CN105496968B - A kind of quality of colloidal bismmth pectin pharmaceutical composition and the control method of safety - Google Patents
A kind of quality of colloidal bismmth pectin pharmaceutical composition and the control method of safety Download PDFInfo
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Abstract
This application involves the control methods of a kind of quality of colloidal bismmth pectin pharmaceutical composition and safety, described pharmaceutical composition dosage form is dry suspensoid agent, it is 130-160 parts of bulk pharmaceutical chemicals colloidal bismmth pectins including parts by weight (in terms of bismuth), the filler mannitol that parts by weight are 420-460 parts, the flocculant disodium hydrogen phosphate and/or corrigent that parts by weight are 10-20 parts, it is characterized in that, the intrinsic viscosity of the pharmaceutical composition is controlled, improve the medicine stability and therapeutic effect of colloid pectin bismuth dry suspensoid, significant impact will be generated to the technological progress for improving the product and pharmaceutical industry, apparent scientific and technological progress and impetus will be generated in colloidal bismmth pectin field of quality control.
Description
Technical field
This application involves a kind of preparation of colloid pectin bismuth dry suspensoid and its method of quality control, specifically, the application
Further relate to a kind of control method of colloidal bismmth pectin pharmaceutical composition safety.
Background technique
Colloidal bismmth pectin is that the indefinite compound that forms that a kind of pectin and bismuth generate belongs to gastric mucosa as bulk pharmaceutical chemicals
Protect medicine, it is characterised in that its molecule is by D- galacturonic acid methyl esters, D- galacturonic acid bismuth and D- galacturonic acid potassium
The new bismuth salt compounds that the high-molecular compound and large biological molecule acid group that structure fragment is formed are formed.
Colloidal bismmth pectin can form stable colloidal dispersion in water, and gel is formed in simulated gastric fluid, have relatively strong
Colloid property, with skin surface have very strong affinity, promote the healing of ulcer and the disappearance of inflammation, can also stimulate mucous membrane
Epithelial cells mucus and killing helicobacter pylori (Helicobacter Pylori, HP), can form one layer on gastric mucosa
Firm protective film, enhances the barrier protection effect of gastric mucosa, and distinguishing feature is colloid property and glues with stomach and intestine are damaged
The highly selective adhesive attraction of the pathogenic bacteria helicobacter pylori of film and gastrointestinal disease.The power of this adhesiveness adhesive attraction, with
It is damaged gastrointestinal mucosa protective effect and the effect of killing HP is proportional to, is i.e. this selective attachment effect is stronger, to impaired
Injure one's stomach intestinal mucosa protective effect and stronger to helicobacter pylori killing effect, is more conducive to eliminating pylorus, more has
Conducive to the healing of gastroenteritic ulcer and the elimination of inflammation, the recurrence rate after gastrointestinal disease is cured more is advantageously reduced.With other colloidal state
Bismuth preparation compares, and the colloid property of colloidal bismmth pectin is good, is 7.4 times of colloidal bismuth subcitrate potassium.But bismuth belongs to micro- poison
Class, bismuth are distributed in body everywhere after absorbing, and most with kidney, liver takes second place, and the colloidal state bismuth preparation that gumminess is good, and blood bismuth is in treatment
Rise slowly, it absorbs less, bismuth accumulation can be reduced and influence liver kidney.
Secondly, bismuth category micro-virus kind substance.Bismuth is distributed in body everywhere after absorbing, and most with kidney, liver takes second place.Most of storage
Bismuth in vivo, in several weeks so that can be discharged by urine in the several months.
For these reasons, the dose each because of strict control bismuth reduces bismuth accumulation to the greatest extent and is poisoned.
It is at present " Chinese Pharmacopoeia " 2010 version second about colloid referring especially to standard in colloidal bismmth pectin bulk pharmaceutical chemicals
Colloidal bismuth pectin regulation, but the control range of its intrinsic viscosity is not provided.
In addition, standard No. is that WS1- (X-104) -96Z colloidal bismmth pectin new drug standard of becoming a full member defines bulk pharmaceutical chemicals colloid fruit
The drug standards of glue bismuth, but the standard of intrinsic viscosity in colloidal bismmth pectin bulk pharmaceutical chemicals is not provided, and for different glue
Body pectin bismuth medicine composition, dosage form is different, and the standard of intrinsic viscosity is different, and curative effect is also different.
Application No. is 201110300984.1 Chinese patents to propose the quality testing of colloidal bismmth pectin pharmaceutical composition
Method exists for the method for quality control of existing colloidal bismmth pectin and its pharmaceutical preparation to index matter related with curative effect
Control is not rigorous enough, so that leading to the problem of the product poor controllability poor to curative effect.Increase intrinsic viscosity, uniformity, gala
Glucuronic acid content measurement item and index, the effective clinical efficacy for guaranteeing product, but wherein each technical parameter is not done more
Careful research, so that those skilled in the art can not further improve the curative effect of colloidal bismmth pectin.
Summary of the invention
The application's is designed to provide a kind of colloidal bismmth pectin pharmaceutical composition, and dosage form is dry suspensoid agent.
Further object is to provide a kind of method of quality control of colloidal bismmth pectin pharmaceutical composition, make up
The blank that colloid pectin bismuth preparation controls quality in the prior art improves the quality of colloid pectin bismuth preparation, faces for product
The safely, effectively offer guarantee of bed medication.
The third of the application is designed to provide a kind of method for controlling the safety of colloidal bismmth pectin pharmaceutical composition.
For the purpose for realizing the application, can be accomplished by the following way:
Ingredient and the content proportion of the application colloid pectin bismuth dry suspensoid are as follows:
Colloidal bismmth pectin (in terms of bismuth): 130-160 parts；420-460 parts of filler；10-20 parts of flocculant.
The wherein optional mannitol of filler.
