CN105461823B - A kind of preparation method of colloidal bismmth pectin and its control method of pharmaceutical composition adhesion - Google Patents
A kind of preparation method of colloidal bismmth pectin and its control method of pharmaceutical composition adhesion Download PDFInfo
- Publication number
- CN105461823B CN105461823B CN201610009844.1A CN201610009844A CN105461823B CN 105461823 B CN105461823 B CN 105461823B CN 201610009844 A CN201610009844 A CN 201610009844A CN 105461823 B CN105461823 B CN 105461823B
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- bismuth
- pectin
- colloidal
- colloidal bismuth
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0045—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Galacturonans, e.g. methyl ester of (alpha-1,4)-linked D-galacturonic acid units, i.e. pectin, or hydrolysis product of methyl ester of alpha-1,4-linked D-galacturonic acid units, i.e. pectinic acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/245—Bismuth; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N11/00—Investigating flow properties of materials, e.g. viscosity, plasticity; Analysing materials by determining flow properties
- G01N11/02—Investigating flow properties of materials, e.g. viscosity, plasticity; Analysing materials by determining flow properties by measuring flow of the material
- G01N11/04—Investigating flow properties of materials, e.g. viscosity, plasticity; Analysing materials by determining flow properties by measuring flow of the material through a restricted passage, e.g. tube, aperture
- G01N11/06—Investigating flow properties of materials, e.g. viscosity, plasticity; Analysing materials by determining flow properties by measuring flow of the material through a restricted passage, e.g. tube, aperture by timing the outflow of a known quantity
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
- G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
- G01N21/78—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator producing a change of colour
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/416—Systems
- G01N27/42—Measuring deposition or liberation of materials from an electrolyte; Coulometry, i.e. measuring coulomb-equivalent of material in an electrolyte
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Physics & Mathematics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- General Physics & Mathematics (AREA)
- Veterinary Medicine (AREA)
- Pathology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Analytical Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Materials Engineering (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Polymers & Plastics (AREA)
- Plasma & Fusion (AREA)
- Organic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Electrochemistry (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The application is related to a kind of preparation method of colloidal bismmth pectin and its control method of pharmaceutical composition adhesion, the preparation process of wherein colloidal bismmth pectin and included（1）The preparation of bismuth salt solution；（2）The preparation of colloidal bismmth pectin and（3）It is refined; its pharmaceutical composition dry suspensoid agent adhesion control method is to intrinsic viscosity; one or more of indexs in the content of bismuth ion uniformity of dosage units and galacturonic acid are measured and controlled; the index contents such as colloidal bismmth pectin its galacturonic acid, the content of bismuth ion and the bismuth ion uniformity of dosage units that are prepared in the application are reasonable; intrinsic viscosity is also higher; clinical effectiveness is universal higher; the therapeutic effect of the application product in the treatment is improved, greatly promotes its protective effect of cure rate and gastric mucosa and Hp eradication rate to gastritis.
Description
The technical field is as follows:
the application relates to a preparation method of colloidal bismuth pectin and a control method of the adhesiveness of a pharmaceutical composition of the colloidal bismuth pectin.
Background art:
the colloidal bismuth pectin is a compound formed by pectin and bismuth in an indefinite composition, is used as a raw material medicament, belongs to a gastric mucosa protective medicament, and is characterized in that the molecule of the colloidal bismuth pectin is a novel bismuth salt compound formed by a macromolecular compound formed by structural fragments of D-methyl galacturonate, D-bismuth galacturonate and D-potassium galacturonate and a biomacromolecule acid radical.
The preparation method of the colloidal bismuth pectin comprises the following steps: patent document CN92114663.9 provides a preparation method of colloidal bismuth pectin medicine, which comprises preparation of bismuth salt solution, preparation of pectin soft material, preparation and refining of colloidal bismuth pectin.
Patent document No. CN201310330840.X provides a simple production process of colloidal bismuth pectin with short production flow.
The colloidal bismuth pectin compound has high selective adhesion, the strength of the adhesive adhesion is in a direct proportion relation with the protective effect of injured gastrointestinal mucosa and the effect of killing HP, the high selective adhesion of the compound depends not only on bismuth ions, but also depends on acid radicals combined with the bismuth ions to a greater extent, the colloidal characteristics and the mucosa of injured intestines and stomach and the high selective adhesion of helicobacter pylori are determined by the proportion of the content of the bismuth ions to the content of pectic acid radicals, in the existing colloidal bismuth pectin quality detection method, only the content of cationic bismuth is controlled, acid radical pectic acid radicals are not determined, galacturonic acid is a monomer after the degradation of the pectic acid radicals, and acid and alkali can break the glycosidic bonds connected with the galacturonic acid to change the galacturonic acid radicals from galacturonic acid polymer acid radicals into galacturonic acid monomers, so the content determination of the galacturonic acid has important significance for controlling the colloidal bismuth pectin compound.
In addition, the colloidal bismuth pectin or the pharmaceutical composition thereof forms a stable colloidal dispersion system in water, forms gel in artificial gastric juice, has strong colloidal property, has strong affinity with the ulcer surface, promotes the healing of the ulcer and the disappearance of inflammation, can stimulate mucous epithelial cells of mucous membrane to secrete mucus and kill helicobacter pylori, can form a layer of firm protective film on the gastric mucosa, and enhances the barrier protection effect of the gastric mucosa. It features its colloid nature and high selective adhesion to pyloric spirobacterium, which is the pathogenic bacterium of gastrointestinal mucosa and gastrointestinal diseases. The strength of the selective adhesion is positively correlated with the protective effect of the compound on the injured gastrointestinal mucosa and the effect of killing helicobacter pylori, namely, the stronger the selective adhesion is, the stronger the protective effect on the injured gastrointestinal mucosa and the killing effect on the helicobacter pylori are, the more beneficial to eradicating the helicobacter pylori, the more beneficial to healing the gastrointestinal ulcer and eliminating the inflammation, and the more beneficial to reducing the recurrence rate of the gastrointestinal disease after healing. The colloidal bismuth pectin or pharmaceutical composition thereof has a colloidal character which is 7.4 times better than that of the colloidal bismuth potassium citrate, compared to other colloidal bismuth preparations. Thus, colloidal bismuth pectin or a pharmaceutical composition thereof has a clinical benefit that is related to its intrinsic viscosity, which is superior to other colloidal bismuth preparations.
At present, the standard of colloidal bismuth pectin raw material medicines mainly refers to the colloidal bismuth pectin regulation of the second department of Chinese pharmacopoeia 2010 edition, but the standard does not comprise the measurement of characteristic viscosity or the content of galacturonic acid and the like.
The new drug conversion standard of the WS1- (X-104) -96Z colloidal bismuth pectin stipulates the drug standard of the bulk drug colloidal bismuth pectin, but the indexes are not detected.
The two-part colloid bismuth pectin capsule part of the Chinese pharmacopoeia 2010 edition discloses that the content of bismuth pectin (calculated by bismuth) is 90-110% of the labeled amount, but other indexes are not measured. And the colloidal bismuth pectin pharmaceutical composition has different standards and different curative effects for different dosage forms.
Chinese patent 102507381 proposes a quality detection method of colloidal bismuth pectin compound or its pharmaceutical composition (capsule), and a large number of experiments show that when the bismuth content of colloidal bismuth pectin compound is 15 + -2% and the galactose content is 60 + -2%, the highest intrinsic viscosity is 147-154; the uniformity of the colloidal bismuth pectin compound is that the bismuth ion content of the screenings and undersize products which pass through a standard sieve with 200 meshes are 14-16%, and the difference is less than 1%. However, there is no disclosure in the patent about colloidal bismuth pectin preparations, especially a method for controlling the intrinsic viscosity, galacturonic acid content and bismuth ion content uniformity of colloidal bismuth pectin pharmaceutical compositions other than the dosage forms mentioned in the patent, so as to improve the adhesiveness of the colloidal bismuth pectin compound or the pharmaceutical composition thereof.
The traditional production process of the colloidal bismuth pectin at present comprises the steps of dissolving pectin and reacting with bismuth salt to obtain the colloidal bismuth pectin. The traditional production process of the colloidal bismuth pectin has the defects of complex preparation process, complex process, more required equipment and manpower and high production cost, and the pectin product needs to be prepared firstly and then reacts with bismuth salt, and the drying and sol-dissolving steps of the pectin are required. And the quality control method of the existing colloidal bismuth pectin pharmaceutical preparation (capsule) has the problem that the quality control of indexes related to curative effect is not strict enough, so that the controllability of products with poorer curative effect is poor, and the application is provided.
