CN105709226A - Applications of CB2R (cannabinoid receptor 2) agonist in preparing medicines for treating hypertensive cerebral hemorrhage - Google Patents
Applications of CB2R (cannabinoid receptor 2) agonist in preparing medicines for treating hypertensive cerebral hemorrhage Download PDFInfo
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Abstract
The invention relates to the field of medicines for treating cerebral hemorrhage, and in particular relates to applications of a CB2R (cannabinoid receptor 2) agonist in preparing medicines for promoting the neural functional recovery and treating the encephalatrophy after the hypertensive cerebral hemorrhage. The invention provides the applications of the CB2R agonist in preparing medicines for promoting the neural functional recovery and treating the encephaledema after the hypertensive cerebral hemorrhage. The in-vivo experiment shows that the CB2R agonist can reduce the autoblood-induced edema degree of the brain tissue and prevent the encephalatrophy; the medicine has an obvious improvement effect for the neural functional recovery after the hypertensive cerebral hemorrhage. In addition, the CB2R agonist is matched with minocyline for use, and minocyline can obviously increase the blood brain barrier transmittance of the CB2R agonist, and also enhance the anti-inflammatory treatment effect.
Description
Technical field
The present invention relates to cerebral hemorrhage drug world, in particular to the application in neurological functional recovery and cerebral edema medicine after preparation treatment hypertensive cerebral hemorrhage of II type cannabinoid receptor agonists.
Background technology
Hypertensive cerebral hemorrhage is one of complication that hypertension is the most serious, often betides 50～70 years old, is common in basal ganglia region artery of cerebral hemorrhage Rupture haemorrhag, with neurological sequelae such as serious brain atrophy, delayed ischemic neurological deficits.Except removing the operation method such as hematoma, drainage of cerebrospinal fluid except operation, medicine is the Main Means improving hypertensive cerebral hemorrhage sequela.Still lack effective Drug therapy clinically at present.
II type Cannabined receptor (CannabinoidReceptor2, CB2R) is one of major receptors of endocannabinoids, is mainly expressed in the microglia of central nervous system.JWH133 is the selective agonist of CB2R, has additive little, and easily through features such as blood brain barrier, it is widely regarded as the prognosis improving nervous system disease by playing anti-inflammatory effect.So far, about JWH133, the research improving function of nervous system after hypertensive cerebral hemorrhage is not reported.
In view of this, the special proposition present invention.
Summary of the invention
It is an object of the invention to provide the application in neurological functional recovery and cerebral edema medicine after preparation treatment hypertensive cerebral hemorrhage of II type cannabinoid receptor agonists.
In order to realize the above-mentioned purpose of the present invention, spy by the following technical solutions:
II type cannabinoid receptor agonists is the application in neurological functional recovery and cerebral edema medicine after preparation treatment hypertensive cerebral hemorrhage.
The present invention is found by experiments in vivo, and II type cannabinoid receptor agonists can reduce autologous blood induction cerebral tissue edema degree, prevents brain atrophy；Use this medicine that neurological functional recovery is had after hypertensive cerebral hemorrhage to improve significantly.
Specifically, II type cannabinoid receptor agonists is applied to treatment hypertensive cerebral hemorrhage, and the cerebral edema and the function of nervous system that are particularly caused by hypertensive cerebral hemorrhage are impaired.
The Therapeutic Method of hypertensive cerebral hemorrhage, including the II type cannabinoid receptor agonists giving experimenter's effective dose.
Administering mode can be oral, intravenous injection or transdermal penetration mode, puts on the patient needing treatment, specifically according to the state of an illness of patient, age etc., doctor can determine.
Minocycline is the tetracycline antibiotics of a kind of broad-spectrum antiseptic, can be combined with tRNA, reaches antibacterial effect.Minocycline has wider array of antimicrobial spectrum than similar drugs, has bacteriostatic activity.
Find through test, II type cannabinoid receptor agonists and minocycline with the use of, minocycline can dramatically increase the transmitance of the blood brain barrier of II type cannabinoid receptor agonists, and increases antiinflammatory action therapeutic effect.Preferably, described medicine also includes minocycline.
Preferably, in described medicine, the part by weight of II type cannabinoid receptor agonists and minocycline is 2-3:45.
Specifically, II type cannabinoid receptor agonists and minocycline are united and applied in treatment hypertensive cerebral hemorrhage, and the cerebral edema and the function of nervous system that are particularly caused by hypertensive cerebral hemorrhage are impaired.
