CN103083323A - Application of fasudil hydrochloride in preparation of medicament for promoting in-vivo survival and repair of mesenchymal stem cells and preparation of fasudil hydrochloride - Google Patents
Application of fasudil hydrochloride in preparation of medicament for promoting in-vivo survival and repair of mesenchymal stem cells and preparation of fasudil hydrochloride Download PDFInfo
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Abstract
The invention belongs to application of fasudil hydrochloride in preparation of a medicament for promoting in-vivo survival and repair of mesenchymal stem cells and a preparation of the fasudil hydrochloride, and provides application of fasudil hydrochloride in preparation of a medicament for promoting in-vivo survival and repair of mesenchymal stem cells, in particular application of fasudil hydrochloride in preparation of an auxiliary medicament for treating cardiovascular diseases by using mesenchymal stem cells and application in preparation of an auxiliary medicament for treating acute myocardium infarction by using mesenchymal stem cells. The formulation of the medicament containing the fasudil hydrochloride comprises capsules, tablets or injection. The application range of the fasudil hydrochloride is enlarged; and through the provided medicament, ROCK and downstream signals are directly inhibited, severe myocardial microenvironments of infarct post-inflammation, fibrosis and the like are improved, the in-vivo survival of transplanted cells is enhanced, the stem cells exert effects, the myocardium is repaired, the infarct area is reduced, and the cardiac function is improved.
Description
Technical field
The present invention relates to a kind of new purposes and preparation thereof of medicine.
Background technology
The molecular structure of Fasudic hydrochloride is the 5-isoquinoline sulfone amide derivative, is Rho kinases ROCK mortifier, is mainly used in brain diseases smelting treatment.It reduces the tension force of endotheliocyte by increasing the active blood vessel dilating of Myosin light chain phosphatase, improves the cerebral tissue microcirculation, does not produce and increase the weight of robber's blood of brain, but while antagonism inflammatory factor, and the anti-apoptosis of neuroprotective promotes neuranagenesis.
Acute myocardial infarction (acute myocardial infarction, AMI) because the coronary artery acute occlusion directly causes the large tracts of land myocardial necrosis, is the main cause that coronary heart disease is lethal and disable.To the early stage myocardial revascularization of AMI patient (comprising arteria coronaria intervention, surgical operation and thromboembolism treatment) though can save the part ischemic myocardium, curative effect is clear and definite, but the necrotic myocardium cell can't be regenerated, but secondary remodeling ventricle and heart failure thus, further survival and quality of life can be had a strong impact on again, and a large amount of medical resources and expense will be consumed.
Stem cell is the cell that a class has the of self-replication capacity and the various histoorgan potential of regeneration; stem cell myocardium regeneration namely makes stem cell move to damaged myocardium position realization by medical procedure and repairs, be treatment large tracts of land AMI; the cardioprotection function, the optimum selection of control heart failure.The stem cell of derived from bone marrow because of himself source, draw materials conveniently, without immunological rejection, also without dispute of ethic, Cardiomyocytes and blood vessel differentiation regeneration capacity can be arranged in theory, be suitable for clinical practice treatment AMI.But the AMI district is due to a large amount of existence and the expression of oxidative stress, inflammatory factor etc., and the microenvironment that stem cell depends on for existence is very abominable, is difficult to survival, causes the Bone Marrow Stem Cells Transplantation in Treating curative effect low, and the raising of Left Ventricular Ejection Fraction (LVEF) is limited.The pharmaceutical intervention of therefore carrying out for the infarcted myocardium microenvironment may promote bone marrow stem cell in body survival and performance curative effect more effectively.
Have and studies confirm that in a large number, small molecular G protein RhoA-ROCK activation after AMI, bring the Negative effects such as oxidative stress aggravation, inflammatory factor expression-secretion, there are a lot of explorations to attempt to reach by affecting its upstream molecule the effect of improvement microenvironment, go back neither one for the therapeutic scheme of ROCK and prove its application in body survival and curative effect medicine after preparation improves Bone Marrow Mesenchymal Stem Cells Transplantation.
