CN1692916A - Pharmaceutical prepn. of compound mannite, and its prepn. method - Google Patents
Pharmaceutical prepn. of compound mannite, and its prepn. method Download PDFInfo
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Abstract
A compound mannitol for treating hepatitis, gastritis, intestinal obstruction, and cardiovascular and cerebrovascular diseases is prepared from mannitol and the red sage root and/or notoginseng.
Description
Technical field: the present invention is pharmaceutical preparation of a kind of compound formula mannitol and preparation method thereof, belongs to the technical field of medicine.
Technical background: mannitol is a kind of clinical practice medicine widely, can control acute cholecystitis, acute viral hepatitis, liver cirrhosis, Type B gastritis, intestinal obstruction, clean perfusion, digestive tract disease such as cholangiography, and it is anxious, chronic renal failure, fascia spacer syndrome before the pulmonary heart disease right heart failure, surpass accumulation of heat nuclearity pleuritis, intractable angina pectoris, treatment brain blood nuclear, cerebral infarction, various forms cerebral traumas such as cerebral hemorrhage, rib angiopathy and cerebral edema, edema of spinal cord etc., and can improve myocardial ischemia, blood viscosity lowering is taken in to increase cardiac muscle, and the treatment glaucoma, urinary system calculus, acute pancreatitis, organophosphate poisoning etc.Be treatment cerebral edema, cerebral infarction, the medicine commonly used of reduction intracranial pressure, drug of first choice.And cardiovascular and cerebrovascular disease such as cerebral infarction, cerebral thrombosis, cerebral edema etc. all are one of the most common and diseases that harm is maximum in the world today, have become human mortality's one of the main reasons in many countries; Prevent and treat purpose in order to reach, a large amount of research has been done by many inventors and medicine enterprise, and the product of some treatments also is provided; Mainly contain Chinese medicine preparation and Western medicine product; Find in the use: Chinese medicine is quick-acting inadequately, is unfavorable for the treatment of emergency and severe disease, and Western medicine is rapid-action but toxic and side effects is bigger; Acute renal failure produces effect though mannitol is used for the treatment of, rapid-action characteristics, and its side effect is serious, obvious to kidney damage, and especially the gerontal patient is difficult to use this medicine to be treated; In view of such circumstances, how to give full play to, utilize mannitol clinical practice characteristics widely, seek a kind of compatibility rationally, efficacy enhancing and toxicity reducing, therapeutic effect ideal, toxic and side effects is little, the thing that pharmaceutical preparation easy to use has just become people to be badly in need of solving.
Summary of the invention: the objective of the invention is to: pharmaceutical preparation of a kind of compound formula mannitol and preparation method thereof is provided; The present invention is directed to prior art, adopt the Chinese and Western combination, mannitol and Radix Salviae Miltiorrhizae, Radix Notoginseng compatibility are made compound preparation; Wherein mannitol has function of gallbladder promoting, promote pancreatic secretion, quicken small intestinal peristalsis, improve the microcirculatory effect in abdominal cavity, can increase the cerebral blood flow of normal and ischemic region, reduce packed cell volume, plasma viscosity and erythrocyte aggregation, increase red cell deformability, thereby protection ischemic region microcirculation, it also has the effect of removing free radical as antioxidant, can alleviate cerebral edema, can also reduce blood viscosity, improve cerebral circulation, be used for treatment digestive tract such as hepatitis, gastritis, intestinal obstruction, cardiovascular and cerebrovascular disease; Radix Salviae Miltiorrhizae, Radix Notoginseng are blood circulation promoting and blood stasis dispelling blood medicine, cardio-cerebrovascular are had the effect of blood vessel dilating, arrhythmia, anti-hypoxia, protection cardiac muscle, shock, arteriosclerosis and enhancing immunity; Also have effects such as anti-hepatitis, anti-hepatic fibrosis, antibiotic, treatment gastritis; With the mannitol fit applications, the mutual reinforcement between mutual-assistance, Synergistic, the more important thing is effects such as to protect kidney, inhibition kidney inflammation, minimizing urine protein, can increase simultaneously the secretion of adrenal cortex function, have certain antiinflammatory, antiallergic, adjusting immunologic function, and can influence the release of some bioactive substance in the body, improve the kidney microcirculation, anticoagulant, adjusting metabolism, adjusting immunity, be used for the treatment of medicine kidney damage and medicine and cause that the renal insufficiency patient plays good efficacy, can prevent and treat the side effect that mannitol causes, prevent infringement kidney; Among the present invention also cleverly with mannitol as tablet filler, correctives, lyophilizing excipient, cosolvent, suspensoid injectio stabilizing agent; Chinese and Western is share, and efficacy enhancing and toxicity reducing is had complementary advantages; And the associating of the more simple Chinese medicine and western medicine of compound medicinal formulation is easy to use, applied range.