The optional disodium hydrogen phosphate of flocculant.
One or both of Steviosin, orange oil essence can also be added in the application, as corrigent.
Preferably, the weight ratio of the application each component are as follows:
150 parts of colloidal bismmth pectin (in terms of bismuth)；455 parts of mannitol；15 parts of disodium hydrogen phosphate.
The technical solution of the application are as follows:
Quality control is carried out to the intrinsic viscosity of colloidal bismmth pectin pharmaceutical composition.
Wherein, the measuring method of the pharmaceutical composition intrinsic viscosity is according to two VI G of annex of " Chinese Pharmacopoeia " version in 2010
Third method in viscosimetry is measured.
Its measuring method is that precision weighs colloid pectin bismuth dry suspensoid 50mg, is placed in 100ml volumetric flask, adds water about
30ml, shaking or ultrasound keep its evenly dispersed, and add water to be settled to scale and shake up, and are filtered, are discarded just with No. 3 sintered glass funnels
Filtrate, taking subsequent filtrate 20ml to be packed into clean, dry Ubbelohde viscometer, (two annex of Chinese Pharmacopoeia version in 2010, VI G viscosity is surveyed
Determine the third method in method) ball B in, viscosmeter is perpendicularly fixed in constant temperature (25 DEG C ± 0.1 DEG C) water-bath, and make the liquid of water-bath
Face is higher than ball C, and after placing 15 minutes, the sebific duct that nozzle 1,3 is respectively connect an emulsion tube, clamps nozzle 3 is evacuated from nozzle 1, makes
The liquid level of test solution is slowly increasing to the middle part of ball C, decontrols nozzle 3, then decontrol nozzle 1, makes test solution in pipe
Naturally it falls, with stopwatch accurate recording liquid level to measurement line m1Drop to measurement line m2The delivery time at place, replication twice,
Measured value difference must not exceed 0.1 second twice, take average value twice for the delivery time (T) of test solution；It learns from else's experience No. 3 and hangs down
The pure water of molten glass funnel filtration, is equally repeated 2 times, and it is the delivery time (T of pure water that 2 measured values, which are answered identical,0)；It calculates special
Property glutinous number [η].
C is the concentration of bismuth in test solution, g/ml in formula.
The Con trolling index of described pharmaceutical composition intrinsic viscosity is not less than 1000.
Preferably, technical indicator possessed by the resulting colloidal bismmth pectin pharmaceutical composition of the application method of quality control is
1) described pharmaceutical composition character should be micro-yellow powder or particle；Gas fragrance, it is sweet；
2) described pharmaceutical composition basicity pH value should be 8.5~10.5,
3) described pharmaceutical composition less loss weight must not cross 2.0%；
4) described pharmaceutical composition sedimentation volume ratio must not be lower than 0.9
5) galacturonic acid content is not less than 0.4g in every 1.46g pharmaceutical composition；
6) the specification 150mg of described pharmaceutical composition, in terms of bismuth；
7) 36 months validity periods of described pharmaceutical composition.
The technical indicator is measured according to related content in " Chinese Pharmacopoeia " version in 2010 second and its annex.
The application also controls the safety of the resulting colloidal bismmth pectin pharmaceutical composition of above-mentioned method of quality control,
Its method are as follows: intrinsic viscosity and bismuth ion uniformity of dosage units to described pharmaceutical composition control.
Wherein, the control method of intrinsic viscosity shines " Chinese Pharmacopoeia " version in 2010 in the colloidal bismmth pectin pharmaceutical composition
Third method in two VI G viscosimetries of annex is measured；
The control method of bismuth ion uniformity of dosage units shines two annex X of Chinese Pharmacopoeia version in 2010 in described pharmaceutical composition
E uniformity of dosage units control method, method particularly includes:
(1) measurement of bismuth ion content takes 10 bags of herein described colloidal bismmth pectin pharmaceutical composition, and every bag of 1.46g is set
In 500ml conical flask, nitric acid solution 10ml is added, the volume ratio of concentrated nitric acid and water is 1:2 in nitric acid solution, and heating makes to dissolve,
It adds water 300ml and xylenol orange indicator solution 4 drips, be titrated to yellow with Calcium Disodium Versenate titrating solution (0.05mol/L)；
The Calcium Disodium Versenate titrating solution (0.05mol/L) of every 1ml is equivalent to the bismuth (Bi) of 10.45mg,
(2) average value of 10 bags of colloidal bismmth pectin pharmaceutical composition bismuth ion contents is sought in the calculating of bismuth ion uniformity of dosage units
With the absolute value of the difference A of standard deviation S and labelled amount and mean value (A=| 100- average value |), the numerical value of A+1.8S is calculated.
By measurement, bismuth ion content should be the 90-110% of labelled amount in the colloidal bismmth pectin pharmaceutical composition, contain
The range of the amount uniformity should be A+1.8S no more than 5.
In addition, to guarantee that herein described colloidal bismmth pectin pharmaceutical composition is easier to form, herein described colloid fruit
The less loss weight of glue bismuth medicine composition can also be that must not exceed 3.0%；And pass through animal experiments show that, when the colloidal bismmth pectin
When the bismuth ion uniformity of dosage units A+1.8S of pharmaceutical composition is 5 or so, without any adverse effect, therefore, the colloid pectin
The bismuth ion uniformity of dosage units of bismuth medicine composition also can be controlled in A+1.8S no more than 5.02.
The beneficial effect of the application is:
1, the application guarantees the application colloidal bismmth pectin system by the intrinsic viscosity of control colloidal bismmth pectin pharmaceutical composition
The clinical efficacy of agent keeps the application target level of product quality more scientific and reasonable controllable.
