Summary of the invention
The object of the present invention is to provide a kind of pharmaceutical composition and preparation method for the treatment of the apoplexy and the thoracic obstruction.Its advantage is simple for process, and cost is low.
A kind of pharmaceutical composition that is used for the treatment of the apoplexy and the thoracic obstruction of the present invention, mainly obtained by the processing of following materials of weight proportions: get 66 parts of the Radixs Astragali, 27 parts of Radix Paeoniae Rubra, 27 parts of Radix Salviae Miltiorrhizaes, 27 parts of Radix Angelicae Sinensis, 27 parts of Rhizoma Chuanxiongs, 27 parts in Semen Persicae, 13 parts on Flos Carthami, 13 parts of Olibanum (processed)s, 13 parts of Myrrha (processed)s, 20 parts of Caulis Spatholobis, 27 parts of Radix Achyranthis Bidentataes, 20 parts of Ramulus Cinnamomi, 27 parts of Ramulus Moris, 27 parts of Pheretimas, 13 parts of Scorpios, 27 parts of Hirudos, the pharmaceutically acceptable active ingredient that makes according to a conventional method mixes the granule that technology is routinely made with adjuvant.Specifically, this pharmaceutical composition that is used for the treatment of apoplexy and thoracic obstruction disease, used adjuvant are dextrin, sodium carboxymethyl cellulose, microcrystalline Cellulose, stevioside, polyvinylpyrrolidone k30 chooses any one kind of them or two or more adjuvants.The pharmaceutical composition that more particularly is used for the treatment of apoplexy and thoracic obstruction disease, if used mixing back medicinal powder 240-300 part, used adjuvant is that the alcoholic solution of dextrin 640-700 part, sodium carboxymethyl cellulose 15-25 part, microcrystalline Cellulose 15-25 part, stevioside 5-15 part, polyvinylpyrrolidone k30 is an amount of.
The preparation method that is used for the treatment of the Chinese medicine composition of the apoplexy and the thoracic obstruction of the present invention is: get Pheretima, Scorpio, be ground into fine powder, all the other Radixs Astragali, Radix Paeoniae Rubra, Radix Salviae Miltiorrhizae, Radix Angelicae Sinensis, Rhizoma Chuanxiong, Semen Persicae, Flos Carthami, Olibanum (processed), Myrrha (processed), Caulis Spatholobi, Radix Achyranthis Bidentatae, Ramulus Cinnamomi, Ramulus Mori, Hirudo 14 flavors are ground into fine powder, with above-mentioned powder facing-up, sieve, mixing, standby; Get and mix back medicinal powder 267g, add dextrin 683g, sodium carboxymethyl cellulose 20g, stevioside 10g, microcrystalline Cellulose 20g mix homogeneously, 10% the alcoholic solution system soft material that adds an amount of polyvinylpyrrolidone k30,16 mesh sieves are granulated, 70 ℃ of forced air dryings, 16 mesh sieve granulate, make 1000g, packing, every bag of 3g, promptly.
The flour extraction of medical material is investigated
Do three tests (in each medical material total amount 200g), take by weighing at every turn and get Pheretima, Scorpio in the crude drug, be ground into fine powder; 14 flavors such as all the other Radixs Astragali, Radix Paeoniae Rubra, Radix Salviae Miltiorrhizae, Radix Angelicae Sinensis, Rhizoma Chuanxiong, Semen Persicae, Flos Carthami, Olibanum (system), Myrrha (processed), Caulis Spatholobi, Radix Achyranthis Bidentatae, Ramulus Cinnamomi, Ramulus Mori, Hirudo are ground into fine powder, with above-mentioned powder facing-up, sieve, cross 80 eye mesh screens, fine powder weight after mensuration is sieved, promptly.
The flour extraction of table 1 medical material is investigated result of the test
Tested number | No. 1 | No. 2 | No. 3 |
Medical material total amount (g) fine powder amount (g) fine powder yield (%) | 200 197.2 98.6 | 200 195.8 97.9 | 200 197.6 98.8 |
Above-mentioned medical material flour extraction result of the test shows that the fine powder loss is less, and yield is more stable, and this process stabilizing is feasible.
The preparations shaping technical study
Prescription screening
The recipe quantity of medical material of the present invention is identical with former invention capsule medical material recipe quantity, and former invention capsule is once taken the 2-4 grain, so granule of the present invention is equivalent to 2 of former invention capsules for 1 bag.According to medicinal powder under the experimental condition and adjuvant physical property, do following prescription screening according to 500 recipe quantities of former invention capsule.Mainly to the adhesive kind, the ratio of stevioside and dextrin is carried out prescription screening, with whether easily granulation, particulate hardness, the uniformity, color and luster, etc. index screen, granule dissolving of the present invention back is a suspension solution, in order to prolong the suspendible time, we add a certain amount of sodium carboxymethyl cellulose, microcrystalline Cellulose, screen with indexs such as suspendible times.
