CN108295065A - A kind of calculus bovis factitius preparation method - Google Patents
A kind of calculus bovis factitius preparation method Download PDFInfo
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- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
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Abstract
The invention discloses a kind of calculus bovis factitius preparation methods, pass through the artificial extraction to important component in various cow-bezoars, by realizing cholic acid, deoxycholic acid, bilirubin, the artificial extraction of cholesterol, and add some other ingredient, and according to content of bilirubin 72% 76.5%, bile acid 4.3% 6.1%, cholic acid 0.8% 1.8%, deoxycholic acid 3.33% 4.3%, bile salt 3.3% 3.96%, total cholesterol 2.5% 4, 3%, aliphatic acid 1.0% 2.1%, lecithin 0.17% 0.2%, the ratio of calcium 2.3% 2.5%, iron is being added, potassium, sodium, magnesium, copper, after molybdenum ion, realize the manual manufacture synthesis of cow-bezoar.
Description
Technical field：
The present invention relates to calculus bovis factitius preparation field, more particularly to a kind of calculus bovis factitius preparation method.
Background technology：
Cow-bezoar is the gall stone of Chordata Mammalia bovid cattle gallbladder；The title " jaundice due to fright or traumatic injury " that is generated in gall-bladder or
" yolk ", the title generated in bile duct " pipe is yellow ", the title generated in common hepatic duct " liver is yellow "；This calculus is mainly containing bilirubin
Calculus, China are always cow-bezoar quality good or not and to be discerned the false from the genuine with the red rope color and luster of courage to evaluate；Cow-bezoar is a kind of curative effect really
Rare traditional Chinese medicine, in an earliest book on Chinese herbal medicine of China《Variorum of Shennong》In be just put into top grade, in European quattrocento
When also have cow-bezoar note cut out.
Calculus bovis factitius, this product is by bilein, cholic acid, hyodesoxycholic acid, taurine, bilirubin, cholesterol, trace element etc.
It is processed into；For yellow loose powder.With the effect of clearing heat and detoxicating, resolving sputum is calmed the frightened；Be usually used in phlegm heat rave it is mad, coma in silence,
Pediatric acute convulsion, abscess of throat, aphthae, the treatment of the illnesss such as carbuncle swells furunculosis.
Invention content：
The purpose of the present invention is to overcome the deficiencies of the prior art, provides a kind of calculus bovis factitius preparation method, simple easy
Row, can complete, to the artificial synthesized of cow-bezoar, solve the problems of the prior art.
To achieve the above object, the present invention provides the following technical solutions：A kind of calculus bovis factitius preparation method：Ingredient is：Courage
The red content 72%-76.5% that feeds, bile acid 4.3%-6.1%, cholic acid 0.8%-1.8%. deoxycholic acid 3.33%-4.3%,
Bile salt 3.3%-3.96%, total cholesterol 2.5%-4,3%, aliphatic acid 1.0%-2.1%, lecithin 0.17%-
0.2%, calcium 2.3%-2.5%, other also contain iron, potassium, sodium, magnesium, copper, molybdenum ion, are below the extraction of each important component
Method：
1, cholic acid molecules amount 408.6, solubility when 198 degrees Celsius, 15 degrees Celsius of fusing point in water is 0.28 grams per liter,
It is 30.56 grams per liters in ethanol；In production using bovine and sheep bile as raw material, using " alcohol crystal, which is dispelled, " to be extracted, operating procedure
For：
(1) it hydrolyzes, be acidified the sodium hydroxide that ox, sheep bile are added on to 1/10 amount, boil saponification in jacketed pan heating
18 hours or more, the water that evaporation is gone was continuously replenished in centre, and reaction terminates, and filtrate is saponification liquor；Wait for that saponification liquor cools down, in Bu Shi
It is filtered on funnel, under stiring, 30% dilute sulfuric acid, which is slowly added dropwise, makes pH value reach 2-3, and saponification liquor is placed in appearance by thick courage at this time
In device, add equivalent water to mix and boil Buddhist 10-20 juice acid and float on liquid layer, up to thick courage meter acid tide product after filtering, places it in container,
Make into granular precipitate, cooled and filtered, filter cake is washed with clear water repeatedly to neutrality, after taking out thousand, in 50-60 DEG C of vacuum drying oven
Or dried to constant weight in air -oven, obtain thick bile acid dry product；
(2) crystallization, drying take thousand product of thick bile acid to put in reactor of the people equipped with flask, 0.75 times of 75% ethyl alcohol is added,
It is heated to reflux to solids and all dissolves, then add people's 10%-15% activated carbons reflux decoloration 15-20 minutes, filter while hot；Filter
Liquid is cooled to 0-5 degrees Celsius with ice-water bath, then places 4 hours or more, so that cattle and sheep bile acid crystallization is precipitated, then filters, and is used in combination suitable
Ethyl alcohol wash crystallization is measured, after draining, obtains cholic acid coarse crystallization；
(3) decolourize, it is refined above-mentioned coarse crystallization cholic acid is set again in decoloring reaction bottle, add 4 times of amounts of people 95% ethyl alcohol and
4%-5% activated carbons are heated to reflux decoloration 30-45 minutes, filter while hot；It is distilled to recover ethyl alcohol in the filtrate distiller of falling people, until
After total volume is the 1/4 of original volume, it first is cooled to room temperature with cold bath, is then cooled to 0-50 DEG C with ice-water bath, crystallization 4
After hour, vacuum filter, after draining, crystallizes and is washed 1-2 times with a small amount of 95% cold ethyl alcohol on a buchner funnel, drain again,
Knot product in 70 DEG C of vacuum drying chambers under it is dry to constant weight to get cattle and sheep bile acid fine work, yield 2%-3%.