The present invention constitutes like this: calculate according to components by weight percent, it is by 99～1 parts in mannitol, a kind of in Radix Salviae Miltiorrhizae, the Radix Notoginseng or two kinds 1～99 part are made, or a kind of in the Radix Salviae Miltiorrhizae extract that obtains after extracting of mannitol and corresponding weight fraction, Radix Notoginseng extract or two kinds are made.Perhaps: calculate according to components by weight percent, it is by 90～10 parts in mannitol, a kind of in Radix Salviae Miltiorrhizae, the Radix Notoginseng or two kinds 10～90 parts are made, or a kind of in the Radix Salviae Miltiorrhizae extract that obtains after extracting of mannitol and corresponding weight fraction, Radix Notoginseng extract or two kinds are made.Say accurately: calculate according to components by weight percent, it is by 20 parts in mannitol, a kind of in Radix Salviae Miltiorrhizae, the Radix Notoginseng or two kinds 80 parts are made, or a kind of in the Radix Salviae Miltiorrhizae extract that obtains after extracting of mannitol and corresponding weight fraction, Radix Notoginseng extract or two kinds are made.Preparation of the present invention is: injection comprises: all acceptable dosage forms on the pharmaceuticss such as injection, powder pin, freeze-dried powder, tablet, capsule, soft capsule, microcapsule, granule, pill, powder, drop pill, slow releasing preparation, controlled release preparation, oral liquid, soft extract, extractum and membrane.Say accurately: described preparation is an injection, comprises injection, injectable powder (lyophilized injectable powder or common flour injection), infusion solution.Radix Salviae Miltiorrhizae extract of the present invention can be the highly finished product of tanshinol extract, Radix Salviae Miltiorrhizae water extract, Radix Salviae Miltiorrhizae water extract-alcohol precipitation extract, Radix Salviae Miltiorrhizae semi-bionic extraction thing, red sage root super critical extract or above extract.Radix Notoginseng extract of the present invention can be the highly finished product of Radix Notoginseng alcohol extract, pseudo-ginseng water extract, Radix Notoginseng water extract-alcohol precipitation extract, Radix Notoginseng semi-bionic extraction thing, Radix Notoginseng supercritical extract or above extract.The preparation method of the pharmaceutical preparation of compound formula mannitol of the present invention is: get Radix Salviae Miltiorrhizae, pulverize the back and add 3～15 times of amount ethanol, reflux, extract,, filter, 3～15 times of amounts of medicinal residues reuse alcohol reflux, merge extractive liquid, filters, 3～15 times of water gagings of medicinal residues reuse decoct, filter, merge extractive liquid, reclaims ethanol and is condensed into extractum, add mannitol and mix, the reuse diverse ways is made different preparations.The preparation method of the pharmaceutical preparation of this compound formula mannitol of the present invention is: get Radix Notoginseng, pulverize the back and add 3～8 times of amount ethanol, reflux, extract, 1～5 time, filter, filtrate recycling ethanol also is condensed into extractum, adds mannitol and mixes, and the reuse diverse ways is made different preparations.The preparation method of the pharmaceutical preparation of this compound formula mannitol of the present invention is: get Radix Salviae Miltiorrhizae, pulverize the back and add 3～15 times of amount ethanol, reflux, extract,, filter 3～15 times of amounts of medicinal residues reuse alcohol reflux, merge extractive liquid,, filter, 3～15 times of water gagings of medicinal residues reuse decoct, and filter merge extractive liquid; Get Radix Notoginseng, pulverize the back and add 3～8 times of amount ethanol, reflux, extract, 1～5 time is filtered, and merges Radix Salviae Miltiorrhizae extract, reclaims ethanol and is condensed into extractum, adds mannitol and mixes, and the reuse diverse ways is made different preparations.
Its granule is like this preparation: get Radix Salviae Miltiorrhizae, with 12 times of amount 95% alcohol reflux 1.5 hours, medicinal residues were measured 50% alcohol reflux 1.5 hours with 12 times, 12 times of water gagings of medicinal residues reuse decocted 1.5 hours, filter, merge extractive liquid, reclaims ethanol and is condensed into extractum, after adding the mannitol mixing, the system soft material is granulated drying, granulate, promptly.Its tablet is like this preparation: get Radix Notoginseng, with 70% ethanol 2 times, add 6 times of amounts the first time, refluxed 2 hours, and added 5 times of amounts for the second time, refluxed 1.5 hours, filter, filtrate recycling ethanol also is condensed into extractum, adds mannitol and mixes, the system soft material is granulated drying, granulate, add 0.3% magnesium stearate, tabletting, promptly.Its injection prepares like this: get Radix Salviae Miltiorrhizae, with 12 times of amount 95% alcohol reflux 1.5 hours, medicinal residues were with 12 times of amount 50% alcohol reflux 1.5 hours, and 12 times of water gagings of medicinal residues reuse decocted 1.5 hours, filtration, merge extractive liquid; Get Radix Notoginseng,, add 6 times of amounts for the first time with 70% ethanol 2 times, refluxed 2 hours, for the second time add 5 times of amounts, refluxed 1.5 hours, filter, merge Radix Salviae Miltiorrhizae extract, reclaim ethanol and be condensed into extractum, add mannitol and mix, add hot distilled water and make dissolving, transfer pH value 5～9 with 10% sodium chloride solution, add to the full amount of water for injection, 0.22 μ m microporous filter membrane filters, embedding, 30 minutes its injections of 100 ℃ of sterilizations prepare like this: get Radix Salviae Miltiorrhizae, with 12 times of amount 95% alcohol reflux 1.5 hours, medicinal residues are with 12 times of amount 50% alcohol reflux 1.5 hours, 12 times of water gagings decoctions of medicinal residues reuse 1.5 hours, filter merge extractive liquid; Get Radix Notoginseng,, add 6 times of amounts for the first time, refluxed 2 hours with 70% ethanol 2 times, for the second time add 5 times of amounts, refluxed 1.5 hours, filter, merge Radix Salviae Miltiorrhizae extract, reclaim ethanol and be condensed into extractum, add mannitol and mix, add hot distilled water and make dissolving, add active carbon, static 10min behind the mixing, filter, 5% sodium hydroxide is transferred pH value 5-7, and 0.22 μ m microporous filter membrane filters, vacuum lyophilization or aseptic filtration or spray drying or in organic solvent recrystallization, packing, the sealing promptly.
