CN104188900A - Pachymaran injection and preparation method thereof - Google Patents
Pachymaran injection and preparation method thereof Download PDFInfo
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- CN104188900A CN104188900A CN201410332928.XA CN201410332928A CN104188900A CN 104188900 A CN104188900 A CN 104188900A CN 201410332928 A CN201410332928 A CN 201410332928A CN 104188900 A CN104188900 A CN 104188900A
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- pachyman
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- 238000002347 injection Methods 0.000 title claims abstract description 95
- 239000007924 injection Substances 0.000 title claims abstract description 95
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims abstract description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 53
- 238000010992 reflux Methods 0.000 claims abstract description 25
- 235000008599 Poria cocos Nutrition 0.000 claims abstract description 22
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims abstract description 17
- 229920000053 polysorbate 80 Polymers 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000008215 water for injection Substances 0.000 claims abstract description 13
- 238000000746 purification Methods 0.000 claims abstract description 7
- 235000019445 benzyl alcohol Nutrition 0.000 claims abstract description 6
- 239000000843 powder Substances 0.000 claims abstract description 5
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- 150000004676 glycans Chemical class 0.000 claims description 43
- 229920001282 polysaccharide Polymers 0.000 claims description 43
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 28
- 239000000243 solution Substances 0.000 claims description 28
- 238000001556 precipitation Methods 0.000 claims description 25
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
- 238000001035 drying Methods 0.000 claims description 24
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 22
- 244000197580 Poria cocos Species 0.000 claims description 21
- 239000006228 supernatant Substances 0.000 claims description 20
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- 239000007787 solid Substances 0.000 claims description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 12
- 238000009835 boiling Methods 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
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- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 238000001291 vacuum drying Methods 0.000 claims description 12
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- 238000004108 freeze drying Methods 0.000 claims description 8
- 239000002244 precipitate Substances 0.000 claims description 8
- 239000011780 sodium chloride Substances 0.000 claims description 8
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- 150000002148 esters Chemical class 0.000 claims description 4
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- 239000003814 drug Substances 0.000 abstract description 19
- 238000006243 chemical reaction Methods 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 10
- 239000007927 intramuscular injection Substances 0.000 abstract description 7
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Landscapes
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a pachymaran injection and a preparation method thereof. The injection comprises carboxymethyl pachymaran, water for injection, benzyl alcohol and Tween 80. Each milliliter of the injection comprises 2 mg of carboxymethyl pachymaran; and 10 mL of benzyl alcohol and Tween 80 is added in every 2 g of carboxymethyl pachymaran. The method comprises the steps of extracting poria cocos powder by refluxing and removing impurities to obtain pachymaran; then adding an organic solvent for modification and purification to obtain a carboxymethyl pachymaran pure product; and finally adding the water for injection, benzyl alcohol and Tween 80, thus obtaining the pachymaran injection. The injection is suitable for intramuscular injection, is good in drug absorption, has no irritant reaction, and is safe and reliable for use.
Description
Technical field
The present invention relates to a kind of pachyman injection and preparation method thereof.
Background technology
Poria (formal name used at school: Poria cocos (Schw.) Wolf.), medicinal part is the sclerotium of On Polyporaceae Poria.There is promoting diuresis to eliminate damp pathogen, spleen invigorating, the effect of calming the nerves.Can also be made into powdery and be used for the cleawhite pack of Ms hobby.Ancients claim that Poria is " god medicine " at 4 o'clock, because its effect is very extensive, regardless of the four seasons, by it and various compatibility of drugs, no matter cold, temperature, wind, all diseases that wets can be brought into play its unique effects.Poria sweet in the mouth, light, property are flat, be used as medicine there is promoting diuresis to eliminate damp pathogen, the function of strengthening the spleen stomach function regulating, mind tranquilizing and the heart calming.Modern medicine study: Poria energy enhancing human body immunity function, pachyman has obvious antitumor and protects the liver dirty effect.But deficiency and coldness essence is sliding or collapse of QI person avoids clothes.
Have in the market the exploitation of oral liquor of poria polysaccharide product, but do not see the exploitation of injection product.Practice shows, the activity of pachyman, because oral meeting is restricted, directly plays drug action and injection pachyman can directly enter human body by intravenous injection or lumbar injection, is that oral drug effect is incomparable.
Summary of the invention
One of the technical problem to be solved in the present invention, is to provide a kind of preparation method of pachyman injection, and its injection of preparing is applicable to intramuscular injection, and drug absorption is good, and nonirritant reaction is safe and reliable.