Summary of the invention
The purpose of this invention is to provide Fasudic hydrochloride promotes mesenchymal stem cells MSCs at application and the preparation thereof of body survival and repair medicine as preparation, proposing Fasudic hydrochloride promotes mesenchymal stem cells MSCs at body survival and repair medicine as preparation, further propose preparation with ancillary drug and the preparation thereof of bone mesenchymal stem cells treatment cardiovascular disease, make this medicine effectively promote bone marrow stem cell in body survival and the effect of performance curative effect.
For this reason, purposes of the present invention is that Fasudic hydrochloride promotes mesenchymal stem cells MSCs in the purposes of body survival and repair medicine as preparation.The preferred scheme of described purposes is that Fasudic hydrochloride is preparing with the application in the ancillary drug of bone mesenchymal stem cells treatment cardiovascular disease.The preferred scheme of described purposes is that Fasudic hydrochloride is preparing with the application in the ancillary drug of bone mesenchymal stem cells treatment acute myocardial infarction.
A kind of promotion mesenchymal stem cells MSCs includes Fasudic hydrochloride at body survival and repair medicine in this medicine.The described dosage form that includes the medicine of Fasudic hydrochloride is capsule, tablet, or injection.Because nitric oxide (NO) is effective for myocardium microenvironment after improveing AMI, add NO precursor substance L-arginine to form compound recipe in oral formulations, be beneficial to the better drug effect of performance.
Described tablet formulation is:
Fasudic hydrochloride 10g
Lactose 150g
Hydroxypropyl cellulose 8g
Water 1080ml
L-arginine 100g
Opadry AMB 12.5g
Carboxymethyl starch Na 12g
Titanium dioxide 6g
Preparation method: the 10g Fasudic hydrochloride is dissolved in 250ml water, and 8g hydroxypropyl cellulose and 100g L-arginine are dissolved in 670ml water, and 12.5g Opadry AMB is dissolved in 160ml water and gets respectively fasudil, hydroxypropyl cellulose/arginine and Opadry solution; 150g lactose and 12g carboxymethyl starch Na adopt sulfuration boiling granulating method fluidized state to spray into Fasudic hydrochloride solution, lactose, carboxymethyl starch Na and the fasudil granule that congeals into; Granule is added hydroxypropyl cellulose/arginine solution mixing tabletting; The 6g titanium dioxide is added Opadry solution mixing to get the coating suspension and it is uniformly coated on granule hydroxypropyl cellulose tabletting surface, and drying namely gets 1000 of Fasudic hydrochloride waterproof coating oral tablets.
The formula of described capsule is:
Fasudic hydrochloride 10g
Lactose 150g
Hydroxypropyl cellulose 8g
Water 410ml
Carboxymethyl starch Na 12g
Ethanol 80ml
The arginine granule contains L-arginine 100g
Preparation method: the 100g Fasudic hydrochloride is dissolved in 250ml water, and the 8g hydroxypropyl cellulose is dissolved in 160ml water, gets respectively fasudil and 5% hydroxypropyl cellulose solution; 150g lactose and 12g carboxymethyl starch Na adopt sulfuration boiling granulating method fluidized state to spray into Fasudic hydrochloride solution, lactose, carboxymethyl starch Na and the fasudil granule that congeals into; With 5% hydroxypropyl cellulose+alcoholic solution, granule is carried out coating after granulate, then through the granulate that sieves, add capsule namely to get 1000 of Fasudic hydrochloride capsules gained granule and arginine granule mixing.
The preparation of described injection:
Pharmaceutical formulation is: Fasudic hydrochloride 30mg
Normal saline 100ml;
Preparation method: Fasudic hydrochloride is dissolved in normal saline, and fully dissolving by the degerming of 0.22 micron filter membrane fine straining, namely gets fasudil hydrochloride injection.
In described medicine, the dosage of Fasudic hydrochloride is 20mg～120mg every day.
Inventor's data shows, the Fasudic hydrochloride intervention is played facilitation to using mesenchymal stem cells MSCs to carry out myocardial repair, improve the violent inflammatory reaction and continuous mutually fibrosis in acute stage infarction position, significantly improve the survival of stem cell of implantation and blood vessel and the survival myocardium amount at infarction position, thus significant to the clinical practice of Bone Marrow Mesenchymal Stem Cells Transplantation.