The mannitol clinical practice is extensive, can control acute cholecystitis, acute viral hepatitis, and digestive tract disease such as liver cirrhosis, Type B gastritis, intestinal obstruction, cleaning perfusion, cholangiography alleviate cerebral edema, can also reduce blood viscosity, improve cerebral circulation; Radix Salviae Miltiorrhizae, bitter can drop-down, being slightly cold can heat clearing away, people's conscience two is through blood system, has removing heat from blood and do not stay the stasis of blood, dissipating blood stasis and the characteristics of unlikely abnormal circulation of blood, kind especially promoting tissue regeneration by removing blood stasis; Radix Notoginseng, promoting blood circulation to remove blood stasis is more arrogated to oneself analgesic therapy, and Chinese and Western is share, treating both the principal and secondary aspects of a disease, efficacy enhancing and toxicity reducing.Compared with prior art, the present invention is the Chinese medicine and western medicine compound preparation, compatibility is simple, rationally feasible, be used for treatment, good effect to digestive tract such as hepatitis, gastritis, intestinal obstruction, cardiovascular and cerebrovascular disease, toxic and side effects is little, and the preparation method of different dosage form is provided, and wide application has enlarged the scope of application.The applicant finds by a large amount of experiment sievings, the compound preparation good effect of mannitol and drug for invigorating blood circulation and eliminating stasis Radix Salviae Miltiorrhizae, Radix Notoginseng, easy to use, preparation technology is rationally feasible, mannitol not only can be brought into play therapeutical effect, can also reduce the consumption that does not have the drug effect adjuvant as the adjuvant of preparation, improve drug safety; Radix Salviae Miltiorrhizae, Radix Notoginseng can prevent and treat the renal damage that causes when heavy dose is used mannitol again, make that the utilization of mannitol is safer, have fully shown the superiority of therapy of combining Chinese and Western medicine method, and clinical effectiveness is good.Simultaneously, can also improve the symptom that merges the cardiovascular and cerebrovascular vessel ischemic diseases, reduce the probability of clinical drug combination amount of patient and generation adverse effect.
Screening can reduce mannitol, and to cause the activating blood and removing stasis drug of renal damage and the development of compound preparation be key technology of the present invention, and the applicant has carried out a series of experiments, can prove that compound medicinal formulation provided by the invention has effective effect; The preparation technology who provides is reasonable, science.
Experimental example 1: drug screening: healthy male new zealand white rabbit, body weight 1.8～2.5kg, single cage is fed, and numbers after chemical examination urine protein, the glucose in urine feminine gender again.Be divided into eight groups at random: 1. normal saline matched group; 2. model group; 3. Radix Salviae Miltiorrhizae extract group; 4. Radix Notoginseng extract group; 5. Rhizoma Chuanxiong extract group; 6. Rhizoma Curcumae extract group; 7. Radix Curcumae extract group; 8. Lignum Dalbergiae Odoriferae extract group; Matched group: give normal saline 20ml/kg; All the other groups were given 20% mannitol in first day and second day, pressed 4g/ (kg.h) speed and instiled from auricular vein continuously, and White Rabbit is freely drunk water in the whole process, the record discrepancy water yield.The 3rd day, anesthesia, intubate is given 20% mannitol 4g/kg from the input of jugular vein intubate, and 40min is totally lost, mannitol accumulated dose 40g/ (kg.60h), 2. group gives drinking water 2mLkg
-1D
-1, 3.～8. group gives 1.2gkg
-1D
-1Extract is irritated stomach.Administration 3 days, the observation period is 7 days, 3,7d leaves and takes the 24h urine respectively.
Measure every index, in the 3rd, 7d gets blood respectively and put to death animal, get nephridial tissue observation index and detection method to be: urine N-acetyl-NAG), the colorimetry detection kit,, the 24h urine protein quantitation is with examining the bright blue method of Ma Shi; Serum creatinine (Scr), blood urea nitrogen (BUN), automatic clinical chemistry analyzer.
Extract is to the influence of the heavy dose of mannitol injury of kidney of rat (x ± s)
| Group (mg/L) | ???????????Scr(μmol/L) | ???????????BUN(moml/L) | Urine NAG (u/gcr) | The 24h urine protein quantitation | ||||
| Normal group model group red sage root group pseudo-ginseng group Ligusticum wallichii group curcuma zedoary group root tuber of aromatic turmeric group dalbergia wood group | ??3d(n＝14) ??24.4±2.8 ??152.1±54.6 ??77.1±43.5 ??78.1±43.5 ??121.6±72.2 ??131.1±50.5 ??142.3±44.6 ??122.1±50.2 | ??7d(n＝7) ??30.0±4.2 ??73.4±34.2 ??44.4±39.2 ??45.4±39.2 ??39.8±19.6 ??63.1±30.2 ??70.4±33.0 ??70.4±14.3 | ??3d(n＝14) ??5.5±0.8 ??26.8±10.2 ??14.2±5.8 ??15.1±5.0 ??19.3±9.2 ??20.8±10.1 ??22.4±13.2 ??16.8±11.7 | ??7d(n＝7) ??63.0±1.7 ??18.1±20.1 ??7.1±4.2 ??7.4±4.3 ??8.3±2.3 ??10.1±22.1 ??15.3±20.3 ??11.1±23.0 | ??3d(n＝14) ??65.6±23.4 ??718.8±613.2 ??326.1±301.2 ??337.3±212.4 ??447.0±377.1 ??618.8±431.2 ??623.4±313.5 ??517.8±413.9 | ??7d(n＝7) ??49.5±32.1 ??67.0±85.9 ??44.3±23.0 ??45.5±21.3 ??46.8±61.0 ??57.0±89.1 ??55.2±83.9 ??57.3±75.3 | ??3d(n＝14) ??8.5±4.2 ??81.2±27.0 ??56.8±36.6 ??57.2±30.3 ??64.9±32.9 ??71.4±21.0 ??61.7±27.3 ??73.2±17.0 | ??7d(n＝7) ??9.3±2.0 ??28.2±11.2 ??26.7±4.9 ??27.1±4.3 ??24.0±5.4 ??22.8±10.2 ??23.2±12.2 ??24.6±13.8 |
The result shows: by screening, Radix Salviae Miltiorrhizae, Radix Notoginseng extract can reduce mannitol to be damaged kidney of rats.
