity adhesive attractions is damaged, such as intrinsic viscosity, gelling, content
Uniformity etc. is relevant with the inherent quality of product, and above-mentioned quality control index is increased in quality standard, to improving the product
Quality, ensure clinical efficacy, it is to avoid the generation of toxicity, to product quality controllability, to improving the product and pharmaceutical industry
Technological progress will produce significant impact, it will produce obvious scientific and technological progress in colloidal bismmth pectin field of quality control and push away
Action is used.
Specific embodiment
Following examples are that the scope of the claims of the present invention is carried out in order to test and understand technical solution of the present invention, but do not constitute
Limit.
Embodiment 1
The inspection of gelling under [discriminating] item：Colloidal bismmth pectin or Couoidal bismuth pectin capsules content is finely ground, weigh
0.75g is placed in 50ml color comparison tubes, plus appropriate amount of water is mixed, and adds water to constant volume scale, and shaking is made into after rubber cement, addition hydrochloric acid (1 →
2) 4 drop, strength shake after stand, formation do not flow, be not dehydrated, without fracture, bubble-free gel.
Embodiment 2
The inspection of intrinsic viscosity under [inspection] item：By colloidal bismmth pectin or the finely ground mistake 200 of Couoidal bismuth pectin capsules content
Mesh sieve, precision weighs 50mg and is placed in 100ml volumetric flasks, adds water to constant volume scale, shakes up, and shines《Chinese Pharmacopoeia》Version two in 2010
The 3rd method inspection in portion's annex VI G viscosimetries, as a result [η] is 149.
Embodiment 3
The inspection of uniformity under [inspection] item：Colloidal bismmth pectin 10g is weighed, 200 mesh standard sieves are crossed, the sieve of equivalent is taken respectively
Excess and siftage shine《Chinese Pharmacopoeia》Method determines bismuth and contains under two P853 colloidal bismmth pectin [assay] items of version in 2010
Amount.As a result：Residue on sieve bi content is 15.71%, and siftage bi content is 15.53%, and both differences are 0.18%, meet quality
Require.
Embodiment 4
The measure of galacturonic acid content under [assay] item：Colloidal bismmth pectin 5.0g is taken, it is accurately weighed, put beaker
In, plus 5ml concentrated hydrochloric acid and 100ml60% isopropanols, stir 10 minutes, the Bu Shi that the mixture passes through a known weight being dried
Funnel (capacity 60ml) vacuum filtration, wherein being put into the filter paper (known weight) of two-layer constant weight, is washed with hydrochloric acid-isopropanol mixed liquor
Filtering residue 6 times is washed, each 15ml, continuation (drops to nothing till being washed till filtrate without chloride ion with 60% isopropanol with 1% silver nitrate test solution
White precipitate), then add isopropanol 20ml washings, residue to be dried 3-4 hours at 105 DEG C, let cool, weigh.
Precision weighs 1/10 weight for being dried residue, in putting 250ml conical flasks, plus ethanol 2ml moistenings, plus carbon dioxide removal
Distilled water 100m, shakes to whole dissolvings, plus instructions phenolphthalein solution 5 drips, and is titrated to sodium hydroxide titration liquid (0.1mol/L) micro-
Redness, it is V to consume volumetric solution volume1(initial titration value).Repeated hydrogenation sodium oxide volumetric solution (0.5mol/L) 20.0ml, acutely shakes
After shaking 5 minutes, place 15 minutes, plus HCI liquid (0.5mol/L) 20.0ml, shake to red disappearance, then add phenolphthalein to indicate
Liquid 3 drips, and continues acutely shaking, and with sodium hydroxide titration liquid (0.1mol/L) faint pink endpoint is titrated to, and record volume is V2(soap
Change titration value).Sodium hydroxide titration liquid (0.1mol/L) (i.e. total titer=initial titration value V of total titer per 1ml1+ soap
Change titration value V2) galacturonic acid equivalent to 19.414mg.Galacturonic acid content is 60.57%.
