CN1772089B - Freeze dried oldenlandia powder for injection and its preparation method - Google Patents
Freeze dried oldenlandia powder for injection and its preparation method Download PDFInfo
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- CN1772089B CN1772089B CN 200510115179 CN200510115179A CN1772089B CN 1772089 B CN1772089 B CN 1772089B CN 200510115179 CN200510115179 CN 200510115179 CN 200510115179 A CN200510115179 A CN 200510115179A CN 1772089 B CN1772089 B CN 1772089B
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Abstract
The freeze dried oldenlandia powder for injection consists of oldenlandia extract as main material 20-140 weight portions, supplementary material including mannitol 80-200 weight portions, Tween-80 20-100 weight portions and sodium bisulfite 1-6 weight portions, and proper amount of water for injection. The preparation process includes mixing the materials in the weight proportion via stirring todissolve, adding active carbon for injection in 0.1-1 wt%, regulating pH to 6.0-7.0, filtering with 0.4 and 0.22 micron microporous filtering membrane, packing, and freeze drying at 5-10 Pa inside the freeze drying case. The freeze dried oldenlandia powder for injection is used in treating various kinds of inflammation, post-operational infection, etc. as well as the assisting treatment of cancer.
Description
Technical field
The present invention relates to utilize made pharmaceutical preparation of the extract of vegetable material and preparation method thereof, more specifically say so, belong to the field of Chinese medicines with made lyophilized injectable powder of Herba Hedyotidis Diffusae extract and preparation method thereof.
Background technology
Chinese crude drug Herba Hedyotidis Diffusae genus rubia section annual herb plant, the herb of Herba Hedyotidis Diffusae--Oldenlan-diadiffusa. (Willd.) Roxd..The another name Herba Hedyotidis Diffusae is distributed widely in areas to the south, China the Changjiang river, is born in limit, field, field and wilderness, contains the chemical compound of abundant organic germanium, flavone, polyphenol, immune polysaccharide, ursolic acid etc.The medical material character: herb is wound in lumps, celadon or taupe, and stem is slim and frahile, and is cylindrical, and branch is arranged.Leaf is to life, nearly stockless, and normal shrinkage, fragmentation or come off, it is linear that intact leaves flattens rear blade, grows 1～2 centimetre or mistake; Long about 0.1 centimetre of stipule.Flower or the normal single leave axil of capsule, floral white, capsule is little, oblate spheroid.Feeble QI, mildly bitter flavor., color grayish green person many with leaf is good.Nature and flavor and function: cold in nature, mildly bitter flavor, little sweet, cold, GUIXIN, liver, spleen channel.
Herba Hedyotidis Diffusae has the function of heat-clearing and toxic substances removing, inducing diuresis to remove edema, promoting blood circulation and stopping pain with the herb hyoscine.Cure mainly diseases such as malignant tumor, appendicitis, hepatitis, respiratory tract infection, bronchitis, tonsillitis, laryngitis, pneumonia, cholecystitis, appendicitis, urinary system infection, pelvic inflammatory disease, adnexitis and post-operative infection; Furuncle carbuncle, venom are controlled in external.The clinical multiple cancers such as gastric cancer, the esophageal carcinoma, intestinal cancer, uterus carcinoma, nasopharyngeal carcinoma that are used for the treatment of of modern Chinese medicine.
The medicament that contains Herba Hedyotidis Diffusae now on the market is more, such as the Herba Hedyotidis Diffusae aqueous injection that is prepared from according to the preparation method that provides among the drug standard WS3-B-3176-98 promulgated by the ministries or commissions of the Central Government, has heat-clearing and toxic substances removing, inducing diuresis and reducing edema effect, be used for the treatment of damp and hot respiratory tract infection of accumulateing due to the poison, diseases such as tonsillitis, pneumonia, cholecystitis, appendicitis, carbuncle furuncle abscess and post-operative infection, the pure Chinese medicine aqueous injection that also can be used for assistant treating cancer, through clinical verification, determined curative effect is the common drug that clinical and family is used for the treatment of this type of disease.
Because the influence that existing aqueous injection is prepared technical limitations and Chinese medicinal ingredients complexity, the Chinese medicine aqueous injection often is easy to generate acute allergic reaction or untoward reaction, puts easy precipitation for a long time, increases shortcomings such as pain during injection.And aqueous injection in use also more inconvenience: 1, purity is low, dosage is inaccurate; 2, need to take out in practical operation more and use liquid, preparation very easily infects thermal source or by germ contamination; 3, in actual clinical, various disease conditions requires to reduce the patient infusion amount, and aqueous injection then can't solve; 4, in cold season, particularly in the north and the transportation of extremely frigid zones and storage all have an inconvenience; 5, liquid preparation breakage very easily causes cross-contamination to packing and inner packing; 6, range of application is narrower.
In addition, the oral formulations of most drug, oral formulations such as Herba Hedyotidis Diffusae, have all that purity is low, side effect is big, dissolve scattered time limit is long, dissolution is low, problem such as absorbance difference, liver sausage first pass effect and bioavailability are lower, thereby influence the performance of drug effect, also directly affect therapeutic effect.Simultaneously, conventional peroral dosage form, regular meeting produces bigger dust pollution in preparation process, can staff's health be worked the mischief to a certain extent, also can cause certain pollution to environment simultaneously.The production technology of conventional oral formulations is also complicated, and production cost is higher, thereby patient's drug cost is also improved thereupon, is unfavorable for improving the ability of seeking medical advice of extensive patients, also is unfavorable for improving the general health level of society.
Lyophilized injectable powder because of it has plurality of advantages such as the storage time is long, easy to use, has been subjected to the trust of manufacturer of drugs, hospital deeply since using.But be not the former medicine injectable powder that all suits to make, and preparation technology, technology of preparing etc. are comparatively complicated, so also do not have the lyophilized injectable powder of Herba Hedyotidis Diffusae extract to emerge on the market now.Through applicant retrieval, just there are two patent applications that contain hedyotis herba powder injection to disclose at present, application number is 200510042044.1 and 200510055292.X.Though it is now comparatively similar to the present invention, but the present invention has not only solved problems such as the extraction, injectable powder preparation of Herba Hedyotidis Diffusae extract, and, make that the aspect such as active constituent content, quality stability, therapeutic effect, result of use of this injectable powder is all even better because of the particularity of extraction of the present invention, preparation method.
