CN110787163A - Pharmaceutical composition for neuroprotection and promoting nerve regeneration and preparation thereof - Google Patents
Pharmaceutical composition for neuroprotection and promoting nerve regeneration and preparation thereof Download PDFInfo
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- CN110787163A CN110787163A CN201911235368.5A CN201911235368A CN110787163A CN 110787163 A CN110787163 A CN 110787163A CN 201911235368 A CN201911235368 A CN 201911235368A CN 110787163 A CN110787163 A CN 110787163A
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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Abstract
The invention discloses a pharmaceutical composition for neuroprotection and nerve regeneration promotion, which comprises a compound shown as a structural formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The invention also provides the use of a pharmaceutical composition of the invention in the manufacture of a medicament for the prevention or treatment of a disease or condition involving, or at risk of developing, neuronal damage.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a pharmaceutical composition for protecting nerves and promoting nerve regeneration and a preparation thereof.
Background
Stroke is an acute cerebrovascular disease that seriously threatens human life and health. From the pathological point of view, stroke is a disease that the blood cannot perfuse cerebral vessels due to the blockage of cerebral vessels, or the cerebral vessels suddenly break to cause brain tissue damage, which is also called cerebrovascular accident and is commonly called stroke. The cerebral apoplexy comprises ischemic stroke and hemorrhagic stroke, wherein the ischemic stroke comprises transient ischemic attack, cerebral thrombosis, cerebral embolism and the like, the incidence rate of the ischemic stroke is higher than that of the hemorrhagic stroke and accounts for 60-70% of the total number of the cerebral stroke, the serious cerebral stroke can cause death, the hemorrhagic stroke comprises cerebral hemorrhage and subarachnoid hemorrhage, and the death rate is higher than that of the ischemic stroke.
The most common cause of cerebral apoplexy is the detachment of small embolus on the inner wall of cerebral vessels or mural thrombus of heart valves, the blockage of cerebral vessels, the arterial-arterial embolism, namely ischemic stroke, or the hemorrhagic stroke caused by cerebral vessels or thrombus bleeding due to factors such as hypertension, cerebral arteriovenous malformation and aneurysm. Hypertension, diabetes, hyperlipidemia, unhealthy diet, obesity, smoking, lack of proper exercise, excessive drinking, and homocysteine all increase the risk of stroke.
The clinical characteristics of stroke mainly include speech, cognitive, motor and sensory dysfunction, dysphagia, balance disorder, psychological disorder and the like, and the stroke has the characteristics of high morbidity, high mortality and high disability rate. Different types of stroke have different treatment modes. However, only few kinds of thrombolytic drugs, surgical operations, etc. are clinically available for treating stroke until now, and the clinical use time window is very short. Currently, research focus in the field is on finding drugs that can be used for neuroprotection and promoting nerve regeneration, thereby prolonging neuronal tolerance time to ischemia and the therapeutic window, supplementing damaged or dead neurons, and promoting recovery of central nervous system function after stroke. However, in view of the severe harmfulness of stroke itself and the complexity of the structure and function of the central nervous system, there is an unmet need in the art for such drugs.
Disclosure of Invention
The technical problem to be solved by the present invention is to provide a pharmaceutical composition and a preparation thereof, which can be used for preventing or treating diseases or disorders involving neuronal damage or at risk of developing neuronal damage, in particular for preventing or treating ischemic stroke.
The inventor of the invention unexpectedly finds that (6S) -5' -fluoro-2 ' -oxo-1 ',2',5, 7-tetrahydrospiro [ cyclopenta [ b ] pyridine-6, 3' -pyrrolo [2,3-b ] pyridine ] -3-formic acid (hereinafter referred to as compound I) with the following structural formula has the effects of protecting nerves and promoting nerve regeneration
And thus may be used for the prevention or treatment of diseases or conditions involving or at risk of developing neuronal damage, in particular for the prevention or treatment of ischemic stroke.