Claims (3)
1. the quality determining method of a kind of colloidal bismuth pectin compound or its pharmaceutical composition, it is characterised in that including determining colloid
The step of intrinsic viscosity of pectin bismuth compound or its pharmaceutical composition, gelling, uniformity and galacturonic acid content, its
In：
The determination step of described intrinsic viscosity is：Colloidal bismuth pectin compound or its pharmaceutical composition is finely ground, weigh appropriate
In being placed in container, constant volume scale is added water to, shaken up, according to《Chinese Pharmacopoeia》In the two annex VI G viscosimetries of version in 2010
The 3rd method be measured；
The determination step of described gelling is：Colloidal bismuth pectin compound or its pharmaceutical composition is finely ground, weigh and put in right amount
In container, plus appropriate amount of water is mixed, and shaking is made into after rubber cement, adds hydrochloric acid, forms gel；
The determination step of described uniformity is：Colloidal bismuth pectin compound is weighed respectively or its pharmaceutical composition crosses 200 targets
Quasi- sieve residue on sieve and siftage, respectively according to《Chinese Pharmacopoeia》Two colloidal bismmth pectin [assay] the item lower sections of version in 2010
Method determines bi content；
The determination step of described galacturonic acid content is：According to《Chinese Pharmacopoeia》Two pectin [assay] of version in 2010
Method is determined under, measures initial titration value V1With saponification titration value V2And as total titer, per 1ml 0.1mol/L hydrogen
Galacturonic acid of the sodium oxide volumetric solution equivalent to 19.414mg；
And wherein：
Described intrinsic viscosity is to be not less than 125；
Described gelling be in rubber cement add hydrochloric acid formed do not flow, be not dehydrated, without fracture, bubble-free gel；
Described uniformity was that the bi content of the residue on sieve of 200 mesh standard sieves and siftage should be 14～16%, and its
Difference cannot be greater than 1.0%；
The galacturonic acid content must not be less than 60% of the drying sample after isopropanol washing.
2. the quality determining method of colloidal bismuth pectin compound according to claim 1 or its pharmaceutical composition, wherein institute
The pharmaceutical composition stated is selected from capsule, tablet or granule.
3. the quality determining method of colloidal bismuth pectin compound according to claim 1 or its pharmaceutical composition, its feature
It is：
The determination step of described intrinsic viscosity be according to《Chinese Pharmacopoeia》In the two annex VI G viscosimetries of version in 2010
The 3rd method be measured, the precision colloidal bismmth pectin or Couoidal bismuth pectin capsules content 50mg that weigh by 200 mesh sieves are put
In 100ml volumetric flasks, add water and be settled to scale, shake up, filtered with No. 3 sintered glass funnels, discard just filtrate, take subsequent filtrate
10ml loads in the ball B of Ubbelohde viscometer that is clean, being dried, and viscometer is perpendicularly fixed at into bath temperature for 75 ± 0.05 DEG C
In water bath with thermostatic control, and make the liquid level of water-bath higher than ball C, after placing 15 minutes, the mouth of pipe 1,3 is respectively connect into a latex tubing, clamp the mouth of pipe 3
Sebific duct, be evacuated from the mouth of pipe 1, the liquid level for making need testing solution is slowly increasing to the middle part of ball C, first opens the mouth of pipe 3, then opens
The mouth of pipe 1, makes need testing solution whereabouts naturally in pipe, is tested oneself alignment m with stopwatch accurate recording liquid level1Drop to measure line m2Place
Delivery time, twice, twice measured value difference must not exceed 0.1 second replication, and it is that test sample is molten to take meansigma methodss twice
The delivery time T of liquid；The purified water that No. 3 sintered glass funnels of learning from else's experience are filtered, equally operates, replication 2 times, twice measured value