Summary of the invention
The object of the present invention is to provide the lyophilized injectable powder that contains Herba Hedyotidis Diffusae extract that a kind of active constituent content is higher, stability is better, dissolution velocity is faster, therapeutic effect is more excellent.
Another object of the present invention is to provide a kind of preparation method that contains the Herba Hedyotidis Diffusae extract lyophilized injectable powder.
The consumption of lyophilized injectable powder drug component of the present invention is groped to sum up to draw through the inventor in a large number, and each amounts of components all has curative effect preferably in the following weight parts scope:
One, major ingredient
Herba Hedyotidis Diffusae extract 20-140 part
Preferably:
28 parts of Herba Hedyotidis Diffusae extracts
The said extracted thing can adopt following method to be prepared:
Get clean, dried Herba Hedyotidis Diffusae 1000g is ground into the 20-40 coarse powder, uses 70-90%, preferred 80% ethanol 2000ml makes solvent, heating and refluxing extraction 3-5 time, preferred 4 times, each 1-2h, preferred 1.5h, merge extractive liquid,, cold preservation 8-12 hour, centrifugal, collect supernatant, join in the polyamide resin column, the adjusting flow velocity is 2-4ml/min, preferred 3ml/min, with distilled water flush away impurity, with 70-90%, preferred 80% ethanol is the mobile phase desorption, reclaim ethanol, regulate pH value to 2-4, left standstill 8-12 hour with the 40-60% sulfuric acid solution, filter, filtrate reuse 30-50%NaOH solution transfers pH value to neutral, adds 70-90%, preferred 80% ethanol 1000-3000ml, preferred 2000ml, cold preservation 8-12 hour, filter, filtrate decompression is concentrated into 200-400ml, preferred 300ml, each 2-8% that uses, preferred 5% sodium carbonate liquor 500ml heating is dissolved 4-6 time repeatedly, preferred 5 times, filtered while hot, filtrate adds hydrochloric acid, and the adjusting pH value is 1-3, put the precipitation that cold leaching is separated out, vacuum drying gets final product.Wherein Herba Hedyotidis Diffusae extract is with rutin (C
27H
30O
16) meter contain the 5-8% total flavones, preferably contain 7.1% total flavones.
Two, adjuvant
Mannitol 80-200 part
Tween 80 20-100 part
Sodium sulfite 1-6 part
Sterilized water for injection is an amount of
Preferably:
150 parts in mannitol
40 parts of tween 80s
2 parts of sodium sulfitees
Sterilized water for injection is an amount of
The prepared of medicament freeze-drying injectable powder of the present invention:
It is fixed that main ingredient is accurately claimed, stirring makes it all dissolvings fully, add 0.1-1%, preferred 0.5% pin activated carbon fully stirs, use 30-50%, preferred 40% sodium hydroxide solution, the adjusting pH value is 6.0-7.0, preferred pH value is 6.5, with the microporous filter membrane decarburization filtration of 0.4 μ and 0.22 μ and aseptic filtration, packing, change freeze drying box behind the false add plug over to and carry out lyophilization.
The filtrate temperature of putting into freeze drying box is reduced to rapidly-30--55 ℃ after, preferably-42 ℃, form frozen block, start the vacuum pump evacuation, at 5-10Pa, under the condition of preferred 8Pa, the temperature of frozen block is risen to-25--32 ℃, preferred-28 ℃, with 0.5-1.5 ℃/1.5 hours, preferred 1.0 ℃/1.5 hours programming rate rises to-22--15 ℃ after, be preferably-18 ℃, again with 3-5 ℃/hour, preferred 4 ℃/hour programming rate rises to 25-40 ℃, be preferably 32 ℃, under 25-40 ℃ temperature, preferred 32 ℃ of insulations 5-20 hour, preferred 13 hours, making the contained moisture content of lyophilized injectable powder is Herba Hedyotidis Diffusae extract, the 1-6% of adjuvant gross weight, preferred 3.5%, can go out machine and roll lid.
The resulting product specification is propped up for containing total flavones 1-11.2mg/.
Medicament freeze-drying injectable powder of the present invention meets the injection check criteria, and is safe in utilization, stable in properties, and check result is as follows:
PH value is checked: get lyophilized powder, add the injection water, be mixed with injection, pH value is 6.0-7.0.
Clarity test: get lyophilized powder, add the injection water, be mixed with injection, sampling, visual, do not see foreign body.
Bacterial endotoxin is measured: check according to two appendix XI of Chinese Pharmacopoeia version in 2000 E, contain the amount of bacterial endotoxin less than 5EU among the every 1mL of injection of the present invention.
The undue toxicity measures: check no abnormality seen according to two appendix XI of Chinese Pharmacopoeia version in 2000 C intravenous injection.
Protein is checked: get lyophilized powder, add the injection water, be mixed with injection.Get 1ml, add freshly prepared 30% sulfosalicylic acid test solution 1ml, mix and place 5min, do not occur muddy.
Acute toxicity test: the LD50 of mice (median lethal dose(LD 50)) is 129 ± 0.15mg/kg scale of construction.
Chronic toxicity test: give dosage successive administration that each experimental group Mus press 9mg/kg, 12mg/kg after 90 days, put to death and respectively organize experiment mice, check its platelet, hemocyte, cardiac function, hepatic and renal function and histopathological examination, no abnormal situation generation.
Medicament freeze-drying injectable powder stability test result of the present invention is good.
Medicament freeze-drying injectable powder of the present invention has heat-clearing and toxic substances removing, and is inducing diuresis and reducing edema, is used for damp and hot respiratory tract infection, tonsillitis, pneumonia, cholecystitis, appendicitis, carbuncle furuncle abscess and the post-operative infection that accumulates due to the poison, also can be used for assistant treating cancer.
The amount of application of medicine of the present invention can be according to variations such as route of administration, pill taker's age, body weight, and its daily dose can be the 0.01-12mg/kg body weight, and preferred 1-6mg/kg body weight can be used by one or many.