To this end, in one aspect, the present invention provides a pharmaceutical composition for neuroprotection and promoting nerve regeneration, comprising compound I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The compounds I used according to the invention were previously described in patent document WO2012/064910A 1. Patent document WO2012/064910a1 relates generally to calcitonin gene-related peptide (CGRP) receptor antagonist compounds which are believed to be very potent antagonists of CGRP receptors and are useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. In this document, compound I is described as being disclosed as INTERMEDIATE 34 (INTERMEDIATE 34) and can be prepared according to the synthetic methods described on pages 66-68. However, this patent document does not mention any biological and/or pharmacological activity of said compounds, nor does it mention the neuroprotective and neuroregenerative promoting effects of said compounds, which constitutes an unexpected finding of the present invention.
The pharmaceutical composition of the present invention may further comprise other drugs for preventing or treating ischemic stroke, including, but not limited to, drugs for improving microcirculation, expanding blood volume such as low molecular dextran, thrombolytics such as urokinase, anti-coagulants such as heparin, calcium antagonists such as nimodipine, and drugs for preventing platelet aggregation such as aspirin.
The pharmaceutical composition of the invention also comprises a pharmaceutically acceptable carrier. The pharmaceutical composition may be prepared using any pharmaceutically acceptable carrier commonly used in the art.
For example, to prepare solid dosage forms for oral administration, solid carriers known in the art such as lactose, microcrystalline cellulose, sucrose, cyclodextrin, mannitol, acacia, sodium carboxymethyl starch, corn starch, potato starch, talc, magnesium stearate, gelatin, and the like, may be used. In addition, any other carrier which is compatible with the active ingredient or ingredients used, and which is commonly used for coloring, flavoring, preserving, etc., may also be used.
For preparing liquid dosage forms for oral administration, water, ethanol, glycerol, propylene glycol, polyethylene glycol, and vegetable oils such as peanut oil, sesame oil, soybean oil, olive oil, and the like, as known in the art, may be used.
For preparing parenteral dosage forms, water for injection, oil for injection such as soybean oil, peanut oil, castor oil, other solvents for injection such as ethanol, propylene glycol, glycerol, polyethylene glycol, dimethylacetamide and the like can be used as known in the art of sterile carriers. Various additives such as wetting agents, solubilizers, suspending agents, emulsifiers, buffers, bacteriostats, antioxidants, isotonicity adjusting agents, and the like may also be used if desired. For preparing sterile powder for injection, bulking agents and protecting agents such as lactose, trehalose, mannitol, glycine, and human serum albumin can also be used.
The pharmaceutical composition of the present invention can be prepared into various pharmaceutically acceptable dosage forms, such as tablets, powders, granules, pills, capsules, solutions, emulsions, suspensions, injectable solutions, sterile powders for injection, and the like, according to conventional preparation techniques in the art.
The pharmaceutical compositions of the present invention may be administered by any suitable route of administration. Preferably, the pharmaceutical composition according to the invention is administered by parenteral route.
To this end, in one aspect, the present invention provides a pharmaceutical composition for neuroprotection and promotion of nerve regeneration, wherein the pharmaceutical composition is in the form of a parenteral formulation consisting of Compound I or a pharmaceutically acceptable salt thereof, optionally other drugs for the prevention or treatment of ischemic stroke and a pharmaceutically acceptable carrier, wherein said compound I or a pharmaceutically acceptable salt thereof is present at a concentration of 5-20mg/ml, the pharmaceutically acceptable carrier consists of polysorbate 80, hydroxymethyl propyl cellulose, a phosphate buffer, NaCl and water, and the weight ratio of the compound I or the pharmaceutically acceptable salt thereof, polysorbate 80, hydroxymethyl propyl cellulose, phosphate buffer and NaCl is 5-20:5-20:2-8:0.6-2.4: 4.2-16.8.
