CN100574752C - A kind of pharmaceutical composition of preventing and treating ischemic cerebrovascular and preparation method thereof - Google Patents
A kind of pharmaceutical composition of preventing and treating ischemic cerebrovascular and preparation method thereof Download PDFInfo
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Abstract
The invention provides a kind of pharmaceutical composition of preventing and treating ischemic cerebrovascular and preparation method thereof, it contains active ingredient and carrier, described active ingredient is that 100: 0.5～10 ferulic acid or its are formed at pharmaceutically acceptable salt and Borneolum Syntheticum by weight ratio, can be prepared as the pharmaceutical dosage form that is suitable for clinical practice and comprise: granule, capsule, tablet, drop pill, suppository, injection.The present invention has disclosed the neuroprotective of the compositions of ferulic acid or its salt and Borneolum Syntheticum to the transience global brain ischemia; two medicines are united the synergism of having brought into play two medicines; compare with single ferulic acid; absorb the half-life prolongation; peak time is faster; and reduced the dose of ferulic acid, increased the safety of medicine.The medicine that the present invention lacks the courageous and upright cerebrovascular disease of brain as control have the pharmacological action cooperative compensating, rapid-action, effective time prolongs, taking dose is little, the advantage of determined curative effect.
Description
[technical field]
The present invention relates to a kind of pharmaceutical composition of preventing and treating ischemic cerebrovascular and preparation method thereof.
[background technology]
Along with the aging of current social population, the cerebrovascular sickness rate constantly increases, and has sickness rate height, disability rate height, " three-hypers " characteristics that mortality rate is high, has become one of principal disease of serious harm human health.In 57 countries of the WHO of the United Nations investigation, die from the cerebrovascular patient and account for 11.3%, wherein have 40 national cerebrovascular to account for cause of the death front three.The sum of U.S.'s patients with cerebral apoplexy reaches more than 4,000,000 person-times.China dies from about 1,000,000 people of cerebrovascular every year, and cerebrovascular disease in 2003 position of all being number two in the city and the rural disease cause of death is only second to malignant tumor.In cerebrovascular, ischemic cerebrovascular accounts for 80%.Ischemic cerebrovascular is department of neurology commonly encountered diseases, frequently-occurring disease, disability rate is high, is a kind of disease of present keypoint control, and it comprises cerebral arteriosclerosis, cerebral infarction etc., this class patient causes that easily apoplexy, vascular dementia, cognitive dysfunction merge diseases such as Alzheimer.
(Ferulic acid, FA), chemistry 4-hydroxy 3-methoxybenzene acrylic acid by name is one of effective ingredient of plurality of Chinese such as Resina Ferulae, Rhizoma Chuanxiong, Radix Angelicae Sinensis, Rhizoma Cimicifugae, Herba Equiseti Hiemalis to ferulic acid.The ferulic acid water solublity is little, and (Sodium ferulate SF) uses therefore often to make sodium salt.Ferulic acid has tangible pharmacologically active, has very strong antioxidant activity, can remove free radical, regulates human physiological functions, suppresses to produce the enzyme of free radical, has the generation of the enzyme that promotes the removing free radical, effects such as anti-platelet aggregation and thrombosis.Current research shows that ferulic acid has the DEVELOPMENT PROSPECT of treatment Alzheimer's disease; Ischemic brain injury there is protective effect.But because ferulic acid is difficult to by blood brain barrier, its bioavailability is low, unsatisfactory curative effect.Weakened the effect that ferulic acid should be brought into play the central nervous system.
Borneolum Syntheticum is divided into natural Broneolum Syntheticum and synthetic borneol, and the main constituent of natural Broneolum Syntheticum is Borneolum Syntheticum (Borneol, a 2-baras camphor; Molecular formula C
10H
18O), synthetic borneol also records in Chinese Pharmacopoeia, and Main Ingredients and Appearance is Borneolum Syntheticum and isoborneol (containing 35% isoborneol approximately), all is the fat-soluble monoterpenes materials of micromolecule, can absorb rapidly through intestinal.Current research finds that also Borneolum Syntheticum has the effect of the reparation of anti-cerebral ischemia damnification and acceleration cerebral ischemia hindbrain blood vessel endothelium.
Treated the ischemic cerebrovascular medicine in recent years and constantly came out, but curative effect and unsatisfactory, and some poisonous side effect of medicine is big.