The invention content is as follows:
the application aims to provide a preparation method of colloidal bismuth pectin;
it is another object of the present application to provide a method for controlling the adhesion of a pharmaceutical composition comprising colloidal bismuth pectin prepared by the preparation method described herein.
In order to achieve the first object, the following technical solutions are adopted in the present application:
the preparation method of the bulk drug colloidal bismuth pectin comprises the steps of (1) preparing bismuth salt solution; preparing colloidal bismuth pectin and refining the colloidal bismuth pectin (3).
Preferably, the preparation method of the colloidal bismuth pectin comprises the following steps: (1) The preparation method of the middle bismuth salt solution comprises the steps of adding purified water into a reaction bottle, and adding bismuth nitrate; adding potassium hydroxide solution, adjusting pH to 6-8, hydrolyzing completely (i.e. repeatedly measuring pH value is constant), and filtering to obtain filter cake bismuth hydroxide; putting the purified water and sorbitol into a beaker, adding the filter cake bismuth hydroxide after the sorbitol is dissolved, stirring to disperse, adding the potassium hydroxide solution, and stirring to fully dissolve the potassium hydroxide solution to obtain a bismuth salt solution for later use; (2) Preparing colloidal bismuth pectin, namely adding the bismuth salt solution prepared in the step (1) into a reaction bottle, stirring, adding purified water, adding the soft pectin material at room temperature, heating to stir after the addition is finished, preserving heat, adding the purified water, and stirring at controlled temperature; after the reaction is finished, pouring the reaction system into ethanol, stirring, standing, filtering, rinsing with proper amount of ethanol, and pumping to obtain a colloidal bismuth pectin crude product wet product; (3) And refining the colloidal bismuth pectin, namely adding the colloidal bismuth pectin crude product wet product into ethanol, stirring, standing, filtering, leaching with a proper amount of ethanol, drying a filter cake in vacuum, crushing the product, then drying in vacuum, and packaging to obtain the colloidal bismuth pectin product.
More preferably, the preparation method of the colloidal bismuth pectin in the application comprises the following steps: (1) Adding 166.67g of purified water into a reaction bottle, and adding 29.22g of bismuth nitrate; adding about 23.78g of 40% potassium hydroxide solution, adjusting the pH value to 6-8, completely hydrolyzing (namely, repeatedly measuring the pH value to be constant), and filtering to obtain a filter cake bismuth hydroxide; putting 40.56g of purified water and 17.89g of sorbitol into a beaker, adding the filter cake bismuth hydroxide after the sorbitol is dissolved, stirring to disperse, adding about 50g of 40% potassium hydroxide solution, and stirring to fully dissolve the bismuth hydroxide solution to obtain a bismuth salt solution for later use;
(2) Adding the bismuth salt solution prepared in the step (1) into a reaction bottle, stirring, adding 49ml of purified water, adding the pectin soft material at room temperature, heating to about 40 ℃, stirring, keeping the temperature for reaction for 0.5 hour, adding 105g of purified water, controlling the temperature to be 30-35 ℃, and stirring for 1.5 hours; after the reaction is finished, pouring the reaction system into 550ml of 95% ethanol, stirring for 30 minutes, standing for 30 minutes, filtering, leaching with a proper amount of 95% ethanol, and draining to obtain a colloidal bismuth pectin crude product wet product;
(3) And (3) adding the colloidal bismuth pectin crude product wet product into 400ml of 95% ethanol, stirring for 15 minutes, standing for 30 minutes, filtering, leaching with a proper amount of 95% ethanol, drying a filter cake at about 75 ℃ in vacuum for 5 hours, crushing the product, drying at 95 ℃ in vacuum for 5 hours, and packaging to obtain the colloidal bismuth pectin product.
In order to achieve the second objective of the present application, the technical solution of the present application is:
(1) And measuring and controlling one or more indexes of the characteristic viscosity, the bismuth ion content uniformity and the content of galacturonic acid of the colloidal bismuth pectin compound obtained by the preparation method or the pharmaceutical composition containing the colloidal bismuth pectin compound obtained by the preparation method.
Specifically, the intrinsic viscosity and the content of galacturonic acid of the colloidal bismuth pectin compound obtained by the preparation method are measured and controlled, and the intrinsic viscosity, the content uniformity of bismuth ions and the content of galacturonic acid of the pharmaceutical composition containing the colloidal bismuth pectin compound obtained by the preparation method are measured and controlled.
(2) The method for controlling each index of the colloidal bismuth pectin compound obtained by the preparation method or the pharmaceutical composition containing the colloidal bismuth pectin compound obtained by the preparation method comprises the following steps
The measuring method of the characteristic viscosity number is measured according to a third method in the VI G viscosity measuring method in the second appendix of the 2010 edition of Chinese pharmacopoeia;
the content uniformity of bismuth ions is controlled according to the content uniformity method in appendix XE of the second part of 2010 edition of Chinese pharmacopoeia;
the content of galacturonic acid is determined according to the method of the item for determining pectin content in the second part of the Chinese pharmacopoeia 2010 and the potentiometric titration method of the appendix VII A in the second part of the Chinese pharmacopoeia 2010 edition.
In particular, the method comprises the following steps of,
in the colloidal bismuth pectin compound or the pharmaceutical composition thereof
The method for measuring the characteristic viscosity number comprises the steps of precisely weighing 50mg of colloidal bismuth pectin compound obtained by the preparation method or a pharmaceutical composition containing the colloidal bismuth pectin compound obtained by the preparation method, placing the colloidal bismuth pectin compound or the pharmaceutical composition into a 100ml volumetric flask, adding about 30ml of water, shaking or ultrasonically dispersing the colloidal bismuth pectin compound uniformly, adding water to a constant volume to reach a scale, shaking uniformly, filtering the mixture by using a No. 3 vertical melting glass funnel, discarding primary filtrate, taking 20ml of subsequent filtrate, placing the filtrate into a ball B of a clean and dry Ubbelohde viscometer, vertically fixing the viscometer in a water bath with a constant temperature of 25 +/-0.1 ℃, enabling the liquid level of the water bath to be higher than the ball C, placing the mixture for 15 minutes, connecting pipe orifices 1 and 3 respectively to a latex tube, clamping the rubber tube of the pipe orifices 3 by the pipe orifices, exhausting air from the position of the pipe orifices 1, enabling the liquid level of the sample solution to slowly rise to the middle part of the ball C, releasing the pipe orifices 3, enabling the sample solution to naturally fall in the pipe, and accurately recording the liquid level to the measurement line m by using a stopwatch 1 Down to the measuring line m 2 Repeatedly measuring the flowing-out time twice, wherein the difference of the measured values of the two times does not exceed 0.1 second, and taking the average value of the two times as the flowing-out time (T) of the test solution; the pure water filtered through No. 3 sintered glass funnel is taken out, the same is repeated for 2 times, the measured value of 2 times is the same, and the flowing-out time (T) of the pure water is 0 ) (ii) a Calculating a characteristic viscosity [ eta ]]
Wherein C is the concentration of bismuth in the test solution, g/ml;
according to the method for measuring the content uniformity of bismuth ions, according to the content uniformity of appendix X E of the second part of 2010 edition of Chinese pharmacopoeia, 10 bags of the colloidal bismuth pectin pharmaceutical composition prepared by the preparation method are respectively placed in 500ml conical bottles, 1.46g of each bag is added with 10ml of nitric acid solution (1 → 2), the mixture is heated to be dissolved, 300ml of water and 4 drops of xylenol orange indicating solution are added, and ethylene diamine tetraacetic acid disodium titrate solution (0.05 mol/L) is used for titrating until the solution is yellow. Each 1ml of disodium ethylenediaminetetraacetate titration solution (0.05 mol/L) corresponded to 10.45mg of bismuth (Bi).
The average value and standard deviation S of 10 bags of colloidal bismuth pectin pharmaceutical compositions with known bismuth ion content and the absolute value A (A = | 100-average |) of the difference between the marked amount and the average value are calculated, and the numerical value of A +1.8S is calculated.