2, through a large number of experiments studies have shown that the application colloidal bismmth pectin pharmaceutical composition intrinsic viscosity be not less than 1000 when,
The adhesiveness effect of the drug is relatively strong, to the gastrointestinal mucosa protective effect being damaged and the effect for killing helicobacter pylori infection
It is stronger, be conducive to eliminating pylorus, healing gastroenteritic ulcer and diminish inflammation, and reduces answering after gastrointestinal disease is cured
Hair rate.
3, the uniformity of dosage units of the bismuth ion in colloidal bismmth pectin pharmaceutical composition is measured, increases raising colloid
The index of pectin bismuth medicine combinatorial security compensates for and only judges colloid pectin by measurement bismuth ion content in the prior art
Caused by the safety of bismuth and pharmaceutical composition may because bismuth ion content uniformity it is not up to standard brought by potential secondary make
With.
4, by intrinsic viscosity in the control colloidal bismmth pectin pharmaceutical composition not less than 1000, colloidal bismmth pectin (with
Bismuth meter) bismuth ion uniformity of dosage units A+1.8S no more than 5 or be not more than 5.02, avoid the generation of toxicity, realize to production
Product it is quality controllable, the safety of colloidal bismmth pectin pharmaceutical composition is further improved, to improving the product and pharmaceutical industry
Technological progress will generate significant impact, it will generate apparent scientific and technological progress in colloidal bismmth pectin field of quality control and push away
Movement is used.
In conclusion the application is effectively controlled by the quality index to colloidal bismmth pectin pharmaceutical composition, mention
The high medicine stability and therapeutic effect of colloid pectin bismuth dry suspensoid, can to improve the technology of the product and pharmaceutical industry into
Step generates significant impact, it will generates apparent scientific and technological progress and impetus in colloidal bismmth pectin field of quality control.
Specific embodiment
Embodiment
1. the preparation of colloidal bismmth pectin
(1) 166.67g purified water is added in reaction flask, bismuth nitrate 29.22g is added；It is added 23.78g's or so
40% potassium hydroxide solution adjusts PH to 6-8, and after so that it is hydrolyzed (i.e. repetition measurement PH is constant) completely, filtering obtains filter cake hydroxide
Bismuth；Purified water 40.56g, sorbierite 17.89g are put into beaker again, again add filter cake bismuth hydroxide after sorbierite dissolution
Enter, stir after dissipating and 40% potassium hydroxide solution 50g or so is added, stirring dissolves it sufficiently, obtains bismuth salt solution for standby；
(2) step (1) is prepared bismuth salt solution to be added in reaction flask, stirring adds 49ml purified water, pectin is added at room temperature
Softwood finishes, and is warming up to 40 DEG C or so stirrings, insulation reaction 0.5 hour, purified water 105g is added, 30-35 DEG C of temperature control is stirred
It mixes 1.5 hours；Reaction terminates, and reaction system is poured into 95% ethyl alcohol of 550ml, stirs 30 minutes, stands 30 minutes, mistake
Filter, appropriate 95% ethanol rinse are drained, and colloidal bismmth pectin crude product wet product is obtained；
(3) colloidal bismmth pectin crude product wet product is added in 95% ethyl alcohol of 400ml, is stirred 15 minutes, stand 30 minutes, mistake
Filter, appropriate 95% ethanol rinse, filter cake is first dried in vacuo 5 hours for 75 DEG C or so, then product is crushed, and then carries out 95 DEG C again very
Sky is 5 hours dry, packs to get colloidal bismmth pectin product.
The preparation of 2. colloid pectin bismuth dry suspensoid of embodiment
Prescription: colloidal bismmth pectin 1000 (in terms of 150g bismuth)
Mannitol 455g
Disodium hydrogen phosphate 15g
Production method: 1) each supplementary material in prescription according to proportion in prescription on electronic scale is weighed；2) will
Colloidal bismmth pectin, disodium hydrogen phosphate and the mannitol weighed up, which is successively put into total mix machine, to be mixed, and incorporation time is 30 minutes,
The speed of total mixing machine is 50Hz；3) (sampling amount is about 30g) detection is sampled to product after mixing to be distributed into after qualified
1000 bags, vacuum sealing is labelled, and is stored, and is packed, storage.
The preparation of 3. colloid pectin bismuth dry suspensoid of embodiment
Prescription: colloidal bismmth pectin 900kg
Mannitol 409.5kg
Disodium hydrogen phosphate 13.5kg
Specification: 150mg (in terms of bismuth)
Production method: 1) each supplementary material in prescription according to proportion in prescription on electronic scale is weighed；2) will
Colloidal bismmth pectin, disodium hydrogen phosphate and the mannitol weighed up, which is successively put into total mix machine, to be mixed, and incorporation time is 30 minutes,
The speed of total mixing machine is 50Hz；3) (sampling amount is about 30g) detection is sampled to product after mixing to be distributed into after qualified
900000 bags, vacuum sealing is labelled, and is stored, and is packed, storage.
Embodiment 4
Prescription: colloidal bismmth pectin (in terms of bismuth) 130g
Mannitol 420g
Disodium hydrogen phosphate 10g
Production method: 1) each supplementary material in prescription according to proportion in prescription on electronic scale is weighed；2) will
Colloidal bismmth pectin, disodium hydrogen phosphate and the mannitol weighed up, which is successively put into total mix machine, to be mixed, and incorporation time is 30 minutes,
The speed of total mixing machine is 50Hz；3) (sampling amount is about 30g) detection is sampled to product after mixing to be distributed into after qualified
1000 bags, vacuum sealing is labelled, and is stored, and is packed, storage.