In application scheme of the present invention, Fasudic hydrochloride is made a kind of in capsule, tablet, pill, oral liquid, soft capsule, drop pill or injection, for realizing the preparation of these dosage forms, need to add the acceptable adjuvant of pharmacy such as disintegrating agent, correctives, filler, lubricant, binding agent, anti-photodissociation agent, antiseptic and substrate and solubilizing agent, antioxidant, pH value regulator, isoosmotic adjusting agent etc. when these dosage forms of preparation.
Application scheme of the present invention, the use amount of Fasudic hydrochloride: it is 20mg/ day that tablet is recommended initial dose, dosage range 20-120mg/ day, minute 2-3 time oral, it is 60mg/ day that injection is recommended initial dose, dosage range 60-120mg/ day, minute 2-3 intravenous drip.
For confirming that Fasudic hydrochloride promotes the application of mesenchymal stem cells MSCs in the medicine of body survival and curative effect in preparation, the inventor has carried out following experiment:
Get whole bone marrow of 3 all male rat femurs and tibia, external through 10% hyclone+low sugar DMEM culture medium culturing, the adherent screening method amplification of mesenchymal stem cells (Y chromosome is arranged) that goes down to posterity.
Select the female sd inbred rats of body weight 200-220g, be divided at random 5 groups: 1. sham operated rats; 2. AMI matched group; 3. the simple mesenchymal stem cell transplantation group of AMI; 4. AMI Fasudic hydrochloride group (physiological saline solution Fasudic hydrochloride, 10mg/kg intraperitoneal injection every day was to drawing materials thereafter with the 20mg/kg intraperitoneal injection in front 2 hours in modeling); 5. AMI Fasudic hydrochloride+mescenchymal stem cell group.
Female rats is connected with the chloral general anesthesia with water and is connected the respirator assisted respiartion.The 3rd～4 intercostal incision skin on the left of breastbone is opened the thoracic cavity, extrudes heart, at left auricle and arterial cone place's following coronary artery occlusion left anterior descending branch (left anterior descending, LAD); Closed-chest after success, skin suture and extubation cause the AMI model.Mesenchymal stem cell transplantation group 30min after ligation LAD injects male rat mesenchymal stem cells MSCs (5 * 10 in infarction central authorities and 3 of both sides
6Individual being resuspended in 60 μ LPBS cardiac muscles injected), to observe without closed-chest after obvious medullary cell seepage, control animals is only injected PBS.
One week of female rats AMI, rear echocardiography was respectively organized left chamber interior warp diastasis (LVEDd), left chamber end systolic diameter (LVESd) and LVEF, concrete grammar: with water and chloral general anesthesia, and the capable two dimensional echocardiogram of left lateral position mitral level.After Bone Marrow Mesenchymal Stem Cells Transplantation, surrounding as assessment endpoint, detects
Ultrasoundcardiogram.2. left cardic catheter: put to death the front female rats dorsal position of drawing materials and separate the right carotid left ventricular cannulation that drives in the wrong direction, conduit is through the carrier amplifier of physiograph, record the left ventricular pressure curve, measure or calculate left ventricular end diastolic and press (LVEDP) and left ventricular pressure differential (dp/dt).
Histology: make diastole stop jumping the execution rat latter stage with the potassium chloride injection, each group is selected 3-4 rat heart at random, and the formalin infusion prepares paraffin section, carries out cardinal principle staining examine (HE, ET-VG and Masson Trichrome dyeing).
In situ hybridization: use the Y chromosome positive cell number that in situ hybridization FISH detection kit is survived in to each transplantation group to compare in the tissue slice level.
Molecular Biological Detection: western blot method is estimated IL-6 in cardiac muscular tissue, CTGF, ROCK, phosphorylation MYPT(ROCK downstream molecules), the equimolecular variation of phosphorylation ERK1/2.
Data adopt one factor analysis of variance (ANOVA) to calculate p value between each group after test of normality and homogeneity test of variance, and p＜0.05 is thought significant difference, and p＜0.01 is thought notable difference.All statistical analysiss all carry out with the SPSS16.0 software kit.