[summary of the invention]
Purpose of the present invention is exactly existing single with the shortcoming of ferulic acid with Borneolum Syntheticum treatment ischemic cerebrovascular unsatisfactory curative effect in order to overcome, provide a kind of have the pharmacological action cooperative compensating, rapid-action, effective time prolongs, taking dose is little, the control of determined curative effect lacks pharmaceutical composition of brain courage and uprightness cerebrovascular disease and preparation method thereof.
For achieving the above object, the invention provides a kind of pharmaceutical composition of preventing and treating ischemic cerebrovascular, it contains active ingredient and carrier, described active ingredient is that 100: 0.5～10 ferulic acid or its are formed at pharmaceutically acceptable salt and Borneolum Syntheticum by weight ratio, can be prepared as any pharmaceutical dosage form that is suitable for clinical practice, include but not limited to: granule, capsule, tablet, drop pill, suppository, injection.
The pharmaceutically acceptable pharmaceutical salts of ferulic acid of the present invention can be sodium salt, potassium salt, ammonium salt, calcium salt, magnesium salt, iron salt and other acceptable pharmaceutical salts, also can directly adopt ferulic acid.
Borneolum Syntheticum of the present invention can be a natural Broneolum Syntheticum, also can be artificial Borneolum Syntheticum.
In the pharmaceutical composition of control ischemic cerebrovascular of the present invention, described ferulic acid or its weight ratio at pharmaceutically acceptable salt and Borneolum Syntheticum are preferable with 100: 1～5.
In the pharmaceutical composition of control ischemic cerebrovascular of the present invention, described ferulic acid or its weight ratio at pharmaceutically acceptable salt and Borneolum Syntheticum were the best with 100: 2.
Auxiliary adding ingredients such as corresponding pharmaceutic adjuvant of acceptable or carrier also by corresponding pharmaceutical methods processing, can become corresponding oral drug preparation and injectable drug preparation in pharmaceutical composition of the present invention and the medicine.As common granule (agent), capsule, tablet, drop pill, suppository, injection, also can be processed into slow releasing preparation and controlled release preparation.Oral formulations contain commonly used can received auxiliary adding ingredient, as binding agent, filler, diluent, disintegrating agent, lubricant, coloring agent, correctives etc., can carry out coating to tablet, drop pill in case of necessity.Can received solvent for injection in injection system, auxiliary adding ingredients commonly used such as buffer agent, additives, handle by corresponding common process method, make injection, injection freeze-dried powder, infusion preparation.
The using dosage of medicine of the present invention in the adult be 0.2～2g/ people/time, every day one to three time.
The present invention also further provides the preparation of drug combination method of above-mentioned control ischemic cerebrovascular.
The preparation method of medicine of the present invention comprises the steps:
The preparation of granule (agent):
(1) by weight taking by weighing sodium ferulate or ferulic acid and Borneolum Syntheticum respectively, porphyrize is crossed 80 mesh sieves respectively, gets 3% dissolve with ethanol Borneolum Syntheticum, adds ferulate or ferulic acid, and mix homogeneously gets raw material;
(2) in the mixed material of step (1), add suitable amount of sucrose powder, dextrin, make soft material, granulate through 14 mesh sieves, be dried to moisture below 3% in 50～60 ℃.Promptly get granule.
The preparation of capsule:
(1) with particulate step (1);
(2) in the mixed material of step (1), add appropriate amount of starch, dextrin, make soft material, granulate through 14 mesh sieves, be dried to moisture below 3% in 50～60 ℃.In No. 2 capsule shells of packing into, promptly get capsule.
The preparation of tablet:
(1) with particulate step (1);
(2) in the mixed material of step (1), adding and mixed material weight ratio are 1: 0.25 starch, 1: 0.15 cane sugar powder, 1: 0.1 the dextrin (material for adding behind the colon, down together), make soft material, granulate, be dried to moisture below 3% in 50～60 ℃ through 14 mesh sieves, get dried particles, the magnesium stearate that adds 1: 0.01 again, tabletting promptly gets tablet.
The preparation of drop pill:
(1) with particulate step (1);
(2) in the mixed material of step (1), adding and mixed material weight ratio are 1: 1 drop pill substrate polyethylene glycol 6000, heating and melting, and temperature is 80～95 ℃, stirs, and moves into the drop pill machine, is that coolant drips system with the simethicone, promptly gets drop pill.
The preparation of suppository:
(1) with particulate step (1);
(6) getting respectively with the mixed material weight ratio is 1: 5 PEG400 and Macrogol 4000 heat fused in water-bath, the mixed material that adds step (1), be stirred to dissolving, and impouring has been coated with in the bolt mould of lubricant rapidly, to overflowing die orifice a little, scabble after cold, take out packing and promptly get suppository.