2, deoxycholic acid molecular weight 302.6, readily soluble in ethyl alcohol and glacial acetic acid, slightly soluble in acetone is almost insoluble in water,
Operating procedure is：
(1) the alkalinity filter night after bile acid preparation will produce calcium cholates with calcium salt method sets in acid-resistant container, cools down at room temperature
It standing to 30 DEG C hereinafter, then, side is stirred, 15% hydrochloric acid of people is slowly added dropwise in side, and pH value is transferred to 1-2, stands 12-18 hours,
The viscous thick bile acid of paste of green is sunken to device bottom, takes out, and after being rinsed with water, is dried in vacuo up to bile acid crude；
(2) prepared by deoxycholic acid crude product, by bile acid:Solid sodium hydroxide：Water=1：1.5：9 weight ratio, first by water
Adding people's flask, then adds people's solid sodium hydroxide, shaking to sodium hydroxide is all dissolved, then adds human bile's acid crude, is fully shaken up,
It is heated to reflux saponification 16 hours or more, after reaction, is cooled to 15 DEG C at room temperature hereinafter, stratification；Top is gone in siphon
Weak yellow liquid, sediment, which supplements a small amount of water, makes dissolving, is acidified to pH=1-2 with 20% sulfuric acid under stiring, deoxycholic acid is thick
Product are suspended in liquid level in golden Huang, place 2 hours or more, filtering discards filtrate, and filter cake is placed in beaker, appropriate cold water is added
Mix, refilter, is used in combination proper amount of clear water to wash 1-2 times, filtering again is drained, and drying obtains deoxycholic acid crude product；
(3) it refines and above-mentioned crude product is placed in flask, add the ethyl acetate of 4 times of weight, 15% one 20% activated carbon, heat
Reflux decoloration 30-45 minutes, after being cooled to room temperature, filtering, filter cake adds 4 times of weight ethyl acetates again, is handled by upper method, obtains second
Secondary refined liquid, is so repeated once, and obtains third time and refines quilt,
(4) merge above-mentioned first, second and third ethyl acetate refined liquid, be placed in tool plug boiling flask；It is anhydrous to be added 20%
Sodium sulphate is vibrated 5-10 minutes, is then stood overnight at room temperature, to remove the moisture in ethyl acetate, next day filtering, filtrate
It moves in cucurbit, heating recovery ethyl acetate is to there is a small amount of white solid object to be precipitated, until the 1/3-1/5 of original volume, cooling knot
After 8 hours brilliant, filter to doing, washed 1-2 times with appropriate ethyl acetate numerous, drained again, 70 degrees Celsius or less are dried under vacuum to perseverance
Weight is to get colourless deoxycholic acid fine work.