The lyophilized injectable powder of medicine of the present invention is a Herba Hedyotidis Diffusae extract, adds other adjuvant again and forms.Adjuvant can be acceptable various adjuvants on the pharmaceutics.Because Herba Hedyotidis Diffusae extract has heat-clearing and toxic substances removing, inducing diuresis and reducing edema effect so the lyophilized injectable powder of its compositions is with the injectable sterile powder of lyophilization principle preparation, is the freeze-dried powder dosage form, compared with prior art, possesses following advantage:
1, preparation technology is simple, and process is easy to control; 2, dissolution velocity is fast, the purity height, and side effect is little, determined curative effect; 3, good stability, effect duration is long, and physical stability is temperature influence not; 4, accurately also visual sentiment is whole for dosage, can accomplish accurate administration; 5, finished product preparation is a solid preparation, and volume is little, is convenient to transportation and preservation; 6, overcome aqueous injection and put sedimentary shortcoming for a long time, patient's pain in the time of alleviating injection; 7, accurate controlled quentity controlled variable has reduced patient's amount of infusion, and many disease kinds that require amount of liquid clinically (as heart failure etc.) are obtained medical treatment, and has alleviated patient's burden; 8, solved the cross-contamination issue of damaged back product; 9, the transportation and the storage problem in the north and cold district winter have been solved; 10, applied range, it is many to be suitable for disease, also can provide the intravenous drip administration.
The specific embodiment:
The following examples can make the professional and technical personnel understand the present invention comprehensively, better, but cannot limit the present invention by any way:
The preparation of embodiment 1 medicament freeze-drying injectable powder of the present invention
One, major ingredient
Herba Hedyotidis Diffusae extract 28mg (containing the 2mg total flavones)
Its preparation can be adopted following method
Get clean, dried Herba Hedyotidis Diffusae 1000g, be ground into 30 order coarse powder, make solvent, heating and refluxing extraction 4 times, each 1.5h with 80% ethanol 2000ml.Merge extractive liquid,, cold preservation 10 hours, centrifugal, collect supernatant, join in the polyamide resin column, the adjusting flow velocity is 3ml/min, with distilled water flush away impurity, be the mobile phase desorption with 80% ethanol, reclaim ethanol, regulate pH value to 3 with 50% sulfuric acid solution, left standstill 10 hours, filter, filtrate reuse 40%NaOH solution transfers pH value to neutral, adds 80% ethanol 2000ml, cold preservation 10 hours, filter, filtrate decompression is concentrated into 300ml, heats with 5% sodium carbonate liquor 500ml at every turn, dissolve repeatedly 5 times, filtered while hot, filtrate adds hydrochloric acid, and regulating pH value is 2, put the precipitation that cold leaching is separated out, vacuum drying promptly gets Herba Hedyotidis Diffusae extract 4g, is pale yellow powder.
" assay "
The preparation precision of reference substance solution takes by weighing rutin standard substance (Chinese pharmaceutical biological product identifies that institute provides) 10mg, put in the 50ml measuring bottle, add an amount of 70% ethanol, put that slight fever makes dissolving in the water-bath, put cold, add 70% ethanol dilution to scale, shake up, promptly get (containing anhydrous rutin 0.2mg among every 1ml).
The preparation precision of standard curve is measured titer 0.0,1.0,2.0,3.0,4.0,5.0 and 6.0ml, put respectively in the 25ml measuring bottle, respectively add 70% ethanol to 6ml, add 5% sodium nitrite solution 1ml, shake up, placed 15 minutes, according to spectrophotography (appendix VB of Chinese Pharmacopoeia version in 2000), wavelength place at 507nm measures trap, is that vertical coordinate, concentration are abscissa with the trap, the drawing standard curve.
The algoscopy precision is measured this product 1 gram, uses the 50ml water elution, discards eluent, use 70% ethanol elution, collect the about 25ml of eluent, put in the 25ml measuring bottle, add 70% ethanol dilution to scale, shake up, precision is measured 5ml respectively, puts first, in two 25ml measuring bottles of second, add 5% sodium nitrite solution 1ml in the first bottle, shake up, placed 6 minutes, and added 10% aluminum nitrate solution 1ml, shake up, placed 6 minutes, in first, each hydro-oxidation sodium test solution 10ml in two bottles of the second adds ethanol dilution again to scale, shakes up, placed 15 minutes, according to spectrophotography (appendix VB of Chinese Pharmacopoeia version in 2000), be blank with the second bottle, measure trap at the wavelength place of 507nm, read the content of rutin the need testing solution from standard curve, be 2.8mg/ml.
As calculated, contain total flavones with rutin (C in per 1 gram of this product
27H
30O
16) count 71mg, content is 7.1%.
Two, adjuvant
Mannitol 150mg
Tween 80 40mg
Sodium sulfite 2mg
Sterilized water for injection is an amount of
The prepared of Hedyotidis Diffusae lyophilized injectable powder
It is fixed that main ingredient is accurately claimed, stirs and make it whole dissolvings fully, adds 0.5% pin activated carbon, fully stir, use 40% sodium hydroxide solution, regulating pH value is 6.5, with microporous filter membrane decarburization filtration and the aseptic filtration of 0.4 μ and 0.22 μ, packing, change freeze drying box behind the false add plug over to and carry out lyophilization.
Make put into freeze drying box the temperature of filtrate filtered reduced to-42 ℃ rapidly after, form frozen block, start the vacuum pump evacuation, under the condition of 8Pa, the temperature of frozen block is risen to-28 ℃, rise to-18 ℃ with 1.0 ℃/1.5 hours programming rates after, rise to 32 ℃ with 4 ℃/hour programming rate again, insulation is 13 hours under 32 ℃ temperature, and making the contained moisture content of lyophilized injectable powder is 3.5% of Herba Hedyotidis Diffusae extract, adjuvant gross weight, can go out machine and roll lid.
Resulting product specification general flavone content is that 2mg/ props up.
The preparation of embodiment 2 medicament freeze-drying injectable powder of the present invention
One, major ingredient
Herba Hedyotidis Diffusae extract 56mg (containing the 4mg total flavones)
Its preparation can be adopted following method
Get clean, dried Herba Hedyotidis Diffusae 1000g, be ground into 30 order coarse powder, make solvent, heating and refluxing extraction 4 times, each 1.5h with 80% ethanol 2000ml.Merge extractive liquid,, cold preservation 10 hours, centrifugal, collect supernatant, join in the polyamide resin column, the adjusting flow velocity is 3ml/min, with distilled water flush away impurity, be the mobile phase desorption with 80% ethanol, reclaim ethanol, regulate pH value to 3 with 50% sulfuric acid solution, left standstill 10 hours, filter, filtrate reuse 40%NaOH solution transfers pH value to neutral, adds 80% ethanol 2000ml, cold preservation 10 hours, filter, filtrate decompression is concentrated into 300ml, heats with 5% sodium carbonate liquor 500ml at every turn, dissolve repeatedly 5 times, filtered while hot, filtrate adds hydrochloric acid, and regulating pH value is 2, put the precipitation that cold leaching is separated out, vacuum drying promptly gets Herba Hedyotidis Diffusae extract 4g, is pale yellow powder.