The preparation of injection:
(1) with particulate step (1);
(7) in the mixed material of step (1), the sodium chloride adjusting of adding 0.9% (w/v) etc. is oozed, and adds the water for injection of total preparation amount 30%～80% (percent by volume), stirring makes abundant dissolving, adds water for injection to preparation amount, with filtering with microporous membrane, packing promptly gets injection.
Zoopery shows, after share, sodium ferulate and Borneolum Syntheticum can alleviate the cerebral edema of transience global brain ischemia mice, improve its behavior disorder, strengthen the space learning memory ability, its mechanism may be to remove the free radical antioxidation by collaborative performance, reduce the permeability of blood brain barrier, minimizing activity gel cell plastid and minimizing Death of hippocampus neurons realize; Compound use ferulic acid or its acceptable pharmaceutical salts and Borneolum Syntheticum to the more remarkable treatment effect of transience global brain ischemia mice, especially can obviously improve its cognitive disorder than single use ferulic acid or its salt, Borneolum Syntheticum and positive drug piracetam.The present invention has disclosed the neuroprotective of the compositions of ferulic acid or its salt and Borneolum Syntheticum to the transience global brain ischemia; two medicines are united the synergism of having brought into play two medicines; compare with single sodium ferulate; absorb the half-life prolongation; peak time is faster; and reduced the dose of ferulic acid, increased the safety of medicine.The medicine that the present invention lacks the courageous and upright cerebrovascular disease of brain as control have the pharmacological action cooperative compensating, rapid-action, effective time prolongs, taking dose is little, the advantage of determined curative effect.
[specific embodiment]
The invention will be further described below in conjunction with specific embodiment.
The specific embodiment of form is that foregoing of the present invention is further described again, but the invention is not restricted to following examples by the following examples.All under technological thought of the present invention inspires, various modifications, replacement and change with ordinary skill knowledge and process are made include in the present invention.
Example of formulations 1: get sodium ferulate 65.9g respectively, Borneolum Syntheticum 1.32g, cane sugar powder 673g, dextrin 67.3g, porphyrize is crossed 80 mesh sieves respectively, gets 3% dissolve with ethanol Borneolum Syntheticum, add the sodium ferulate mixing, add cane sugar powder again and dextrin is made soft material, granulate, be dried to moisture below 3% in 50～60 ℃ through 14 mesh sieves, promptly get granule, make 100 bags altogether.Usage: 8g/ bag/time * 2 times/day.
Example of formulations 2: get sodium ferulate 65.9g respectively, Borneolum Syntheticum 0.33g, porphyrize is crossed 80 mesh sieves respectively, get 3% dissolve with ethanol Borneolum Syntheticum, add sodium ferulate and make soft material, granulate through 14 mesh sieves, be dried to moisture below 3% in 50～60 ℃, in No. 2 capsule shells of packing into, promptly get capsule.Make 168 altogether.Usage: 1～2/time, 2～3/day
Example of formulations 3: get sodium ferulate 65.9g respectively, Borneolum Syntheticum 6.59g, starch 16.8g, cane sugar powder 10g, dextrin 6.7g, magnesium stearate 0.673g, porphyrize is crossed 80 mesh sieves respectively, gets 3% dissolve with ethanol Borneolum Syntheticum, add sodium ferulate, add starch, cane sugar powder again, be mixed and made into soft material with the water dissolution dextrin, granulate through 14 mesh sieves, be dried to moisture below 3% in 50～60 ℃, add magnesium stearate again, tabletting promptly gets tablet, makes 202 altogether.Usage: 2 slices/time, 2 times/day.
Example of formulations 4: get Potassium ferulate. 65.9g respectively, Borneolum Syntheticum 0.659g, polyethylene glycol 6000 67.3g, get Potassium ferulate. and Borneolum Syntheticum porphyrize respectively, cross 80 mesh sieves, 3% dissolve with ethanol Borneolum Syntheticum takes a morsel, adding Potassium ferulate. stirs, add polyethylene glycol 6000 again, heating and melting, temperature is 80～95 ℃, stir, moving into the drop pill machine, is that coolant drips system with the simethicone, promptly gets drop pill.Make 5384 altogether, usage: 10/time, 2 times/day.