The method for measuring galacturonic acid comprises the steps of uniformly mixing the contents in terms of weight difference, taking 5.0g of the colloidal bismuth pectin compound obtained by the preparation method or the pharmaceutical composition containing the colloidal bismuth pectin compound obtained by the preparation method, precisely weighing, placing the colloidal bismuth pectin compound or the pharmaceutical composition containing the colloidal bismuth pectin compound in a beaker, adding 150ml of 60% ethanol-hydrochloric acid (20); precisely weighing 1/5 of the weight of the dry residue, placing the dry residue in a 250ml beaker, adding 2ml of ethanol for wetting, adding 100ml of newly boiled cold water, placing the beaker on a magnetic stirrer, stirring the mixture to uniformly disperse the mixture, adding 5 drops of phenolphthalein test solution, adding 20.0ml of sodium hydroxide titration solution (0.5 mol/L), stirring the mixture for 15 minutes, adding 20.0ml of hydrochloric acid titration solution (0.5 mol/L), shaking the mixture until pink disappears, measuring the pink with the sodium hydroxide titration solution (0.5 mol/L) according to a potentiometric titration method (appendix VII A), and recording the volume of the consumed sodium hydroxide titration solution. The titration solution (0.5 mol/L) of sodium hydroxide per 1ml is equivalent to 97.07mg galacturonic acid (C) 6 H 10 O 7 )。
(3) The dosage form of the pharmaceutical composition containing the colloidal bismuth pectin prepared by the preparation method is a dry suspension, and the pharmaceutical composition comprises the following components in percentage by weight:
150 parts of colloidal bismuth pectin (calculated as bismuth); 455 parts by weight of a filler; 15 parts of flocculant.
The specification of the colloidal bismuth pectin dry suspension is 150mg;
the quality control of the pharmaceutical composition containing colloidal bismuth pectin obtained by the preparation method described herein was performed according to the measurement and control method described herein, and the result was that
A characteristic viscosity number of not less than 1000, and
the content of bismuth ions is 90-110% of the marked amount, and the content uniformity is A +1.80S less than or equal to 5; and is
The content of galacturonic acid is not less than 0.4g per 1.46g of the pharmaceutical composition;
preferably, the colloidal pectin bismuth dry suspension contains mannitol as filler, disodium hydrogen phosphate as flocculant, and optionally steviosin and/or orange oil essence as correctant.
Preferably, the colloidal bismuth pectin pharmaceutical composition described herein further has other indexes, which are:
the pharmaceutical composition is yellowish powder or granule; fragrant smell and sweet taste;
the alkalinity pH value of the pharmaceutical composition is 8.5-10.5;
the weight loss reduction amount of the pharmaceutical composition is not more than 2.0%;
the sedimentation volume ratio of the pharmaceutical composition is not less than 0.9; (ii) a
The indexes are detected according to the corresponding index items in the second part of Chinese pharmacopoeia and a detection method under the colloidal bismuth pectin item.
In addition, in order to ensure that the colloidal bismuth pectin pharmaceutical composition is easier to form, the weight loss reduction amount of the colloidal bismuth pectin pharmaceutical composition can be not more than 3.0%, and the bismuth ion content A +1.8S of the pharmaceutical composition can also be not more than 5.02.
The beneficial effect of this application does:
1. the control indexes of the adhesive property of the colloidal bismuth pectin obtained by the preparation method disclosed by the application or the pharmaceutical composition containing the colloidal bismuth pectin obtained by the preparation method disclosed by the application, particularly the control indexes of the adhesive property of the pharmaceutical composition, increase the content uniformity of bismuth ions and the determination of galacturonic acid, and control the adhesive property of the colloidal bismuth pectin compound or the pharmaceutical composition thereof, particularly the pharmaceutical composition, according to the ratio of the bismuth ions to the pectate radical by controlling the amount of the pectate radical.
2. A potentiometric titration method is adopted in the determination of the galacturonic acid, and the determination result proves that the colloidal bismuth pectin compound or the galacturonic acid of the pharmaceutical composition thereof determined by the method has an obvious potential jump point and good repeatability, can accurately judge the titration end point, reduce the measurement error, enhance the dehydration effect and reduce the drying time, and can be used for determining the content of the galacturonic acid in the colloidal bismuth pectin compound or the pharmaceutical composition thereof, particularly the pharmaceutical composition.
3. In the method for determining and controlling the content uniformity of bismuth ions in the pharmaceutical composition containing the colloidal bismuth pectin obtained by the preparation method, a content uniformity method of annex X E of the second part of the Chinese pharmacopoeia 2010 edition is adopted instead of determining the difference value of the content of the bismuth ions or the content of the bismuth pectin in a screened substance, so that the content and the uniformity of the bismuth ions or the bismuth pectin are more reasonable and controllable, and the colloidal bismuth pectin or the pharmaceutical composition thereof, particularly the adhesive adhesion performance of the pharmaceutical composition thereof is judged more intuitively according to the ratio of the bismuth ions to galacturonic acid.
4. Surprisingly, the colloidal bismuth pectin compound or the pharmaceutical composition thereof, particularly the pharmaceutical composition thereof obtained by the control method of the application has greatly improved adhesion performance, the characteristic viscosity number is more than 1000, and animal experiments show that the colloidal bismuth pectin compound or the pharmaceutical composition thereof has obvious effects of protecting injured gastrointestinal mucosa and killing HP, is beneficial to eradicating helicobacter pylori, promoting healing of gastrointestinal ulcer and eliminating inflammation, so as to reduce the recurrence rate of gastrointestinal diseases after healing, and has generally higher clinical effect and obvious treatment effect.
The specific embodiment is as follows:
example 1
Preparing colloidal bismuth pectin: (1) 166.67g of purified water is added into a reaction bottle, and 29.22g of bismuth nitrate is added; adding about 23.78g of 40% potassium hydroxide solution, adjusting the pH value to 6-8, completely hydrolyzing (namely, repeatedly measuring the pH value to be constant), and filtering to obtain a filter cake bismuth hydroxide; putting 40.56g of purified water and 17.89g of sorbitol into a beaker, adding bismuth hydroxide filter cake after the sorbitol is dissolved, stirring to disperse, adding about 50g of 40% potassium hydroxide solution, and stirring to fully dissolve the bismuth hydroxide filter cake to obtain bismuth salt solution for later use;
(2) Adding the bismuth salt solution prepared in the step (1) into a reaction bottle, stirring, adding 49ml of purified water, adding a pectin soft material at room temperature, heating to about 40 ℃, stirring, keeping the temperature for reaction for 0.5 hour, adding 105g of purified water, controlling the temperature to be 30-35 ℃, and stirring for 1.5 hours; after the reaction is finished, pouring the reaction system into 550ml of 95% ethanol, stirring for 30 minutes, standing for 30 minutes, filtering, leaching with a proper amount of 95% ethanol, and drying to obtain a colloidal bismuth pectin crude product wet product;
(3) And (3) adding the colloidal bismuth pectin crude product wet product into 400ml of 95% ethanol, stirring for 15 minutes, standing for 30 minutes, filtering, leaching with a proper amount of 95% ethanol, drying a filter cake at about 75 ℃ in vacuum for 5 hours, crushing the product, drying at 95 ℃ in vacuum for 5 hours, and packaging to obtain the colloidal bismuth pectin product.
Example 2
Preparing colloidal bismuth pectin: (1) preparation of bismuth salt solution: 166.67g of purified water is added into a reaction bottle, and 29.22g of bismuth nitrate is added; adding 20g of 40% potassium hydroxide solution, adjusting the pH value to 6, completely hydrolyzing (namely, repeatedly measuring the pH value to be constant), and filtering to obtain a filter cake bismuth hydroxide; putting 40.56g of purified water and 17.89g of sorbitol into a beaker, adding the filter cake bismuth hydroxide after the sorbitol is dissolved, stirring to disperse, adding 48g of 40% potassium hydroxide solution, and stirring to fully dissolve the bismuth hydroxide solution to obtain a bismuth salt solution for later use;
(2) Preparing colloidal bismuth pectin: adding the prepared bismuth salt solution into a reaction bottle, stirring, adding 49ml of purified water, adding a pectin soft material at room temperature, heating to 45 ℃, stirring, reacting for 0.5 hour under the condition of heat preservation, adding 105g of purified water, and stirring for 1.5 hours under the condition of controlling the temperature to be 30-35 ℃; and after the reaction is finished, pouring the reaction system into 550ml of 95% ethanol, stirring for 30 minutes, standing for 30 minutes, filtering, leaching with a proper amount of 95% ethanol, and draining to obtain a colloidal bismuth pectin crude product wet product.