The present invention realizes one of above-mentioned technical problem like this:
A preparation method for pachyman injection, described method step is as follows:
The extraction of step 1, carboxymethyl pachyman, purification:
A, 60-100 DEG C is dried to the Indian Bread of the constant weight 4-6h that refluxes in apparatus,Soxhlet's, except Ester, the slag of getting it filled, wherein reflux, extract, solvent is ethyl acetate, reflux, extract, 2 ~ 3 times;
The medicinal residues of B, acquisition reflux, extract, 4-6h in boiling water bath in reflux, reflux, extract, 2 ~ 3 times, centrifuging and taking supernatant;
It is 10-15% that C, supernatant are concentrated into moisture content in Rotary Evaporators,, get supernatant and add ethanol precipitation polysaccharide except albumen by Severge method, 0-4 DEG C of refrigerator cold-storage spends the night, the centrifugal 10-15min taking precipitate of 3000-4000r/min, cold drying obtains water solublity Poria crude polysaccharides;
D, by obtained water solublity Poria crude polysaccharides successively with dehydrated alcohol, acetone, ether washing, cold drying obtains Poria time polysaccharide;
E, Poria time polysaccharide is added to sodium periodate oxidation 10-20min, pH 3～4 acidolysis 20-30mim, filter to obtain solid; Add NaOH aqueous solution dissolved solid, alkalization 40-120min, then add successively isopropyl alcohol, monoxone, 40-50 DEG C of rapid stirring is dissolved to sample in the pasty state, crosses leaching precipitation; Add dilute hydrochloric acid solution, vigorous stirring, adds 100% ethanol to filter, and gets precipitation again; To be precipitated and dissolved in distilled water, then by 95% ethanol precipitation of 3 times of distilled water amount volumes, spend the night, centrifuging and taking precipitation, cold drying obtains carboxymethyl pachyman crude product;
F, by carboxymethyl pachyman dissolving crude product in distilled water, first carry out DEAE-32 cellulose chromatography post, carry out again SephadesG-200 chromatographic column chromatography, by after chromatographic solution dialysis desalting, precipitate with 3 times of 95% ethanol of measuring volumes of dialysis solution again, spend the night, centrifuging and taking precipitation, lyophilization obtains white powder solids, is carboxymethyl pachyman sterling;
Step 2, the preparation of carboxymethyl pachyman injection
G, get carboxymethyl pachyman, add water for injection fully to dissolve, add injection active carbon to remove thermal source, fully stir 20-30min, after dissolving completely, be repeatedly filtered to clarification, get filtrate, in filtrate, add benzyl alcohol, Tween 80, 3000-4000r/min is centrifugal, and 10-15min gets supernatant, supernatant is with after water for injection standardize solution, be sub-packed in ampulla, every bottle of 2mL, hot-pressing processing 20-30min at 100 DEG C, cooling rear 4 DEG C of refrigerator cold-storages are preserved, after 48-52h, under light, check whether ampulla has precipitation, if any removing by filter, embedding again, 121 DEG C of high pressure moist heat sterilization 20-30min, be carboxymethyl pachyman injection
,every milliliter of injection is containing carboxymethyl pachyman 2mg.
Further, in described steps A, Indian Bread: ethyl acetate=1:200-220, i.e. 1g Indian Bread 200-220mL acetic acid ethyl dissolution, 80 DEG C of boiling points.
Further, in described step B, Indian Bread: water=1:250-300, i.e. 1g Indian Bread 250-300mL water dissolution, 100 DEG C of boiling points, centrifugal 3000-4000r/min, 10-15min.
Further, in described step C, Rotary Evaporators rotating speed 100-150r/min, 65-75 DEG C of water-bath; Severge method: add the chloroform of solution 1/5-1/4 volume, add again the n-butyl alcohol of 1/5-1/4 volume thereupon, concuss 10-15min, in triplicate, until albumen eliminates; The ethanol consumption of precipitation polysaccharide: 3 times of amount liquor capacities, 95% concentration; Cold drying temperature, below 40 DEG C, is carried out in vacuum drying oven.
Further, in described step D, dehydrated alcohol, acetone, ether washing consumption are 2-3 times of Poria crude polysaccharides, and 1g Poria crude polysaccharides washs with dehydrated alcohol, acetone, the ether of 2-3mL successively; Cold drying temperature, below 40 DEG C, is carried out in vacuum drying oven.