Example of formulations 5: get ferulic acid calcium 65.9g respectively, Borneolum Syntheticum 1.32g, PEG400 336.5g, Macrogol 4000 336.5g gets ferulic acid calcium and Borneolum Syntheticum porphyrize respectively, crosses 80 mesh sieves, and 3% dissolve with ethanol Borneolum Syntheticum takes a morsel.In addition taking polyethylene glycol 400 and Macrogol 4000 heat fused (bath temperature is 50 ℃) in water-bath, add ferulic acid calcium and Borneolum Syntheticum, be stirred to dissolving, and impouring has been coated with in the bolt mould of lubricant rapidly, to overflowing die orifice a little, scabble after cold, take out packing and promptly get suppository: make 296 altogether, usage: 1/time, 3 times/day.
Example of formulations 6: get ferulic acid magnesium 131.8g respectively, Borneolum Syntheticum 2.64g, sodium chloride 9g, water for injection 800ml stirs and makes abundant dissolving, adds water for injection to 1000ml, with filtering with microporous membrane, packing, every 5ml promptly gets injection.1 of every day.
Make test specimen with the embodiment of the invention, carry out pharmacodynamics test the multinomial pharmacodynamic index of transience global brain ischemia animal model.And compare test with single sodium ferulate high and low dose, single Borneolum Syntheticum and positive drug piracetam, with proof medicinal composition of the present invention in the effect of prevention with the treatment ischemic cerebrovascular.
Of short duration global brain ischemia model preparation: select the C57BL/6J mice for use, behind 10% chloral hydrate, 35 μ l/10g intraperitoneal anesthesia mices, face upward and be fixed on the operating-table, with 75% alcohol disinfecting skin of neck, row cervical region median incision.Peel off lower jaw gland and bilateral sternohyoid, omohyoid and breastbone Papillary muscle, expose common carotid artery, passivity is separated bilateral common carotid arteries, reach especially vagus nerve of companion's row nerve, with bulldog clamp press from both sides simultaneously close bilateral common carotid arteries 30min after, recover blood confession, skin suture and the wound of sterilizing.Sham operated rats is only separated bilateral common carotid arteries, not all right ischemia-reperfusion art.
Animal grouping: divide 10 groups at random: (1) sham operated rats (SAM, n=30): only separate bilateral CCA, do not close but do not press from both sides.(2) the ischemia model group (VEH, n=30): modeling, ig equivalent normal saline.(3) the positive drug group (PIRACETAMUM, n=30): modeling, ig 0.5g/kg piracetam solution.(4) positive drug blank group (PIRACETAMUM SAM, n=12): only separate bilateral CCA, do not close, and ig 0.5g/kg piracetam aqueous solution but do not press from both sides.(5) single sodium ferulate (SF) low dose group (SF100, n=30): modeling, ig 100mg/kg SF 3% alcoholic solution.(6) single SF high dose group (SF400, n=30): modeling, ig 400mg/kg SF solution 3% alcoholic solution.(7) single Borneolum Syntheticum group (B, n=30): modeling, ig 2mg/kg Borneolum Syntheticum 3% alcoholic solution.(8) example of formulations 1 low dose group (SF 100+B, n=30): modeling, ig 100mg/kg SF+2mg/kg Borneolum Syntheticum 3% ethanol composite solution.(9) dosage group in the example of formulations 3 (SF 200+B, n=30): modeling, ig 200mg/kgSF+2mg/kg Borneolum Syntheticum 3% ethanol composite solution.(10) example of formulations 2 high dose group (SF 400+B, n=30): modeling, ig 400mg/kg SF+2mg/kg Borneolum Syntheticum 3% ethanol composite solution.
Administration: the 30min administration is 1 time before the modeling of medicine group, and ischemia is irritated back 5min administration 1 time, totally 2 administrations again.Sham operated rats and ischemia group ig equivalent normal saline.
Pharmacodynamics embodiment 1: to the comparison of of short duration global brain ischemia mice postoperative death rate, epilepsy rate
Global brain ischemia can be brought out epilepsy.Every group of mice of postoperative observed death condition respectively and whether can bring out epilepsy.The epilepsy form mainly contains following 4 kinds: 1. bolt: the persistence of directionless change is run, not avoiding obstacles initiatively.Can be when bolting with the twitch of beard and very loud breathing sound.Closed in cage as mice, it will clash into chamber wall or takeoff bump cage lid.Sustainable about 30s to 1min bolts.2. general clonic spasm: refer to health and extremity clonic spasm.3. locality clonic spasm: refer to the head/forelimb or the hind leg/tail generation clonic spasm of limiting to.4. limbs are twitched: the mice back leg is stood, and forelimb is twitched, and visible disequilibrium.