Result:
1. after one week of ultrasoundcardiogram modeling, LVEDd, LVESd and LVEF zero difference between each treated animal of AMI illustrate the success of heart infarction model.After surrounding, AMI matched group LVEF obviously descends, and LVEDd and LVESd obviously increase.Compare with the AMI matched group, though the simple mesenchymal stem cell transplantation group of AMI and AMI Fasudic hydrochloride group LVEF raise to some extent, do not reach significant difference, obviously increase in AMI Fasudic hydrochloride+mescenchymal stem cell group.Compare with the AMI matched group, LVEDd and LVESd all descend in AMI Fasudic hydrochloride group and AMI Fasudic hydrochloride+mescenchymal stem cell group, and the latter's decline degree is greater than the former (p＜0.05).
2. after left cardic catheter evaluation myocardial infarction, cardiac function and AMI matched group compare, LVEDP all descends in AMI Fasudic hydrochloride group and AMI Fasudic hydrochloride+mescenchymal stem cell group, and the latter's decline degree is obviously greater than the former (being respectively p＜0.05 and p＜0.01).Compare with the AMI matched group, though dp/dt raises to some extent in the simple mesenchymal stem cell transplantation group of AMI and AMI Fasudic hydrochloride group, do not reach significant difference, and in AMI Fasudic hydrochloride+mescenchymal stem cell group, dp/dt obviously increases.
3. during the tissue staining terminal point, HE dyeing shows AMI matched group infarction surrounding zone inflammatory cell infiltration, and AMI Fasudic hydrochloride+mescenchymal stem cell group inflammatory infiltration obviously reduces.ET-VG dyeing shows AMI, and Fasudic hydrochloride+the little vascularity in mescenchymal stem cell group infarction surrounding zone is many than other groups.Masson Trichrome dyeing shows that AMI matched group left ventricular fibrosis is serious, and AMI Fasudic hydrochloride+mescenchymal stem cell group fibrosis area obviously reduces, and in fibrous tissue, visible island cardiac muscle distributes.
4. in confocal microscope observation cardiac muscle, the transplanted cells quantity AMI Fasudic hydrochloride of Y chromosome probe stained positive+mescenchymal stem cell is survived transplanted cells (approximately 18/high power field) significantly more than the simple mesenchymal stem cell transplantation group of AMI (approximately 7/high power field).
In cardiac muscle in the expression of the inflammation fibrosis factor and coherent signal path AMI matched group infarction surrounding zone cardiac muscular tissue the expression of inflammation fibrosis factor IL-6 and CTGF significantly raise, by comparison, the expression of AMI Fasudic hydrochloride group and AMI Fasudic hydrochloride+mescenchymal stem cell group IL-6 and CTGF all descend (p＜0.05); Because Fasudic hydrochloride is the inhibitor of ROCK activity, therefore between each group, the ROCK level is unchanged.In the cardiac muscular tissue of AMI matched group infarction surrounding zone, phosphorylation MYPT and phosphorylation ERK significantly raise, prompting ROCK-ERK1/2 Pathway Activation, compare with the AMI matched group, the simple mesenchymal stem cell transplantation group of AMI phosphorylation MYPT and phosphorylation ERK are unchanged, and AMI Fasudic hydrochloride group and AMI Fasudic hydrochloride+mescenchymal stem cell group reduce.
Conclusion:
Inject mescenchymal stem cell in early stage simple cardiac muscle after 1, AMI limited to the improvement effect of cardiac function.
2, use Fasudic hydrochloride, by directly suppressing ROCK and downstream signal, after the improvement infarction, the abominable myocardium microenvironments such as inflammation, fibrosis, strengthen transplanted cells to survive at body, and these stem cell are played a role, repair cardiac muscle, dwindle infarct size and improve cardiac function.
3, studies show that in the Fasudic hydrochloride oral agent to add L-arginine, fit over together and can support better cardiac rehabilitation.
The specific embodiment
Fasudic hydrochloride promotes mesenchymal stem cells MSCs in the application of body survival and repair medicine as preparation, and purposes is: Fasudic hydrochloride promotes mesenchymal stem cells MSCs in the purposes of body survival and repair medicine as preparation.The preferred scheme of described purposes is that Fasudic hydrochloride is preparing with the application in the ancillary drug of autologous bone marrow mesenchymal stem cells Cardiovarscular.The preferred scheme of described purposes is that Fasudic hydrochloride is preparing with the application in the ancillary drug of autologous bone marrow mesenchymal stem cells treatment acute myocardial infarction.