Further, in described step e, the NaOH aqueous solution of interpolation is 5-10 times of Poria crude polysaccharides, and 1g Poria crude polysaccharides dissolves with the NaOH of 5-10mL, concentration 1%; The NaOH consumption that the isopropyl alcohol amount of adding is same volume; Monoxone amount is the 15-20% of pachyman quality; Dilute hydrochloric acid solution addition is to reactant liquor and pH5-6; Cold drying temperature, below 40 DEG C, is carried out in vacuum drying oven.
Further, in described step F, DEAE-32 cellulose chromatography condition: 10*50cm, the NaCl solution gradient eluting of 0～4 moL/L, every 10 mL of flow velocity 0.5 mL/min. are 1 unit fraction collection; SephadesG-200 chromatography condition: the NaCl solution gradient eluting of 0～4 moL/L, every 10 mL of flow velocity 0.5 mL/min. are 1 unit fraction collection; Lyophilization condition: carry out in vacuum freeze drier.
Further, in described step G, the mass fraction of injection active carbon is 0.5%, and 0.5g active carbon is dissolved in the sterilized water of 100mL; Benzyl alcohol, Tween 80 that every 2g carboxymethyl pachyman adds are 10mL; Twice filtration all used the nylon filtering with microporous membrane of 0.22um.
Two of the technical problem to be solved in the present invention, is to provide a kind of pachyman injection, and this injection is applicable to intramuscular injection, and drug absorption is good, and nonirritant reaction is safe and reliable
The present invention realizes two of above-mentioned technical problem like this:
A kind of pachyman injection, described injection comprises carboxymethyl pachyman, water for injection, benzyl alcohol and Tween 80, wherein every milliliter of injection is containing carboxymethyl pachyman 2mg, and benzyl alcohol, Tween 80 that every 2g carboxymethyl pachyman adds are 10mL.
Tool of the present invention has the following advantages:
Practice shows, the activity of pachyman, because oral meeting is restricted, directly plays drug action and injection pachyman can directly enter human body by intravenous injection or lumbar injection, is that oral drug effect is incomparable.Extraction process of the present invention is extracted polysaccharide from Chinese medicine Poria, and carries out that carboxy methylation is structurally-modified, purification, improves its water solublity and biologic activity, prepares carboxymethyl pachyman injection.
Pachyman injection of the present invention is water solublity pachyman, meets state-promulgated pharmacopoeia regulation through its clarity test of evidence; PH7.2 ± 0.2; Under 4 DEG C of refrigerators or room temperature, deposit 6 months, all do not find that any solid separates out, mode of appearance meets state-promulgated pharmacopoeia requirement.Safety testing shows: hemopoietic, blood cell shape, hemopoietic function and liver, the renal function all harmless effect of injection to mice animal; Pachyman injection was injected after drug withdrawal a period of time, the tardy effect of non-toxic reaction and reversibility toxic reaction.Pyrogen inspection shows after thorough autoclaving sterilization, and this injection apyrogeneity matter existence is safe and reliable.Zest checkout facility shows that this injection is applicable to intramuscular injection, and drug absorption is good, and nonirritant reaction is safe and reliable.Therefore, pachyman injection of the present invention is safe and effective, can, for clinical medicine, particularly aspect chemotherapy of tumors, play auxiliary therapeutic action.
Detailed description of the invention
The present invention relates to a kind of preparation method of pachyman injection, described method step is as follows:
The extraction of step 1, carboxymethyl pachyman, purification:
A, 60-100 DEG C is dried to the Indian Bread of the constant weight 4-6h that refluxes in apparatus,Soxhlet's, except Ester, the slag of getting it filled, wherein reflux, extract, solvent is ethyl acetate, reflux, extract, 2 ~ 3 times;
The medicinal residues of B, acquisition reflux, extract, 4-6h in boiling water bath in reflux, reflux, extract, 2 ~ 3 times, centrifuging and taking supernatant;
It is 10-15% that C, supernatant are concentrated into moisture content in Rotary Evaporators,, get supernatant and add ethanol precipitation polysaccharide except albumen by Severge method, 0-4 DEG C of refrigerator cold-storage spends the night, the centrifugal 10-15min taking precipitate of 3000-4000r/min, cold drying obtains water solublity Poria crude polysaccharides;
D, by obtained water solublity Poria crude polysaccharides successively with dehydrated alcohol, acetone, ether washing, cold drying obtains Poria time polysaccharide;