Embodiment 5
Prescription: colloidal bismmth pectin (in terms of bismuth) 160g
Mannitol 460g
Disodium hydrogen phosphate 20g
Production method: 1) each supplementary material in prescription according to proportion in prescription on electronic scale is weighed；2) will
Colloidal bismmth pectin, disodium hydrogen phosphate and the mannitol weighed up, which is successively put into total mix machine, to be mixed, and incorporation time is 30 minutes,
The speed of total mixing machine is 50Hz；3) (sampling amount is about 30g) detection is sampled to product after mixing to be distributed into after qualified
1000 bags, vacuum sealing is labelled, and is stored, and is packed, storage.
Embodiment 6, bismuth ion Determination of Content Uniformity and control method
The measurement of bismuth ion content takes obtained by the embodiment of the present application 2-5 10 bags of pharmaceutical composition, and every bag of 1.46g sets 500ml
Conical flask in, add nitric acid solution (1 → 2) 10ml, heating makes to dissolve, and adds water 300ml and xylenol orange indicator solution 4 drips, use
Calcium Disodium Versenate titrating solution (0.05mol/L) is titrated to solution in yellow.The Calcium Disodium Versenate of every 1ml titrates
Liquid (0.05mol/L) is equivalent to the bismuth (Bi) of 10.45mg.
The average value and mark of 10 bags of colloid pectin bismuth dry suspensoid bismuth ion contents are asked in the control of bismuth ion uniformity of dosage units
The absolute value of the difference A (A=| 100- average value |) of quasi- difference S and labelled amount and mean value, calculates the numerical value of A+1.8S.
The measurement of 7. intrinsic viscosity of embodiment
Precision, which is weighed, prepares colloid pectin bismuth dry suspensoid 50mg according to the embodiment of the present application 2-5, is placed in 100ml volumetric flask
In, add water about 30ml, shaking or ultrasound keep its evenly dispersed, and water is added to be settled to scale, shake up, with No. 3 sintered glass funnels
Filtration, discards primary filtrate, takes subsequent filtrate 20ml to be packed into the ball B of clean, dry Ubbelohde viscometer, viscosmeter is vertically fixed
In constant temperature (25 DEG C ± 0.1 DEG C) water-bath, and the liquid level of water-bath is made to be higher than ball C, after placing 15 minutes, nozzle 1,3 is respectively connect one
Emulsion tube, the sebific duct for clamping nozzle 3 are evacuated from nozzle 1, so that the liquid level of test solution is slowly increasing to the middle part of ball C, put
Open pipe mouth 3, then nozzle 1 is decontroled, so that test solution is fallen naturally in pipe, with stopwatch accurate recording liquid level to measurement line m1Under
It is down to measurement line m2The delivery time at place, twice, measured value difference must not exceed 0.1 second replication twice, take twice flat
Mean value is the delivery time (T) of test solution；The pure water of No. 3 sintered glass funnels of learning from else's experience filtration, is equally repeated 2 times, 2 surveys
Definite value answer it is identical, be pure water delivery time (T0)；The glutinous number [η] of estimated performance
C is the concentration of bismuth in test solution, g/ml in formula.
The measurement of 8. other indexs of embodiment
Pharmaceutical composition described in [character] the embodiment of the present application 2-5 is micro-yellow powder or particle；Gas fragrance, it is sweet.
The fine powder of [identification] (1) the embodiment of the present application 2-5 described pharmaceutical composition is appropriate (being approximately equivalent to bismuth 0.75mg), adds
Water 10ml, stirring, is acidified with dilute sulfuric acid, adds 10% thiourea solution few drops, i.e. generation buff.
(2) fine powder of the embodiment of the present application 2-5 described pharmaceutical composition is appropriate (being approximately equivalent to bismuth 1.5mg), adds water 25ml,
Stirring generates flocculent deposit after the drop acidification of dilute sulfuric acid 3~5, adds potassium iodide test solution, i.e., raw yellow to brown color precipitates.
(3) fine powder of the embodiment of the present application 2-5 described pharmaceutical composition is appropriate (being approximately equivalent to bismuth 15mg), heats water
10ml is stirred evenly, and is let cool, and is added ethyl alcohol 10ml, that is, is gelled.
[inspection] basicity takes the fine powder of the embodiment of the present application 2-5 described pharmaceutical composition appropriate (being approximately equivalent to bismuth 15mg),
Add water 100ml, shake, measures (two VI H of annex of Chinese Pharmacopoeia version in 2010) in accordance with the law, pH value should be 8.5~10.5.
Loss on drying takes the embodiment of the present application 2-5 described pharmaceutical composition, and dry to constant weight at 105 DEG C, less loss weight is not
Obtained 2.0% (two VIII L of annex of Chinese Pharmacopoeia version in 2010)
Sedimentation volume ratio takes the fine powder of the embodiment of the present application 2-5 described pharmaceutical composition to be approximately equivalent to bismuth 15mg, adds water
100ml firmly shakes 1 minute, stands 1 hour, should meet regulation (two annex I O of Chinese Pharmacopoeia version in 2010), be less than
0.9。
The measurement of 9. other indexs of experimental example
Pharmaceutical composition described in [character] the embodiment of the present application 2-5 is micro-yellow powder or particle；Gas fragrance, it is sweet.
The fine powder of [identification] (1) the embodiment of the present application 2-5 described pharmaceutical composition is appropriate (being approximately equivalent to bismuth 0.75mg), adds
Water 10ml, stirring, is acidified with dilute sulfuric acid, adds 10% thiourea solution few drops, i.e. generation buff.
(2) it takes the fine powder of pharmaceutical composition described in application embodiment 2-5 appropriate (being approximately equivalent to bismuth 1.5mg), adds water
25ml, stirring generate flocculent deposit after the drop acidification of dilute sulfuric acid 3~5, add potassium iodide test solution, i.e. generation yellow is heavy to brown color
It forms sediment.
(3) fine powder of the embodiment of the present application 2-5 described pharmaceutical composition is appropriate (being approximately equivalent to bismuth 15mg), heats water
10ml is stirred evenly, and is let cool, and is added ethyl alcohol 10ml, that is, is gelled.