" assay "
The preparation of the preparation standard curve of reference substance solution prepares with the standard curve among the embodiment 1.
The algoscopy precision is measured this product 1 gram, uses the 50ml water elution, discards eluent, use 70% ethanol elution, collect the about 25ml of eluent, put in the 25ml measuring bottle, add 70% ethanol dilution to scale, shake up, precision is measured 5ml respectively, puts first, in two 25ml measuring bottles of second, add 5% sodium nitrite solution 1ml in the first bottle, shake up, placed 6 minutes, and added 10% aluminum nitrate solution 1ml, shake up, placed 6 minutes, in first, each hydro-oxidation sodium test solution 10ml in two bottles of the second adds ethanol dilution again to scale, shakes up, placed 15 minutes, according to spectrophotography (appendix VB of Chinese Pharmacopoeia version in 2000), be blank with the second bottle, measure trap at the wavelength place of 507nm, read the content of rutin the need testing solution from standard curve, be 2.8mg/ml.
As calculated, contain total flavones with rutin (C in per 1 gram of this product
27H
30O
16) count 71mg, content is 7.1%.
Two, adjuvant
Mannitol 200mg
Tween 80 80mg
Sodium sulfite 4mg
Sterilized water for injection is an amount of
The prepared of Hedyotidis Diffusae lyophilized injectable powder
It is fixed that main ingredient is accurately claimed, stirs and make it whole dissolvings fully, adds 0.5% pin activated carbon, fully stir, use 40% sodium hydroxide solution, regulating pH value is 6.5, with microporous filter membrane decarburization filtration and the aseptic filtration of 0.4 μ and 0.22 μ, packing, change freeze drying box behind the false add plug over to and carry out lyophilization.
Make put into freeze drying box the temperature of filtrate filtered reduced to-42 ℃ rapidly after, form frozen block, start the vacuum pump evacuation, under the condition of 8Pa, the temperature of frozen block is risen to-28 ℃, rise to-18 ℃ with 1.0 ℃/1.5 hours programming rates after, rise to 32 ℃ with 4 ℃/hour programming rate again, insulation is 13 hours under 32 ℃ temperature, and making the contained moisture content of lyophilized injectable powder is 3.5% of Herba Hedyotidis Diffusae extract, adjuvant gross weight, can go out machine and roll lid.
Resulting product specification general flavone content is that 4mg/ props up.
The preparation of embodiment 3 medicament freeze-drying injectable powder of the present invention
One, major ingredient
Herba Hedyotidis Diffusae extract 20mg (containing the 1mg total flavones)
Its preparation can be adopted following method:
Get clean, dried Herba Hedyotidis Diffusae 1000g, be ground into 40 order coarse powder, make solvent, heating and refluxing extraction 3 times, each 1h with 70% ethanol 2000ml.Merge extractive liquid,, cold preservation 8 hours, centrifugal, collect supernatant, join in the polyamide resin column, the adjusting flow velocity is 4ml/min, with distilled water flush away impurity, be the mobile phase desorption with 70% ethanol, reclaim ethanol, regulate pH value to 4 with 40% sulfuric acid solution, left standstill 8 hours, filter, filtrate reuse 30%NaOH solution transfers pH value to neutral, adds 70% ethanol 1000ml, cold preservation 8 hours, filter, filtrate decompression is concentrated into 200ml, heats with 2% sodium carbonate liquor 500ml at every turn, dissolve repeatedly 4 times, filtered while hot, filtrate adds hydrochloric acid, and regulating pH value is 1, put the precipitation that cold leaching is separated out, vacuum drying promptly gets Herba Hedyotidis Diffusae extract 3g, is buff powder.
" assay "
The preparation of the preparation standard curve of reference substance solution prepares with the standard curve among the embodiment 1.
The algoscopy precision is measured this product 1 gram, uses the 50ml water elution, discards eluent, use 70% ethanol elution, collect the about 25ml of eluent, put in the 25ml measuring bottle, add 70% ethanol dilution to scale, shake up, precision is measured 5ml respectively, puts first, in two 25ml measuring bottles of second, add 5% sodium nitrite solution 1ml in the first bottle, shake up, placed 6 minutes, and added 10% aluminum nitrate solution 1ml, shake up, placed 6 minutes, in first, each hydro-oxidation sodium test solution 10ml in two bottles of the second adds ethanol dilution again to scale, shakes up, placed 15 minutes, according to spectrophotography (appendix VB), be blank with the second bottle, measure trap at the wavelength place of 507nm, read the content of rutin the need testing solution from standard curve, be 2.0mg/ml.
As calculated, contain total flavones with rutin (C in per 1 gram of this product
27H
30O
16) count 50mg, content is 5%.
Two, adjuvant
Mannitol 80mg
Tween 80 20mg
Sodium sulfite 1mg
Sterilized water for injection is an amount of
Prepared
It is fixed that main ingredient is accurately claimed, stirs and make it whole dissolvings fully, adds 0.1% pin activated carbon, fully stir, use 50% sodium hydroxide solution, regulating pH value is 6.0, with microporous filter membrane decarburization filtration and the aseptic filtration of 0.4 μ and 0.22 μ, packing, change freeze drying box behind the false add plug over to and carry out lyophilization
Make put into freeze drying box the temperature of filtrate filtered reduced to-30 ℃ rapidly after, form frozen block, start the vacuum pump evacuation, under the condition of 10Pa, the temperature of frozen block is risen to-25 ℃, rise to-22 ℃ with 1.5 ℃/1.5 hours programming rates after, rise to 25 ℃ with 5 ℃/hour programming rate again, insulation is 5 hours under 25 ℃ temperature, and making the contained moisture content of lyophilized injectable powder is 6% of Herba Hedyotidis Diffusae extract, adjuvant gross weight, can go out machine and roll lid.