(3) Refining: and (3) adding the colloidal bismuth pectin crude product wet product into 400ml of 95% ethanol, stirring for 15 minutes, standing for 30 minutes, filtering, leaching with a proper amount of 95% ethanol, drying a filter cake at 78 ℃ in vacuum for 5 hours, crushing the product, drying at 95 ℃ in vacuum for 5 hours, and packaging to obtain the colloidal bismuth pectin product.
Example 3
Preparing colloidal bismuth pectin: (1) preparation of bismuth salt solution: 166.67g of purified water is added into a reaction bottle, and 29.22g of bismuth nitrate is added; adding 25g of 40% potassium hydroxide solution, adjusting the pH value to 8, completely hydrolyzing (namely, repeatedly measuring the pH value to be constant), and filtering to obtain a filter cake bismuth hydroxide; putting 40.56g of purified water and 17.89g of sorbitol into a beaker, adding the filter cake bismuth hydroxide after the sorbitol is dissolved, stirring to disperse, adding 53g of 40% potassium hydroxide solution, and stirring to fully dissolve the mixture to obtain a bismuth salt solution for later use;
(2) Preparing colloidal bismuth pectin: adding the prepared bismuth salt solution into a reaction bottle, stirring, adding 49ml of purified water, adding a pectin soft material at room temperature, heating to 45 ℃ and stirring after adding, carrying out heat preservation reaction for 0.5 hour, adding 105g of purified water, controlling the temperature to be 30-35 ℃ and stirring for 1.5 hours, pouring a reaction system into 550ml of 95% ethanol after reaction, stirring for 30 minutes, standing for 30 minutes, filtering, leaching with a proper amount of 95% ethanol, and pumping to dryness to obtain a colloidal bismuth pectin crude wet product.
(3) Refining: and adding the colloidal bismuth pectin crude product wet product into 400ml of 95% ethanol, stirring for 15 minutes, standing for 30 minutes, filtering, leaching with a proper amount of 95% ethanol, drying a filter cake at 78 ℃ in vacuum for 5 hours, crushing the product, drying at 95 ℃ in vacuum for 5 hours, and packaging to obtain the colloidal bismuth pectin product.
Example 4 preparation of colloidal bismuth pectin dry suspensions
Prescription: colloidal bismuth pectin 1000 (calculated as 150g bismuth) in examples 1-3
Mannitol 455g
Disodium hydrogen phosphate 15g
Specification: 150mg (in terms of bismuth)
The production method comprises the following steps: 1) Weighing the raw and auxiliary materials in the prescription on an electronic scale according to the mixture ratio in the prescription; 2) Sequentially putting the weighed colloidal bismuth pectin, disodium hydrogen phosphate and mannitol into a total mixer for mixing for 30 minutes at the speed of 50Hz; 3) After mixing, sampling (the sampling amount is about 30 g) and detecting the product, after the product is qualified, subpackaging the product into 1000 bags, sealing in vacuum, labeling, storing, packaging and warehousing.
Example 5 preparation of colloidal bismuth pectin Dry suspensions
Prescription: colloidal bismuth pectin 1000 from examples 1-3 (calculated as 150g bismuth)
Specification: 150mg (in bismuth)
The production method comprises the following steps: 1) Weighing the raw and auxiliary materials in the prescription on an electronic scale according to the proportion in the prescription; 2) Sequentially putting the weighed colloidal bismuth pectin, disodium hydrogen phosphate and mannitol into a total mixer for mixing, wherein the mixing time is 30 minutes, and the speed of the total mixer is 50Hz; 3) After mixing, sampling (the sampling amount is about 30 g) and detecting the product, after the product is qualified, subpackaging the product into 1000 bags, sealing in vacuum, labeling, storing, packaging and warehousing.
Example 6 determination of galacturonic acid content in colloidal bismuth pectin drug substance
About 5.0g of a sample in any one of the batches of examples 1 to 3 was taken, precisely weighed, placed in a beaker, added 150ml of 60% ethanol-hydrochloric acid (20). Weighing 1/5 weight of dry residue, placing in 250ml beaker, adding 2ml ethanol for wetting, and adding 100m boiled cold waterAnd L, shaking, putting on a magnetic stirrer, stirring to uniformly disperse, adding 5 drops of phenolphthalein test solution, adding 20.0ml of sodium hydroxide titration solution (0.5 mol/L), stirring for 15 minutes, adding 20.0ml of hydrochloric acid titration solution (0.5 mol/L), shaking until pink disappears, measuring by using sodium hydroxide titration solution (0.5 mol/L) according to a potentiometric titration method (appendix VII A), and recording the volume of the consumed sodium hydroxide titration solution. The amount of galacturonic acid (C) added to the titration solution (0.5 mol/L) is 97.07 mg/1 ml sodium hydroxide 6 H 10 O 7 )。
Example 7 determination of the content of galacturonic acid in colloidal bismuth pectin pharmaceutical compositions
About 5.0g of the sample in example 4 or 5, in terms of weight difference, was weighed precisely, placed in a beaker, 150ml of 60% ethanol-hydrochloric acid (20. Washing with 60% ethanol each time 15ml until the filtrate does not show chloride reaction, adding ethanol 20ml, washing, drying the residue at 105 deg.C for 1 hr, cooling, and weighing. Weighing 1/5 of the weight of the dry residue, placing the dry residue in a 250ml beaker, adding 2ml of ethanol for wetting, adding 100ml of newly boiling cold water, shaking, placing the beaker on a magnetic stirrer, stirring the beaker to uniformly disperse, adding 5 drops of phenolphthalein test solution, adding 20.0ml of sodium hydroxide titration solution (0.5 mol/L), stirring the solution for 15 minutes, adding 20.0ml of hydrochloric acid titration solution (0.5 mol/L), shaking until pink disappears, measuring the pink with the sodium hydroxide titration solution (0.5 mol/L) according to a potentiometric titration method (appendix VII A), and recording the volume of the consumed sodium hydroxide titration solution. The titration solution (0.5 mol/L) of sodium hydroxide per 1ml is equivalent to 97.07mg galacturonic acid (C) 6 H 10 O 7 )。
Example 8 determination of bismuth ion content in colloidal bismuth pectin pharmaceutical compositions
10 bags of the pharmaceutical composition described in example 4 or 5, 1.46g each, were placed in a 500ml conical flask, 10ml of nitric acid solution (1 → 2) was added, heated to dissolve, 300ml of water and 4 drops of xylenol orange indicator were added, and the solution was titrated with disodium ethylenediaminetetraacetate titrator (0.05 mol/L) to yellow. Each 1ml of disodium ethylenediaminetetraacetate titration solution (0.05 mol/L) corresponded to 10.45mg of bismuth (Bi).
Example 9 control of the uniformity of bismuth ion content in colloidal bismuth pectin pharmaceutical compositions
The average and standard deviation S of the bismuth ions of the pharmaceutical composition of example 8, in which the content of bismuth ions was known, was calculated for 10 bags, 1.46g of the pharmaceutical composition per bag, and the absolute value a of the difference between the indicated amount and the average value (a = | 100-average |), and the value of a +1.8S was calculated.