[inspection] basicity takes the fine powder of the embodiment of the present application 2-5 described pharmaceutical composition appropriate (being approximately equivalent to bismuth 15mg),
Add water 100ml, shake, measures (two VI H of annex of Chinese Pharmacopoeia version in 2010) in accordance with the law, pH value should be 8.5~10.5.
Loss on drying takes the embodiment of the present application 2-5 described pharmaceutical composition, and dry to constant weight at 105 DEG C, less loss weight is not
Obtained 2.0% (two VIII L of annex of Chinese Pharmacopoeia version in 2010)
Sedimentation volume ratio takes the fine powder of the embodiment of the present application 2-5 described pharmaceutical composition to be approximately equivalent to bismuth 15mg, adds water
100ml firmly shakes 1 minute, stands 1 hour, should meet regulation (two annex IO of Chinese Pharmacopoeia version in 2010), less than 0.9.
Comparative example
1、
The colloidal bismmth pectin bulk pharmaceutical chemicals of standard under Chinese Pharmacopoeia second colloidal bismmth pectin item of version in 2010 will be met according to this
Method prepares colloid pectin bismuth dry suspensoid in application embodiment 2 or 3.
2、
The colloidal bismmth pectin bulk pharmaceutical chemicals of standard described in patent CN102507381A will be met, and shine the embodiment of the present application 2
Or method prepares colloid pectin bismuth dry suspensoid in 3.
3、
Preparation meets the Couoidal bismuth pectin capsules of standard described in patent CN102507381A, granule or tablet.
Experimental example
1. the research of the intrinsic viscosity of colloid pectin bismuth dry suspensoid
Method: research survey is carried out referring to the third method in Chinese Pharmacopoeia two annex VI G viscosimetries of version in 2010
It is fixed:
Influence of the 1.1 Ubbelohde viscometer capillary dimensions to experimental result
Ubbelohde viscometer capillary (1) 0.57mm, (2) 0.47mm (3) 0.5-0.6mm
Precision claims the 120902 crowdes of 50mg of colloid pectin bismuth dry suspensoid prepared according to the embodiment of the present application 2, is placed in 100ml
In volumetric flask, water is added to be settled to scale, shaken up, filtered with No. 3 sintered glass funnels, discard primary filtrate, subsequent filtrate 20ml is taken to fill
In the ball B for entering clean, dry Ubbelohde viscometer, viscosmeter is perpendicularly fixed in constant temperature (25 DEG C ± 0.1 DEG C) water-bath, and is made
The liquid level of water-bath is higher than ball C, after placing 15 minutes, the sebific duct that nozzle 1,3 is respectively connect into an emulsion tube, clamps nozzle 3, from nozzle 1
Place's pumping, makes the liquid level of test solution be slowly increasing to the middle part of ball C, decontrols nozzle 3, then decontrol nozzle 1, keeps test sample molten
Liquid falls naturally in pipe, with stopwatch accurate recording liquid level to measurement line m1Drop to measurement line m2The delivery time at place repeats to survey
Fixed measured value difference must not exceed 0.1 second twice twice, take average value twice for the delivery time (T) of test solution；It takes
Through No. 3 sintered glass funnels filter pure water, be equally repeated 2 times, 2 measured values answer it is identical, be pure water delivery time (T0)；
The glutinous number [η] of estimated performance
C is the concentration of bismuth in test solution, g/ml in formula
Above-mentioned solution is taken to be surveyed respectively at the Ubbelohde viscometer of 0.47mm, 0.57mm, 0.5-0.6mm size capillary
It is fixed, as a result as follows:
1 Ubbelohde viscometer capillary dimensions selection result of table
Conclusion: selected capillary dimensions is different, as a result no significant difference, therefore selects sample minute close to pharmacopeia
The research work in 120 seconds~180 seconds 0.57mm Ubbelohde viscometers of specified value progress later period.
Influence of 1.2 stabilities of solution to experimental result
It takes and prepares 130902 crowdes of 125mg of colloid pectin bismuth dry suspensoid according to the embodiment of the present application 2, be placed in 250ml capacity
In bottle, add water to be settled to scale, shake up, filtered with No. 3 sintered glass funnels, discard primary filtrate, as test solution, respectively
In 0 minute, 15 minutes, 30 minutes, 45 minutes, 60 minutes, according to the above method from " taking subsequent filtrate 20ml to be packed into clean ... " according to
Method operation.
2 stability of solution of table investigates result
Conclusion: sample solution is measured in 60 minutes, will not influence measurement result.
Influence of the soaking time of 1.3 solution to experimental result:
Precision, which is weighed, prepares 120902 crowdes of 50mg of colloid pectin bismuth dry suspensoid according to the embodiment of the present application 2, is placed in 100ml
In volumetric flask, water is added to be settled to scale, shaken up, filtered with No. 3 sintered glass funnels, discard primary filtrate, subsequent filtrate 20ml is taken to fill
In the ball B for entering clean, dry Ubbelohde viscometer, viscosmeter is perpendicularly fixed in constant temperature (25 DEG C ± 0.1 DEG C) water-bath, and is made
The liquid level of water-bath is higher than ball C, after placing 10,15,20,30 minutes respectively, measures in accordance with the law.
3 soaking time of table investigates result
Conclusion: preferably such as environment temperature control, detected solution is basicly stable after ten minutes for heat preservation.