Table 1 is respectively organized global brain ischemia mice postoperative 24h mortality rate, epilepsy rate relatively
Note:
▲P＜0.05vs SAM (blank group);
#P＜0.05vs VEH (model group)
Model group mice postoperative is higher than other groups to the mortality rate in the 24h, the probability that epilepsy takes place during 24h model group after surgery is higher than blank group, illustrate that this experiment modeling method can make mice transience global brain ischemia, thereby bring out epilepsy, be embodied in mice and in cage, clash into chamber wall or takeoff bump cage lid.Bolt and continue about 30s to 1min; Whole body and afterbody are interrupted generation clonic spasm.Single medicine group generation epilepsy probability is all low than model group, but does not have significant difference.Positive drug group, the middle and high dosage group of combination drug epilepsy incidence rate are than the remarkable reduction of model group, and prompting positive drug, combination drug can alleviate the mouse brain ischemic injuries, and the single medicine group has certain effect, but not as good as the combination drug group.(the results are shown in Table 1)
Pharmacodynamics embodiment 2: to the scoring of of short duration global brain ischemia mice postoperative function of nervous system
Every group of mice respectively at the clear-headed back of operation (4～6h), 24h and 48h carry out function of nervous system's scoring in equivalent environment.Adopt 5 fens systems of Zea Longa standards of grading: 0 minute, the symptom of impassivity infringement; 1 minute, not tensible fore paw; 2 minutes, turn-take laterally; 3 minutes, topple over laterally; 4 minutes, can not spontaneously walk, loss of consciousness, mark are high more, and the behavior disorder of animal is serious more.
Table 2 is respectively organized relatively (x ± s) of global brain ischemia mice postoperative function of nervous system scoring
Note:
▲ ▲P＜0.01;
▲ ▲ ▲P＜0.001vs SAM (blank group);
##P＜0.01;
###P＜0.001vsVEH (model group);
$P＜0.01vs SF100 (single sodium ferulate low dose group)
Each is organized mice and wakes up fully at about 4～6h, the scoring of model group function of nervous system is apparently higher than blank group (P＜0.001), each medicine group scoring is starkly lower than model group, wherein with the minimum branch of combination drug group (P＜0.001) of SF and Borneolum Syntheticum, mice function of nervous system recovers gradually later on, except that model group, other groups all return to normal level, return to normal level behind the model group 48h behind the 24h.Point out single or compound use SF and Borneolum Syntheticum all can alleviate the mouse brain ischemic injuries to a certain extent, but the effect of compound medication is than single SF low dose group good (P＜0.05).(the results are shown in Table 2)
Pharmacodynamics embodiment 3: to of short duration global brain ischemia mice Morris water maze test
Mainly be divided into hidden platform test and exploratory experiment.The round pool diameter 100cm of water maze device, high 40cm, depth of water 25cm, 22 ± 0.5 ℃ of water temperatures; Transparent circular platform diameter 10cm, high 24cm are placed on Southwest Quadrant, and the underwater 1cm that submerges makes and can't see undersurface platform when mice is swum in the pond.Every group of 12 mices, postoperative the 4th day are put into water maze device pond free swimming 90s with mice, and placement platform not has the animal of swimming obstacle with eliminating.Postoperative began to test hidden platform test on the 5th day, respectively mice was put into the pond from four quadrants towards pool wall every day 4 times, continued 5d.The image automatic monitor system is followed the trail of the swimming track (time (incubation period) of record mice searching fixed platform at every turn≤90s), of mice.If mice is found platform, write down the actual time of finding and allow it on platform, to stop 15s; If do not find platform in the 90s, then be recorded as 90s and it is guided to and stop 15s on the platform, put into the cage 10～15min that has a rest, begin afterwards to test next time.The meansigma methods of 4 achievements is an achievement on the same day.And the search strategy of every mice pressed: 1. orthoscopic; 2. tend to formula; 3. random mode; 4. marginal mode carries out record.Orthoscopic and trend formula swimming track are effective search strategy, and marginal mode and random mode swimming track are invalid search strategy, calculate effective search strategy percentage ratio every day.After finishing hidden platform test, mice is put into cage rest 1h, begin to do exploratory experiment afterwards.Remove platform, mice is put into water maze device pond free swimming 90s from southeast quadrant towards pool wall, the record mice is at the number of times of all quadrants time of staying and spanning platform.