Example 10 determination of intrinsic viscosity of colloidal bismuth pectin drug substance
Precisely weighing any one batch of 50mg of the drug in the embodiments 1-3 of the application, placing the drug in a 100ml volumetric flask, adding about 30ml of water, shaking or ultrasonically dispersing the drug uniformly, adding water to a constant volume to a scale, shaking uniformly, filtering by using a No. 3 vertical melting glass funnel, discarding an initial filtrate, taking 20ml of a subsequent filtrate, placing the subsequent filtrate into a ball B of a clean and dry Ubbelohde viscometer (the third method in VI G viscometry in the second appendix of 2010 edition of Chinese pharmacopoeia), vertically fixing the viscometer in a constant-temperature (25 +/-0.1 ℃) water bath, enabling the liquid level of the water bath to be higher than that of the ball C, placing the mixture for 15 minutes, respectively connecting a latex tube to the tube openings 1 and 3, clamping the rubber tube of the tube opening 3, pumping air from the tube opening 1, slowly raising the liquid level of the test solution to the middle part of the ball C, releasing the tube opening 3, then releasing the tube opening 1, enabling the test solution to naturally fall in the tube, and accurately recording the liquid level to the measuring line m by using a stopwatch 1 Down to the measuring line m 2 Repeatedly measuring the outflow time twice, wherein the difference between the two measured values does not exceed 0.1 second, and taking the average value of the two measured values as the outflow time (T) of the test solution; taking pure water filtered through No. 3 sintered glass funnel, repeating the same for 2 times, wherein the measured value of 2 times is the same, and is the flowing-out time (T) of pure water 0 ) (ii) a Calculating characteristic viscosity [. Eta. ]]
Wherein C is the concentration of bismuth in the test solution, g/ml;
EXAMPLE 11 determination of intrinsic viscosity in colloidal bismuth pectin pharmaceutical compositions
Precisely weighing 50mg of the pharmaceutical composition described in embodiment 4 or 5 of the application, placing the pharmaceutical composition in a 100ml volumetric flask, adding about 30ml of water, shaking or ultrasonically dispersing the pharmaceutical composition uniformly, adding water to a constant volume to a scale, shaking uniformly, filtering by using a No. 3 vertical melting glass funnel, discarding an initial filtrate, taking 20ml of a subsequent filtrate, placing the subsequent filtrate in a ball B of a clean and dry Ubbelohde viscometer (the third method in VI G viscometry in the second appendix of 2010 edition of Chinese pharmacopoeia), vertically fixing the viscometer in a water bath at constant temperature (25 +/-0.1 ℃), making the liquid level of the water bath higher than that of the ball C, placing for 15 minutes, connecting a latex tube to each of the tube openings 1 and 3, clamping the rubber tube of the tube opening 3, pumping air from the tube opening 1, slowly raising the liquid level of the test solution to the middle of the ball C, releasing 3, then releasing the tube opening 1, making the test solution naturally fall in the tube, and accurately recording the liquid level to a measuring line m by using a stopwatch 1 Down to the measuring line m 2 Repeatedly measuring the flowing-out time twice, wherein the difference of the measured values of the two times does not exceed 0.1 second, and taking the average value of the two times as the flowing-out time (T) of the test solution; the pure water filtered through No. 3 sintered glass funnel is taken out, the same is repeated for 2 times, the measured value of 2 times is the same, and the flowing-out time (T) of the pure water is 0 ) (ii) a Calculating characteristic viscosity [. Eta. ]]
Wherein C is the concentration of bismuth in the test solution, g/ml;
example 12 determination of other indicators in colloidal bismuth pectin pharmaceutical compositions
Taking a proper amount of the fine powder (about 15mg equivalent to bismuth) in example 4 or 5, adding 100ml of water, shaking, and determining according to a method (appendix VI H in the second part of the 2010 edition of Chinese pharmacopoeia), wherein the pH value is 8.5-10.5;
the medicines in the embodiment 4 or 5 are taken out after drying, and dried to constant weight at 105 ℃, and the weight loss reduction amount is not more than 2.0% (appendix VIII L of the second part of the Chinese pharmacopoeia 2010 edition); in addition, in order to facilitate the forming of the medicine, the weight loss of the medicine can be controlled not to exceed 3.0 percent.
The drugs in example 4 or 5 are added with water according to the proportion of the drugs in use according to the sedimentation volume ratio, shaken vigorously for 1 minute, and kept stand for 1 hour, which is in accordance with the regulations (appendix I O of the second part of the 2010 edition of Chinese pharmacopoeia).
Comparative example 1
Preparing colloidal bismuth pectin: the colloidal bismuth pectin product is prepared according to the method in Chinese patent CN 92114663.9.
Comparative example 2
Preparing colloidal bismuth pectin: the colloidal bismuth pectin product was prepared as described in the chinese patent No. cn201310330840. X.
Comparative example 3
The colloidal bismuth pectin bulk drug meeting the standard under the second part of the colloidal bismuth pectin item in the 2010 edition of Chinese pharmacopoeia is prepared into the colloidal bismuth pectin dry suspension according to the method in the embodiment 4 or 5 of the application.
Comparative example 4
The colloidal bismuth pectin raw material drug meeting the standard of CN102507381A is prepared into a colloidal bismuth pectin dry suspension according to the method of the application example 4 or 5.
Comparative example 5
Colloidal bismuth pectin capsules, granules or tablets were prepared that met the criteria described in CN 102507381A.
Examples of the experiments
1. Quality study of colloidal bismuth pectin compounds
1.1 measurement of content of colloidal pectin bismuth galacturonic acid
The determination method comprises the following steps: measured according to potentiometric titration (appendix VII A of the second part of the 2010 version of the Chinese pharmacopoeia)
Taking the colloidal bismuth pectin raw material drug prepared in example 1 as an example, 120805 batches of the colloidal bismuth pectin raw material drug prepared according to the method of example 1 are taken, samples with the weight difference of about 5.0g are taken,precisely weighing, placing in a beaker, adding 150ml of 60% ethanol-hydrochloric acid (20). Precisely weighing 1/5 of the weight of the dry residue, placing the dry residue in a 250ml beaker, adding 2ml of ethanol for wetting, adding 100ml of newly boiled cold water, shaking, placing on a magnetic stirrer, stirring for uniform dispersion, adding 5 drops of phenolphthalein test solution, adding 20.0ml of sodium hydroxide titration solution (0.5 mol/L), stirring for 15 minutes, adding 20.0ml of hydrochloric acid titration solution (0.5 mol/L), shaking until pink disappears, measuring by using the sodium hydroxide titration solution (0.5 mol/L) according to a potentiometric titration method (appendix VII A), and recording the volume of the consumed sodium hydroxide titration solution. The amount of galacturonic acid (C) added to the titration solution (0.5 mol/L) is 97.07 mg/1 ml sodium hydroxide 6 H 10 O 7 )。
TABLE 1 colloidal bismuth pectin raw material potentiometric titration curves (120805 batches)
TABLE 2 galacturonic acid assay results
1.2 study of intrinsic viscosity
The measuring method comprises the following steps: taking the colloidal bismuth pectin obtained in example 1 as an example, precisely weighing 50mg of the colloidal bismuth pectin obtained in the preparation method of example 1, placing the colloidal bismuth pectin into a 100ml volumetric flask, adding about 30ml of water, shaking or ultrasonically dispersing the colloidal bismuth pectin uniformly, adding water to a constant volume to obtain a scale, shaking the scale, filtering the scale by using a No. 3 sintered glass funnel, discarding the primary filtrateTaking 20ml of continuous filtrate, placing into ball B of clean and dry Ubbelohde viscometer, vertically fixing the viscometer in a constant-temperature (25 ℃ +/-0.1 ℃) water bath, making the liquid level of the water bath higher than that of ball C, standing for 15 minutes, connecting pipe orifices 1 and 3 with a latex tube respectively, clamping the rubber tube of pipe orifice 3, exhausting air from pipe orifice 1, slowly raising the liquid level of the solution of the sample to the middle part of ball C, releasing pipe orifice 3, then releasing pipe orifice 1, making the solution of the sample naturally fall in the pipe, and accurately recording the liquid level to a measuring line m by using a stopwatch 1 Down to the measuring line m 2 Repeatedly measuring the outflow time twice, wherein the difference between the two measured values does not exceed 0.1 second, and taking the average value of the two measured values as the outflow time (T) of the test solution; the pure water filtered through No. 3 sintered glass funnel is taken out, the same is repeated for 2 times, the measured value of 2 times is the same, and the flowing-out time (T) of the pure water is 0 ) (ii) a Calculating characteristic viscosity [. Eta. ]]。
Wherein C is the concentration of bismuth in the test solution, g/ml
TABLE 3 determination of intrinsic viscosity
2. Quality contrast of colloidal bismuth pectin obtained by the method with the prior art
2.1 content comparison of galacturonic acid
Taking example 1 as an example, the colloidal bismuth pectins of example 1, comparative example 1 and comparative example 2 were used to determine the content of galacturonic acid according to the method of example 1.1, and the results are shown in the following table:
TABLE 4 content of galacturonic acid
2.2 comparison of intrinsic viscosity
The intrinsic viscosity of the colloidal bismuth pectins obtained in experimental example 1, comparative example 1 and comparative example 2 was measured according to the method of experimental example 1.2, and the results are shown in the following table:
TABLE 5 comparison of characteristic viscosity numbers
2.3 comparison of other indicators of colloidal bismuth pectin
The properties, basicity, loss on drying, and the like of the colloidal bismuth pectin products of example 1, comparative example 1, and comparative example 2 were observed and compared, and the measurement method of each index was as described in the section of colloidal bismuth pectin according to the "chinese pharmacopoeia". The results are as follows:
table 6 colloidal bismuth pectin obtained in example 1
TABLE 7 indexes of colloidal bismuth pectin obtained in comparative example 1
TABLE 8 colloidal bismuth pectin obtained in comparative example 2
Experimental example 3 study on data on adhesiveness of colloidal bismuth pectin dry suspension
The respective indices of the compounds or pharmaceutical compositions of examples 1-5 will be determined using the methods described for examples 6-12 herein.