Adhesive type prescription screening
Take by weighing 4 parts of medical material fine powders respectively, every part of 200g uses 50% alcoholic solution respectively, and 5%PVPK30 alcoholic solution, 10%PVPK30 alcoholic solution, 15%PVPK30 alcoholic solution are crossed 16 mesh sieves and granulated drying.As the investigation project, the result is as shown in table 2 with the granulation difficulty or ease.
Table 2 adhesive type prescription screening
The prescription number | 1 | 2 | 3 | 4 |
Mix back medicinal powder (g) adhesive type | 200 50% alcoholic solution | 200 5%PVP
K30 | 200 10%PVP
K30 | 200 15%PVP
K30 |
Granulation, granulate sieve number granulation difficulty or ease | Alcoholic solution 16 is granulated difficult, not granulating | Alcoholic solution 16 is granulated difficult, not granulating | Alcoholic solution 16 can be made into granule, dry back loose particles | Alcoholic solution 16 can be made into granule, dry back loose particles |
Above-mentioned result of the test shows that prescription 3 is better with prescription 4 results, and according to optimizing the prescription principle, we select for use the 10%PVPK30 alcoholic solution as adhesive, and needs to add an amount of diluent.
The diluent prescription screening
Dextrin is adjuvant commonly used, and safe, low price is so we select for use dextrin as diluent.Take by weighing 4 parts of medical material fine powders respectively, every part of 200g adds 300g, 400g, 500g, 600g dextrin respectively as diluent, behind the mix homogeneously, add an amount of 10%PVPK30 alcoholic solution system soft material, cross 16 mesh sieves and granulate, drying, as the investigation project, the result is as shown in table 3 with the granulation difficulty or ease.
Table 3 granule prescription screening of the present invention
The prescription number | 1 | 2 | 3 | 4 |
Mix back medicinal powder (g) adhesive type dextrin (g) granulation difficulty or ease | 200 10%PVP
K30Alcoholic solution 300 is difficult for granulating, dry back loose particles, fine powder is more
| 200 10%PVP
K30Alcoholic solution 400 is difficult for granulating, dried granule is more diffusing, and fine powder is too many
| 200 10%PVP
K30Alcoholic solution 500 granule viscosity are moderate, can granulate, and pellet hardness, the uniformity, color and luster are all better.
| 200 10%PVP
K30Alcoholic solution 600 granule viscosity are moderate, can granulate, and pellet hardness, the uniformity, color and luster are all better.
|
Above-mentioned result of the test shows, prescription 3 is better with prescription 4 results, and granule viscosity is moderate, can granulate, and pellet hardness, the uniformity, color and luster are all better.According to optimizing the prescription principle, we select for use supplementary product consumption less relatively as recipe quantity, so select prescription 3 for use.
The suspending agent prescription screening
Granule dissolving of the present invention back is a suspension solution, and for improving granule suspendible effect, we add an amount of suspending agent and improve its suspendible effect, and according to pharmaceutical properties, we select for use sodium carboxymethyl cellulose, microcrystalline Cellulose as suspending agent; Take by weighing 4 parts of medical material fine powders respectively, every part of 200g, add the 500g dextrin as diluent, add respectively sodium carboxymethyl cellulose, microcrystalline Cellulose 5g/5g, 10g/10,15g/15g, 20g/20g as the suspending agent mix homogeneously after, add an amount of 10%PVPK30 alcoholic solution system soft material, cross 16 mesh sieves and granulate drying.One one (appendix I) checks that the result is as shown in table 4 according to " Chinese Pharmacopoeia 2000 editions ".
Table 4 suspending agent prescription screening
The prescription number | 1 | 2 | 3 | 4 |
Medicinal powder (g) binder type dextrin (g) sodium carboxymethylcellulose (g) microcrystalline cellulose (g) dissolves (min) the suspendible sedimentation time even time (min) after mixing | 200 10%PVP
K30Alcoholic solution 300 55<5<0.5
| 200 10%PVP
K30Alcoholic solution 400 10 10<5<1
| 200 10%PVP
K30Alcoholic solution 500 15 15<5>1
| 200 10%PVP
K30Alcoholic solution 600 20 20>5>1
|
Above-mentioned result of the test shows that we prolong the sedimentation time to greatest extent under the condition that can reach the dissolution time requirement, makes the even suspendible time lengthening of suspension, and 3 results that write out a prescription are better, and according to optimizing the prescription principle, we select prescription 3 for use.