The Therapeutic Method of hypertensive cerebral hemorrhage, including the II type cannabinoid receptor agonists and the minocycline that give experimenter's effective dose.
Administering mode can be oral, intravenous injection or transdermal penetration mode, puts on the patient needing treatment, specifically according to the state of an illness of patient, age etc., doctor can determine.
According to clinical requirement, medicine can be made into various dosage form.Further, described medicine also includes pharmaceutically acceptable adjuvant.
Further, described pharmaceutically acceptable adjuvant includes any one or more combination in diluent, excipient, disintegrating agent, filler, binding agent, lubricant, correctives, surfactant, stabilizer.
Further, described excipient includes any one or more combination in mannitol, lactose, starch, dextran, microcrystalline Cellulose.
Further, described disintegrating agent includes any one or more combination in polyvinylpyrrolidone, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose.
Further, described lubricant includes any one or two kinds of combinations in Pulvis Talci, magnesium stearate.
Further, the dosage form of described medicine includes any one in injection, injection, tablet, electuary, granule, pill, capsule.
The diluent related in the present invention such as water etc.；Filler is starch, sucrose etc. such as；Binding agent, such as starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, Polyethylene Glycol etc.；Surfactant such as cationic, anionic, amphoteric ion type and non-ionic；Stabilizer such as cadmium stearate, zinc stearate, dimercapto 2-ethyl hexyl ethanoate dioctyltin, di-n-butyltin dilaurate etc..
The dosage form of medicine provided by the invention is prepared according to the conventional method of this area.As in order to the effective ingredient of the present invention is made tablet, it is possible to widely use various excipient well known in the art, including diluent, binding agent, wetting agent, disintegrating agent, lubricant, fluidizer.Diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline Cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate etc.；Wetting agent can be water, ethanol, isopropanol etc.；Binding agent can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, Polyethylene Glycol etc.；Disintegrating agent can be dried starch, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, dodecyl sodium sulfate etc.；Lubricant and fluidizer can be Pulvis Talci, silicon dioxide, stearate, tartaric acid, liquid paraffin, Polyethylene Glycol etc..
Tablet can also be made coated tablet further, for instance sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablet and multilayer tablet.
As: in order to administration unit is made capsule, it is possible to the effective ingredient of the present invention is mixed with diluent, fluidizer, mixture is placed directly within hard capsule or soft capsule.Also effective ingredient first can be made granule or micropill with diluent, adhesive, disintegrating agent, then be placed in hard capsule or soft capsule.For preparing each diluent of the compounds of this invention tablet, adhesive, wetting agent, disintegrating agent, fluidizer kind can also be used for preparing the capsule of the compounds of this invention.
And for example: for the effective ingredient of the present invention is made injection, it is possible to water, ethanol, isopropanol, propylene glycol or their mixture as solvent addition solubilizing agent commonly used in the art in right amount, cosolvent, pH adjusting agent, osmotic pressure regulator.Solubilizing agent or cosolvent can be poloxamer, lecithin, HP-β-CD etc.；PH adjusting agent can be phosphate, acetate, hydrochloric acid, sodium hydroxide etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate etc..As prepared lyophilized injectable powder, mannitol, glucose etc. also can be added as proppant.
Additionally, if desired, coloring agent, preservative, spice, correctives or other additive can also be added in pharmaceutical preparation.
Preferably, the dosage form of described medicine is injection.Effective active composition can be made aqueous solution or powder etc. and be applicable to the medicament forms of injection, convenient and swift, it is easy to use.
Injection can carry out intravenous drip or intramuscular injection in use, general 1 day 1 time, within 7 days, is a course for the treatment of.
Compared with prior art, the invention have the benefit that
(1) present invention is found by experiments in vivo, and II type cannabinoid receptor agonists can reduce autologous blood induction cerebral tissue edema degree, prevents brain atrophy；Use this medicine that neurological functional recovery is had after hypertensive cerebral hemorrhage to improve significantly.
(2) it have also been found that, II type cannabinoid receptor agonists and minocycline with the use of, minocycline can dramatically increase the transmitance of the blood brain barrier of II type cannabinoid receptor agonists, increases therapeutic effect.
(3) present invention also offers the various dosage forms of medicine, in order to application.
Accompanying drawing explanation
In order to be illustrated more clearly that the embodiment of the present invention or technical scheme of the prior art, the accompanying drawing used required in embodiment or description of the prior art will be briefly described below.