Experimental example 2: preparation process research
1. granule preparation: test 1 group: extractum: lactose=1: 1; Test 2 groups: extractum: dextrin=1: 1; Extractum: soluble starch=1: 1; Extractum: mannitol=1: 1;
| Group | The granulation difficulty | Outward appearance | Dissolubility |
| ??1 ??2 ??3 ??4 | The difficult granulation, cross sticking difficult the granulation, granule looses and easily granulates, and uniform particles is easily granulated, and uniform particles | Granule dissolves distortion and the adhesion granule dissolves distortion and the not moist distortion of the not moist distortion granule of adhesion granule | All dissolving t＞30s all dissolve t＞30s and all dissolve t＜30s and all dissolve t＜30s |
2. preparation tablets:
Compressibility is investigated: once granulate the granule yield more than 70%, tablet hardness is well for well; The granule yield of once granulating 50-70%, tablet hardness is poor slightly to be better; Once granulate the granule yield below 50%, loose particles, the tablet hardness difference is for poor.
Average disintegration time (min): adopting changes the basket method, and lift disintegration tester, tablet are got 6, calculates fully
Meansigma methods by the screen cloth time.
Hygroscopicity is investigated: get test sample, about 2g puts in the weighing botle, and accurate the title decides, the weighing bottle cap is opened,
Put into relative humidity respectively and be 92% environment, placed 24 hours in 25 ℃ of constant incubators, what color burn, surface were sticking is +++; What color was dark, the surface is sticking is ++; Color is dark a little, the surface is sticking is+; Color outward appearance no change is-.
| Tablet | Lubricant | ||||||||
| Pulvis Talci | Sodium stearate | Magnesium stearate | |||||||
| The average disintegration time of consumption compressibility hygroscopicity | 1% is better ++ and 22 | 3% poor+25 | 5% poor+22 | 0.1% is better ++ and 27 | 0.5% is better ++ and 35 | 1% good+37 | 0.1% good+23 | 0.3% good-20 | 1% better-21 |
3. freeze-dried powder excipient screening
| Excipient | Consumption (mg/ml) | Outward appearance | Dissolubility |
| Only mannitol adds lactose and adds biphosphate sodium and add glycine | ??10 ??10 ??10 ? ??10 | Pale brown, structural strength is good pale brown, Yi Zhen looses brown, duricrust is arranged, crisp diffusing pale brown, insufficient formability | Adding behind the solvent i.e. dissolving in 20 seconds adds behind the solvent i.e. dissolving in 30 seconds and adds behind the solvent jolting and can not dissolve fully in 2 minutes and add i.e. dissolving in 22 seconds behind the solvent |
The result shows: the forming of mannitol compound preparation, mannitol can play the effect of adjuvant, has reduced the consumption that does not have the drug effect adjuvant.
Experimental example 3: to the influence of rat brain index and brain water content
Get 80 of female rats, 275g ± 25g is divided into 8 groups: Sham-operated control group at random, the cerebral ischemic model group is tested 1 group: the Radix Salviae Miltiorrhizae Injection group, test 2 groups: the Radix Notoginseng injection group, test 3 groups: the formula mannitol injection liquid group, test 4 groups: mannitol Radix Salviae Miltiorrhizae Injection group, test 5 groups: mannitol Radix Notoginseng injection group, test 6 groups: mannitol Salvia miltiorrhiza and Panax notoginseng injection group, intraperitoneal injection, 1 time/d, continuous 10d, Sham-operated control group and cerebral ischemic model group give the equivalent distilled water.Check the 1st and 10 day 24h urine protein and serum creatinine value.30min after the last administration, urethane anesthesia,, except that the Sham-operated control group rat, all ligation rat bilateral common carotid arteries forms acute experiment imperfection cerebral ischemic model, and Sham-operated control group is removed not ligation tremulous pulse, and operation technique is with cerebral ischemic model group rat.Behind the bilateral ligation 3h, broken end is opened cranium and is got brain, weighs, and calculates cerebral index (heavy * 100/ body weight of cerebral index=brain), is dried to constant weight at 110 ℃ then, calculates brain water content %=(weight in wet base-dry weight)/weight in wet base * 100%.