3, bilirubin also known as the red matter of courage, molecular weight 584.65,198-200 degrees Celsius of molten point is not soluble in water, dissolve in benzene,
, Wei Rong is in ethyl alcohol and ether, operating procedure in chloroform, chlorine extraction, carbon disulfide and lye：
(1) preparation of BILE PIGMENTS calcium salt, fresh pig gall meter add the 3-4 times of clear feelings saturated limewater measured, under constant stirring,
It is heated to boiling, Lao Qu Piao float on the red rope calcium salt of straw red courage of liquid level, are filtered with fine cloth immediately, obtain calcium salt, and mother liquor inclines through standing
It after removing supernatant liquor, precipitates and is filtered, be incorporated in calcium salt and take out the mother liquor after calcium salt and be used as producing deoxycholic acid；
(2) the primary acidification of calcium bilirubinate takes BILE PIGMENTS calcium salt, and half times of water is added to stir into paste, crosses 80 mesh sieve, is added
1% sodium hydrogensulfite is slowly added dropwise 1 under constant stirring：1 dilute hydrochloric acid makes pH1-2, stands 10 minutes, releases sour water,
Precipitation filtering；
(3) bilirubin sodium salt after-souring precipitation first plus a small amount of ethyl alcohol stir into paste, then again plus about 10 times amount
The ethyl alcohol of 90%-95% and 0.5% sodium hydrogensulfite adjust pH3-4, staticly settle 1 hour, Aspirate supernatant, bottom courage color
Rope is spent primary so that 10 times of amount ethyl alcohol washings are heavy again, sucks supernatant, and bottom BILE PIGMENTS is filtered with silk, content generally 30% with
On；
(4) it refines and takes crude bilirubin, the chloroforms of 4 times of amounts are added, in 35 degrees Celsius of refluxing extractions 3 hours, by chloroform layer
Upper layer residue is detached to extract 3-4 times repeatedly again:Until bilirubin is extracted to the greatest extent, chloroform extracted solution merges filtering, adds in filtrate few
Antioxidant is measured, chloroform to hematoidin crystals is distilled to recover and is precipitated, appropriate 95% ethyl alcohol is added, continues to distill, until boiling off solution
The chloroform of interior remnants filters remaining bilirubin ethanol solution, and one is respectively washed with 95% ethyl alcohol and distilled water of a small amount of low-grade fever
It is secondary, it is finally washed with absolute ethyl alcohol, is dried in vacuo, obtains refined bilirubin.
4, cholesterol molecule amount 386.67, is the main sterol in higher mammal body, and 148.5 degrees Celsius of fusing point is slightly soluble in
Water can be dissolved in alcohol, ether, xenon and imitate, acetone, and operating procedure is：
(1) acetone extraction takes fresh bone marrow, the impurity such as striping and the trace of blood to rub, and 3 times of amount acetone soaks is added, for the second time
2.5 times of amounts, 1.5 times of amounts of third time, 24 hours every time, are often stirred, and filtrate is collected in filtering and squeezing；
(2) concentration is distilled to recover acetone, until occurring a large amount of yellow solids in concentrate；
(3) ethyl alcohol dissolving yellow solid adds 95% ethyl alcohol of 10 times of amounts, and being heated to reflux makes dissolving, filtering；
(4) cold crystallization filtrate stands knot product and is precipitated, filter to obtain thick cholesterol crystal in 0-5 degrees Celsius of cooling；
(5) the thick cholesterol knot product of sour water solution add 5 times of 95% ethyl alcohol of amount and the sulfuric acid of 5%-6%, and it is small to be heated to reflux hydrolysis 8
When, solution filters out crystallization and is washed till neutrality with 95% ethyl alcohol in 0-5 degrees Celsius of crystallisation by cooling, filtering；
(6) ethyl alcohol recrystallization cholesterol knot product add 10 times of 95% ethyl alcohol measured and 3% activated carbon, are heated to reflux decoloration 1
Hour, heat preservation filtering is carried out, filtrate is in 0-5 degrees Celsius of crystallisation by cooling, and repeatedly three times, cholesterol crystal is filtered, is pressed dry,
After ethyl alcohol is removed in volatilization, it is dried in vacuo at 70-80 DEG C up to fine work cholesterol.
5, it according to the formula of calculus bovis factitius and quality requirement, accurately calculates and prepares various raw materials needed for a certain amount of finished product；
First bilirubin is dissolved in a small amount of organic solvent, adds cholic acid, cholesterol, inorganic salts and excipient etc. are uniformly mixed, very
Sky thousand is dry；Take out thousand dry objects；The de- radon cholic acid that full dose is added carries out ball milling, sieves with 100 mesh sieve, is packaged in brown bottle.
Through the above technical solutions, the present invention provides a kind of calculus bovis factitius preparation method, by weight in various cow-bezoars
The artificial extraction for wanting ingredient realizes the manual manufacture synthesis of cow-bezoar.
Specific implementation mode：
Below in conjunction with the embodiment of the present invention, technical scheme in the embodiment of the invention is clearly and completely described,
Obviously, described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments；Based in the present invention
Embodiment, every other embodiment obtained by those of ordinary skill in the art without making creative efforts, all
Belong to the scope of protection of the invention.
Embodiment：
A kind of calculus bovis factitius preparation method：Ingredient is：Content of bilirubin 72%-76.5%, bile acid 4.3%-6.1%.