The indices measured in comparative examples 3-5 were compared with the control method of the present application.
Three batches of colloidal bismuth pectin bulk drugs and dry suspensions prepared according to the methods of examples 1 to 5 of the application are taken, and the results are as follows:
TABLE 9 results of measurements of adhesion data of three batches of colloidal bismuth pectin and dry suspensions obtained in the present application and comparative examples
And (4) conclusion: as can be seen from Table 9, when the content of galacturonic acid in the colloidal pectin bismuth dry suspension product obtained by the control method of the present application is not less than 0.4g/1.46g, and the uniformity A +1.8S of bismuth ions is not more than 5, the intrinsic viscosity of the product is greater than 1000, which proves that the colloidal property is relatively stable, and the selective adhesion effect on damaged gastrointestinal mucosa Hp is strongest. On the contrary, the colloidal bismuth pectin dry suspensions controlled by the prior art can not intuitively and reliably judge the adhesiveness and curative effect of the product (comparative example 3), or the obtained product has low intrinsic viscosity and low adhesiveness and curative effect (comparative examples 4 and 5). Therefore, compared with the prior art, the method for controlling the adhesive property of the colloidal bismuth pectin and the pharmaceutical composition thereof, in particular the colloidal bismuth pectin dry suspension, has remarkable advantages.
Experimental example 4 comparison of adhesive Properties
The colloidal bismuth pectin compounds and the intrinsic viscosity of the products of comparative example 3 were measured by the methods described in the present application and CN102507381A, respectively, and compared with the intrinsic viscosity of the products of comparative example 4, comparative example 5 and the present application, and the results are shown in table 10.
TABLE 10 measurement results of intrinsic viscosity
And (4) conclusion: the colloidal bismuth pectin dry suspension obtained by the control method has high characteristic viscosity and good adhesiveness.
Experimental example 5 animal experiments
The colloidal pectin bismuth dry suspension can be used as a gastrointestinal mucosa protective agent and a helicobacter pylori killing agent, and can be used for treating gastric or duodenal ulcer, chronic atrophic gastritis, chronic erosive gastritis, abdominal pain, abdominal distension, diarrhea, gastrointestinal mucosa bleeding, particularly gastrointestinal ulcer or inflammation related to helicobacter pylori, and preventing canceration of atrophic gastritis; it can be used in combination with antibiotic, proton pump inhibitor or H2 receptor antagonist, or other bismuth salt compounds, or be administered alone after bismuth triple therapy, or in 1-2 times of conventional dosage for eradicating helicobacter pylori.
The therapeutic effect of the colloidal bismuth pectin pharmaceutical composition (dry suspension) obtained by the control method is compared with that of the colloidal bismuth pectin pharmaceutical composition meeting the prior art or the standard.
5.1 therapeutic test on gastric ulcer in rat
The experimental method comprises the following steps: taking 50 Wistar rats with the same week age and the same variety and sex, dividing the Wistar rats into 5 groups, fasting, respectively feeding physiological saline, feeding 1ml of absolute ethyl alcohol into each rat after 1h, killing cervical dislocation after 60min, picking the whole stomach, injecting 10ml of 1% formaldehyde solution, fixing in formaldehyde with the same concentration for more than 10min, cutting the stomach wall along the greater curvature of the stomach, and observing the damage condition of the gastric mucosa, wherein the Wistar rats with the same week age and the same variety and sex are divided into 5 groups, and the groups are respectively fasted and respectively fed with the physiological saline, the colloidal bismuth pectin dry suspension obtained by the control method of the application, the colloidal bismuth pectin dry suspension obtained by the control method of comparative example 3, the comparative example 4 and the comparative example 5 or the colloidal bismuth pectin dry suspension or the pharmaceutical composition obtained by the standard, and each rat is drenched with 1ml of absolute ethyl alcohol after 60min, and then the cervical dislocation is killed, the whole stomach is picked and injected with 1% formaldehyde solution, and the same concentration of formaldehyde solution is fixed in the formaldehyde for more than 10min, and then the stomach wall is cut along the greater curvature of the stomach, and the gastric mucosa is observed, and the damage condition of the gastric mucosa is seen in Table 11
TABLE 11 comparison of the therapeutic effects of gastric ulcers in mice
Note: * P is less than 0.01, and the experimental group is compared with the control group
And (4) conclusion: the treatment effect of the colloidal bismuth pectin pharmaceutical composition on gastric ulcer is higher than that of the product in the comparative example. .
5.2 anti-inflammatory therapy in rats
The experimental method comprises the following steps: 50 rats with the same week age and the same variety and sex are divided into 5 groups and respectively given with physiological saline, the colloidal bismuth pectin obtained by the control method of the application and the products obtained by the control method or the standard of the comparative examples 3, 4 and 5 are coated with 2% of croton oil inside and outside the left ear of each animal after 1h, the rats are sacrificed after 4h, two ears are cut off, the round ear pieces are punched by a perforator with the diameter of 9mm, a torsion balance is used for weighing, and the swelling inhibition rate is calculated. See Table 11
TABLE 11 anti-inflammatory treatment of rats
Note: compared with the control group, the P of the experimental group is less than 0.01, and the difference is significant.
And (4) conclusion: the anti-inflammatory effect of the colloidal bismuth pectin pharmaceutical composition obtained in the application is higher than that of the comparative example group.
5.3 Chronic gastritis test
50 rabbits with the same week age and the same variety and sex for experiment are divided into 5 groups, after the chronic gastritis is artificially induced, the colloidal bismuth pectin obtained by the control method of the application is treated with the products obtained by the control method or the standard of the comparative examples 3, 4 and 5, and the treatment effect is observed after 12 weeks, which is shown in table 12.
TABLE 12 experiment for chronic gastritis
Note: * P is less than 0.01, and the experimental group is compared with the control group
And (4) conclusion: the colloidal pectin bismuth dry suspension obtained by the control method has better treatment effect on chronic gastritis than corresponding medicines under other standards or quality requirements, and compared with a control group, the experimental group has a P <0.01, and the difference is significant.
5.4 eradication Rate of Hp
The experimental method comprises the following steps: 50 rats with the same week age and the same variety and sex are divided into 5 groups and are subjected to artificial molding. The normal saline, the colloidal bismuth pectin dry suspension obtained by the control method of the application and the dry suspension or the pharmaceutical composition obtained by the control method or the standard of the comparative examples 3-5 are respectively administered for treatment, and the treatment effect is observed.
TABLE 13 eradication Rate testing of Hp
Note: compared with the control group, the P of the experimental group is less than 0.01, and the difference is significant.