The correctives prescription screening
Granule of the present invention is used as medicine for the medical material fine powder, considers the influence of its abnormal smells from the patient to patient, and we add an amount of correctives, and for the crowd that is suitable for is widely arranged, we select for use stevioside as correctives; Take by weighing 4 parts of medical material fine powders respectively, every part of 200g, after adding dextrin 500g, sodium carboxymethyl cellulose 15g, microcrystalline Cellulose 15g mix homogeneously respectively, add 2.5g, 5g, 7.5g, 10g stevioside respectively as correctives, mix homogeneously, add an amount of 10%PVPK30 alcoholic solution system soft material, cross 16 mesh sieves and granulate drying.The result is as shown in table 5.
Table 5 correctives prescription screening (250 bags of recipe quantities)
The prescription number | 1 | 2 | 3 | 4 |
Mix back medicinal powder (g) adhesive type dextrin (g) sodium carboxymethyl cellulose (g) | 200 10%PVP
K30Alcoholic solution 500 15
| 200 10%PVP
K30Alcoholic solution 500 15
| 200 10%PVP
K30Alcoholic solution 500 15
| 200 10%PVP
K30Alcoholic solution 500 15
|
Microcrystalline Cellulose (g) stevioside (g) taste | 15 2.5 littlely have fishy smell | 15 5 is little sweet | 15 7.5 is sweet | 15 10 is sweet, little hardship |
Annotate: equal 70 ℃ of bake out temperature
By the prescription screening result, the 3 flavoring effects of writing out a prescription are better than other prescription, and prescription 3 can be made into the 750g granule, is equivalent to 250 bags, and every bag of 3g granule determines to use prescription 3 to be granule preparation technology of the present invention.
The test of technology repeatability:
By granule is the recipe quantity of 1000g (333 bags), feeds intake three batches, carries out the test of technology repeatability.Get and mix back medical material fine powder 267g, add dextrin 683g, sodium carboxymethyl cellulose 20g, microcrystalline Cellulose 20g, stevioside 10g, mix homogeneously, 10% the alcoholic solution system soft material that adds an amount of polyvinylpyrrolidone k30,16 mesh sieves are granulated, 70 ℃ of forced air dryings, 16 mesh sieve granulate, make 1000g, packing, every bag of 3g, promptly.The result is as follows:
Particulate prescription of table 6 the present invention and technology reproducible test results
Lot number | 031101 | 031102 | 031103 |
Medicinal material fine powder (g) dextrin (g) sodium carboxymethylcellulose (g) microcrystalline cellulose (g) Stevioside (g) is done the average actual finished product total amount of the theoretical output of loading amount (g) (bag) (bag) the finished product yield (%) of pellet moisture (%) after mixing | 267 683 20 20 10 3.8 3.00 333 318 95.5 | 267 683 20 20 10 4.4 3.01 333 316 94.9 | 267 683 20 20 10 3.6 3.01 333 321 96.4 |
By reproducible test results as can be known,, carried out three batches of particulate preparations of the present invention by granule technology of the present invention, the every index basically identical of sample, this prescription and technology have repeatability preferably.
The research of granule main pharmacodynamics of the present invention aspect
1. granule of the present invention is to the influence of rat local cerebral ischemia damage
1.1 method
The dosage design: 6~12/day of former invention capsule humans, closed 2.4g~4.8g/ days, press body surface area and calculate that the rat effective dose is about 240mg/kg~480mg/kg; We find by preliminary experiment, former invention capsule a little more than effective dose (240mg/kg) can show the Mus cerebral ischemia effect of the tangible Chinese People's Anti-Japanese Military and Political College, therefore we select for use the former invention capsule of 280mg/kg as the rat effective dose, calculate by crude drug to be equivalent to granule 1048mg/kg of the present invention.(down together)
Animal is divided into sham operated rats (medical Oleum Glycines) at random, model control group (medical Oleum Glycines), former invention Capsules group (280mg/kg), granule small dose group of the present invention (524mg/kg), middle dosage group (1048mg/kg), heavy dose of group (2096mg/kg), 10 every group.Continuously gastric infusion is 3 days, and fasting is 16 hours after the administration in the 2nd day, and the last administration is after 90 minutes, and chloral hydrate (360mg/kg, ip) anesthesia separates right carotid, and folder closes in the neck, common carotid artery, external carotid artery proximal part and distal end ligation, cut off the centre.The external carotid artery free-end is pulled to internal carotid artery in alignment, bolt line (selecting diameter 0.24mm nylon wire for use, length 5.0cm) is inserted into intracranial by external carotid artery, stop when meeting slight resistance, insertion depth is about 2cm.Ligation external carotid artery opening, and open the common carotid artery bulldog clamp, the disinfection and stitching wound causes right side middle cerebral artery ischemia model; Sham operated rats is only carried out the separation (above experiment is all carried out at 23 ℃~25 ℃) of right carotid, internal carotid artery, external carotid artery.The behavior disorder of rat is observed and write down to the standard that reaches as follows after 24 hours: (1) is carried the Mus tail and is observed forelimb flexing situation, stretch to ground as two forelimb symmetries, count 0 fen, as the offside forelimb of performing the operation the wrist flexing occurs and counts 1 fen, the elbow flexing is counted 2 fens, and the shoulder inward turning is counted 3 fens, existing wrist flexing and/or elbow flexing, shoulder inward turning person is arranged again, count 4 fens.(2) animal is placed on the plane earth, push away both shoulders respectively, check resistance to side shifting.As bilateral resistance equity and strong, count 0 fen, as resistance descender when the operation offside promotes, according to decline degree difference be divided into gently, in, weigh three degree, count 1,2 and 3 fen respectively.(3) the two forelimbs of animal are put on the wire netting, observed the muscular tension of two forelimbs.Two muscle of anterior limb tension force equities and strong person count 0 fen.Count 1,2 and 3 fen according to operation offside muscular tension decline degree difference equally.(4) animal has ceaselessly to a side person of turn-taking, and counts 1 fen.According to the standard scoring, full marks are 11 minutes, and mark is high more, and expression animal behavior obstacle is serious more.Data are represented with x ± SD, carry out statistical test with the reference differential technique.