To the influence of cerebral index and brain water content (X ± SD)
| Group | Dosage (g/kg) | Mus number (only) | Cerebral index | Brain water content (%) | Urine protein is unusual | Serum creatinine is unusual |
| Sham-operation contrast cerebral ischemic model is tested 1 group and is tested 2 groups and test 3 groups and test 4 groups and test 5 groups and test 6 groups | ??- ??- ??1.5g/kg ??1.5g/kg ??1.5g/kg ??1.5g/kg ??1.5g/kg ??1.5g/kg | ??10 ??10 ??10 ??10 ??10 ??10 ??10 ??10 | ??0.68±0.08 ??0.77±0.09 ??0.76±0.12 ??0.76±0.36 ??0.71±0.04 ??0.70±0.41 ??0.71±0.25 ??0.69±0.01 | ??78.92±0.50 ??79.51±0.17 ??79.20±0.23 ??79.01±0.13 ??78.99±0.29 ??78.89±0.05 ??78.87±0.04 ??78.91±0.44 | ??0 ??0 ??0 ??0 ??4 ??1 ??2 ??0 | ??0 ??0 ??0 ??0 ??5 ??0 ??1 ??0 |
The result shows: cerebral ischemic model group rat brain index and brain water content obviously increase, and compound injection curative effect of the present invention is better than independent medication experimental group, especially mannitol Salvia miltiorrhiza and Panax notoginseng group.
Experimental example 4: to the therapeutical effect of rat ischemia cerebral edema
Laboratory animal is the Sprague-Dawley adult rat, body weight 250～300g, and male and female are regardless of.Adopt line bolt method to make rats with left middle cerebral artery occlusion (LMCAO) model.Experimental group is divided into 7 groups, 16h medication behind the ischemia.Test 1 group: injection of danshen dosage group, test 2 groups: Radix Notoginseng injection group, test 3 groups: mannitol injection group, test 4 groups: mannitol Danshen root injection group, test 5 groups: mannitol Radix Notoginseng injection group, test 6 groups: mannitol Salvia miltiorrhiza and Panax notoginseng injection group, test 7 groups: mannitol injection and Danshen root injection drug combination group.Every group each 7.Medication, intravenous administration, dosage are the 0.5g/Kg body weight, administration time is 5～10 minutes.The brain water content assay method: each group after administration 45min respectively with weight method, measure left side and right side cerebral hemisphere the first two/water content of an one (before the optic chiasma) (brainwatercontent, BWC).
(x ± s) (%) of the variation of different time brain water content behind the LMCAO
| Group | The focus side | Offside |
| ??1 ??2 ??3 | ??82.73±0.72 ??83.35±0.62 ??83.67±0.78 | ??79.40±0.63 ??78.82±0.40 ??77.01±0.58 |
| ??4 ??5 ??6 ??7 | ??83.67±1.08 ??82.54±0.72 ??83.31±0.64 ??82.77±0.65 | ??76.91±0.67 ??74.41±0.64 ??73.82±0.62 ??78.69±0.29 |
The result shows: compound injection of the present invention is evident in efficacy, is better than mannitol combined medication group and mannitol independent medication group, especially mannitol Salvia miltiorrhiza and Panax notoginseng group.
The treatment of 5 pairs of rat experiment liver cirrhosis of experimental example
Male Wistar rat, body weight 200～250g is divided into 6 groups; Test 1 group: the liver cirrhosis matched group, test 2 groups: the normal control group, test 3 groups: the mannitol treatment group, test 4 groups: mannitol Treated with Radix Salviae Miltiorrhizae group, test 5 groups: mannitol Radix Notoginseng treatment group, test 6 groups: mannitol Salvia miltiorrhiza and Panax notoginseng treatment group.Remove 2 groups of experiments, all the other experimental grouies adopt complex disease because of stimulating the system Hepatocirrhosis Model, promptly raise with low albumen high lipid diet, and 30% ethanol is beverage, subcutaneous injection CCL
4Treatment group beginning in second day administration, once a day, subcutaneous injection formula mannitol injection liquid, mannitol Radix Salviae Miltiorrhizae Injection, mannitol Radix Notoginseng injection, mannitol Salvia miltiorrhiza and Panax notoginseng injection 0.05ml/100g, matched group injection equivalent normal saline.In 6～8 of experiment every group of execution at the 2nd, 4,6,8 weekends animals.Get fritter hepatic tissue 2% sodium cacodylate buffer glutaraldehyde and fix, make electron microscope specimen and observe, all the other hepatic tissue 95% dehydration of alcohols, the acetone defat is carried out collagen protein and is measured.
Influence (8 weekend) to degree of cirrhosis regulating liver-QI collagen content
| Group | Degree of cirrhosis | The liver collagen content | ||||
| ??1 ??2 ??3 ??4 ??5 ??6 | ??- ??0 ??6 ??1 ??1 ??1 ??1 | ??+ ??0 ??0 ??3 ??2 ??2 ??1 | ??++ ??0 ??0 ??1 ??1 ??0 ??0 | ??+++ ??9 ??0 ??2 ??1 ??1 ??0 | Average 3.0 0 1.75 1.25 1 0.5 | The dried liver 30.1 of mg/g ± 6.0 14.4 ± 1.8 22.1 ± 2.7 20.0 ± 1.6 18.7 ± 1.5 15.2 ± 0.4 |
The result shows: test 8 weekend 9 of liver cirrhosis control animals all form liver cirrhosis, effect of the present invention is better than the mannitol treatment group, especially mannitol Salvia miltiorrhiza and Panax notoginseng treatment group.
Experiment is 3～5 results show: compound preparation of the present invention can effectively strengthen the drug effect of mannitol.