E, Poria time polysaccharide is added to sodium periodate oxidation 10-20min, pH 3～4 acidolysis 20-30mim, filter to obtain solid; Add NaOH aqueous solution dissolved solid, alkalization 40-120min, then add successively isopropyl alcohol, monoxone, 40-50 DEG C of rapid stirring is dissolved to sample in the pasty state, crosses leaching precipitation; Add dilute hydrochloric acid solution, vigorous stirring, adds 100% ethanol to filter, and gets precipitation again; To be precipitated and dissolved in distilled water, then by 95% ethanol precipitation of 3 times of distilled water amount volumes, spend the night, centrifuging and taking precipitation, cold drying obtains carboxymethyl pachyman crude product;
F, by carboxymethyl pachyman dissolving crude product in distilled water, first carry out DEAE-32 cellulose chromatography post, carry out again SephadesG-200 chromatographic column chromatography, by after chromatographic solution dialysis desalting, precipitate with 3 times of 95% ethanol of measuring volumes of dialysis solution again, spend the night, centrifuging and taking precipitation, lyophilization obtains white powder solids, is carboxymethyl pachyman sterling;
Step 2, the preparation of carboxymethyl pachyman injection
G, get carboxymethyl pachyman, add water for injection fully to dissolve, add injection active carbon to remove thermal source, fully stir 20-30min, after dissolving completely, be repeatedly filtered to clarification, get filtrate, in filtrate, add benzyl alcohol, Tween 80, 3000-4000r/min is centrifugal, and 10-15min gets supernatant, supernatant is with after water for injection standardize solution, be sub-packed in ampulla, every bottle of 2mL, hot-pressing processing 20-30min at 100 DEG C, cooling rear 4 DEG C of refrigerator cold-storages are preserved, after 48-52h, under light, check whether ampulla has precipitation, if any removing by filter, embedding again, 121 DEG C of high pressure moist heat sterilization 20-30min, be carboxymethyl pachyman injection
,every milliliter of injection is containing carboxymethyl pachyman 2mg.
In described steps A, Indian Bread: ethyl acetate=1:200-220, i.e. 1g Indian Bread 200-220mL acetic acid ethyl dissolution, 80 DEG C of boiling points.
In described step B, Indian Bread: water=1:250-300, i.e. 1g Indian Bread 250-300mL water dissolution, 100 DEG C of boiling points, centrifugal 3000-4000r/min, 10-15min.
In described step C, Rotary Evaporators rotating speed 100-150r/min, 65-75 DEG C of water-bath; Severge method: add the chloroform of solution 1/5-1/4 volume, add again the n-butyl alcohol of 1/5-1/4 volume thereupon, concuss 10-15min, in triplicate, until albumen eliminates; The ethanol consumption of precipitation polysaccharide: 3 times of amount liquor capacities, 95% concentration; Cold drying temperature, below 40 DEG C, is carried out in vacuum drying oven.
In described step D, dehydrated alcohol, acetone, ether washing consumption are 2-3 times of Poria crude polysaccharides, and 1g Poria crude polysaccharides washs with dehydrated alcohol, acetone, the ether of 2-3mL successively; Cold drying temperature, below 40 DEG C, is carried out in vacuum drying oven.
In described step e, the NaOH aqueous solution of interpolation is 5-10 times of Poria crude polysaccharides, and 1g Poria crude polysaccharides dissolves with the NaOH of 5-10mL, concentration 1%; The NaOH consumption that the isopropyl alcohol amount of adding is same volume; Monoxone amount is the 15-20% of pachyman quality; Dilute hydrochloric acid solution addition is to reactant liquor and pH5-6; Cold drying temperature, below 40 DEG C, is carried out in vacuum drying oven.
In described step F, DEAE-32 cellulose chromatography condition: 10*50cm, the NaCl solution gradient eluting of 0～4 moL/L, every 10 mL of flow velocity 0.5 mL/min. are 1 unit fraction collection; SephadesG-200 chromatography condition: the NaCl solution gradient eluting of 0～4 moL/L, every 10 mL of flow velocity 0.5 mL/min. are 1 unit fraction collection; Lyophilization condition: carry out in vacuum freeze drier.
In described step G, the mass fraction of injection active carbon is 0.5%, and 0.5g active carbon is dissolved in the sterilized water of 100mL; Benzyl alcohol, Tween 80 that every 2g carboxymethyl pachyman adds are 10mL; Twice filtration all used the nylon filtering with microporous membrane of 0.22um.
The invention still further relates to a kind of pachyman injection prepared by above-mentioned preparation method, described injection comprises carboxymethyl pachyman, water for injection, benzyl alcohol and Tween 80, wherein every milliliter of injection is containing carboxymethyl pachyman 2mg, and benzyl alcohol, Tween 80 that every 2g carboxymethyl pachyman adds are 10mL.
Below in conjunction with specific embodiment, the present invention is further described.