Fig. 1 is different group ability of learning and memory and motor memory ability measurement result curve chart in the embodiment of the present invention 1；
Fig. 2 is the bar diagram of different group cerebral tissue protein electrophoresis figure and corresponding protein content in the embodiment of the present invention 1；
Fig. 3 is different group SABC fluorescence double; two mark colored graph in the embodiment of the present invention 1；
Fig. 4 is children's Mus brain water content change bar diagram after different group medications 3 days in the embodiment of the present invention 2；
Fig. 5 be in the embodiment of the present invention 2 JWH133 and minocycline with the use of neuron number purpose microgram and bar diagram after 7 days.
Detailed description of the invention
Below in conjunction with embodiment, embodiment of the present invention are described in detail, it will be appreciated by those skilled in the art that the following example is merely to illustrate the present invention, and are not construed as restriction the scope of the present invention.Unreceipted actual conditions person in embodiment, conventionally the condition of condition or manufacturer's suggestion carries out.Agents useful for same or the unreceipted production firm person of instrument, being can by the conventional products of commercially available acquisition.
Embodiment 1
SD rat (250g-300g) is model animal, anatomical isolation right common femoral artery, 1ml insulin needle takes Autologous arterial blood 200 microlitre (being not added with anticoagulant) and injects basal ganglia region on the right side of rat (in 15 minutes slowly injection) through stereotaxic instrument, micro-injection pump immediately, inserting needle coordinate is mouth side 0.2mm, right side 2.2mm, inserting needle 5mm after needle point breakthrough cerebral dura mater.Set up blank group (i.e. the normal SD rats of non-underwent operative), normal saline group (postoperative lumbar injection normal saline), JWH133 treatment group (postoperative lumbar injection JWH133 aqueous solution 1.5mg/kg, 2 times/day, totally 7 days) and II type Cannabined receptor selective antagonist group (injection SR144258), often 10 animals of group.
After model sets up 28 days, employing water maze (WaterMorrisMaze) detects ability of learning and memory, NegativegeotaxisTest and RotoradTest detects rat motor memory ability.
NegativegeotaxisTest and RotoradTest testing result is respectively as shown in Figure 1A and Fig. 1 C, and determined with Morris water result is as shown in Figure 1B.
As can be seen from Figure 1, JWH133 treatment group is consistent with the ability of learning and memory of normal SD rats and motor memory ability, substantially strong than the ability of learning and memory of normal saline group and injection SR144258 group and motor memory ability, visible, the recovery of the function of nervous system after hypertensive cerebral hemorrhage is had significant curative effect by JWH133.
Quickly taking brain after Behavior Examination to weigh, result is as shown in Figure 2.Figure it is seen that rat cerebral tissue's weight relatively saline rats brain weight dramatically increases after JWH133 treatment, statistically significant.
Separately setting above group again, often 6 animals of group, in medication last day, namely the 7th day through lumbar injection Brdu (bromodeoxyribouridine, 100mg/kg, puts to death first 2 hours 1 time, 3 times totally), fixing then through heart concern, take brain section, row immunohistochemical staining checks, result is as shown in Figure 3.
From figure 3, it can be seen that rat hippocampus district cell proliferation dramatically increases (A, B) after JWH133 treatment, cell content relatively normal saline group substantially increases.
It addition, in experiments it is found that, after model sets up 3 days, JWH133 group rat brain brain water content relatively normal saline group substantially reduces.Visible, JWH133 does not affect rat blood pressure, body temperature and routine blood test, and safety has no side effect.Can prepare into JWH133 for active component and improve the medicine of function of nervous system after hypertensive cerebral hemorrhage.
Embodiment 2
Minocycline (Minocycline), also known as " minocycline " or " happy ring element ", is the tetracycline antibiotics of a kind of broad-spectrum antiseptic, has the pharmacological property such as long half time, lipotropy.
Owing to brain exists blood brain barrier, directly take JWH133 and be not easy to enter brain, thus realizing its function.Finding through clothes for patients, JWH133 is matched with minocycline, and effect is significantly better than the patient individually taking JWH133.
In consideration of it, carry out following zoopery:
Newborn 7 days (P7) SD Intracerebral Hemorrhage in Rats companion's ventricular hemorrhage (GMH/IVH) models of test group 1:VII Collagenase Type induction are with embodiment 1, being divided into sham operated rats, normal saline group, independent JWH133 group and JWH133+ minocycline group, medication detects children's Mus brain water content change after 3 days.Result is as shown in Figure 4.