Experiments prove that the size of Ubbelohde viscometer capillary, soaking time is molten in the measurement of the application intrinsic viscosity
Influence of the standing time of liquid to the measurement result of the application intrinsic viscosity is little
Influence of the holding temperature of 1.4 solution to experimental result
Precision, which is weighed, prepares colloid pectin bismuth dry suspensoid 50mg according to the embodiment of the present application 2, is placed in 100ml volumetric flask
In, add water about 30ml, shaking or ultrasound keep its evenly dispersed, and water is added to be settled to scale, shake up, with No. 3 sintered glass funnels
Filtration, discards primary filtrate, and taking subsequent filtrate 20ml to be packed into clean, dry Ubbelohde viscometer, (Chinese Pharmacopoeia 2010 version two attached
Record the third method in VI G viscosimetry) ball B in, viscosmeter is perpendicularly fixed in water bath with thermostatic control, and make the liquid level of water-bath
Higher than ball C, after placing 15 minutes, the sebific duct that nozzle 1,3 is respectively connect an emulsion tube, clamps nozzle 3 is evacuated from nozzle 1, makes to supply
The liquid level of test sample solution is slowly increasing to the middle part of ball C, decontrols nozzle 3, then decontrol nozzle 1, make test solution in pipe from
It so falls, with stopwatch accurate recording liquid level to measurement line m1Drop to measurement line m2The delivery time at place, replication twice, two
Secondary measured value difference must not exceed 0.1 second, take average value twice for the delivery time (T) of test solution；It learns from else's experience No. 3 incipient fusions
Glass funnel filtration pure water, be equally repeated 2 times, 2 measured values answer it is identical, be pure water delivery time (T0)；Estimated performance
Glutinous number [η].
Wherein, holding temperature is respectively (1) 15 ± 0.1 DEG C (2) 25 ± 0.1 DEG C (3) 50 ± 0.1 DEG C (4) 75 ± 0.1 DEG C
Resulting measurement result is shown in Table 4.
Under 4 different temperatures of table, the measurement result of intrinsic viscosity
| Temperature | 15±0.1℃ | 25±0.1℃ | 50±0.1℃ | 75±0.1℃ |
| Intrinsic viscosity | 960 | 1067 | 970 | 880 |
Conclusion: the intrinsic viscosity measured at 25 DEG C ± 0.1 DEG C is greater than 1000.
1.5 precision tests:
It takes and prepares colloid pectin bismuth dry suspensoid 130902 batches according to the embodiment of the present application 2, precision weighs 125mg, is placed in
In 250ml volumetric flask, water is added to be settled to scale, shaken up, filtered with No. 3 sintered glass funnels, primary filtrate is discarded, as test sample
Solution measures according to 7 the method for embodiment and calculates its intrinsic viscosity.
5 Precision test result of table
Conclusion: the result shows that this method precision is preferable.
1.6 repetitive test
It taking and prepares colloid pectin bismuth dry suspensoid 130902 batches according to the embodiment of the present application 2, precision weighs 50mg, and totally 6 parts,
It is placed in 100ml volumetric flask, water is added to be settled to scale, shake up, filtered with No. 3 sintered glass funnels, primary filtrate is discarded, as confession
Test sample solution, according to the measurement of 7 the method for embodiment and the glutinous number of estimated performance.
6 repetitive test result of table
Conclusion: learning from above-mentioned data, and this method repeatability is preferably.
1.7 methods determine:
Precision, which is weighed, prepares each 50mg of colloid pectin bismuth dry suspensoid according to the embodiment of the present application 2, is placed in 100ml volumetric flask
In, add water about 30ml, shaking or ultrasound keep its evenly dispersed, and water is added to be settled to scale, shake up, with No. 3 sintered glass funnels
Filtration, discards primary filtrate, takes subsequent filtrate 20ml to be packed into the ball B of clean, dry Ubbelohde viscometer, viscosmeter is vertically fixed
In constant temperature (25 DEG C ± 0.1 DEG C) water-bath, and the liquid level of water-bath is made to be higher than ball C, after placing 15 minutes, nozzle 1,3 is respectively connect one
Emulsion tube, the sebific duct for clamping nozzle 3 are evacuated from nozzle 1, so that the liquid level of test solution is slowly increasing to the middle part of ball C, put
Open pipe mouth 3, then nozzle 1 is decontroled, so that test solution is fallen naturally in pipe, with stopwatch accurate recording liquid level to measurement line m1Under
It is down to measurement line m2The delivery time at place, twice, measured value difference must not exceed 0.1 second replication twice, take twice flat
Mean value is the delivery time (T) of test solution；The pure water of No. 3 sintered glass funnels of learning from else's experience filtration, is equally repeated 2 times, 2 surveys
Definite value answer it is identical, be pure water delivery time (T0)；The glutinous number [η] of estimated performance.
According to method measurement colloid pectin bismuth dry suspensoid (120902,121101,121102 batches) after above-mentioned determination and correspond to
The intrinsic viscosity of raw material, as a result as follows:
7 sample measurement result of table
Conclusion: the intrinsic viscosity result of three batches of samples can be greater than 1000, and testing result and raw material testing result are without aobvious
Write difference.
2 bismuth ion of experimental example contains quantifier elimination
The result measured in embodiment 6 is recorded, colloidal bismuth pectin (in terms of the bismuth) content and the uniformity measured is recorded
Numerical value.
8 bismuth ion assay result of table
Conclusion: in the application colloid pectin bismuth dry suspensoid, the content of colloidal bismuth pectin (in terms of bismuth) is the 90- of labelled amount
Between 110%, and it is computed and show that the value of the uniformity of dosage units A+1.80S of wherein bismuth ion is no more than 5 or 5 or so.
According to test result, colloidal bismuth pectin (in terms of the bismuth) content in the application colloid pectin bismuth dry suspensoid is positioned into mark
90-the 110% of amount, uniformity of dosage units is set to: the value of A+1.80S is no more than 5 or no more than 5.02.
The comparison of 3. different quality control method of experimental example
In conjunction with existing method of quality control, the method for quality control in the application is studied, method is as follows:
In the colloid pectin bismuth dry suspensoid and comparative example that will be obtained by herein described control method respective value into
Row measures and compares, and the result is shown in tables 9.