A preparation method for pachyman injection, described method step is as follows:
The extraction of step 1, carboxymethyl pachyman, purification:
A, 105 DEG C are dried to the Indian Bread of the constant weight 6h that refluxes in apparatus,Soxhlet's, except Ester, the slag of getting it filled, wherein reflux, extract, solvent is ethyl acetate, reflux, extract, 2 times; Wherein, Indian Bread: ethyl acetate=1:200-220(m/v, i.e. 1g Indian Bread 200-220mL acetic acid ethyl dissolution), 80 DEG C of boiling points.
The medicinal residues of B, acquisition reflux, extract, 6h in boiling water bath in reflux, reflux, extract, 3 times, centrifuging and taking supernatant; Wherein, Indian Bread: water=1:250-300(m/v, i.e. 1g Indian Bread 250-300mL water dissolution), 100 DEG C of boiling points, centrifugal 4000r/min, 10min.
It is 15% that C, supernatant are concentrated into moisture content in Rotary Evaporators,, gets supernatant and adds ethanol precipitation polysaccharide except albumen by Severge method, 4 DEG C of refrigerator cold-storages spend the night, the centrifugal 10min taking precipitate of 4000r/min, cold drying obtains water solublity Poria crude polysaccharides, and its molecular weight is approximately 4.2 × 10
4da, degree of substitution by carboxymethyl is 0.639; Wherein, Rotary Evaporators rotating speed 100r/min, 75 DEG C of water-baths; Severge method: add the chloroform of solution 1/5 volume, add again the n-butyl alcohol of 1/5 volume thereupon, concuss 10min, in triplicate, until albumen eliminates; The ethanol consumption of precipitation polysaccharide: 3 times of amount liquor capacities, 95% concentration; Cold drying temperature, below 40 DEG C, is carried out in vacuum drying oven.
D, by obtained water solublity Poria crude polysaccharides successively with dehydrated alcohol, acetone, ether washing, cold drying obtains Poria time polysaccharide; Wherein, dehydrated alcohol, acetone, ether washing consumption are doubly (m/v, i.e. each organic solvent washing of 2-3mL for 1g Poria crude polysaccharides) of 2-3 of Poria crude polysaccharides; Cold drying temperature, below 40 DEG C, is carried out in vacuum drying oven.
E, Poria time polysaccharide is added to sodium periodate oxidation 20min, pH 3～4 acidolysis 30mim, filter to obtain solid; Add NaOH aqueous solution dissolved solid, alkalization 40-120min, then add successively isopropyl alcohol, monoxone, 50 DEG C of rapid stirrings are dissolved to sample in the pasty state, cross leaching precipitation; Add dilute hydrochloric acid solution, vigorous stirring, adds 100% ethanol to filter, and gets precipitation again; To be precipitated and dissolved in distilled water, then by the 95% ethanol precipitation with 3 times of distilled water amount volumes again, spend the night, centrifuging and taking precipitation, cold drying obtains carboxymethyl pachyman crude product; Wherein, the NaOH aqueous solution of interpolation is doubly (m/v, 1g Poria crude polysaccharides dissolves with the NaOH of 5-10mL) of 5-10 of Poria crude polysaccharides, concentration 1%; The NaOH consumption that the isopropyl alcohol amount of adding is same volume; Monoxone amount is 15% of pachyman quality; Dilute hydrochloric acid solution addition is to reactant liquor and pH5-6; Cold drying temperature, below 40 DEG C, is carried out in vacuum drying oven.
F, by carboxymethyl pachyman dissolving crude product in distilled water, first carry out DEAE-32 cellulose chromatography post, carry out again SephadesG-200 chromatographic column chromatography, by after chromatographic solution dialysis desalting, precipitate with 3 times of 95% ethanol of measuring volumes of dialysis solution again, spend the night, centrifuging and taking precipitation, lyophilization obtains white powder solids, is carboxymethyl pachyman sterling; Wherein, DEAE-32 cellulose chromatography condition: 10*50cm, the NaCl solution gradient eluting of 0～4 moL/L, every 10 mL of flow velocity 0.5 mL/min. are 1 unit fraction collection; SephadesG-200 chromatography condition: the NaCl solution gradient eluting of 0～4 moL/L, every 10 mL of flow velocity 0.5 mL/min. are 1 unit fraction collection; Lyophilization condition: carry out in vacuum freeze drier.