In one aspect, the weight ratio of compound I or a pharmaceutically acceptable salt thereof, polysorbate 80, hydroxymethylpropyl cellulose, phosphate buffer, and NaCl is 10:10:4:1.2: 8.4.
In one aspect, the phosphate buffer is prepared from NaH2PO4、NaH2PO4:H2O and Na2HPO4The weight ratio of the three components is 1:3: 2.
The invention also provides the use of a pharmaceutical composition of the invention in the manufacture of a medicament for the prevention or treatment of a disease or condition involving, or at risk of developing, neuronal damage. Preferably, the disease or condition involving or at risk of developing neuronal damage is ischemic stroke.
In order that the nature and spirit of the present invention may be further understood, preferred embodiments of the present invention and the effects thereof will be described below with reference to specific examples. It is to be understood, however, that such description is merely illustrative of the features and advantages of the present invention, and is not intended to limit the scope of the appended claims in any way.
Detailed Description
Example 1
Parenteral formulation
5.0g of polysorbate 80 was added to the 500mL flask, and 100mL of water for injection was added to the flask to dissolve. Next, 2.0g of hydroxymethylpropylcellulose was added to the flask with an additional 300mL of water for injection. The contents were stirred with a stir bar to dissolve. Then, phosphate buffer was added: 0.1g NaH2PO4；0.3g NaH2PO4:H2O; and 0.2g of Na2HPO4And 4.2 gNaCl. The mixture was stirred again to dissolve and then made up to 500 mL. The solution was filtered through a 0.22 micron Corning filter. Finally, 50mg of compound I was added to a transparent sterile vial with a stopper under stirring at ambient room temperature, and the aforementioned filtrate was added to prepare a solution with a concentration of 5mg/ml, to obtain a parenteral preparation for intramuscular injection.
Example 2
Parenteral formulation
5.0g of polysorbate 80 was added to the 500mL flask, and 100mL of water for injection was added to the flask to dissolve. Next, 2.0g of hydroxymethylpropylcellulose was added to the flask with an additional 300mL of water for injection. The contents were stirred with a stir bar to dissolve. Then, phosphate buffer was added: 0.1g NaH2PO4；0.3g NaH2PO4:H2O; and 0.2g of Na2HPO4And 4.2 gNaCl. The mixture was stirred again to dissolve and then made up to 500 mL. The solution was filtered through a 0.22 micron Corning filter. Finally, 100mg of compound I was added under stirring at ambient room temperature to a transparent sterile vial with a stopper, and the aforementioned filtrate was added to prepare a solution with a concentration of 10mg/ml, to obtain a parenteral formulation for intramuscular injection.
Example 3
Parenteral formulation
5.0g of polysorbate 80 was added to the 500mL flask, and 100mL of water for injection was added to the flask to dissolve. Next, 2.0g of hydroxymethylpropylcellulose was added to the flask with an additional 300mL of water for injection. The contents were stirred with a stir bar to dissolve. Then, phosphate buffer was added: 0.1g NaH2PO4；0.3g NaH2PO4:H2O; and 0.2g of Na2HPO4And 4.2 gNaCl. The mixture was stirred again to dissolve and then made up to 500 mL. The solution was filtered through a 0.22 micron Corning filter. Finally, 200mg of compound I was added under stirring at ambient room temperature to a transparent sterile vial with a stopper, and the aforementioned filtrate was added to prepare a solution with a concentration of 20mg/ml, to obtain a parenteral formulation for intramuscular injection.
Experimental example 1 evaluation of neuroprotective Effect of Compound I
The aim of this experiment was to investigate the neuronal protective effect of compound I of the invention using the OGD model. The OGD model is an ex vivo glucose deprivation (OGD) cerebral ischemia model that mimics cerebral ischemia in vivo.