Cholic acid 0.8%-1.8%. deoxycholic acid 3.33%-4.3%, bile salt 3.3%-3.96%, total cholesterol 2.5%-4,
3%, aliphatic acid 1.0%-2.1%, lecithin 0.17%-0.2%, calcium 2.3%-2.5%, other also contain iron, potassium, sodium, magnesium,
Copper, molybdenum ion are below the extracting method of each important component：
1, cholic acid molecules amount 408.6, solubility when 198 degrees Celsius, 15 degrees Celsius of fusing point in water is 0.28 grams per liter,
It is 30.56 grams per liters in ethanol；In production using bovine and sheep bile as raw material, using " alcohol crystal, which is dispelled, " to be extracted, operating procedure
For：
(1) it hydrolyzes, be acidified the sodium hydroxide that ox, sheep bile are added on to 1/10 amount, boil saponification in jacketed pan heating
18 hours or more, the water that evaporation is gone was continuously replenished in centre, and reaction terminates, and filtrate is saponification liquor；Wait for that saponification liquor cools down, in Bu Shi
It is filtered on funnel, under stiring, 30% dilute sulfuric acid, which is slowly added dropwise, makes pH value reach 2-3, and saponification liquor is placed in appearance by thick courage at this time
In device, add equivalent water to mix and boil Buddhist 10-20 juice acid and float on liquid layer, up to thick courage meter acid tide product after filtering, places it in container,
Make into granular precipitate, cooled and filtered, filter cake is washed with clear water repeatedly to neutrality, after taking out thousand, in 50-60 DEG C of air -oven
Middle drying obtains thick bile acid dry product to constant weight；
(2) it crystallizes, dry take thousand product of thick bile acid to put people to have in the reactor of flask, 0.75 times of 75% ethyl alcohol is added, add
Heat is back to solids and all dissolves, then adds people's 10%-15% activated carbons reflux decoloration 15-20 minutes, filters while hot；Filtrate
It is cooled to 0-5 degrees Celsius with ice-water bath, then is placed 4 hours or more, so that cattle and sheep bile acid crystallization is precipitated, then filters, is used in combination appropriate
Ethyl alcohol wash crystallization after draining, obtains cholic acid coarse crystallization；
(3) decolourize, it is refined above-mentioned coarse crystallization cholic acid is set again in decoloring reaction bottle, add 4 times of amounts of people 95% ethyl alcohol and
4%-5% activated carbons are heated to reflux decoloration 30-45 minutes, filter while hot；It is distilled to recover ethyl alcohol in the filtrate distiller of falling people, until
After total volume is the 1/4 of original volume, it first is cooled to room temperature with cold bath, is then cooled to 0-50 DEG C with ice-water bath, crystallization 4
After hour, vacuum filter, after draining, crystallizes and is washed 1-2 times with a small amount of 95% cold ethyl alcohol on a buchner funnel, drain again,
Knot product in 70 DEG C of vacuum drying chambers under it is dry to constant weight to get cattle and sheep bile acid fine work, yield 2%-3%.
2, deoxycholic acid molecular weight 302.6, readily soluble in ethyl alcohol and glacial acetic acid, slightly soluble in acetone is almost insoluble in water,
Operating procedure is：
(1) the alkalinity filter night after bile acid preparation will produce calcium cholates with calcium salt method sets in acid-resistant container, cools down at room temperature
It standing to 30 DEG C hereinafter, then, side is stirred, 15% hydrochloric acid of people is slowly added dropwise in side, and pH value is transferred to 1-2, stands 12-18 hours,
The viscous thick bile acid of paste of green is sunken to device bottom, takes out, and after being rinsed with water, is dried in vacuo up to bile acid crude；
(2) prepared by deoxycholic acid crude product, by bile acid:Solid sodium hydroxide：Water=1：1.5：9 weight ratio, first by water
Adding people's flask, then adds people's solid sodium hydroxide, shaking to sodium hydroxide is all dissolved, then adds human bile's acid crude, is fully shaken up,
It is heated to reflux saponification 16 hours or more, after reaction, is cooled to 15 DEG C at room temperature hereinafter, stratification；Top is gone in siphon
Weak yellow liquid, sediment, which supplements a small amount of water, makes dissolving, is acidified to pH=1-2 with 20% sulfuric acid under stiring, deoxycholic acid is thick
Product are suspended in liquid level in golden Huang, place 2 hours or more, filtering discards filtrate, and filter cake is placed in beaker, appropriate cold water is added
Mix, refilter, is used in combination proper amount of clear water to wash 1-2 times, filtering again is drained, and drying obtains deoxycholic acid crude product；
(3) it refines and above-mentioned crude product is placed in flask, add the ethyl acetate of 4 times of weight, 15% one 20% activated carbon, heat
Reflux decoloration 30-45 minutes, after being cooled to room temperature, filtering, filter cake adds 4 times of weight ethyl acetates again, is handled by upper method, obtains second
Secondary refined liquid, is so repeated once, and obtains third time and refines quilt；
(4) merge above-mentioned first, second and third ethyl acetate refined liquid, be placed in tool plug boiling flask；It is anhydrous to be added 20%
Sodium sulphate is vibrated 5-10 minutes, is then stood overnight at room temperature, to remove the moisture in ethyl acetate, next day filtering, filtrate
It moves in cucurbit, heating recovery ethyl acetate is precipitated to the 1/3-1/5 of original volume, crystallisation by cooling to there is a small amount of white solid object
After 8 hours, filters to doing, washed 1-2 times with appropriate ethyl acetate numerous, drained again, 70 degrees Celsius or less are dried under vacuum to perseverance
Weight is to get colourless deoxycholic acid fine work.