The comparison of 9 different quality control method of table
Conclusion: compared with prior art, the colloid pectin bismuth dry suspensoid prepared using herein described control method, energy
Enough contents for more accurately controlling wherein bismuth ion, and intrinsic viscosity also opposite raising, can be realized the application and improve medicine group
Close the purpose of object efficacy and saferry.
For the efficacy and saferry for confirming the application colloidal bismmth pectin pharmaceutical composition, following zoopery has also been carried out.
4 zoopery of experimental example
Colloid pectin bismuth dry suspensoid described herein is as gastrointestinal mucosa protective agent and kills helicobacter pylori
Purposes, can be used for treating gastric and duodenal ulcer, atrophic gastritis, chronic erosive gastritis, abdominal pain, abdominal distension, diarrhea,
Gastrointestinal mucosal bleeding, especially helicobacter pylori correlation stomach intestine anabrosis disease or inflammation, prevent the canceration of atrophic gastritis；With
Antibiotic, proton pump inhibitor or bisfentidine combination, perhaps with the combination of other bismuth salt compounds or in bismuth agent three
Continue individually to take after connection therapy, or routinely 1-2 times of escalated dose of dosage, the eradication therapy for helicobacter pylori.
Using the quality control index of the resulting colloidal bismmth pectin pharmaceutical composition of the application, to the medicine group in the application
It closes object to be screened, and carries out the inspection of pharmacodynamics to the drug filtered out.
The therapeutic test of 4.1 pairs of rat gastric ulcers
Experimental method: taking consistent week old, kind and the identical Wistar rat of gender 50, is divided into 5 groups, and fasting is distinguished
Give physiological saline, the resulting colloid pectin bismuth dry suspensoid of the application control method, comparative example 1, comparative example 2 and comparative example 3
Colloid pectin bismuth dry suspensoid obtained by control method or standard or pharmaceutical composition, every rats gavaged 1ml dehydrated alcohol after 1h,
After 60min cervical dislocation put to death, pluck full stomach and inject 1% formalin 10ml, set fixed in the formaldehyde of same concentration 10min with
It is upper then to cut off stomach wall along greater curvature, observe gastric mucosa damage situation.
The comparison of 10 mouse gastric ulcer curative effect of table
Note: * * P < 0.01, experimental group is compared with the control group
Conclusion: the application colloid pectin bismuth dry suspensoid is obvious to the effect of gastric ulcer, and inhibiting rate is higher than comparative example group.
The anti-inflammatory therapeutic test of 4.2 pairs of rats
Experimental method: consistent week old, kind and the identical rat of gender 50 are taken, is divided into 5 groups, gives physiology salt respectively
Water, the application control method gained colloidal bismmth pectin and comparative example 1, comparative example 2 and 3 control method of comparative example or standard gained produce
Product, the croton oil of external application 2% is smeared in the left ear of every animal after 1h, is put to death rat after 4h, is cut two ears, beaten with diameter 9mm
Hole device lays round auricle, weighing scale to test twisting force weighing, and calculates swelling inhibiting rate.
The anti-inflammatory treatment condition of 11 rat of table
Conclusion: the anti-inflammatory effect of colloidal bismmth pectin pharmaceutical composition obtained by the application is higher than comparative example group.
The experiment of 4.3 chronic gastritis
It takes consistent week old, kind and the identical experiment of gender with rabbit 50, is divided into 5 groups, after artificial modeling causes chronic gastritis,
Physiological saline, colloidal bismmth pectin obtained by the application control method and 3 controlling party of comparative example 1, comparative example 2 and comparative example are given respectively
Method or the treatment of standard products obtained therefrom, observe therapeutic effect after 12 weeks
12 chronic gastritis Experiment on therapy of table
Note: * * P < 0.01, experimental group is compared with the control group
Conclusion: the colloid pectin bismuth dry suspensoid that herein described control method obtains is excellent to the therapeutic effect of chronic gastritis
Relative medicine under other standards or quality requirement, and experimental group P < 0.01 compared with the control group, there was a significant difference.
The eradication rate of 4.4Hp
Experimental method: consistent week old, kind and the identical rat of gender 50 are taken, is divided into 5 groups, artificial modeling.It gives respectively
Give physiological saline, colloid pectin bismuth dry suspensoid obtained by the application control method and comparative example 1-3 control method or standard gained
Dry suspensoid agent or pharmaceutical composition are treated, and therapeutic effect is observed.
The eradication rate of table 13Hp is tested
Note: experimental group P < 0.01 compared with the control group, there was a significant difference.
4.5 blood bi concns measure
The drug of rabbit continuous gavage therapeutic dose 3 weeks measures blood bi concns.Wherein be divided into physiological saline to drug,
Dry suspensoid agent or medicine obtained by colloid pectin bismuth dry suspensoid obtained by the application control method and comparative example 1-3 control method or standard
Compositions, the result is shown in tables 14.
The experiment of 14 blood bi concns of table
Conclusion: resulting through the application control method through result in experimental example 4.5 it is found that compared with prior art products
Blood bi concns are low after colloid pectin bismuth dry suspensoid administration, improve safety.