The experimental method of this experiment is as follows:
(1) primary cortical neuron culture scheme
The brains of newborn SD rats were placed in a Hank's balanced salt solution free of magnesium and calcium ions containing 1mM sodium pyruvate and 10mM phees buffer. Next, the dermal tissue was separated in Hank's balanced salt solution (containing 0.125% trypsin solution) and incubated at 37 ℃ for 10 minutes. The tissue was then thoroughly dispersed by pasteur pipette (pateurpipette). Digestion was stopped by adding DMEM medium containing 10% heat-inactivated calf serum. The dispersed tissue was allowed to stand for 3 minutes and the supernatant was removed and transferred to a new centrifuge tube and centrifuged at 600 Xg for 3 minutes. The pellet was resuspended in serum-free NEUROBASAL medium supplemented with B27 cell culture supplement, 0.5 mML-Glutamine, 100IU/mL penicillin, and 100mg/mL streptomycin. Cells were plated at 2X 10 per well5Individual cell densities were seeded into 24-well cell culture plates coated with poly-D-lysine. The cell culture was maintained at 37 ℃ with 5% CO2Under saturated humidity conditions. Half-change of medium was performed every 2-3 days with fresh medium without glutamic acid.
(2) Cerebral ischemia model of sugar oxygen deprivation isolated body
After one week of culture, the primary cortical neuron culture media prepared according to step (1) was serum-starved overnight in high-glucose DMEM medium containing 1% (v/v) calf serum and 1% (v/v) penicillin-streptomycin. To establish a model of sugar oxygen deprivation (OGD) ex vivo cerebral ischemia, cultures were washed (× 2) with OGD medium (sugar-free DMEM medium containing 1% (v/v) calf serum and 1% penicillin-streptomycin (v/v) and supplemented with B27 as a neuronal culture). Cultures and drugs (compound I, formulated with OGD medium as solutions at concentrations of 5mg/ml, 10mg/ml and 20mg/ml, respectively) were incubated for half an hour, converted to OGD medium, and then cultures were transferred to a hypoxic incubator for 2 hours, followed by removal of the OGD medium. Subsequently, the culture was cultured with oxygen-containing high-glucose DMEM medium containing 1% (v/v) calf serum and 1% (v/v) penicillin-streptomycin and B27. After 8 hours, the reperfusion medium was collected for LDH analysis.
(3) Determination of cell viability
Cell viability was determined using Lactate Dehydrogenase (LDH) release. LDH is a living endoplasmic enzyme that normally cannot pass through the cell membrane and is released into the culture medium when cell damage causes a change in the permeability of the cell membrane. The activity of the enzyme in the culture is therefore proportional to the number of cells lysed.
In this experiment, LDH in cell culture medium and total LDH after cell lysis were measured separately, and the ratio of the two was calculated and normalized to a multiple of the control. The degree of neuroprotection was evaluated at different drug concentrations by measuring the rate of inhibition of LDH release. In general, a greater rate of inhibition of LDH release indicates a greater degree of neuroprotection by the drug. The inhibition results are shown in table 1 below.
TABLE 1 inhibition of LDH Release from cultured neurons by Compound I at various concentrations
Note: results are expressed as mean ± standard deviation.
From the above results, compound I has a significant neuroprotective effect on sugar-oxygen deprived ex vivo cortical neurons and is significantly dose-dependent.
Experimental example 2 evaluation of nerve regeneration-promoting Effect of Compound I
The purpose of this experiment was to investigate the nerve regeneration promoting effect of compound I of the present invention using the middle cerebral artery occlusion model.
1. Laboratory animal
60 adult male SD rats weighing 290 g. + -.10 g were used in this experiment. Animals were acclimated for two days at 25 ℃ room temperature, 50% relative humidity and 12 hours light-12 hours dark conditions. Animals can eat and drink water freely.
2. Molding die
(1) Middle cerebral artery occlusion model group: the rat middle cerebral artery occlusion model is established by referring to the method disclosed in Chinese patent application publication No. CN 106474113A. Successfully modelled rats were randomly divided into a model control group (20) and a compound I treated group (20).