3, bilirubin also known as the red matter of courage, molecular weight 584.65,198-200 degrees Celsius of molten point is not soluble in water, dissolve in benzene,
, Wei Rong is in ethyl alcohol and ether, operating procedure in chloroform, chlorine extraction, carbon disulfide and lye：
(1) preparation of BILE PIGMENTS calcium salt, fresh pig gall meter add the 3-4 times of clear feelings saturated limewater measured, under constant stirring,
It is heated to boiling, Lao Qu Piao float on the red rope calcium salt of straw red courage of liquid level, are filtered with fine cloth immediately, obtain calcium salt, and mother liquor inclines through standing
It after removing supernatant liquor, precipitates and is filtered, be incorporated in calcium salt and take out the mother liquor after calcium salt and be used as producing deoxycholic acid；
(2) the primary acidification of calcium bilirubinate takes BILE PIGMENTS calcium salt, and half times of water is added to stir into paste, crosses 80 mesh sieve, is added
1% sodium hydrogensulfite is slowly added dropwise 1 under constant stirring：1 dilute hydrochloric acid makes pH1-2, stands 10 minutes, releases sour water,
Precipitation filtering；
(3) bilirubin sodium salt after-souring precipitation first plus a small amount of ethyl alcohol stir into paste, then again plus about 10 times amount
The ethyl alcohol of 90%-95% and 0.5% sodium hydrogensulfite adjust pH3-4, staticly settle 1 hour, Aspirate supernatant, bottom courage color
Rope is spent primary so that 10 times of amount ethyl alcohol washings are heavy again, sucks supernatant, and bottom BILE PIGMENTS is filtered with silk, content generally 30% with
On；
(4) it refines and takes crude bilirubin, the chloroforms of 4 times of amounts are added, in 35 degrees Celsius of refluxing extractions 3 hours, by chloroform layer
Upper layer residue is detached to extract 3-4 times repeatedly again:Until bilirubin is extracted to the greatest extent, chloroform extracted solution merges filtering, adds in filtrate few
Antioxidant is measured, chloroform to hematoidin crystals is distilled to recover and is precipitated, appropriate 95% ethyl alcohol is added, continues to distill, until boiling off solution
The chloroform of interior remnants filters remaining bilirubin ethanol solution, and one is respectively washed with 95% ethyl alcohol and distilled water of a small amount of low-grade fever
It is secondary, it is finally washed with absolute ethyl alcohol, is dried in vacuo, obtains refined bilirubin；
4, cholesterol molecule amount 386.67, is the main sterol in higher mammal body, and 148.5 degrees Celsius of fusing point is slightly soluble in
Water can be dissolved in alcohol, ether, xenon and imitate, acetone, and operating procedure is：
(1) acetone extraction takes fresh bone marrow, the impurity such as striping and the trace of blood to rub, and 3 times of amount acetone soaks is added, for the second time
2.5 times of amounts, 1.5 times of amounts of third time, 24 hours every time, are often stirred, and filtrate is collected in filtering and squeezing；
(2) concentration is distilled to recover acetone, until occurring a large amount of yellow solids in concentrate；
(3) ethyl alcohol dissolving yellow solid adds 95% ethyl alcohol of 10 times of amounts, and being heated to reflux makes dissolving, filtering；
(4) cold crystallization filtrate stands knot product and is precipitated, filter to obtain thick cholesterol crystal in 0-5 degrees Celsius of cooling；
(5) the thick cholesterol knot product of sour water solution add 5 times of 95% ethyl alcohol of amount and the sulfuric acid of 5%-6%, and it is small to be heated to reflux hydrolysis 8
When, solution filters out crystallization and is washed till neutrality with 95% ethyl alcohol in 0-5 degrees Celsius of crystallisation by cooling, filtering；
(6) ethyl alcohol recrystallization cholesterol knot product add 10 times of 95% ethyl alcohol measured and 3% activated carbon, are heated to reflux decoloration 1
Hour, heat preservation filtering is carried out, filtrate is in 0-5 degrees Celsius of crystallisation by cooling, and repeatedly three times, cholesterol crystal is filtered, is pressed dry,
After ethyl alcohol is removed in volatilization, it is dried in vacuo at 70-80 DEG C up to fine work cholesterol.