It is that 1.0mg/ props up that the resulting product specification contains total flavones.
Embodiment 4 contains the preparation of extract freeze dried powder injection of the present invention
One, major ingredient
Herba Hedyotidis Diffusae extract 140mg (containing the 11.2mg total flavones)
Its preparation can be adopted following method:
Get clean, dried Herba Hedyotidis Diffusae 1000g, be ground into 20 order coarse powder, make solvent, heating and refluxing extraction 5 times, each 2h with 90% ethanol 2000ml.Merge extractive liquid,, cold preservation 12 hours, centrifugal, collect supernatant, join in the polyamide resin column, the adjusting flow velocity is 2ml/min, with distilled water flush away impurity, be the mobile phase desorption with 90% ethanol, reclaim ethanol, regulate pH value to 2 with 60% sulfuric acid solution, left standstill 12 hours, filter, filtrate reuse 50%NaOH solution transfers pH value to neutral, adds 90% ethanol 3000ml, cold preservation 12 hours, filter, filtrate decompression is concentrated into 400ml, heats with 8% sodium carbonate liquor 500ml at every turn, dissolve repeatedly 6 times, filtered while hot, filtrate adds hydrochloric acid, and regulating pH value is 3, put the precipitation that cold leaching is separated out, vacuum drying promptly gets Herba Hedyotidis Diffusae extract 5g, is buff powder.
" assay "
The preparation of the preparation standard curve of reference substance solution prepares with the standard curve among the embodiment 1.
The algoscopy precision is measured this product 1 gram, uses the 50ml water elution, discards eluent, use 70% ethanol elution, collect the about 25ml of eluent, put in the 25ml measuring bottle, add 70% ethanol dilution to scale, shake up, precision is measured 5ml respectively, puts first, in two 25ml measuring bottles of second, add 5% sodium nitrite solution 1ml in the first bottle, shake up, placed 6 minutes, and added 10% aluminum nitrate solution 1ml, shake up, placed 6 minutes, in first, each hydro-oxidation sodium test solution 10ml in two bottles of the second adds ethanol dilution again to scale, shakes up, placed 15 minutes, according to spectrophotography (appendix VB of Chinese Pharmacopoeia version in 2000), be blank with the second bottle, measure trap at the wavelength place of 507nm, read the content of rutin the need testing solution from standard curve, be 3.2mg/ml.
As calculated, contain total flavones with rutin (C in per 1 gram of this product
27H
30O
16) count 80mg, content is 8%.
Two, adjuvant
Mannitol 150mg
Tween 80 40mg
Sodium sulfite 2mg
Sterilized water for injection is an amount of
Prepared
It is fixed that main ingredient is accurately claimed, stirs and make it whole dissolvings fully, adds 1% pin activated carbon, fully stir, use 30% sodium hydroxide solution, regulating pH value is 7.0, with microporous filter membrane decarburization filtration and the aseptic filtration of 0.4 μ and 0.22 μ, packing, change freeze drying box behind the false add plug over to and carry out lyophilization.
After the filtrate temperature of putting into freeze drying box reduced to-55 ℃ rapidly, form frozen block, start the vacuum pump evacuation, under the condition of 5Pa, the temperature of frozen block is risen to-32 ℃, rise to-15 ℃ with 0.5 ℃/1.5 hours programming rates after, rise to 40 ℃ with 3 ℃/hour programming rate again, insulation is 20 hours under 40 ℃ temperature, and making the contained moisture content of lyophilized injectable powder is 1% of Herba Hedyotidis Diffusae extract, adjuvant gross weight, can go out machine and roll lid.
It is that 11.2mg/ props up that the resulting product specification contains total flavones.
The preparation of embodiment 5 medicament freeze-drying injectable powder of the present invention
One, major ingredient
Herba Hedyotidis Diffusae extract 20mg (containing the 1.6mg total flavones)
Its preparation can be adopted following method:
Get clean, dried Herba Hedyotidis Diffusae 1000g, be ground into 20 order coarse powder, make solvent, heating and refluxing extraction 5 times, each 2h with 90% ethanol 2000ml.Merge extractive liquid,, cold preservation 12 hours, centrifugal, collect supernatant, join in the polyamide resin column, the adjusting flow velocity is 2ml/min, with distilled water flush away impurity, be the mobile phase desorption with 90% ethanol, reclaim ethanol, regulate pH value to 2 with 60% sulfuric acid solution, left standstill 12 hours, filter, filtrate reuse 50%NaOH solution transfers pH value to neutral, adds 90% ethanol 3000ml, cold preservation 12 hours, filter, filtrate decompression is concentrated into 400ml, heats with 8% sodium carbonate liquor 500ml at every turn, dissolve repeatedly 6 times, filtered while hot, filtrate adds hydrochloric acid, and regulating pH value is 3, put the precipitation that cold leaching is separated out, vacuum drying promptly gets Herba Hedyotidis Diffusae extract 5g, is buff powder.
" assay "
The preparation of the preparation standard curve of reference substance solution prepares with the standard curve among the embodiment 1.
The algoscopy precision is measured this product 1 gram, uses the 50ml water elution, discards eluent, use 70% ethanol elution, collect the about 25ml of eluent, put in the 25ml measuring bottle, add 70% ethanol dilution to scale, shake up, precision is measured 5ml respectively, puts first, in two 25ml measuring bottles of second, add 5% sodium nitrite solution 1ml in the first bottle, shake up, placed 6 minutes, and added 10% aluminum nitrate solution 1ml, shake up, placed 6 minutes, in first, each hydro-oxidation sodium test solution 10ml in two bottles of the second adds ethanol dilution again to scale, shakes up, placed 15 minutes, according to spectrophotography (appendix VB of Chinese Pharmacopoeia version in 2000), be blank with the second bottle, measure trap at the wavelength place of 507nm, read the content of rutin the need testing solution from standard curve, be 3.2mg/ml.
As calculated, contain total flavones with rutin (C in per 1 gram of this product
27H
30O
16) count 80mg, content is 8%.