A kind of promotion mesenchymal stem cells MSCs includes Fasudic hydrochloride at body survival and repair medicine in this medicine.The described dosage form that includes the medicine of Fasudic hydrochloride is capsule, tablet, or injection.
Embodiment 1: described tablet formulation is:
Fasudic hydrochloride 10g
Lactose 150g
Hydroxypropyl cellulose 8g
Water 1080ml
L-arginine 100g
Opadry AMB 12.5g
Carboxymethyl starch Na 12g
Titanium dioxide 6g
Preparation method: the 10g Fasudic hydrochloride is dissolved in 250ml water, and 8g hydroxypropyl cellulose and 100g L-arginine are dissolved in 670ml water, and 12.5g Opadry AMB is dissolved in 160ml water and gets respectively fasudil, hydroxypropyl cellulose/arginine and Opadry solution; 150g lactose and 12g carboxymethyl starch Na adopt sulfuration boiling granulating method fluidized state to spray into Fasudic hydrochloride solution, lactose, carboxymethyl starch Na and the fasudil granule that congeals into; Granule is added hydroxypropyl cellulose/arginine solution mixing tabletting; The 6g titanium dioxide is added Opadry solution mixing to get the coating suspension and it is uniformly coated on granule hydroxypropyl cellulose tabletting surface, and drying namely gets 1000 of Fasudic hydrochloride waterproof coating oral tablets.
Drug dose of the present invention, initial dose are 20mg/ day, and dosage range 20-120mg/ day, minute 2-3 time oral.
Embodiment 2: the formula of described capsule is:
Fasudic hydrochloride 10g
Lactose 150g
Hydroxypropyl cellulose 8g
Water 410ml
Carboxymethyl starch Na 12g
Ethanol 80ml
The arginine granule contains L-arginine 100g
Preparation method: the 100g Fasudic hydrochloride is dissolved in 250ml water, and the 8g hydroxypropyl cellulose is dissolved in 160ml water, gets respectively fasudil and 5% hydroxypropyl cellulose solution; 150g lactose and 12g carboxymethyl starch Na adopt sulfuration boiling granulating method fluidized state to spray into Fasudic hydrochloride solution, lactose, carboxymethyl starch Na and the fasudil granule that congeals into; With 5% hydroxypropyl cellulose+alcoholic solution, granule is carried out coating after granulate, then through the granulate that sieves, add capsule namely to get 1000 of Fasudic hydrochloride capsules gained granule and arginine granule mixing.
Drug dose of the present invention, initial dose are 20mg/ day, and dosage range 20-120mg/ day, minute 2-3 time oral.
Embodiment 3: the preparation of described injection:
Pharmaceutical formulation is: Fasudic hydrochloride 30mg
Normal saline 100ml;
Preparation method: Fasudic hydrochloride is dissolved in normal saline, and fully dissolving by the degerming of 0.22 micron filter membrane fine straining, namely gets fasudil hydrochloride injection.
Drug dose of the present invention, initial dose are 30mg/ day, once-a-day, but dosage to days three times, i.e. 120mg/ day intravenous drip was no more than for 2 weeks service time.
In described medicine, the dosage of Fasudic hydrochloride is 20mg～120mg every day.
In a word, the present invention has enlarged the range of application of Fasudic hydrochloride, given medicine directly suppresses ROCK and downstream signal, the abominable myocardium microenvironments such as inflammation, fibrosis after the improvement infarction, strengthening transplanted cells survives at body, these stem cell are played a role, repair cardiac muscle, dwindle infarct size and improve cardiac function.
Claims (9)
1. Fasudic hydrochloride promotes mesenchymal stem cells MSCs in the application of body survival and repair medicine as preparation, it is characterized in that: Fasudic hydrochloride promotes mesenchymal stem cells MSCs in the purposes of body survival and repair medicine as preparation.
2. by application claimed in claim 1, it is characterized in that: the preferred scheme of described purposes is that Fasudic hydrochloride is preparing with the application in the ancillary drug of bone mesenchymal stem cells treatment cardiovascular disease.
3. by application claimed in claim 1, it is characterized in that: the preferred scheme of described purposes is that Fasudic hydrochloride is preparing with the application in the ancillary drug of bone mesenchymal stem cells treatment acute myocardial infarction.