5, it according to the formula of calculus bovis factitius and quality requirement, accurately calculates and prepares various raw materials needed for a certain amount of finished product；
First bilirubin is dissolved in a small amount of organic solvent, adds cholic acid, cholesterol, inorganic salts and excipient etc. are uniformly mixed, very
Sky thousand is dry；Take out thousand dry objects；The de- radon cholic acid that full dose is added carries out ball milling, sieves with 100 mesh sieve, is packaged in brown bottle.
In summary：By the artificial extraction to important component in various cow-bezoars, by realizing cholic acid, deoxycholic acid, courage
Red pigment, the artificial extraction of cholesterol, and some other ingredient is added, and according to content of bilirubin 72%-76.5%, bile acid
4.3%-6.1%, cholic acid 0.8%-1.8%, deoxycholic acid 3.33%-4.3%, bile salt 3.3%-3.96%, total courage are solid
Alcohol 2.5%-4,3%, aliphatic acid 1.0%-2.1%, lecithin 0.17%-0.2%, the ratio of calcium 2.3%-2.5% are being added
After iron, potassium, sodium, magnesium, copper, molybdenum ion, the manual manufacture synthesis of cow-bezoar is realized.
The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention, for this field skill
For art personnel, it is clear that invention is not limited to the details of the above exemplary embodiments, and without departing substantially from the present invention spirit or
In the case of essential characteristic, the present invention can be realized in other specific forms, therefore, in all respects, should all incite somebody to action
Embodiment regards exemplary as, and is non-limiting, the scope of the present invention by appended claims rather than on state
Bright restriction, it is intended that including all changes that come within the meaning and range of equivalency of the claims in the present invention
It is interior.
In addition, it should be understood that although this specification is described in terms of embodiments, but not each embodiment is only wrapped
Containing an independent technical solution, this description of the specification is merely for the sake of clarity, and those skilled in the art should
It considers the specification as a whole, the technical solutions in the various embodiments may also be suitably combined, forms those skilled in the art
The other embodiment being appreciated that.
Claims (1)
1. a kind of calculus bovis factitius preparation method, which is characterized in that be made of following component by weight：The red content that feeds of courage
72%-76.5%, bile acid 4.3%-6.1%. cholic acid 0.8%-1.8%. deoxycholic acid 3.33%-4.3%, bile salt
3.3%-3.96%, total cholesterol 2.5%-4,3%, aliphatic acid 1.0%-2.1%, lecithin 0.17%-0.2%, calcium
2.3%-2.5%, also contains iron, potassium, sodium, magnesium, copper, molybdenum ion, and preparation method includes the following steps：
1. cholic acid molecules amount 408.6, solubility when 198 degrees Celsius, 15 degrees Celsius of fusing point in water is 0.28 grams per liter, in second
It is 30.56 grams per liters in alcohol；In production using bovine and sheep bile as raw material, using " alcohol crystal is dispelled, and " extraction, operating procedure are：
(1) it hydrolyzes, be acidified the sodium hydroxide (bile paste 1 that ox, sheep bile (or bile paste) are added on to 1/10 amount:1, separately plus water 9 divides),
Saponification 18 hours or more is boiled in jacketed pan (or in vial) heating, the water that evaporation is gone, reaction knot is continuously replenished in centre
Beam, filtrate are saponification liquor；It waits for that saponification liquor cools down, is filtered on a buchner funnel, under stiring, 30% dilute sulphur is slowly added dropwise
Acid makes pH value reach 2-3, and saponification liquor is placed in container by thick courage at this time, adds equivalent water to mix and boils Buddhist 10-20 juice acid and float on liquid layer, mistake
Up to thick courage meter acid tide product after filter, place it in container, make into granular precipitate, cooled and filtered, filter cake with clear water repeatedly
Washing is to neutrality, minute, after taking out thousand, dries to constant weight that obtain thick bile acid dry in the vacuum drying oven or air -oven of 50-60C
Product；
(2) it crystallizes, drying takes thousand product of thick bile acid to put people and is equipped in flask or reactor, 0.75 times of 75% ethyl alcohol, heating is added
It is back to solids all to dissolve, then adds people's 10%-15% activated carbons reflux decoloration 15-20 minutes, filter while hot；Filtrate ice
Water-bath cooling is to 0-5 degrees Celsius, then places 4 hours or more, so that cattle and sheep bile acid crystallization is precipitated, then filters, ethanol in proper amount is used in combination
Wash crystallization after draining, obtains cholic acid coarse crystallization；
(3) it decolourizes, refine and above-mentioned coarse crystallization cholic acid is set into 95% ethyl alcohol and 4%-5% that in decoloring reaction bottle adds 4 times of amounts of people again
Activated carbon is heated to reflux decoloration 30-45 minutes, filters while hot；It is distilled to recover ethyl alcohol in the filtrate distiller of falling people, until total volume is
Behind the 1/4 of original volume, it first is cooled to room temperature with cold bath, is then cooled to 0-50C with ice-water bath, after crystallizing 4 hours,
Vacuum filter on Buchner funnel, after draining, crystallization is washed 1-2 times with a small amount of 95% cold ethyl alcohol, is drained again, knot product are in 70C
Under in vacuum drying chamber it is dry to constant weight up to cattle and sheep bile acid fine work, yield 2%-3%.