Claims (4)
1. a kind of quality determining method of colloidal bismmth pectin pharmaceutical composition, which is characterized in that the colloidal bismmth pectin medicine group
Closing object has index are as follows:
Described pharmaceutical composition dosage form is dry suspensoid agent, the bulk pharmaceutical chemicals colloidal bismmth pectin for being 150 parts including parts by weight, with bismuth weight
Part calculates, the filler mannitol that parts by weight are 455 parts, the flocculant disodium hydrogen phosphate and/or corrigent that parts by weight are 15 parts；
The intrinsic viscosity of the pharmaceutical composition is not less than 1000；
In the described pharmaceutical composition, the content of colloidal bismuth pectin is between the 90-110% of labelled amount, wherein in terms of bismuth parts by weight
It calculates, the value of the uniformity of dosage units A+1.80S of bismuth ion is no more than 5；
Galacturonic acid content is not less than 0.4g in every 1.46g pharmaceutical composition；
The bulk pharmaceutical chemicals colloidal bismmth pectin the preparation method is as follows:
(1) 166.67g purified water is added in reaction flask, bismuth nitrate 29.22g is added；40% hydroxide of 23.78g is added
Potassium solution adjusts pH to 6-8, and after making its hydrolysis completely, filtering obtains filter cake bismuth hydroxide；Again by purified water 40.56g, sorbierite
17.89g is put into beaker, and filter cake bismuth hydroxide is added again after sorbierite dissolution, stirs after dissipating and 40% potassium hydroxide is added
Solution 50g, stirring dissolve it sufficiently, obtain bismuth salt solution for standby；
(2) the bismuth salt solution for preparing step (1) is added in reaction flask, and stirring adds 49ml purified water, and it is soft that pectin is added at room temperature
Material finishes, and is warming up to 40 DEG C of stirrings, insulation reaction 0.5 hour, adds purified water 105g, 30-35 DEG C of temperature control stirring 1.5 is small
When；Reaction terminates, and reaction system is poured into 95% ethyl alcohol of 550ml, stirs 30 minutes, stands 30 minutes, filtering, in right amount
95% ethanol rinse, is drained, and obtains colloidal bismmth pectin crude product wet product；
(3) colloidal bismmth pectin crude product wet product is added in 95% ethyl alcohol of 400ml, is stirred 15 minutes, stand 30 minutes, filtered, fitted
95% ethanol rinse is measured, filter cake is first dried in vacuo 5 hours for 75 DEG C, then product is crushed, and it is small then to carry out 95 DEG C of vacuum drying 5 again
When, it packs to get colloidal bismmth pectin product；The intrinsic viscosity of described pharmaceutical composition is according to " Chinese Pharmacopoeia " 2010 version two
Third method in VI G viscosimetry of annex is measured, and measuring method is that weigh colloid pectin bismuth dry suspensoid each for precision
50mg is placed in 100ml volumetric flask, adds water 30ml, and shaking or ultrasound keep its evenly dispersed, and water is added to be settled to scale, is shaken up,
It is filtered with No. 3 sintered glass funnels, discards primary filtrate, subsequent filtrate 20ml is taken to be packed into the ball B of clean, dry Ubbelohde viscometer
It is interior, viscosmeter is perpendicularly fixed in 25 DEG C ± 0.1 DEG C of water bath with thermostatic control, and the liquid level of water-bath is made to be higher than ball C, is placed 15 minutes
Afterwards, the sebific duct for nozzle 1,3 respectively being connect an emulsion tube, clamping nozzle 3 is evacuated from nozzle 1, makes the liquid level of test solution slowly
It is increased to the middle part of ball C, nozzle 3 is decontroled, then decontrol nozzle 1, so that test solution is fallen naturally in pipe, accurately remembered with stopwatch
Record liquid level drops to the delivery time at measurement line m2 to measurement line m1, and twice, measured value must not differ twice surpasses replication
0.1 second is spent, takes average value twice for the delivery time (T) of test solution；No. 3 sintered glass funnels of learning from else's experience filter pure
Water, same replication 2 times, 2 measured values answer it is identical, be pure water delivery time (T0)；The glutinous number [η] of estimated performance；
C is the concentration of bismuth in test solution, g/ml in formula；
The uniformity of dosage units of bismuth ion shines two annex XE uniformity of dosage units of Chinese Pharmacopoeia version in 2010 in described pharmaceutical composition
Method, wherein the measuring method of bismuth ion content is to take 10 bags of the colloidal bismmth pectin pharmaceutical composition, and every bag of 1.46g is set
In 500ml conical flask, nitric acid solution 10ml is added, the volume ratio of concentrated nitric acid and water is 1:2 in nitric acid solution, and heating makes to dissolve,
It adds water 300ml and xylenol orange indicator solution 4 drips, being titrated to solution with 0.05mol/L Calcium Disodium Versenate titrating solution is in
Yellow；The 0.05mol/L Calcium Disodium Versenate titrating solution of every 1ml is equivalent to the bismuth (Bi) of 10.45mg, asks described 10 bags
The absolute value of the difference A of colloidal bismmth pectin pharmaceutical composition bismuth ion content average and standard deviation S and labelled amount and average value
(A=| 100- average value |), the numerical value of A+1.8S is calculated, and control its numerical value no more than 5.
2. the quality determining method of colloidal bismmth pectin pharmaceutical composition according to claim 1, which is characterized in that the glue
Body pectin bismuth medicine composition is with index
1) described pharmaceutical composition character should be micro-yellow powder or particle；Gas fragrance, it is sweet；
2) described pharmaceutical composition basicity pH value should be 8.5~10.5,
3) described pharmaceutical composition less loss weight must not cross 2.0%；
4) described pharmaceutical composition sedimentation volume ratio must not be lower than 0.9；
5) galacturonic acid content is not less than 0.4g in every 1.46g pharmaceutical composition；
6) the specification 150mg of described pharmaceutical composition, in terms of bismuth；
7) 36 months validity periods of described pharmaceutical composition.
3. the quality determining method of colloidal bismmth pectin pharmaceutical composition according to claim 1, which is characterized in that the glue
Corrigent is one or both of Steviosin and orange oil essence in body pectin bismuth medicine composition.
4. the quality determining method of colloidal bismmth pectin pharmaceutical composition according to claim 3, it is characterised in that: the medicine
Compositions less loss weight must not exceed 3.0%.
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