Step 2, the preparation of carboxymethyl pachyman injection
G, get carboxymethyl pachyman, add water for injection fully to dissolve, add injection active carbon to remove thermal source, fully stir 30min, after dissolving completely, be repeatedly filtered to clarification, get filtrate, in filtrate, add benzyl alcohol, Tween 80, 4000r/min is centrifugal, and 10min gets supernatant, supernatant is with after water for injection standardize solution, be sub-packed in ampulla, every bottle of 2mL, hot-pressing processing 20-30min at 100 DEG C, cooling rear 4 DEG C of refrigerator cold-storages are preserved, after 48-52h, under light, check whether ampulla has precipitation, if any removing by filter, embedding again, 121 DEG C of high pressure moist heat sterilization 20-30min, be carboxymethyl pachyman injection, every milliliter of injection is containing carboxymethyl pachyman 2mg, wherein, in described step G, injection active carbon 0.5%, (being that 0.5g active carbon is dissolved in the sterilized water of 100mL), benzyl alcohol, Tween 80 that every 2g carboxymethyl pachyman adds are 10mL, twice filtration all used the nylon filtering with microporous membrane of the nylon filtering with microporous membrane 0.22um of 0.22um.
Step 3, carboxymethyl pachyman injection character
Get the carboxymethyl pachyman injection preparing and observe, comprise its appearance color, clarity, pH and stability.Result shows: change product appearance faint yellow to yellow micro-aobvious opalescent liquid, shake is without precipitation; Clarity test meets state-promulgated pharmacopoeia regulation; PH7.2 ± 0.2; Under 4 DEG C of refrigerators or room temperature, deposit 6 months, all do not find that any solid separates out.
Step 4, the safety of carboxymethyl pachyman injection
Carry out white mice injection maximum tolerated dose test injection, result shows: by white mice 1kg/1mL dosage lumbar injection, without any bad clinical response, without the phenomena of mortality, drinking-water, appetite are normal in 14d, and spirit normally.
By basic, normal, high dosage group, 10 of clinical medicine dose times, 25 times and 50 times are carried out the subchronic toxicity test of pachyman injection, and mice by intraperitoneal injection is carried out in grouping, once a day, and 7d continuously.Observe 10 weeks always.Detection method for respectively the 2nd weekend and the 10th weekend tail vein blood, get blood with heparin sodium anticoagulant after, measure its hematological indices and blood parameters by the routine clinical method of inspection.Result shows: compared with normal saline matched group, the 2nd weekend, the 10th weekend, the blood parameters such as the hematological indices such as hemoglobin, erythrocyte, leukocyte and the differential leukocyte count of test group and total serum protein, albumin and globulin content are all without significant difference (P>0.05), illustrate that this product of injection can not cause mouse blood to learn the change of index, hemopoietic, blood cell shape, hemopoietic function and liver, the renal function all harmless effect of pachyman injection to mice animal.The testing result at the 10th weekend also illustrates, pachyman injection after injection drug withdrawal a period of time, the tardy effect of non-toxic reaction and reversibility toxic reaction.
The pyrogen of step 5, carboxymethyl pachyman injection checks
The pachyman injection of 37 DEG C is injected in healthy rabbits body by ear vein, detect rabbit body temperature every 6h, the body temperature situation of change of different time before and after the injection of contrast rabbit.Result shows: after test rabbit injection said preparation medicine, each body temperature detecting is substantially unchanged, and the total lift-off value of body temperature is less than 0.5 DEG C, illustrates that this injection apyrogeneity matter exists, safe and reliable after thorough autoclaving sterilization.
The zest inspection of step 6, carboxymethyl pachyman injection
Inject respectively pachyman injection and normal saline at leg muscle musculus quadriceps position, the left and right of rabbit, relatively two kinds of rabbit whether irritant reaction in injection site.Result shows: cut the muscle of two groups of injection sites, all do not find that rabbit has any clinical response, all do not occur the irritative responses such as edema, hyperemia, degeneration, scleroma and necrosis, illustrate that this injection is applicable to intramuscular injection, drug absorption is good, and nonirritant reaction is safe and reliable.
But because this product contains benzyl alcohol, be therefore not suitable for child's intramuscular injection.
Practice shows, the activity of pachyman, because oral meeting is restricted, directly plays drug action and injection pachyman can directly enter human body by intravenous injection or lumbar injection, is that oral drug effect is incomparable.Extraction process of the present invention is extracted polysaccharide from Chinese medicine Poria, and carries out that carboxy methylation is structurally-modified, purification, improves its water solublity and biologic activity, prepares carboxymethyl pachyman injection.