2. deoxycholic acid molecular weight 302.6, readily soluble in ethyl alcohol and glacial acetic acid, slightly soluble in acetone is almost insoluble in water, operation
Step is：
(1) the alkalinity filter night after bile acid preparation will produce calcium cholates with calcium salt method sets in acid-resistant container, cooling and standings at room temperature
To 30C hereinafter, then, 15% hydrochloric acid of people is slowly added dropwise in side stirring, side, pH value is transferred to 1-2, stands 12-18 hours, green is viscous
The thick bile acid of paste is sunken to device bottom, takes out, and after being rinsed with water, is dried in vacuo up to bile acid crude；
(2) prepared by deoxycholic acid crude product, by bile acid:Solid sodium hydroxide：Water=1：1.5：9 weight ratio, first adds people by water
Flask, then add people's solid sodium hydroxide, shaking to sodium hydroxide is all dissolved, then adds human bile's acid crude, is fully shaken up, and is heated
Flow back saponification 16 hours or more, after reaction, is cooled to 15C at room temperature hereinafter, stratification；Siphon goes to top faint yellow
Liquid, sediment, which supplements a small amount of water, makes dissolving, is acidified to pH=1-2 with 20% sulfuric acid under stiring, and deoxycholic acid crude product is in
Golden Huang is suspended in liquid level, place 2 hours or more, filtering discards filtrate, and filter cake is placed in beaker, appropriate cold water is added to mix,
It refilters, is used in combination proper amount of clear water to wash 1-2 times, filtering again is drained, and drying obtains deoxycholic acid crude product；
(3) it refines and above-mentioned crude product is placed in flask, add the ethyl acetate of 4 times of weight, 15% one 20% activated carbon, heat reflux
Decoloration 30-45 minutes, after being cooled to room temperature, filtering, filter cake adds 4 times of weight ethyl acetates again, is handled by upper method, obtains second of essence
Liquid processed, is so repeated once, and obtains third time and refines quilt,
(4) merge above-mentioned first, second and third ethyl acetate refined liquid, be placed in tool plug boiling flask；20% anhydrous slufuric acid is added
Sodium is vibrated or is stirred 5-10 minutes, then stands overnight at room temperature, to remove the moisture in ethyl acetate, next day filtering, filter
Liquid moves in cucurbit, and heating recovery ethyl acetate is cold to there is a small amount of white solid object that (about to the 1/3-1/5 of original volume) is precipitated
But it after crystallizing 8 hours, filters to doing, is washed 1-2 times with appropriate ethyl acetate numerous, drained again, 70 degrees Celsius or less vacuum drying
To constant weight to get colourless deoxycholic acid fine work.