From fig. 4, it can be seen that JWH133 combines Minocycline In The Treatment neonatal apoplexy curative effect is better than simple lumbar injection JWH133.
Newborn 7 days (P7) SD Intracerebral Hemorrhage in Rats companion's ventricular hemorrhage (GMH/IVH) models of test group 2:VII Collagenase Type induction are with embodiment 1, JWH133 group between different groups is different from the consumption of minocycline, and medication detects neuron number change after 7 days.Result is as shown in Figure 5.
In Fig. 5, A group rat (n=6) GMH model gives lumbar injection JWH1331mg/kg after setting up and adds minocycline 45mg/kg；B group rat (n=6) model gives lumbar injection JWH1332mg/kg after setting up and adds minocycline 45mg/kg；C group rat (n=6) model gives lumbar injection JWH1333mg/kg after setting up and adds minocycline 45mg/kg；D is that under microscope, every visual field hippocampus neuronal specificity antibody (NeuN+) positive cell number compares.
From fig. 5, it can be seen that A group rat and B group hippocampus of rats positive number there were significant differences (p<0.01) however use 2mg/kg and 3mg/kgJWH133 no difference of science of statistics (p>0.05).
The effect group of JWH133 with minocycline is organically combined by the present invention, makes a kind of neuroprotective effect simultaneously playing JWH133 and has the medicine of high blood-brain barrier permeability of minocycline, increasing therapeutic effect.
Visible, JWH133 coordinates with minocycline and has better therapeutic effect.It addition, also the ratio of JWH133 Yu minocycline consumption is tested, it is found that be preferred with the part by weight of II type cannabinoid receptor agonists Yu minocycline for 2-3:45.
Embodiment 3
Medicine provided by the invention includes II type cannabinoid receptor agonists and pharmaceutically acceptable adjuvant, makes injection, injection, tablet, electuary, granule, pill, capsule, suspending agent, Emulsion, unguentum, cream, transdermal patch etc..
The preparation of each dosage form carries out illustrated below:
1, injection is prepared
Weigh 1.5gII type cannabinoid receptor agonists, add 50gPEG-400, dissolve；The phosphate buffer of preparation 50gpH5.5, weighs 0.02g sodium sulfite and joins in above-mentioned phosphate buffer；Buffer is joined in PEG solution, mix homogeneously, add 0.01% needle-use activated carbon 100 DEG C and be incubated 30 minutes, G3 sintered glass funnel filters, the filtering with microporous membrane of 0.22 μm, medicinal liquid after filtration is distributed into the 2ml/ injection propped up, and the good injection of subpackage directly tamponade, jewelling lid can become injection.
2, the preparation of freeze-dried powder
Weigh 2gII type cannabinoid receptor agonists, add 50gPEG-400, make saponin dissolve.The phosphate buffer of preparation 50gpH5.5, weighs 0.02g sodium sulfite and joins in above-mentioned phosphate buffer；Buffer is joined in the PEG solution of saponin, mix homogeneously, add 0.01% needle-use activated carbon 100 DEG C and be incubated 30 minutes, G3 sintered glass funnel filters, the filtering with microporous membrane of 0.22 μm；Medicinal liquid after filtration is distributed in the 2ml/ cillin bottle propped up, and freeze-dried powder is made in lyophilised machine lyophilizing.
3, the preparation of tablet
Weigh II type cannabinoid receptor agonists 80g, starch 870g, Pulvis Talci 50g, mix homogeneously, be pressed into 500.
4, the preparation of capsule
Weigh II type cannabinoid receptor agonists 20g, starch 40g, sodium carboxymethyl cellulose 50g, polyvinylpyrrolidone 10g, Pulvis Talci 5g, mix homogeneously, dress up 100 capsules.
Embodiment 4
Medicine provided by the invention includes II type cannabinoid receptor agonists, minocycline and pharmaceutically acceptable adjuvant, makes injection, injection, tablet, electuary, granule, pill, capsule, suspending agent, Emulsion, unguentum, cream, transdermal patch etc..
The preparation of each dosage form carries out illustrated below:
1, injection is prepared
Weigh 2gII type cannabinoid receptor agonists and 45g minocycline, add 100gPEG-400, make saponin dissolve；The phosphate buffer of preparation 150gpH5.5, weighs 0.05g sodium sulfite and joins in above-mentioned phosphate buffer；Buffer is joined in the PEG solution of saponin, mix homogeneously, add 0.01% needle-use activated carbon 100 DEG C and be incubated 30 minutes, G3 sintered glass funnel filters, the filtering with microporous membrane of 0.22 μm, medicinal liquid after filtration is distributed into the 2ml/ injection propped up, and the good injection of subpackage directly tamponade, jewelling lid can become injection.