Pachyman injection of the present invention is water solublity pachyman, meets state-promulgated pharmacopoeia regulation through its clarity test of evidence; PH7.2 ± 0.2; Under 4 DEG C of refrigerators or room temperature, deposit 6 months, all do not find that any solid separates out, mode of appearance meets state-promulgated pharmacopoeia requirement.Safety testing shows: hemopoietic, blood cell shape, hemopoietic function and liver, the renal function all harmless effect of injection to mice animal; Pachyman injection was injected after drug withdrawal a period of time, the tardy effect of non-toxic reaction and reversibility toxic reaction.Pyrogen inspection shows after thorough autoclaving sterilization, and this injection apyrogeneity matter existence is safe and reliable.Zest checkout facility shows that this injection is applicable to intramuscular injection, and drug absorption is good, and nonirritant reaction is safe and reliable.Therefore, pachyman injection of the present invention is safe and effective, can, for clinical medicine, particularly aspect chemotherapy of tumors, play auxiliary therapeutic action.
Although more than described the specific embodiment of the present invention; but being familiar with those skilled in the art is to be understood that; our described specific embodiment is illustrative; instead of for the restriction to scope of the present invention; those of ordinary skill in the art are in equivalent modification and the variation done according to spirit of the present invention, all should be encompassed in the scope that claim of the present invention protects.
Claims (9)
1. a preparation method for pachyman injection, is characterized in that: described method step is as follows:
The extraction of step 1, carboxymethyl pachyman, purification:
A, 60-100 DEG C is dried to the Indian Bread of the constant weight 4-6h that refluxes in apparatus,Soxhlet's, except Ester, the slag of getting it filled, wherein reflux, extract, solvent is ethyl acetate, reflux, extract, 2 ~ 3 times;
The medicinal residues of B, acquisition reflux, extract, 4-6h in boiling water bath in reflux, reflux, extract, 2 ~ 3 times, centrifuging and taking supernatant;
It is 10-15% that C, supernatant are concentrated into moisture content in Rotary Evaporators,, get supernatant and add ethanol precipitation polysaccharide except albumen by Severge method, 0-4 DEG C of refrigerator cold-storage spends the night, the centrifugal 10-15min taking precipitate of 3000-4000r/min, cold drying obtains water solublity Poria crude polysaccharides;
D, by obtained water solublity Poria crude polysaccharides successively with dehydrated alcohol, acetone, ether washing, cold drying obtains Poria time polysaccharide;
E, Poria time polysaccharide is added to sodium periodate oxidation 10-20min, pH 3～4 acidolysis 20-30mim, filter to obtain solid; Add NaOH aqueous solution dissolved solid, alkalization 40-120min, then add successively isopropyl alcohol, monoxone, 40-50 DEG C of rapid stirring is dissolved to sample in the pasty state, crosses leaching precipitation; Add dilute hydrochloric acid solution, vigorous stirring, adds 100% ethanol to filter, and gets precipitation again; To be precipitated and dissolved in distilled water, then by 95% ethanol precipitation of 3 times of distilled water amount volumes, spend the night, centrifuging and taking precipitation, cold drying obtains carboxymethyl pachyman crude product;
F, by carboxymethyl pachyman dissolving crude product in distilled water, first carry out DEAE-32 cellulose chromatography post, carry out again SephadesG-200 chromatographic column chromatography, by after chromatographic solution dialysis desalting, precipitate with 3 times of 95% ethanol of measuring volumes of dialysis solution again, spend the night, centrifuging and taking precipitation, lyophilization obtains white powder solids, is carboxymethyl pachyman sterling;
Step 2, the preparation of carboxymethyl pachyman injection
G, get carboxymethyl pachyman, add water for injection fully to dissolve, add injection active carbon to remove thermal source, fully stir 20-30min, after dissolving completely, be repeatedly filtered to clarification, get filtrate, in filtrate, add benzyl alcohol, Tween 80, 3000-4000r/min is centrifugal, and 10-15min gets supernatant, supernatant is with after water for injection standardize solution, be sub-packed in ampulla, every bottle of 2mL, hot-pressing processing 20-30min at 100 DEG C, cooling rear 4 DEG C of refrigerator cold-storages are preserved, after 48-52h, under light, check whether ampulla has precipitation, if any removing by filter, embedding again, 121 DEG C of high pressure moist heat sterilization 20-30min, be carboxymethyl pachyman injection
,every milliliter of injection is containing carboxymethyl pachyman 2mg.
2. the preparation method of a kind of pachyman injection as claimed in claim 1, is characterized in that: in described steps A, and Indian Bread: ethyl acetate=1:200-220, i.e. 1g Indian Bread 200-220mL acetic acid ethyl dissolution, 80 DEG C of boiling points.