Two, adjuvant
Mannitol 200mg
Tween 80 20mg
Sodium sulfite 6mg
Sterilized water for injection is an amount of
Prepared
It is fixed that main ingredient is accurately claimed, stirs and make it whole dissolvings fully, adds 0.1% pin activated carbon, fully stir, use 50% sodium hydroxide solution, regulating pH value is 6.0, with microporous filter membrane decarburization filtration and the aseptic filtration of 0.4 μ and 0.22 μ, packing, change freeze drying box behind the false add plug over to and carry out lyophilization
Make put into freeze drying box the temperature of filtrate filtered reduced to-30 ℃ rapidly after, form frozen block, start the vacuum pump evacuation, under the condition of 10Pa, the temperature of frozen block is risen to-25 ℃, rise to-22 ℃ with 1.5 ℃/1.5 hours programming rates after, rise to 25 ℃ with 5 ℃/hour programming rate again, insulation is 5 hours under 25 ℃ temperature, and making the contained moisture content of lyophilized injectable powder is 6% of Herba Hedyotidis Diffusae extract, adjuvant gross weight, can go out machine and roll lid.
It is that 1mg/ props up that the resulting product specification contains total flavones.
Embodiment 6 contains the preparation of extract freeze dried powder injection of the present invention
One, major ingredient
Herba Hedyotidis Diffusae extract 140mg (containing the 7.0mg total flavones)
Its preparation can be adopted following method:
Get clean, dried Herba Hedyotidis Diffusae 1000g, be ground into 40 order coarse powder, make solvent, heating and refluxing extraction 3 times, each 1h with 70% ethanol 2000ml.Merge extractive liquid,, cold preservation 8 hours, centrifugal, collect supernatant, join in the polyamide resin column, the adjusting flow velocity is 4ml/min, with distilled water flush away impurity, be the mobile phase desorption with 70% ethanol, reclaim ethanol, regulate pH value to 4 with 40% sulfuric acid solution, left standstill 8 hours, filter, filtrate reuse 30%NaOH solution transfers pH value to neutral, adds 70% ethanol 1000ml, cold preservation 8 hours, filter, filtrate decompression is concentrated into 200ml, heats with 2% sodium carbonate liquor 500ml at every turn, dissolve repeatedly 4 times, filtered while hot, filtrate adds hydrochloric acid, and regulating pH value is 1, put the precipitation that cold leaching is separated out, vacuum drying promptly gets Herba Hedyotidis Diffusae extract 3g, is buff powder.
" assay "
The preparation of the preparation standard curve of reference substance solution prepares with the standard curve among the embodiment 1.
The algoscopy precision is measured this product 1 gram, uses the 50ml water elution, discards eluent, use 70% ethanol elution, collect the about 25ml of eluent, put in the 25ml measuring bottle, add 70% ethanol dilution to scale, shake up, precision is measured 5ml respectively, puts first, in two 25ml measuring bottles of second, add 5% sodium nitrite solution 1ml in the first bottle, shake up, placed 6 minutes, and added 10% aluminum nitrate solution 1ml, shake up, placed 6 minutes, in first, each hydro-oxidation sodium test solution 10ml in two bottles of the second adds ethanol dilution again to scale, shakes up, placed 15 minutes, according to spectrophotography (appendix VB), be blank with the second bottle, measure trap at the wavelength place of 507nm, read the content of rutin the need testing solution from standard curve, be 2.0mg/ml.
As calculated, contain total flavones with rutin (C in per 1 gram of this product
27H
30O
16) count 50mg, content is 5%.
Two, adjuvant
Mannitol 80mg
Tween 80 100mg
Sodium sulfite 1mg
Sterilized water for injection is an amount of
Prepared
It is fixed that main ingredient is accurately claimed, stirs and make it whole dissolvings fully, adds 1% pin activated carbon, fully stir, use 30% sodium hydroxide solution, regulating pH value is 7.0, with microporous filter membrane decarburization filtration and the aseptic filtration of 0.4 μ and 0.22 μ, packing, change freeze drying box behind the false add plug over to and carry out lyophilization.
After the filtrate temperature of putting into freeze drying box reduced to-55 ℃ rapidly, form frozen block, start the vacuum pump evacuation, under the condition of 5Pa, the temperature of frozen block is risen to-32 ℃, rise to-15 ℃ with 0.5 ℃/1.5 hours programming rates after, rise to 40 ℃ with 3 ℃/hour programming rate again, insulation is 20 hours under 40 ℃ temperature, and making the contained moisture content of lyophilized injectable powder is 1% of Herba Hedyotidis Diffusae extract, adjuvant gross weight, can go out machine and roll lid.
It is that 7.0mg/ props up that the resulting product specification contains total flavones.
Below further set forth the beneficial effect of lyophilized injectable powder of the present invention by the test example:
Test example 1 dissolution velocity comparative evaluation test
Test material:
Test sample A gets the prepared lyophilized injectable powder that contains Herba Hedyotidis Diffusae extract of the embodiment of the invention 1, and specification is that 2mg/ props up.
The hedyotis herba powder injection that test sample B obtains with embodiment 1 method that provides in the application number 200510042044.1 (biochemical-pharmaceutical factory, Zhuhai laboratory provides).
The hedyotis herba powder injection that test sample C obtains with preparation embodiment 1 method that provides among the application number 200510055292.X (biochemical-pharmaceutical factory, Zhuhai laboratory provides).
Injection normal saline (biochemical-pharmaceutical factory, Zhuhai laboratory provides)
Test method: under 25 ± 2 ℃ of humidity 60 ± 5% situations of experimental enviroment, three kinds of injectable powder are carried out the dissolution velocity contrast test, statistical result is as follows:
Three kinds of injectable powder dissolution velocity contrasts of table 1 situation statistical table (experimental enviroment: 25 ± 2 ℃ of humidity 60 ± 5%)
Result of the test: lyophilized injectable powder of the present invention, under equal conditions, dissolution velocity is faster, more convenient use.
Other embodiments of the invention 2,3,4,5,6 resulting products adopt said method to test, and obtain essentially identical result.
2 accelerated stability comparative evaluations test of test example and active constituent content contrast
Test material:
Test sample A gets the prepared lyophilized injectable powder that contains Herba Hedyotidis Diffusae extract of the embodiment of the invention 2, and specification is that 4mg/ props up.
The hedyotis herba powder injection that test sample B obtains with embodiment 2 methods that provide in the application number 200510042044.1 (biochemical-pharmaceutical factory, Zhuhai laboratory provides).