4. one kind promotes mesenchymal stem cells MSCs at body survival and repair medicine, it is characterized in that: include Fasudic hydrochloride in this medicine.
5. by medicine claimed in claim 4, it is characterized in that: the described dosage form that includes the medicine of Fasudic hydrochloride is capsule, tablet, or injection.
6. by the described medicine of claim 4 or 5, it is characterized in that: described tablet formulation is:
Fasudic hydrochloride 10g
Lactose 150g
Hydroxypropyl cellulose 8g
Water 1080ml
L-arginine 100g
Opadry AMB 12.5g
Carboxymethyl starch Na 12g
Titanium dioxide 6g
Preparation method: the 10g Fasudic hydrochloride is dissolved in 250ml water, and 8g hydroxypropyl cellulose and 100g L-arginine are dissolved in 670ml water, and 12.5g Opadry AMB is dissolved in 160ml water and gets respectively fasudil, hydroxypropyl cellulose/arginine and Opadry solution; 150g lactose and 12g carboxymethyl starch Na adopt sulfuration boiling granulating method fluidized state to spray into Fasudic hydrochloride solution, lactose, carboxymethyl starch Na and the fasudil granule that congeals into; Granule is added hydroxypropyl cellulose/arginine solution mixing tabletting; The 6g titanium dioxide is added Opadry solution mixing to get the coating suspension and it is uniformly coated on granule hydroxypropyl cellulose tabletting surface, and drying namely gets 1000 of Fasudic hydrochloride waterproof coating oral tablets.
7. by the described medicine of claim 4 or 5, it is characterized in that the formula of described capsule is:
Fasudic hydrochloride 10g
Lactose 150g
Hydroxypropyl cellulose 8g
Water 410ml
Carboxymethyl starch Na 12g
Ethanol 80ml
The arginine granule contains L-arginine 100g
Preparation method: the 100g Fasudic hydrochloride is dissolved in 250ml water, and the 8g hydroxypropyl cellulose is dissolved in 160ml water, gets respectively fasudil and 5% hydroxypropyl cellulose solution; 150g lactose and 12g carboxymethyl starch Na adopt sulfuration boiling granulating method fluidized state to spray into Fasudic hydrochloride solution, lactose, carboxymethyl starch Na and the fasudil granule that congeals into; With 5% hydroxypropyl cellulose+alcoholic solution, granule is carried out coating after granulate, then through the granulate that sieves, add capsule namely to get 1000 of Fasudic hydrochloride capsules gained granule and arginine granule mixing.
8. by the described medicine of claim 4 or 5, it is characterized in that the preparation of described injection:
Pharmaceutical formulation is: Fasudic hydrochloride 30mg
Normal saline 100ml;
Preparation method: Fasudic hydrochloride is dissolved in normal saline, and fully dissolving by the degerming of 0.22 micron filter membrane fine straining, namely gets fasudil hydrochloride injection.
9. by the described medicine of claim 4 or 5, it is characterized in that: in described medicine, the dosage of Fasudic hydrochloride is 20mg～120mg every day.
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| CN2013100553306A CN103083323A (en) | 2013-02-21 | 2013-02-21 | Application of fasudil hydrochloride in preparation of medicament for promoting in-vivo survival and repair of mesenchymal stem cells and preparation of fasudil hydrochloride |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105168176A (en) * | 2015-08-31 | 2015-12-23 | 青岛蓝盛洋医药生物科技有限责任公司 | Pharmaceutical fasudil hydrochloride composition capsule for angiectasis |
| CN109090100A (en) * | 2018-08-27 | 2018-12-28 | 深圳市浊安认证生物技术有限公司 | A kind of mesenchymal stem cell cryopreserving liquid and preparation method thereof and application method |
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| CN105168176A (en) * | 2015-08-31 | 2015-12-23 | 青岛蓝盛洋医药生物科技有限责任公司 | Pharmaceutical fasudil hydrochloride composition capsule for angiectasis |
| CN109090100A (en) * | 2018-08-27 | 2018-12-28 | 深圳市浊安认证生物技术有限公司 | A kind of mesenchymal stem cell cryopreserving liquid and preparation method thereof and application method |
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Application publication date: 20130508 |