The specific embodiment:
Embodiments of the invention 1: the agent of injection lyophilized formulations prepares like this: get Radix Salviae Miltiorrhizae 250g, with 12 times of amount 95% alcohol reflux 1.5 hours, medicinal residues are with 12 times of amount 50% alcohol reflux 1.5 hours, 12 times of water gagings decoctions of medicinal residues reuse 1.5 hours, filter merge extractive liquid; Get Radix Notoginseng 250g,, add 6 times of amounts for the first time, refluxed 2 hours with 70% ethanol 2 times, for the second time add 5 times of amounts, refluxed 1.5 hours, filter, merge Radix Salviae Miltiorrhizae extract, reclaim ethanol and be condensed into extractum, add mannitol 500g and mix, add hot distilled water and make dissolving, add active carbon, static 10min behind the mixing, filter, 5% sodium hydroxide is transferred pH value 5-7, and 0.22 μ m microporous filter membrane filters, vacuum lyophilization or aseptic filtration or spray drying or in organic solvent recrystallization, packing, the sealing promptly.
Embodiments of the invention 2: the agent of injection lyophilized formulations prepares like this: get Radix Salviae Miltiorrhizae 100g, with 3 times of amount 95% alcohol reflux 1.5 hours, medicinal residues are with 3 times of amount 50% alcohol reflux 1.5 hours, 3 times of water gagings decoctions of medicinal residues reuse 1.5 hours, filter merge extractive liquid; Get Radix Notoginseng 400g,, add 3 times of amounts for the first time, refluxed 2 hours with 70% ethanol 2 times, for the second time add 8 times of amounts, refluxed 1.5 hours, filter, merge Radix Salviae Miltiorrhizae extract, reclaim ethanol and be condensed into extractum, add mannitol 500g and mix, add hot distilled water and make dissolving, add active carbon, static 10min behind the mixing, filter, 5% sodium hydroxide is transferred pH value 5-7, and 0.22 μ m microporous filter membrane filters, vacuum lyophilization or aseptic filtration or spray drying or in organic solvent recrystallization, packing, the sealing promptly.
Embodiments of the invention 3: the injection formulation agent prepares like this: get Radix Salviae Miltiorrhizae 50g, with 15 times of amount 95% alcohol reflux 1.5 hours, medicinal residues are with 15 times of amount 50% alcohol reflux 1.5 hours, 12 times of water gagings decoctions of medicinal residues reuse 1.5 hours, filter merge extractive liquid; Get Radix Notoginseng 50g, with 70% ethanol 2 times, add 8 times of amounts for the first time, refluxed 2 hours, add 5 times of amounts for the second time, refluxed 1.5 hours, filter, merge Radix Salviae Miltiorrhizae extract, reclaim ethanol and also be condensed into extractum, adding mannitol 900g mixing adds hot distilled water and makes dissolving, uses 10% chlorine
Change sodium solution and transfer pH value 5～9, add to the full amount of water for injection, 0.22 μ m microporous filter membrane filters, and embedding was sterilized 30 minutes for 100 ℃.
Embodiments of the invention 4: the injection formulation agent prepares like this: get Radix Salviae Miltiorrhizae 70g, with 12 times of amount 95% alcohol reflux 1.5 hours, medicinal residues are with 12 times of amount 50% alcohol reflux 1.5 hours, 12 times of water gagings decoctions of medicinal residues reuse 1.5 hours, filter merge extractive liquid; Get Radix Notoginseng 30g,, add 6 times of amounts for the first time with 70% ethanol 2 times, refluxed 2 hours, and added 5 times of amounts for the second time, refluxed 1.5 hours, filter, merge Radix Salviae Miltiorrhizae extract, reclaim ethanol and be condensed into extractum, add mannitol 900g and mix, add hot distilled water and make dissolving, transfer pH value 5～9 with 10% sodium chloride solution, add to the full amount of water for injection, 0.22 μ m microporous filter membrane filters, embedding was sterilized 30 minutes for 100 ℃.
Embodiments of the invention 5: tablet is like this preparation: get Radix Notoginseng 10g, with 70% ethanol 2 times, add 6 times of amounts the first time, refluxed 2 hours, and added 5 times of amounts for the second time, refluxed 1.5 hours, filter, filtrate recycling ethanol also is condensed into extractum, adds mannitol 990g and mixes, the system soft material is granulated drying, granulate, add 0.3% magnesium stearate, tabletting, promptly.
Embodiments of the invention 6: tablet is like this preparation: get Radix Notoginseng 990g, with 70% ethanol 2 times, add 6 times of amounts the first time, refluxed 2 hours, and added 5 times of amounts for the second time, refluxed 1.5 hours, filter, filtrate recycling ethanol also is condensed into extractum, adds mannitol 10g and mixes, the system soft material is granulated drying, granulate, add 0.3% magnesium stearate, tabletting, promptly.
Embodiments of the invention 7: its granule is like this preparation: get Radix Salviae Miltiorrhizae 990g, with 12 times of amount 95% alcohol reflux 1.5 hours, medicinal residues were measured 50% alcohol reflux 1.5 hours with 12 times, 12 times of water gagings of medicinal residues reuse decocted 1.5 hours, filter, merge extractive liquid, reclaims ethanol and is condensed into extractum, after adding mannitol 10g mixing, the system soft material is granulated drying, granulate, promptly.