The hedyotis herba powder injection that test sample C obtains with preparation embodiment 2 methods that provide among the application number 200510055292.X (biochemical-pharmaceutical factory, Zhuhai laboratory provides).
Test method: 50 ± 2 ℃ of experimental enviroments, under humidity 80 ± 5% situations, three kinds of injectable powder are carried out accelerated stability estimate contrast test, statistical result is as follows:
Three kinds of injectable powder accelerated stability tests of table 2 statistical table (experimental enviroment: 50 ± 2 ℃ of humidity 80 ± 5%)
Result of the test: by above-mentioned accelerated stability contrast experiment, we can draw: lyophilized injectable powder of the present invention is compared with previous disclosed two injectable powder, not only substantially exceed on the content, and after process accelerated stability contrast test, its effective ingredient has kept more than 90%, and two injectable powder effective ingredient then only keep 62%, 73% in addition.Therefore, suffice to show that the injectable powder stability that obtains according to preparation method of the present invention is better, active constituent content is higher.
Other embodiments of the invention 1,3,4,5,6 resulting products adopt said method to test, and obtain essentially identical result.
Test example 3 xylol cause comparative evaluation's test of mice auricular concha inflammation
Test material:
Test sample A gets the prepared lyophilized injectable powder that contains Herba Hedyotidis Diffusae extract of the embodiment of the invention 3, and specification is that 1mg/ props up.
The hedyotis herba powder injection that test sample B obtains with embodiment 3 methods that provide in the application number 200510042044.1 (biochemical-pharmaceutical factory, Zhuhai laboratory provides).
The hedyotis herba powder injection that test sample C obtains with preparation embodiment 3 methods that provide among the application number 200510055292.X (biochemical-pharmaceutical factory, Zhuhai laboratory provides).
Injection normal saline (biochemical-pharmaceutical factory, Zhuhai laboratory provides)
Experimental animal: Kunming mouse (20 ± 2) g, male and female dual-purpose (biochemical-pharmaceutical factory, Zhuhai Animal House provides).
Test method:
30 of mices, be divided into 3 groups, 10 every group, with three kinds of test sample injection physiological saline solutions, give the mouse tail vein administration according to the 3mg/kg dosage, once a day, administration 3 days, normal saline group administration capacity 0.5ml/ is only, every day 1 time, administration 3 days, 1h after the last administration, get dimethylbenzene 0.05ml/ only evenly be applied to left ear before and after the two sides cause inflammation, behind the 15min, put to death animal, cut auricular concha, two ears are overlapping, get disk with diameter for the 8mm card punch, weighing, the difference that left and right sides ear weighs is obtained the inhibitory rate of intumesce of administration group as the swelling degree.The results are shown in Table 3.
Table 3 xylol causes the influence of mice auricular concha inflammation
Annotate: compare with the injection normal saline
*P＜0.01, compare with positive controls [
*] P＜0.05
Result of the test: injectable powder of the present invention has better inhibition effect to caused mice auricular concha inflammation by xylol.
Other embodiments of the invention 1,2,4,5,6 resulting products adopt said method to test, and obtain essentially identical effect.
Test 4 effect duration of example, stable reaction pair compare evaluation test
Test material: get the prepared lyophilized injectable powder that contains Herba Hedyotidis Diffusae extract of the embodiment of the invention 4, specification is that 11.2mg/ props up.
Test method: 1) medicament freeze-drying injectable powder sterilized powder of the present invention is tested through high temperature (40 ℃, 60 ℃, 80 ℃), high humidity (RH92.5%, RH75%, 25 ℃) and illumination 4000LX influence factor.
Result of the test: appearance character, clarity, pH value, content and sterility test all meet the requirements.
Test method: 2) medicament freeze-drying injectable powder accelerated test of the present invention (40 ℃ of RH75%) keeps sample and investigates 1,3,5,7,12,18 month.
Result of the test: appearance character, clarity, pH value, content, and sterility test all meet the requirements.
Conclusion (of pressure testing): injectable powder storage life of the present invention can reach 3 years, has avoided phenomenons such as degraded that injection takes place in long term store, muddiness, precipitation effectively, has prolonged the quality effect duration of Herba Hedyotidis Diffusae pharmaceutical preparation.
Other embodiments of the invention 1,2,3,5,6 resulting injectable powder products adopt said method to test, and obtain essentially identical effect.
Comparative Examples:
Test material: get BAIHUASHESHECAO ZHUSHEYE, specification is that 2mg/ props up, and Long Tai Pharmacy stock Co., Ltd in Jilin provides.
Test method: 1) BAIHUASHESHECAO ZHUSHEYE is tested through high temperature (40 ℃, 60 ℃, 80 ℃), high humidity (RH92.5%, RH75%, 25 ℃) and illumination 4000LX influence factor.
Result of the test: appearance character is faint yellow, muddy.
Test method: 2) BAIHUASHESHECAO ZHUSHEYE accelerated test (40 ℃ of RH75%) is kept sample investigate 1,3,5,6 month.
Result of the test: the flavescence of 6 months beginning outward appearances, muddiness.
Conclusion (of pressure testing): infer that the BAIHUASHESHECAO ZHUSHEYE storage life can reach 2 years.
Test example 5 extract purity comparative evaluations
According to the Chinese medicine ministry standard, BAIHUASHESHECAO ZHUSHEYE: phonetic name BaihuaSheshecao Zhusheye, book page number: Z17-67, standard numbering: WS3-B-3176-98.This product adopts according to the percolation (appendix IO) under fluid extract and the extractum item and extracts, and again Herba Hedyotidis Diffusae extract is made sterile water solution.Contain total flavones with rutin (C among the every 1ml of this product
27H
30O
16) meter, must not be less than 0.25mg.
Adopt Hedyotidis Diffusae preparation method of extract among the embodiment of the invention 1-6, contain total flavones among every 1ml with rutin (C
27H
30O
16) meter, be 1.6-3.2mg, be 6.4-12.8 times of ministry standard, be enough to find out the extract purity height of the inventive method preparation, impurity is few, and side effect is also just little certainly.And can adjust the consumption of adjuvant according to different diseases, patient, with the active component content of control medicament freeze-drying injectable powder of the present invention.