Should be identical, it is the delivery time T of purified water0；Estimated performance viscosity number [η]：
Wherein c for test solution concentration, g/ml；
The determination step of the gelling is：Colloidal bismmth pectin or Couoidal bismuth pectin capsules content is finely ground, weigh 0.75g and put
In 50ml color comparison tubes, plus appropriate amount of water is mixed, and adds water to constant volume scale, and shaking is made into after rubber cement, adds the drop of hydrochloric acid (1 → 2) 4,
Strength shake after stand, formation do not flow, be not dehydrated, without fracture, bubble-free gel；
The determination step of the uniformity is：Take colloidal bismmth pectin appropriate, cross 200 mesh standard sieves, weigh same amount of residue on sieve
And siftage, respectively according to《Chinese Pharmacopoeia》Method determines bismuth and contains under two colloidal bismmth pectin [assay] items of version in 2010
Amount；
The determination step of the galacturonic acid content is：Colloidal bismmth pectin or Couoidal bismuth pectin capsules content 5.0g are taken, essence
It is close weighed, in putting beaker, plus 5ml concentrated hydrochloric acid and 100ml60% isopropanols, stirring 10 minutes, the mixture is by a drying
The buchner funnel vacuum filtration of the capacity 60ml of known weight, wherein be put into the filter paper of the known weight of two-layer constant weight, with hydrochloric acid-
Isopropanol mixed liquor washing filtering residue 6 times, each 15ml, till continuation is washed till filtrate without chloride ion with 60% isopropanol, i.e., with 1%
Silver nitrate test solution is dropped to without white precipitate, then adds isopropanol 20ml washings, residue to be dried 3-4 hours at 105 DEG C, let cool, weigh；
Precision weighs 1/10 weight for being dried residue, in putting 250ml conical flasks, plus ethanol 2ml moistenings, plus carbon dioxide removal distilled water
100m, shakes to whole dissolvings, plus instructions phenolphthalein solution 5 drips, and with 0.1mol/L sodium hydroxide titration liquid blush is titrated to, and consumes
Volumetric solution volume is initial titration value V1；Again plus 0.5mol/L sodium hydroxide titration liquid 20.0ml, acutely put after shaking 5 minutes
Put 15 minutes, plus 0.5mol/L HCI liquid 20.0ml, shake to red disappearance, then add instructions phenolphthalein solution 3 to drip, continue violent
Shaking, with 0.1mol/L sodium hydroxide titration liquid faint pink endpoint is titrated to, and record volume is saponification titration value V2, total titer
For initial titration value V1With saponification titration value V2Sum, total titer per 1ml 0.1mol/L sodium hydroxide titrations liquid equivalent to
19.414mg galacturonic acid.
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| CN105467071B (en) * | 2015-04-07 | 2018-07-17 | 湖南华纳大药厂股份有限公司 | A kind of quality control of colloidal bismmth pectin pharmaceutical composition and its assay method of galacturonic acid content |
| CN105572126B (en) * | 2015-04-07 | 2018-10-23 | 湖南华纳大药厂股份有限公司 | A kind of colloidal bismmth pectin pharmaceutical composition |
| CN105461823B (en) * | 2015-04-07 | 2018-04-06 | 湖南华纳大药厂股份有限公司 | A kind of preparation method of colloidal bismmth pectin and its control method of pharmaceutical composition adhesion |
| CN105560188B (en) * | 2015-04-07 | 2019-03-05 | 湖南华纳大药厂股份有限公司 | A kind of colloid pectin bismuth medicine closes object and its method of quality control |
| CN105496968B (en) * | 2015-04-07 | 2019-03-05 | 湖南华纳大药厂股份有限公司 | A kind of quality of colloidal bismmth pectin pharmaceutical composition and the control method of safety |
| CN104897668B (en) * | 2015-06-23 | 2016-08-24 | 山西振东安特生物制药有限公司 | For the detection method containing colloid pectin bismuth preparation dissolution |
| CN104880428B (en) * | 2015-06-23 | 2016-07-06 | 山西振东安特生物制药有限公司 | A kind of colloidal bismmth pectin or containing the assay method of bi content in colloid pectin bismuth preparation |
| CN110146500B (en) * | 2018-02-12 | 2021-07-23 | 山西振东安特生物制药有限公司 | Method for determining free bismuth in colloidal bismuth pectin or colloidal bismuth pectin-containing preparation |
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