Table 3 is respectively organized the global brain ischemia mice Morris water maze test incubation period of (x ± s) relatively
Note:
$P＜0.05;
$$P＜0.01;
$$$P＜0.001vs the 1
StDay within the group (first day incubation period on the same group);
▲P＜0.05;
▲ ▲P＜0.01vs SAM (blank group);
#P＜0.05;
##P＜0.01;
###P＜0.001vs VEH (model group)
All increase each incubation period of organizing mice and obviously shorten with the test natural law.Model group obviously is longer than sham operated rats (P＜0.05, P＜0.01) the 1st～5 day incubation period.Piracetam sham operated rats and sham operated rats do not have significant difference; Piracetam group and model group do not have significant difference yet.Low dosage sF, high dose SF and Borneolum Syntheticum group were shorter than model group (P＜0.05, P＜0.01) respectively in the single medicine group at the 2nd day, the 1st～2 day, the 1st day, and the prompting single medicine all has certain effect to cerebral ischemia in the early stage.Obviously be shorter than model group (P＜0.05 incubation period of the basic, normal, high dosage of combination drug respectively at the 1st～5 day, the 2nd～5 day, the 2nd～5 day; P＜0.01; P＜0.001); the prompting combination drug can strengthen the space learning ability of transience global brain ischemia mice, and cerebral ischemia is had significant protective effect.(seeing Table 3).
Table 4 is respectively organized relatively (x ± s) of the effective search strategy percentage ratio of global brain ischemia mice Morris water maze
Note:
$P＜0.05;
$$P＜0.01;
$$$P＜0.001vs the 1
StDay within the group; (effective search strategy of first day on the same group)
▲P＜0.05;
▲ ▲P＜0.01vs SAM (blank group);
#P＜0.05;
##P＜0.01;
###P＜0.001vs VEH (model group)
Each is organized effective search strategy percentage ratio and all increases with the test natural law and obviously increase.Model group obviously is less than sham operated rats (P＜0.05, P＜0.01) at effective search strategy percentage ratio of the 1st～2 day, how to search for marginal mode or random mode, promptly moves about or does erratic motion around pool wall in the labyrinth, and ability of learning and memory is poor.Piracetam sham operated rats and sham operated rats do not have significant difference; Piracetam group and model group do not have significant difference yet.In the single medicine group high dose SF and Borneolum Syntheticum group respectively at effective search strategy percentage ratio of the 1st～2 day, the 1st day greater than model group (P＜0.05, P＜0.01), the prompting single medicine has certain effect to cerebral ischemia.Effective search strategy percentage ratio of the basic, normal, high dosage of combination drug all at the 1st～2 day obviously greater than model group (P＜0.05, P＜0.01), animal is many with trend
Formula or orthoscopic are searched for, promptly do around the platform tropism or directly trip return platform, show memory to platform, the prompting combination drug can strengthen the space learning ability of transience global brain ischemia mice, and cerebral ischemia is had significant protective effect.But because of effective search strategy percentage ratio of model group also increases with natural law and obviously increases, so the medicine group did not have significant difference at 3～5 days with model group.(seeing Table 4).
Table 5 is respectively organized the global brain ischemia mice Morri s water maze all quadrants time of staying (x ± s) relatively
Note:
$P＜0.05vs III quadrant within the group (time of staying of III quadrant on the same group);
▲P＜0.05vs SAM (blank group);
#P＜0.05vs VEH (model group)
The sham operated rats mice the III quadrant be time of staying of purpose quadrant all than other three quadrants long (P＜0.05), the spanning platform number of times is more, illustrate that mice through 5 days water maze training, produces platform and remembers.And model group is at the time of staying and other quadrant there was no significant differences of purpose quadrant, and the spanning platform number of times is less.The basic, normal, high dosage group of combination drug is all grown (P＜0.05) than other～two quadrant in the time of staying of purpose quadrant, and the spanning platform number of times is than model group many (P＜0.05).Piracetam group and single medicine group and model group there was no significant difference.(seeing Table 5).
Pharmacodynamics embodiment 4: to of short duration global brain ischemia mice serum, cortex and Hippocampus SOD (superoxide dismutase) activity and MDA (malonaldehyde) assay
Other gets (1) (2) (3) (5) (6) (7) (8) each 6 mice of group, and after irritating 60min again behind the ischemia, broken end is got blood and got brain, with blood on the pre-cold saline wash clean brain.The centrifugal 10min separation of serum of 10000r/min is measured activity of SOD in serum and MDA content.Get mouse cortex and Hippocampus respectively in glass homogenizer, add pre-cold saline, carry out brain homogenate, the centrifugal 10min of 3000r/min gets supernatant, measures protein content and SOD activity and MDA content in the brain to specifications.