Put to death rat behind the behavior scoring, get brain, remove olfactory bulb, cerebellum and low brain stem, crownly be cut into 5, the brain sheet takes on a red color after normal structure is dyed with red tetrazolium (TTC) dyeing, and blocking tissue is white in color, taking a picture in dyeing back, asks the infarct size ratio with Chinese Aero-Space university pathological image analysis software.Data are represented with x ± SD, and are compared the T-test check with the blank group.
1.2 result
Ischemia is after 24 hours as a result, and rat model shows tangible behavior disorder, and tangible kitchen range shape ischemic region also appears in rat cerebral tissue, and necrosis area reaches about 25% of full brain; Give the granule of the present invention of various dose, the animal behavior obstacle has alleviating in various degree, and rat cerebral ischemia district necrosis area also has obvious reduction, and is dose dependent; The granule of the present invention of same materials medicine and capsule action intensity be (P>0.05) quite.
2. granule of the present invention is to the influence of rat heart muscle ischemic injuries
2.1 method
Get 50 of rats, be divided into blank group (medical Oleum Glycines), former invention capsule (280mg/kg), granule small dose group of the present invention (524mg/kg), middle dosage group (1048mg/kg), heavy dose of group (2096mg/kg) at random, 10 every group.Gastric infusion is 3 days continuously, fasting is 16 hours after the administration in the 2nd day, and the last administration was drawn dawn 1.2g/kg anesthesia with 20% crow after 90 minutes, the record normal ECG, 3~4 intercostals are opened breast from the left side immediately, expose heart, find out arteria coronaria left anterior descending branch (LAD) in pulmonary conus and left room, wearing one " 0 " number toe-in at distance starting point 2~3mm place pricks, send heart back to thoracic cavity, extrude thoracic cavity inner blood and gas, sew up thoracic wall immediately.Whole surgery was finished in 30 seconds.5,15,30,45,60,90,120,150,180,210, the 240 minutes electrocardiograms in record operation back.
Perform the operation after 360 minutes, the ventral aorta blood sampling, separation of serum is measured serum creatine kinase (CK), lactic acid dehydrogenase (LDH), aspartate aminotransferase (AST) activity according to the described method of detection kit description.Opening breast cores dirty, remove the atrium, the ventricle crosscut is become 3~4, insert 0.25% chlorination nitro blue tetrazolium (NBT) solution of pH 7.4,37 ℃ of dyeing are treated to take out immediately when the infarcted myocardium boundary line is known, separate infarcted myocardium and normal myocardium, weigh calculating myocardium infarction percentage ratio (infarcted myocardium accounts for the percentage ratio of chamber muscle wet weight whole-heartedly) respectively.
Data are represented with x ± SD, and are compared the T-test check with the blank group.
2.2 result
Ligation rat coronary artery left anterior descending branch can cause Acute Myocardial Ischemia in Rats, showing as electrocardiogram J point obviously raises, serum creatine kinase, lactic acid dehydrogenase, aspartate aminotransferase activity (content) obviously raise, and myocardial infarction percentage ratio obviously increases.
Granule 524k of the present invention, 1048g and former invention capsule 2096kg all can suppress raising of electrocardiogram J point in the certain hour scope after coronary artery ligation; Obviously suppress the rising of serum creatine kinase, lactic acid dehydrogenase, aspartate aminotransferase activity (content); Reduce myocardial infarction percentage ratio.The granule ' Yanming ' capsules for clearing action intensity of the present invention of same materials medicine is (P>0.05) quite.