Embodiments of the invention 8: its granule is like this preparation: get Radix Salviae Miltiorrhizae 10g, with 12 times of amount 95% alcohol reflux 1.5 hours, medicinal residues were measured 50% alcohol reflux 1.5 hours with 12 times, 12 times of water gagings of medicinal residues reuse decocted 1.5 hours, filter, merge extractive liquid, reclaims ethanol and is condensed into extractum, after adding mannitol 990g mixing, the system soft material is granulated drying, granulate, promptly.
Embodiments of the invention 9: the agent of injection lyophilized formulations prepares like this: get Radix Salviae Miltiorrhizae 50g, with 3 times of amount 95% alcohol reflux 1.5 hours, medicinal residues are with 3 times of amount 50% alcohol reflux 1.5 hours, 3 times of water gagings decoctions of medicinal residues reuse 1.5 hours, filter merge extractive liquid; Get Radix Notoginseng 50g,, add 3 times of amounts for the first time, refluxed 2 hours with 70% ethanol 2 times, for the second time add 8 times of amounts, refluxed 1.5 hours, filter, merge Radix Salviae Miltiorrhizae extract, reclaim ethanol and be condensed into extractum, add mannitol 900g and mix, add hot distilled water and make dissolving, add active carbon, static 10min behind the mixing, filter, 5% sodium hydroxide is transferred pH value 5-7, and 0.22 μ m microporous filter membrane filters, vacuum lyophilization or aseptic filtration or spray drying or in organic solvent recrystallization, packing, the sealing promptly.
Embodiments of the invention 10: the agent of injection lyophilized formulations prepares like this: get Radix Salviae Miltiorrhizae 490g, with 3 times of amount 95% alcohol reflux 1.5 hours, medicinal residues are with 3 times of amount 50% alcohol reflux 1.5 hours, 3 times of water gagings decoctions of medicinal residues reuse 1.5 hours, filter merge extractive liquid; Get Radix Notoginseng 500g,, add 3 times of amounts for the first time, refluxed 2 hours with 70% ethanol 2 times, for the second time add 8 times of amounts, refluxed 1.5 hours, filter, merge Radix Salviae Miltiorrhizae extract, reclaim ethanol and be condensed into extractum, add mannitol 10g and mix, add hot distilled water and make dissolving, add active carbon, static 10min behind the mixing, filter, 5% sodium hydroxide is transferred pH value 5-7, and 0.22 μ m microporous filter membrane filters, vacuum lyophilization or aseptic filtration or spray drying or in organic solvent recrystallization, packing, the sealing promptly.
Claims (12)
1, a kind of pharmaceutical preparation of compound formula mannitol, it is characterized in that: calculate according to components by weight percent, it is by 99～1 parts in mannitol, a kind of in Radix Salviae Miltiorrhizae, the Radix Notoginseng or two kinds 1～99 part are made, or a kind of in the Radix Salviae Miltiorrhizae extract that obtains after extracting of mannitol and corresponding weight fraction, Radix Notoginseng extract or two kinds are made.
2, according to the pharmaceutical preparation of the described compound formula mannitol of claim 1, it is characterized in that: calculate according to components by weight percent, it is by 90～10 parts in mannitol, a kind of in Radix Salviae Miltiorrhizae, the Radix Notoginseng or two kinds 10～90 parts are made, or a kind of in the Radix Salviae Miltiorrhizae extract that obtains after extracting of mannitol and corresponding weight fraction, Radix Notoginseng extract or two kinds are made.
3, according to the pharmaceutical preparation of the described compound formula mannitol of claim 1, it is characterized in that: calculate according to components by weight percent, it is by 20 parts in mannitol, a kind of in Radix Salviae Miltiorrhizae, the Radix Notoginseng or two kinds 80 parts are made, or a kind of in the Radix Salviae Miltiorrhizae extract that obtains after extracting of mannitol and corresponding weight fraction, Radix Notoginseng extract or two kinds are made.
4, according to the pharmaceutical preparation of claim 1,2 or 3 described compound formula mannitols, it is characterized in that: preparation of the present invention is: injection comprises: all acceptable dosage forms on the pharmaceuticss such as injection, powder pin, freeze-dried powder, tablet, capsule, soft capsule, microcapsule, granule, pill, powder, drop pill, slow releasing preparation, controlled release preparation, oral liquid, soft extract, extractum and membrane.
5, according to the pharmaceutical preparation of the described this compound formula mannitol of claim 4, it is characterized in that: described preparation is an injection, comprising: injection, injectable powder, lyophilized injectable powder or common flour injection, infusion solution.
6, as the preparation method of the pharmaceutical preparation of the described compound formula mannitol of claim 1-5, it is characterized in that: get Radix Salviae Miltiorrhizae, pulverize the back and add 3～15 times of amount ethanol, reflux, extract, is filtered, 3～15 times of amounts of medicinal residues reuse alcohol reflux, merge extractive liquid,, filter, 3～15 times of water gagings of medicinal residues reuse decoct, and filter, merge extractive liquid,, reclaim ethanol and be condensed into extractum, add mannitol and mix, the reuse diverse ways is made different preparations.
7, according to the preparation method of the pharmaceutical preparation of the described compound formula mannitol of claim 6, it is characterized in that: get Radix Notoginseng, pulverize the back and add 3～8 times of amount ethanol, reflux, extract, 1～5 time, filter, filtrate recycling ethanol also is condensed into extractum, adds mannitol and mixes, and the reuse diverse ways is made different preparations.