Table 6 SOD in serum and MDA activity (x ± s)
Note:
▲P＜0.05;
▲ ▲P＜0.01vs SAM (blank group);
#P＜0.05vs VEH (model group)
Table 7 cortex SOD and MDA activity (x ± s)
No te:
▲P＜0.05;
▲ ▲P＜0.01;
▲ ▲ ▲P＜0.001vs SAM (blank group);
#P＜0.05;
##P＜0.01vs VEH (model group)
Table 8 Hippocampus SOD and MDA activity (x ± s)
Note:
▲P＜0.05vs SAM (blank group);
#P＜0.05vs VEH (model group)
Compare with sham operated rats, model group mice serum, cortex and Hippocampus SOD vigor obviously reduce (P＜0.05, P＜0.001, P＜0.0001), and MDA content obviously increases (P＜0.05).Piracetam group mice serum, cortex and Hippocampus SOD vigor are than the obvious increase of model group (P＜0.05).The SOD vigor of single SF high dose group mice serum, cortex and Hippocampus is than the obvious increase of model group (P＜0.05), and cortex MDA content is than the obvious reduction of model group (P＜0.05).The SOD vigor of single Borneolum Syntheticum group Hippocampus is than the obvious increase of model group (P＜0.05).The serum of combination drug low dose group mice, cortex and Hippocampus S () D vigor are all than the obvious increase of model group (P＜0.05), and MDA content obviously reduces (P＜0.05) (table 6,7,8).Prompting combination drug low dose group has cerebral ischemia that protective effect is arranged to the model group mice.
Pharmacodynamics embodiment 5: to the moisture determination of of short duration global brain ischemia mouse brain
Other gets (1) (2) (3) (5) (6) (7) (8) each 6 mice of group, and after pouring into 24h again behind the ischemia, every mice is got half brain and carries out brain water content mensuration.As above, get left side brain and in-4 ℃ of normal saline, clean and be weighed as weight in wet base after bloodstain blots with absorbent paper, in 120 ℃ of baking ovens dry to constant weight about 18h (twice weight poor≤0.3mg), be weighed as dry weight, the calculating brain water content.
Brain water content (%)=(weight in wet base-dry weight)/weight in wet base * 100%
Table 9 is respectively organized relatively (x ± s) of brain water content
Note:
▲ ▲P＜0.01vs SAM (blank group);
#P＜0.05vs VEH (model group)
The model group brain water content is significantly higher than sham operated rats (P＜0.01), illustrates that transience global brain ischemia mice brain blood for obstacle takes place, causes cerebral edema.Though the brain water content of piracetam, Borneolum Syntheticum group, combination drug low dose group, significantly is lower than model group (P＜0.05) also than normal height.Prompting combination drug low dose group can alleviate the cerebral edema (seeing Table 9) that cerebral ischemia causes.
Pharmacodynamics embodiment 6: of short duration global brain ischemia blood-brain barrier of mice permeability is measured
Other gets (1) (2) (3) (5) (6) (7) (8) each 10 mice of group, pours into 17h again through tail vein iv 2% Azo-Blue solution (4ml/kg) behind ischemia.Get brain behind 15min, with blood on-4 ℃ of normal saline wash clean brains, reuse filter paper blots, and precision is weighed.Press the wet cerebral tissue of 1.5ml/100mg and add Methanamide, make homogenate.Put 24h in 50 ℃ of water isolation type incubators.4000 rev/mins of centrifugal 20min, getting supernatant serves as that blank pipe is measured absorbance with blank brain homogenate parallel pipe, tries to achieve cerebral tissue EB (Azo-Blue) content according to standard curve, represents with the wet cerebral tissue of ng/mg.
Table 10 medicine is to the influence of global brain ischemia mice vascular permeability (x ± s)
Note:
▲ ▲ ▲P＜0.001vs SAM (blank group);
###P＜0.001vs VEH (model group)
EB content in the model group cerebral tissue is obviously greater than sham operated rats (P＜0.001).EB content in piracetam, high dose SF, Borneolum Syntheticum and the combination drug group mouse brain tissue is significantly less than model group (P＜0.001), and wherein the EB content of combination drug is minimum.And the EB content and the model group zero difference of low dosage SF group.Prompting combination drug low dose group can reduce the vascular permeability that cerebral ischemia causes and increase (seeing Table 10).
Pharmacodynamics embodiment 7: to of short duration global brain ischemia mouse tissue pathological examination (HE dyeing)
Other gets each 6 mice of (1) (2) (3) (5) (6) (7) (8) groups, pours into 72h again and get brain behind ischemia, drops in 10% formalin fixedly more than the 24h, conventional dehydration, paraffin embedding, crown section, the thick 4 μ m of sheet, row hematoxylin-eosin (Ematoxylin and eosin, HE) dyeing.