3. the preparation method of a kind of pachyman injection as claimed in claim 1, is characterized in that: in described step B, and Indian Bread: water=1:250-300, it is 1g Indian Bread 250-300mL water dissolution, 100 DEG C of boiling points, centrifugal 3000-4000r/min, 10-15min.
4. the preparation method of a kind of pachyman injection as claimed in claim 1, is characterized in that: in described step C, and Rotary Evaporators rotating speed 100-150r/min, 65-75 DEG C of water-bath; Severge method: add the chloroform of solution 1/5-1/4 volume, add again the n-butyl alcohol of 1/5-1/4 volume thereupon, concuss 10-15min, in triplicate, until albumen eliminates; The ethanol consumption of precipitation polysaccharide: 3 times of amount liquor capacities, 95% concentration; Cold drying temperature, below 40 DEG C, is carried out in vacuum drying oven.
5. the preparation method of a kind of pachyman injection as claimed in claim 1, it is characterized in that: in described step D, dehydrated alcohol, acetone, ether washing consumption are 2-3 times of Poria crude polysaccharides, and 1g Poria crude polysaccharides washs with dehydrated alcohol, acetone, the ether of 2-3mL successively; Cold drying temperature, below 40 DEG C, is carried out in vacuum drying oven.
6. the preparation method of a kind of pachyman injection as claimed in claim 1, is characterized in that: in described step e, the NaOH aqueous solution of interpolation is 5-10 times of Poria crude polysaccharides, and 1g Poria crude polysaccharides dissolves with the NaOH of 5-10mL, concentration 1%; The NaOH consumption that the isopropyl alcohol amount of adding is same volume; Monoxone amount is the 15-20% of pachyman quality; Dilute hydrochloric acid solution addition is to reactant liquor and pH5-6; Cold drying temperature, below 40 DEG C, is carried out in vacuum drying oven.
7. the preparation method of a kind of pachyman injection as claimed in claim 1, it is characterized in that: in described step F, DEAE-32 cellulose chromatography condition: 10*50cm, the NaCl solution gradient eluting of 0～4 moL/L, every 10 mL of flow velocity 0.5 mL/min. are 1 unit fraction collection; SephadesG-200 chromatography condition: the NaCl solution gradient eluting of 0～4 moL/L, every 10 mL of flow velocity 0.5 mL/min. are 1 unit fraction collection; Lyophilization condition: carry out in vacuum freeze drier.
8. the preparation method of a kind of pachyman injection as claimed in claim 1, is characterized in that: in described step G, the mass fraction of injection active carbon is 0.5%, and 0.5g active carbon is dissolved in the sterilized water of 100mL; Benzyl alcohol, Tween 80 that every 2g carboxymethyl pachyman adds are 10mL; Twice filtration all used the nylon filtering with microporous membrane of 0.22um.
9. a pachyman injection, it is to be prepared from by the preparation method of a kind of pachyman injection described in claim 1 ~ 8 any one, it is characterized in that: described injection comprises carboxymethyl pachyman, water for injection, benzyl alcohol and Tween 80, wherein every milliliter of injection is containing carboxymethyl pachyman 2mg, and benzyl alcohol, Tween 80 that every 2g carboxymethyl pachyman adds are 10mL.
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| CN107279648A (en) * | 2017-07-17 | 2017-10-24 | 怀化学院 | Poria cocos solid-state making drinks and preparation method thereof |
| CN109805233A (en) * | 2019-03-07 | 2019-05-28 | 湖南补天药业股份有限公司 | A kind of Poria cocos beverage and preparation method thereof with promotion efficacy of immunity |
| CN109876005A (en) * | 2019-03-15 | 2019-06-14 | 湖南补天药业股份有限公司 | A kind of tuckahoe effervescence tablet and preparation method thereof |
| CN112225831A (en) * | 2020-11-03 | 2021-01-15 | 华中农业大学 | Active pachyman, preparation method and application thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107279648A (en) * | 2017-07-17 | 2017-10-24 | 怀化学院 | Poria cocos solid-state making drinks and preparation method thereof |
| CN109805233A (en) * | 2019-03-07 | 2019-05-28 | 湖南补天药业股份有限公司 | A kind of Poria cocos beverage and preparation method thereof with promotion efficacy of immunity |
| CN109876005A (en) * | 2019-03-15 | 2019-06-14 | 湖南补天药业股份有限公司 | A kind of tuckahoe effervescence tablet and preparation method thereof |
| CN112225831A (en) * | 2020-11-03 | 2021-01-15 | 华中农业大学 | Active pachyman, preparation method and application thereof |
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