Claims (15)
1. The preparation method of the colloidal bismuth pectin is characterized by comprising the following steps: the preparation method comprises the steps of (1) preparing a bismuth salt solution; (2) Preparing colloidal bismuth pectin and refining the colloidal bismuth pectin (3), specifically, the preparation method is (1) a preparation method of a bismuth salt solution, adding purified water into a reaction bottle, and adding bismuth nitrate; regulating the pH value to 6-8 by using a potassium hydroxide solution, completely hydrolyzing the solution, namely, filtering the solution after repeatedly measuring the pH value and keeping the pH value constant to obtain a filter cake bismuth hydroxide; putting the purified water and sorbitol into a beaker, adding the filter cake bismuth hydroxide after the sorbitol is dissolved, stirring to disperse, adding the potassium hydroxide solution, and stirring to fully dissolve the potassium hydroxide solution to obtain a bismuth salt solution for later use; (2) Preparing colloidal bismuth pectin, namely adding the bismuth salt solution prepared in the step (1) into a reaction bottle, stirring, adding purified water, adding the soft pectin material at room temperature, heating to stir, preserving heat, adding the purified water, and stirring at controlled temperature; after the reaction is finished, pouring the reaction system into ethanol, stirring, standing, filtering, rinsing with proper amount of ethanol, and pumping to obtain a colloidal bismuth pectin crude product wet product; (3) Refining colloidal bismuth pectin, namely adding a wet colloidal bismuth pectin crude product into ethanol, stirring, standing, filtering, leaching with a proper amount of ethanol, drying a filter cake in vacuum, crushing the product, drying in vacuum, and packaging to obtain a colloidal bismuth pectin product, wherein one or more indexes of the intrinsic viscosity, the bismuth ion content uniformity and the galacturonic acid content of the colloidal bismuth pectin product are measured, and the intrinsic viscosity of the colloidal bismuth pectin pharmaceutical composition is controlled to be not less than 1000, or the bismuth ion content is 90-110% of the marked amount, and the content uniformity A +1.80S is not more than 5; or the content of galacturonic acid is not less than 0.4g per 1.46g of the pharmaceutical composition.
2. The method for preparing colloidal bismuth pectin according to claim 1, wherein the method comprises the following steps: in the step (1), 166.67g of purified water is added into a reaction bottle, activated carbon with the mass concentration of 0.05% is added, and the mixture is heated and stirred; adding 29.22g of bismuth nitrate at the temperature; adding 20-25g of potassium hydroxide solution, adjusting the pH value to 6-8 to ensure that the solution is completely hydrolyzed, namely filtering after the pH value is determined to be constant again to obtain a filter cake bismuth hydroxide and activated carbon mixture; and putting 40.56g of purified water and 17.89g of sorbitol into a beaker, adding the filter cake bismuth hydroxide after the sorbitol is dissolved, stirring to disperse, adding 48-53g of potassium hydroxide solution, heating and stirring to fully dissolve the filter cake bismuth hydroxide, and performing hot filtration at the temperature to obtain a bismuth salt solution for later use.
3. The method for preparing colloidal bismuth pectin according to claim 1, wherein the method comprises the following steps: the concentration of the potassium hydroxide solution used in the step (1) is 40%.
4. The method for preparing colloidal bismuth pectin according to claim 1, wherein the method comprises the following steps: adding the bismuth salt solution prepared in the step (1) into a reaction bottle, stirring, adding 49ml of purified water, adding a pectin soft material at room temperature, heating to 40-45 ℃ after adding, stirring, carrying out heat preservation reaction for 0.5 hour, adding 105g of purified water, controlling the temperature to be 30-35 ℃, and stirring for 1.5 hours; and after the reaction is finished, pouring the reaction system into 550ml of ethanol, stirring for 30 minutes, standing for 30 minutes, filtering, leaching with a proper amount of ethanol, and draining to obtain a colloidal bismuth pectin crude product wet product.
5. The method for preparing colloidal bismuth pectin according to claim 1, wherein the method comprises the following steps: and (3) adding the colloidal bismuth pectin crude product wet product into 400ml of ethanol, stirring for 15 minutes, standing for 30 minutes, filtering, leaching with a proper amount of ethanol, drying a filter cake at 75-78 ℃ for 5 hours in vacuum, crushing the product, drying at 95 ℃ for 5 hours in vacuum, and packaging to obtain the colloidal bismuth pectin product.
6. The method for preparing colloidal bismuth pectin according to claim 4 or 5, wherein the concentration of ethanol used in the steps (2) and (3) is 95%.
7. A method for controlling the adhesion of a pharmaceutical composition comprising colloidal bismuth pectin prepared by the method of any one of claims 1-6, wherein: measuring one or more indexes of the characteristic viscosity number, the bismuth ion content uniformity and the galacturonic acid content of the colloidal bismuth pectin compound or the pharmaceutical composition thereof, and controlling the characteristic viscosity number in the colloidal bismuth pectin compound or the pharmaceutical composition thereof not to be lower than 1000, or controlling the bismuth ion content to be 90-110% of the marked amount, and controlling the content uniformity A +1.80S to be not more than 5; or the content of galacturonic acid is not less than 0.4g per 1.46g of the pharmaceutical composition.
8. The method for controlling the adhesiveness of a pharmaceutical composition according to claim 7, wherein: determining the characteristic viscosity number, the bismuth ion content uniformity and the galacturonic acid content of the colloidal bismuth pectin compound or the pharmaceutical composition thereof, and controlling the characteristic viscosity number of the colloidal bismuth pectin compound or the pharmaceutical composition thereof to be not less than 1000, the bismuth ion content to be 90-110% of the marked amount, and the content uniformity A +1.80S to be not more than 5; and the content of galacturonic acid is not less than 0.4g per 1.46g of the pharmaceutical composition.
9. The method for controlling the adhesiveness of a pharmaceutical composition according to claim 8, wherein: the method for measuring the characteristic viscosity number of the colloidal bismuth pectin compound or the pharmaceutical composition thereof is measured according to a third method in VI G viscosity measurement method in addendum II of 2010 edition of Chinese pharmacopoeia, and the method comprises the steps of precisely weighing 50mg of the compound or the pharmaceutical composition, placing the compound or the pharmaceutical composition in a 100ml volumetric flask, adding 30ml of water, shaking or ultrasonically dispersing the compound or the pharmaceutical composition uniformly, adding water to a constant volume to reach a scale, shaking uniformly, filtering by a No. 3 vertical melting glass funnel, discarding an initial filtrate, taking 20ml of a subsequent filtrate, placing the subsequent filtrate in a ball B of a clean and dry Ubbelohde viscometer, vertically fixing the viscometer in a water bath with the constant temperature of 25 +/-0.1 ℃, enabling the liquid level of the water bath to be higher than that of the ball C, placing for 15 minutes, connecting pipe orifices 1 and 3 with latex tubes respectively, clamping a rubber tube of the pipe orifice 3, exhausting air from the pipe orifice 1, enabling the liquid level of the test solution to slowly rise to the middle part of the ball C, releasing the pipe orifice 3, enabling the test solution to naturally fall in the tube, accurately recording the liquid level of the test solution in the tube by accurately recording a meter to the measurement line m by using a meter 1 Down to the measuring line m 2 Repeatedly measuring the outflow time twice, wherein the difference between the two measured values does not exceed 0.1 second, and taking the average value of the two measured values as the outflow time (T) of the test solution; taking pure water filtered through No. 3 sintered glass funnel, repeating the same for 2 times, wherein the measured value of 2 times is the same, and is the flowing-out time (T) of pure water 0 ) (ii) a Calculating characteristic viscosity [. Eta. ]]
Wherein C is the concentration of bismuth in the test solution, g/ml; the method for measuring the content uniformity of bismuth ions is according to the content uniformity method of appendix XE of the second part of 2010 edition of Chinese pharmacopoeia, wherein the method for measuring the content uniformity of bismuth ions comprises the steps of taking 10 bags of the pharmaceutical composition, putting 1.46g of each bag into 500ml conical bottles respectively, adding 10ml of nitric acid solution with the volume percentage concentration of 50%, heating to dissolve the nitric acid solution, adding 300ml of water and 4 drops of xylenol orange indicator solution, and titrating the solution to be yellow by using 0.05mol/L of disodium ethylene diamine tetraacetate titrating solution; each 1ml of 0.05mol/L disodium ethylene diamine tetraacetate titration solution is equivalent to 10.45mg of bismuth; calculating the average value and standard deviation S of the bismuth ion content of 10 bags of colloidal bismuth pectin pharmaceutical compositions and the absolute value A of the difference between the marked amount and the average value, wherein A = | 100-average | and calculating the numerical value of A + 1.8S; the method for measuring the content of galacturonic acid comprises the steps of taking contents in terms of weight difference, uniformly mixing, taking 5.0g of colloidal bismuth pectin compound or pharmaceutical composition thereof, precisely weighing, placing the colloidal bismuth pectin compound or pharmaceutical composition thereof in a beaker, adding 150ml of 60% ethanol-hydrochloric acid with a volume ratio of 20 to 1, stirring for 10 minutes, transferring the mixture to a constant-weight filter, washing the filter with 30-60 ml of a vertical melting crucible or a Buchner funnel for 6 times and 15ml each time by using 60% ethanol solution with a volume ratio of 20 to 1, continuously washing the filter with 60% ethanol until the filtrate does not show chloride reaction, adding 20ml of ethanol for washing, drying the residue at 105 ℃ for 1 hour, cooling and weighing; precisely weighing 1/5 weight of dry residue, placing the dry residue in a 250ml beaker, adding 2ml of ethanol for wetting, adding 100ml of newly boiling cold water, placing the beaker on a magnetic stirrer, stirring the mixture to uniformly disperse the mixture, adding 5 drops of phenolphthalein test solution, adding 20.0ml of 0.5mol/L sodium hydroxide titration solution, stirring the mixture for 15 minutes, adding 20.0ml of 0.5mol/L hydrochloric acid titration solution until pink disappears, measuring the pink by using 0.5mol/L sodium hydroxide titration solution according to VIIA potentiometric titration method in the second appendix of 2010 of Chinese pharmacopoeia, and recording the volume of the consumed sodium hydroxide titration solution; each 1ml of 0.5mol/L sodium hydroxide titration solution corresponds to 97.07mg galacturonic acid.