Weigh 3gII type cannabinoid receptor agonists and 45g minocycline, add 100gPEG-400, make saponin dissolve；The phosphate buffer of preparation 150gpH5.5, weighs 0.05g sodium sulfite and joins in above-mentioned phosphate buffer；Buffer is joined in the PEG solution of saponin, mix homogeneously, add 0.01% needle-use activated carbon 100 DEG C and be incubated 30 minutes, G3 sintered glass funnel filters, the filtering with microporous membrane of 0.22 μm, medicinal liquid after filtration is distributed into the 2ml/ injection propped up, and the good injection of subpackage directly tamponade, jewelling lid can become injection.
2, the preparation of freeze-dried powder
Weigh 2gII type cannabinoid receptor agonists and 45g minocycline, add 150gPEG-400, make saponin dissolve.The phosphate buffer of preparation 300gpH5.5, weighs 0.1g sodium sulfite and joins in above-mentioned phosphate buffer；Buffer is joined in the PEG solution of saponin, mix homogeneously, add 0.01% needle-use activated carbon 100 DEG C and be incubated 30 minutes, G3 sintered glass funnel filters, the filtering with microporous membrane of 0.22 μm；Medicinal liquid after filtration is distributed in the 2ml/ cillin bottle propped up, and freeze-dried powder is made in lyophilised machine lyophilizing.
Weigh 3gII type cannabinoid receptor agonists and 45g minocycline, add 150gPEG-400, make saponin dissolve.The phosphate buffer of preparation 300gpH5.5, weighs 0.1g sodium sulfite and joins in above-mentioned phosphate buffer；Buffer is joined in the PEG solution of saponin, mix homogeneously, add 0.01% needle-use activated carbon 100 DEG C and be incubated 30 minutes, G3 sintered glass funnel filters, the filtering with microporous membrane of 0.22 μm；Medicinal liquid after filtration is distributed in the 2ml/ cillin bottle propped up, and freeze-dried powder is made in lyophilised machine lyophilizing.
3, the preparation of tablet
Weigh II type cannabinoid receptor agonists 20g, minocycline 450g, starch 950g, Pulvis Talci 80g, mix homogeneously, be pressed into 500.
4, the preparation of capsule
Weigh II type cannabinoid receptor agonists 30g, minocycline 450g, starch 500g, sodium carboxymethyl cellulose 500g, polyvinylpyrrolidone 100g, Pulvis Talci 20g, mix homogeneously, dress up 800 capsules.
Wherein, the II type cannabinoid receptor agonists in the present invention is JWH133, CAS accession number: 259869-55-1, and chemical structural formula is:
The chemical structural formula of minocycline is:
Although illustrate and describing the present invention with specific embodiment, however it will be appreciated that may be made that when without departing substantially from the spirit and scope of the present invention many other change and amendment.It is, therefore, intended that include all such changes and modifications belonging in the scope of the invention in the following claims.
Claims (10)
1.II type cannabinoid receptor agonists is the application in neurological functional recovery medicine after preparation treatment hypertensive cerebral hemorrhage.
The application in preparation treatment hypertensive cerebral hemorrhage associated with hydrocephalus medicine of the 2.II type cannabinoid receptor agonists.
3. application according to claim 1 and 2, it is characterised in that described medicine also includes minocycline.
4. the part by weight of application according to claim 3, it is characterised in that in described medicine, II type cannabinoid receptor agonists and minocycline is 2-3:45.
5. application according to claim 3, it is characterised in that described medicine also includes pharmaceutically acceptable adjuvant.
6. application according to claim 5, it is characterised in that described pharmaceutically acceptable adjuvant includes any one or more combination in diluent, excipient, disintegrating agent, filler, binding agent, lubricant, correctives, surfactant, stabilizer.
7. application according to claim 6, it is characterised in that described excipient includes any one or more combination in mannitol, lactose, starch, dextran, microcrystalline Cellulose.
8. application according to claim 6, it is characterised in that described disintegrating agent includes any one or more combination in polyvinylpyrrolidone, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose.
9. application according to claim 6, it is characterised in that described lubricant includes any one or two kinds of combinations in Pulvis Talci, magnesium stearate.
10. application according to claim 6, it is characterised in that the dosage form of described medicine includes any one in injection, injection, tablet, electuary, granule, pill, capsule.
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