8, according to the preparation method of the pharmaceutical preparation of claim 6 or 7 described compound formula mannitols, it is characterized in that: get Radix Salviae Miltiorrhizae, pulverize the back and add 3～15 times of amount ethanol, reflux, extract, is filtered, 3～15 times of amounts of medicinal residues reuse alcohol reflux, merge extractive liquid, filters, and 3～15 times of water gagings of medicinal residues reuse decoct, filter merge extractive liquid; Get Radix Notoginseng, pulverize the back and add 3～8 times of amount ethanol, reflux, extract, 1～5 time is filtered, and merges Radix Salviae Miltiorrhizae extract, reclaims ethanol and is condensed into extractum, adds mannitol and mixes, and the reuse diverse ways is made different preparations.
9, according to the preparation method of the pharmaceutical preparation of the described compound formula mannitol of claim 6, it is characterized in that: get Radix Salviae Miltiorrhizae, with 12 times of amount 95% alcohol reflux 1.5 hours, medicinal residues were measured 50% alcohol reflux 1.5 hours with 12 times, and 12 times of water gagings of medicinal residues reuse decocted 1.5 hours, filtered, merge extractive liquid,, reclaim ethanol and be condensed into extractum, after adding mannitol mixes, the system soft material, granulate, drying, granulate promptly gets granule.
10, according to the preparation method of the pharmaceutical preparation of the described compound formula mannitol of claim 7, it is characterized in that: get Radix Notoginseng, with 70% ethanol 2 times, for the first time add 6 times of amounts, refluxed 2 hours, add 5 times of amounts for the second time, refluxed 1.5 hours, and filtered, filtrate recycling ethanol also is condensed into extractum, add mannitol and mix, the system soft material is granulated, drying, granulate adds 0.3% magnesium stearate, tabletting promptly gets tablet.
11, according to the preparation method of the pharmaceutical preparation of the described compound formula mannitol of claim 8, it is characterized in that: get Radix Salviae Miltiorrhizae, measured 95% alcohol reflux 1.5 hours with 12 times, medicinal residues were measured 50% alcohol reflux 1.5 hours with 12 times, 12 times of water gagings of medicinal residues reuse decocted 1.5 hours, filter merge extractive liquid; Get Radix Notoginseng,, add 6 times of amounts for the first time with 70% ethanol 2 times, refluxed 2 hours, and added 5 times of amounts for the second time, refluxed 1.5 hours, filter, merge Radix Salviae Miltiorrhizae extract, reclaim ethanol and be condensed into extractum, add mannitol and mix, add hot distilled water and make dissolving, transfer pH value 5～9 with 10% sodium chloride solution, add to the full amount of water for injection, 0.22 μ m microporous filter membrane filters, embedding, sterilized 30 minutes for 100 ℃, get injection formulation.
12, according to the preparation method of the pharmaceutical preparation of the described compound formula mannitol of claim 8, it is characterized in that: get Radix Salviae Miltiorrhizae, measured 95% alcohol reflux 1.5 hours with 12 times, medicinal residues were measured 50% alcohol reflux 1.5 hours with 12 times, 12 times of water gagings of medicinal residues reuse decocted 1.5 hours, filter merge extractive liquid; Get Radix Notoginseng,, add 6 times of amounts for the first time, refluxed 2 hours with 70% ethanol 2 times, for the second time add 5 times of amounts, refluxed 1.5 hours, filter, merge Radix Salviae Miltiorrhizae extract, reclaim ethanol and be condensed into extractum, add mannitol and mix, add hot distilled water and make dissolving, add active carbon, static 10min behind the mixing, filter, 5% sodium hydroxide is transferred pH value 5-7, and 0.22 μ m microporous filter membrane filters, vacuum lyophilization or aseptic filtration or spray drying or in organic solvent recrystallization, packing, sealing promptly gets lyophilized powder injection.
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| CN 200410022502 CN1692916A (en) | 2004-05-09 | 2004-05-09 | Pharmaceutical prepn. of compound mannite, and its prepn. method |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103432066A (en) * | 2013-07-23 | 2013-12-11 | 蚌埠丰原涂山制药有限公司 | Compound mannitol injection and preparation method thereof |
| CN105943495A (en) * | 2016-06-24 | 2016-09-21 | 苏远芳 | Mannitol injection |
| CN106491747A (en) * | 2016-12-27 | 2017-03-15 | 翔宇药业股份有限公司 | The preparation of Cordycepses QISHEN CAPSULE and quality standard detecting method |
| CN107398092A (en) * | 2017-07-31 | 2017-11-28 | 芜湖杨燕制药有限公司 | Filtrate cycle recovery process in the production of traditional Chinese medicine |
-
2004
- 2004-05-09 CN CN 200410022502 patent/CN1692916A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103432066A (en) * | 2013-07-23 | 2013-12-11 | 蚌埠丰原涂山制药有限公司 | Compound mannitol injection and preparation method thereof |
| CN105943495A (en) * | 2016-06-24 | 2016-09-21 | 苏远芳 | Mannitol injection |
| CN106491747A (en) * | 2016-12-27 | 2017-03-15 | 翔宇药业股份有限公司 | The preparation of Cordycepses QISHEN CAPSULE and quality standard detecting method |
| CN106491747B (en) * | 2016-12-27 | 2020-03-24 | 翔宇药业股份有限公司 | Preparation of cordyceps sinensis-astragalus-ginseng capsule and quality standard detection method |
| CN107398092A (en) * | 2017-07-31 | 2017-11-28 | 芜湖杨燕制药有限公司 | Filtrate cycle recovery process in the production of traditional Chinese medicine |
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