Claims (11)
1. lyophilized injectable powder that contains Herba Hedyotidis Diffusae extract, major ingredient is Herba Hedyotidis Diffusae extract 20-140 part in its component, adjuvant is that mannitol 80-200 part, tween 80 20-100 part, sodium sulfite 1-6 part, sterilized water for injection are an amount of; The preparation method of described Herba Hedyotidis Diffusae extract is as follows:
Get clean, dried Herba Hedyotidis Diffusae 1000g is ground into 20-40 order coarse powder, and 2000ml makes solvent with 70-90% ethanol, heating and refluxing extraction 3-5 time, each 1-2h, merge extractive liquid,, cold preservation 8-12 hour, centrifugal, collect supernatant, join in the polyamide resin column, the adjusting flow velocity is 2-4ml/min, with distilled water flush away impurity, with 70-90% ethanol is the mobile phase desorption, reclaims ethanol, regulates pH value to 2-4 with the 40-60% sulfuric acid solution, left standstill 8-12 hour, filter, filtrate reuse 30-50%NaOH solution adjust pH adds 70-90% ethanol 1000-3000ml to neutral, cold preservation 8-12 hour, filter, filtrate decompression is concentrated into 200-400ml, at every turn with 2-8% sodium carbonate liquor 500ml heating, dissolve 4-6 time repeatedly, filtered while hot, filtrate adds hydrochloric acid, and the adjusting pH value is 1-3, put the precipitation that cold leaching is separated out, vacuum drying gets final product.
2. a kind of lyophilized injectable powder according to claim 1 is characterized in that the preparation method of described Herba Hedyotidis Diffusae extract is as follows:
Get clean, dried Herba Hedyotidis Diffusae 1000g is ground into 20-40 order coarse powder, makes solvent with 80% ethanol 2000ml, heating and refluxing extraction 4 times, each 1.5h, merge extractive liquid,, cold preservation 8-12 hour, centrifugal, collect supernatant, join in the polyamide resin column, the adjusting flow velocity is 3ml/min, with distilled water flush away impurity, with 80% ethanol is the mobile phase desorption, reclaims ethanol, regulates pH value to 2-4 with the 40-60% sulfuric acid solution, left standstill 8-12 hour, filter, filtrate reuse 30-50%NaOH solution adjust pH adds 80% ethanol 2000ml to neutral, cold preservation 8-12 hour, filter, filtrate decompression is concentrated into 300ml, heats with 5% sodium carbonate liquor 500ml at every turn, dissolve repeatedly 5 times, filtered while hot, filtrate adds hydrochloric acid, and the adjusting pH value is 1-3, put the precipitation that cold leaching is separated out, vacuum drying gets final product.
3. a kind of lyophilized injectable powder according to claim 1 and 2 is characterized in that 28 parts of Herba Hedyotidis Diffusae extracts in the described component, 150 parts in mannitol, 40 parts of tween 80s, 2 parts of sodium sulfitees, sterilized water for injection are an amount of.
4. a kind of lyophilized injectable powder according to claim 1 and 2 is characterized in that Herba Hedyotidis Diffusae extract is with rutin C in the described component
27H
30O
16Meter contains the 5-8% total flavones.
5. a kind of lyophilized injectable powder according to claim 4 is characterized in that Herba Hedyotidis Diffusae extract is with rutin C in the described component
27H
30O
16Meter contains 7.1% total flavones.
6. the preparation method of any one lyophilized injectable powder among the claim 1-5 is characterized in that comprising the steps:
A) main ingredient is accurately claimed to decide, stir and make it all dissolvings fully;
B) add 0.1-1% pin activated carbon, fully stir, use the 30-50% sodium hydroxide solution, the adjusting pH value is 6.0-7.0;
C) with the microporous filter membrane decarburization filtration of 0.4 μ m and 0.22 μ m and aseptic filtration, packing, change freeze drying box behind the false add plug over to and carry out lyophilization;
D) the filtrate temperature that will put into freeze drying box is reduced to rapidly-30--55 ℃, forms frozen block;
E) start the vacuum pump evacuation, under the condition of 5-10Pa, the temperature of frozen block is risen to-25--32 ℃;
F) with 0.5-1.5 ℃/1.5 hours programming rate rise to-22--15 ℃ after, rise to 25-40 ℃ with 3-5 ℃/hour programming rate again;
G) be incubated 5-20 hour under 25-40 ℃ temperature, making the contained moisture content of lyophilized injectable powder is the 1-6% of Herba Hedyotidis Diffusae extract, adjuvant gross weight, gets final product.
7. the preparation method of a kind of lyophilized injectable powder according to claim 6 is characterized in that described step B) in the pin activated carbon be 0.5%, concentration of sodium hydroxide solution is 40%, pH value is 6.5.
8. the preparation method of a kind of lyophilized injectable powder according to claim 6 is characterized in that described step D) in will put into freeze drying box the filtrate temperature reduce to-42 ℃ rapidly, form frozen block.
9. the preparation method of a kind of lyophilized injectable powder according to claim 6 is characterized in that described step e) the middle vacuum pump evacuation that starts, under the condition of 8Pa, the temperature of frozen block is risen to-28 ℃.
10. the preparation method of a kind of lyophilized injectable powder according to claim 6 is characterized in that described step F) in rise to-18 ℃ with 1.0 ℃/1.5 hours programming rate after, rise to 32 ℃ with 4 ℃/hour programming rate again.
11. the preparation method of a kind of lyophilized injectable powder according to claim 6, it is characterized in that described step G) in, lyophilized injectable powder is incubated 13 hours under 32 ℃ temperature, making its contained moisture content is 3.5% of Herba Hedyotidis Diffusae extract, adjuvant gross weight, gets final product.
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| CN101011481B (en) * | 2007-01-29 | 2011-08-10 | 周应军 | Herba hedyotis diffusae extract, pharmaceutical preparation, preparing process and application thereof |
| CN101496845B (en) * | 2008-02-01 | 2013-02-20 | 中国科学院大连化学物理研究所 | Hedyotis diffusa Willd. extract and method for separating and preparing the same |
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| CN1679842A (en) * | 2005-01-21 | 2005-10-12 | 山东恒瑞医药科技发展有限公司 | Oldenlandia and powder injection and preparation thereof |
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| CN111150814A (en) * | 2020-01-10 | 2020-05-15 | 四川上好医药科技有限公司 | A Chinese medicinal composition for adjuvant treatment of cancer |
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