10. The method for controlling the adhesiveness of a pharmaceutical composition according to claim 8 or 9, wherein: the dosage form of the colloidal bismuth pectin pharmaceutical composition is dry suspension, and the colloidal bismuth pectin pharmaceutical composition consists of 150 parts by weight of colloidal bismuth pectin, 455 parts by weight of filler and 15 parts by weight of flocculant.
11. The method of claim 10 for controlling the adherence of a pharmaceutical composition, wherein: the filler in the colloidal bismuth pectin pharmaceutical composition is mannitol, and the flocculating agent is disodium hydrogen phosphate.
12. The method of claim 11, wherein the adhesion of the pharmaceutical composition is controlled by: one or two of steviosin and orange oil essence can also be added into the colloidal bismuth pectin pharmaceutical composition as a flavoring agent.
13. The method for controlling the adhesiveness of a pharmaceutical composition according to claim 12, wherein: the colloidal bismuth pectin pharmaceutical composition also has the following indexes
The pharmaceutical composition is yellowish powder or granule; fragrant smell and sweet taste;
the alkalinity pH value of the pharmaceutical composition is 8.5 to 10.5,
the weight loss of the pharmaceutical composition is less than 2.0%;
the sedimentation volume ratio of the pharmaceutical composition is not less than 0.9;
the specification of the pharmaceutical composition is 150mg.
14. The method for controlling the adhesiveness of a pharmaceutical composition according to claim 13, wherein: the weight loss reduction amount of the colloidal bismuth pectin pharmaceutical composition can also be not more than 3.0%.
15. The method of claim 14 for controlling the adherence of a pharmaceutical composition, wherein: the bismuth ion content uniformity A +1.8S of the colloidal bismuth pectin pharmaceutical composition can also be not more than 5.02.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610009844.1A CN105461823B (en) | 2015-04-07 | 2016-01-07 | A kind of preparation method of colloidal bismmth pectin and its control method of pharmaceutical composition adhesion |
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2015101603335 | 2015-04-07 | ||
| CN201510160333 | 2015-04-07 | ||
| CN2015107560263 | 2015-11-09 | ||
| CN201510756026 | 2015-11-09 | ||
| CN2015109790448 | 2015-12-23 | ||
| CN201510979044 | 2015-12-23 | ||
| CN2015110163029 | 2015-12-29 | ||
| CN201511016302 | 2015-12-29 | ||
| CN201610009844.1A CN105461823B (en) | 2015-04-07 | 2016-01-07 | A kind of preparation method of colloidal bismmth pectin and its control method of pharmaceutical composition adhesion |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105461823A CN105461823A (en) | 2016-04-06 |
| CN105461823B true CN105461823B (en) | 2018-04-06 |
Family
ID=55600023
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610009844.1A Active CN105461823B (en) | 2015-04-07 | 2016-01-07 | A kind of preparation method of colloidal bismmth pectin and its control method of pharmaceutical composition adhesion |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105461823B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1919170A (en) * | 2006-09-18 | 2007-02-28 | 黄本东 | Colloid pectin bismuth dry suspensoid and its preparing process |
| CN102391389A (en) * | 2011-08-12 | 2012-03-28 | 于学敏 | Colloidal bismuth pectin compound and medicinal composition thereof, and preparation methods and application thereof |
| CN102507381A (en) * | 2011-10-09 | 2012-06-20 | 于学敏 | Colloid bismuth pectin compound and quality control method of pharmaceutical compositions thereof |
| CN103360513A (en) * | 2013-07-31 | 2013-10-23 | 三门峡富元果胶工业有限公司 | Production method for colloidal pectin bismuth |
-
2016
- 2016-01-07 CN CN201610009844.1A patent/CN105461823B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1919170A (en) * | 2006-09-18 | 2007-02-28 | 黄本东 | Colloid pectin bismuth dry suspensoid and its preparing process |
| CN102391389A (en) * | 2011-08-12 | 2012-03-28 | 于学敏 | Colloidal bismuth pectin compound and medicinal composition thereof, and preparation methods and application thereof |
| CN102507381A (en) * | 2011-10-09 | 2012-06-20 | 于学敏 | Colloid bismuth pectin compound and quality control method of pharmaceutical compositions thereof |
| CN103360513A (en) * | 2013-07-31 | 2013-10-23 | 三门峡富元果胶工业有限公司 | Production method for colloidal pectin bismuth |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105461823A (en) | 2016-04-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Nayak et al. | Trigonella foenum-graecum L. seed mucilage-gellan mucoadhesive beads for controlled release of metformin HCl | |
| CA1117013A (en) | Method for treating kidney stones | |
| CN107406522B (en) | The gelation of esterified cellulose ether | |
| CN102391389B (en) | Colloidal bismuth pectin compound and medicinal composition thereof, and preparation methods and application thereof | |
| CN112516083B (en) | Ibuprofen suspension and preparation method thereof | |
| CN104069228B (en) | A kind of bioadhesive microspheres of nucleocapsid structure and preparation method thereof | |
| CN105461823B (en) | A kind of preparation method of colloidal bismmth pectin and its control method of pharmaceutical composition adhesion | |
| WO1999020285A1 (en) | Gel preparations containing polystyrenesulfonate | |
| CN111419871A (en) | Compound polyethylene glycol electrolyte granules and preparation method thereof | |
| CN108837156A (en) | A kind of preparation method of carbon dots medicine-carried system | |
| CN106963729B (en) | It is a kind of to be used to prevent pharmaceutical preparation of operative hemorrhage and preparation method thereof | |
| CN108309937A (en) | A kind of preparation method for containing the reduction response type nano material of antitumor drug | |
| CN105560188B (en) | A kind of colloid pectin bismuth medicine closes object and its method of quality control | |
| CN105496968B (en) | A kind of quality of colloidal bismmth pectin pharmaceutical composition and the control method of safety | |
| CN109925287A (en) | A kind of Pyrochep and preparation method thereof | |
| CN114126583A (en) | Ornidazole injection and S-ornidazole injection | |
| CN113425685B (en) | Montmorillonite powder and preparation method thereof | |
| CA3076127A1 (en) | Food composition for the preparation of products for subjects with swallowing difficulty and use thereof in automated dispensing machines | |
| CN107903243A (en) | A kind of glug arranges net process for purification | |
| CN105572126B (en) | A kind of colloidal bismmth pectin pharmaceutical composition | |
| CN103893782B (en) | A kind of digestive tract double contrast radiography x-ray checks special barium sulfate suspension and preparation method thereof | |
| Dev et al. | Preparation and evaluation of modified tamarind seed gum as a novel superdisintegrant | |
| CN105147690A (en) | Pharmaceutical sildenafil citrate composition tablets for treating diseases of urinary surgery | |
| CN105748438B (en) | A method of microcapsules are prepared in conjunction with concave convex rod by acetylamino evericin | |
| JP6206420B2 (en) | Method for producing gel composition containing ferric citrate at high concentration |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20190527 Address after: 410329 Liuyang biological medicine Park in Changsha, Hunan Co-patentee after: Hunan Warner Pharmaceutical Co., Ltd. Patentee after: HUNAN WARRANT PHARMACEUTICAL CO., LTD. Address before: 410329 Liuyang biological medicine Park in Changsha, Hunan Patentee before: HUNAN WARRANT PHARMACEUTICAL CO., LTD. |