3. bilirubin also known as the red matter of courage, molecular weight 584.65, molten point 198-200 degrees Celsius of .3 is not soluble in water, dissolves in benzene, chlorine
, Wei Rong is in ethyl alcohol and ether, operating procedure in imitative, chlorine extraction, carbon disulfide and lye：
(1) preparation of BILE PIGMENTS calcium salt, fresh pig gall meter add the 3-4 times of clear feelings saturated limewater measured, under constant stirring, heating
To boiling, Lao Qu Piao float on the red rope calcium salt of straw red courage of liquid level, are filtered immediately with fine cloth, obtain calcium salt, and mother liquor is through on standing and inclining
It after layer clear liquid, precipitates and is filtered, be incorporated in calcium salt and take out the mother liquor after calcium salt and be used as producing deoxycholic acid；
(2) the primary acidification of calcium bilirubinate takes BILE PIGMENTS calcium salt, and half times of water is added to stir into paste, crosses 80 mesh sieve, 1% Asia is added
Niter cake is slowly added dropwise 1 under constant stirring：1 dilute hydrochloric acid makes pH1-2, stands 10 minutes, releases sour water, precipitated
Filter；
(3) the after-souring precipitation of bilirubin sodium salt is first plus a small amount of ethyl alcohol stirs into paste, then adds the 90%- of about 10 times of amounts again
95% ethyl alcohol and 0.5% sodium hydrogensulfite, adjust pH3-4, staticly settle 1 hour, Aspirate supernatant, bottom courage color rope again with
10 times of amount ethyl alcohol washings are heavy to spend primary, sucks supernatant, bottom BILE PIGMENTS silk filter or hang thousand the crude red rope of courage, content
Generally 30% or more,
(4) it refines and takes crude bilirubin, the chloroforms of 4 times of amounts are added, in 35 degrees Celsius of refluxing extractions 3 hours, by chloroform layer separation
Upper layer residue extracts 3-4 times repeatedly again:Until bilirubin is extracted to the greatest extent, chloroform extracted solution merges filtering, adds in filtrate a small amount of anti-
Oxygen agent is distilled to recover chloroform to hematoidin crystals and is precipitated, appropriate 95% ethyl alcohol is added, continues to distill, until boiling off residual in solution
Remaining bilirubin ethanol solution is filtered, respectively be washed once with 95% ethyl alcohol and distilled water of a small amount of low-grade fever, most by remaining chloroform
It is washed afterwards with absolute ethyl alcohol, is dried in vacuo, obtains refined bilirubin.
4. cholesterol molecule amount 386.67, is the main sterol in higher mammal body, 148.5 degrees Celsius of fusing point is slightly soluble in water, energy
It is dissolved in that alcohol, ether, xenon are imitative or acetone, operating procedure are：
(1) acetone extraction takes fresh or freezing brain or marrow, the impurity such as striping and the trace of blood to rub, and 3 times of amount acetone leachings are added
Stain, second of 2.5 times of amount, 1.5 times of amounts of third time 24 hours every time, often stir, and filtering and squeezing, collecting filtrate, (filter residue supplies
Extract lecithin use)；
(2) concentration is distilled to recover acetone, until occurring a large amount of yellow solids in concentrate；
(3) ethyl alcohol dissolving yellow solid adds 95% ethyl alcohol of 10 times of amounts, and being heated to reflux makes dissolving, filtering；
(4) cold crystallization filtrate stands knot product and is precipitated, filter to obtain thick cholesterol crystal in 0-5 degrees Celsius of cooling；
(5) the thick cholesterol knot product of sour water solution add 5 times of 95% ethyl alcohol of amount and the sulfuric acid of 5%-6%, are heated to reflux hydrolysis 8 hours, molten
Liquid filters out crystallization and is washed till neutrality with 95% ethyl alcohol in 0-5 degrees Celsius of crystallisation by cooling, filtering；
(6) ethyl alcohol recrystallization cholesterol knot product add 10 times of 95% ethyl alcohol measured and 3% activated carbon, are heated to reflux decoloration 1 hour,
Heat preservation filtering is carried out, filtrate is in 0-5 degrees Celsius of crystallisation by cooling, and repeatedly three times, cholesterol crystal is filtered, is pressed dry, volatilization
After removing ethyl alcohol, it is dried in vacuo up to fine work cholesterol in 70-80C.
5. according to the formula and quality requirement of calculus bovis factitius, accurately calculates and prepare various raw materials needed for a certain amount of finished product；First will
Bilirubin is dissolved in a small amount of organic solvent, adds cholic acid, cholesterol, and inorganic salts and excipient etc. are uniformly mixed, vacuum thousand
It is dry；Take out thousand dry objects；The de- radon cholic acid that full dose is added carries out ball milling, sieves with 100 mesh sieve, is packaged in brown bottle.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109180766A (en) * | 2018-09-12 | 2019-01-11 | 四川奇格曼药业有限公司 | A kind of extraction cholesterol technique |
| CN112656818A (en) * | 2021-01-14 | 2021-04-16 | 四川菲德力制药有限公司 | Artificial bezoar and preparation method thereof |
| CN113372253A (en) * | 2021-06-11 | 2021-09-10 | 吉林基蛋生物科技有限公司 | Extraction method and application of bilirubin |
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2018
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| Title |
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| 赵景联: "人工牛黄与制备技术", 《适用技术与发展》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109180766A (en) * | 2018-09-12 | 2019-01-11 | 四川奇格曼药业有限公司 | A kind of extraction cholesterol technique |
| CN112656818A (en) * | 2021-01-14 | 2021-04-16 | 四川菲德力制药有限公司 | Artificial bezoar and preparation method thereof |
| CN113372253A (en) * | 2021-06-11 | 2021-09-10 | 吉林基蛋生物科技有限公司 | Extraction method and application of bilirubin |
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