The result shows that sham operated rats mice Hippocampus CA1 district pyramidal cell marshalling, tight is methodically arranged, and nucleus dyeing is clear, is navy blue, and cell space is rounded, and kytoplasm does not have obviously has a liking for Yihong change.Neuron and neurogliocyte degeneration necrosis in various degree appear in the model group mice, decreased number, and arrangement disorder, the dead cell structure is unclear, soft edge, endochylema is the cavity sample and becomes, and nuclear is broken, pyknosis.The most of pericaryons in Hippocampus CA1 district are triangular in shape, and kytoplasm has a liking for that Yihong is dense dyes.Part specimen brain district sees that more circular or oval, kytoplasm enrich, have a liking for Yihong color, examine little, fine and close, as to be partial to cell one side " obese type astrocyte (gemistocytic ast rocyte) " hypertrophy.Piracetam group and single medicine group Hippocampus CA1 district partial nerve unit cell space are triangular in shape, and kytoplasm is had a liking for Yihong part engrain.The combination drug group is compared the cell arrangement with model group regular, and cellular morphology is more complete, and cerebral tissue swelling and astrocyte hypertrophy are lighter.The a small amount of neuron kytoplasm in Hippocampus CA1 district has a liking for that Yihong is dense dyes, and cell space is triangular in shape, and minority pericaryon ellipse only, kytoplasm do not have obviously to be had a liking for Yihong and change.Prompting combination drug low dose group reduces the neuronal death in cerebral ischemia mice CA1 district, and cerebral ischemia is had protective effect.
Pharmacodynamics embodiment 8: to of short duration global brain ischemia mice GFAP immunohistochemical staining
Above-mentioned every group of 6 mices are poured into 72h again and get brain behind ischemia, after the specimens paraffin embedding slices, use gfap (glial fibrillary acidic protein) antibody, detect and respectively organize the number that Hippocampus CA1 district, cortical area contain the gfap positive cell.
The result shows that sham operated rats mice Hippocampus CA1 district and cortex gfap express not obvious, and dendron is thinner in astrocyte.The astrocyte of model group is pale brown color or brown, and quantity increases, and it is darker to dye, and cell space is bigger, and projection is thick.The gfap positive cell number of single medicine group and combination drug group is between sham-operation and model group, and wherein the combination drug group than single medicine group number still less.Prompting combination drug low dose group suppresses the activation of glial cell, and cerebral ischemia is had protective effect.
Claims (7)
1, a kind of pharmaceutical composition of preventing and treating ischemic cerebrovascular, it contains active ingredient and carrier, described active ingredient is that 100: 0.5～10 ferulic acid or its are formed at pharmaceutically acceptable salt and Borneolum Syntheticum by weight ratio, and dosage form is for being fit to the dosage form of clinical practice.
2, a kind of pharmaceutical composition of preventing and treating ischemic cerebrovascular according to claim 1 is characterized in that the pharmaceutically acceptable salt of ferulic acid is selected from sodium salt, potassium salt, ammonium salt, calcium salt, magnesium salt, iron salt and other acceptable pharmaceutical salts.
3, a kind of pharmaceutical composition of preventing and treating ischemic cerebrovascular according to claim 1 is characterized in that Borneolum Syntheticum is a natural Broneolum Syntheticum.
4, a kind of pharmaceutical composition of preventing and treating ischemic cerebrovascular according to claim 1 is characterized in that Borneolum Syntheticum is artificial Borneolum Syntheticum.
5, a kind of pharmaceutical composition of preventing and treating ischemic cerebrovascular according to claim 1 is characterized in that described ferulic acid or its weight ratio at pharmaceutically acceptable salt and Borneolum Syntheticum are 100: 1～5.
6, a kind of according to claim 1 or 5 pharmaceutical composition of preventing and treating ischemic cerebrovascular is characterized in that described ferulic acid or its weight ratio at pharmaceutically acceptable salt and Borneolum Syntheticum are 100: 2.
7, a kind of production method of preventing and treating the pharmaceutical composition of ischemic cerebrovascular comprises the steps:
(1) take by weighing sodium ferulate or ferulic acid and Borneolum Syntheticum respectively by 100: 0.5～10 weight ratio, porphyrize is crossed 80 mesh sieves respectively, gets 3% dissolve with ethanol Borneolum Syntheticum, adds ferulate or ferulic acid, and mix homogeneously gets raw material;
(2) common process by various preparations is prepared into corresponding dosage forms.
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