(2) The sham operation group: another 20 rats were removed as a sham group. Sham rats were subjected to the same craniotomy procedure, but without occluding the middle cerebral artery, and the rest of the procedure was identical to that of the model control group.
3. Administration of drugs
The dosing regimen was as follows:
compound I treatment group: the parenteral formulation of example 2 was administered at a dose of 50mg/kg body weight/day for 4 weeks from intramuscular injection between 6 and 7 pm per day.
Model control group: an equivalent amount of saline was administered by intramuscular injection between 6 and 7 pm every day for 4 weeks.
The sham operation group: the same model as the control group.
After the experiment is finished, the motor function of the rat is measured by adopting a forelimb placing detection method. Rats were tested 10 times per side and the score for that side was determined as the percentage of the number of times the forelimb touched the edge of the table corner.
And respectively scoring at 24h, 7d, 2 and 4 weeks after the molding is successful. After completion of the experiment, the expressions of brain tissue tyrosine receptor kinase B (trk-B) and involutin A (Nogo-A) were observed by immunohistochemistry and in situ hybridization, respectively, and the average gray level of staining was measured.
4. Results
The experimental statistics are shown in tables 2-3 below.
TABLE 2 sports function scores for the groups of rats
Note: results are expressed as mean ± standard deviation, p <0.01 compared to model control group.
TABLE 3 comparison of mean Gray levels of trk-B and Nogo-A rats in each group
Note: results are expressed as mean ± standard deviation, p <0.01 compared to model control group.
The results show that the compound I can obviously improve the motor function of a middle cerebral artery occlusion model rat. In particular, the motor function score of the rats in the compound I treatment group at 2 and 4 weeks after the model building success is obviously higher than that of the model control group, and P is less than 0.01. In addition, compound I treated group (90.9 + -9.7) showed a significant increase (112.7 + -6.3) in P <0.01 for trk-B expression compared to the model control group; and for Nogo-A expression, the expression of a compound I treatment group (137.8 +/-8.8) is obviously weakened (119.5 +/-7.9) compared with that of a model control group, and P is less than 0.01, so that the compound I can obviously enhance trk-B, inhibit the expression of Nogo-A, improve the microenvironment of nerve regeneration and promote the motor function recovery of ischemic stroke rats.
In summary, the above experimental results fully confirm that compound I can be used for neuroprotection and promotion of nerve regeneration, and thus can be used for prevention or treatment of diseases or disorders involving neuronal damage or at risk of developing neuronal damage, such as ischemic stroke.
The foregoing is only a preferred embodiment of the present invention. It should be noted that, for those skilled in the art, without departing from the spirit and principle of the present invention, several improvements, modifications, equivalents and the like can be made, and these improvements, modifications, equivalents and the like also should be regarded as falling within the protection scope of the present invention.
Claims (8)
1. A pharmaceutical composition for neuroprotection and promoting nerve regeneration, comprising a compound of structural formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier
2. The pharmaceutical composition of claim 1, further comprising an additional agent for the prevention or treatment of ischemic stroke.
3. The pharmaceutical composition of claim 2, wherein said drug is selected from the group consisting of a drug that improves microcirculation, expands blood volume, a thrombolytic drug, an anticoagulant drug, a calcium ion antagonist, and a drug that prevents platelet aggregation.
4. A pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition is in the form of a parenteral formulation, the parenteral preparation consists of the compound I or pharmaceutically acceptable salt thereof, optional other medicines for preventing or treating ischemic stroke and pharmaceutically acceptable carriers, wherein said compound I or a pharmaceutically acceptable salt thereof is present at a concentration of 5-20mg/ml, the pharmaceutically acceptable carrier consists of polysorbate 80, hydroxymethyl propyl cellulose, a phosphate buffer, NaCl and water, and the weight ratio of the compound I or the pharmaceutically acceptable salt thereof, polysorbate 80, hydroxymethyl propyl cellulose, phosphate buffer and NaCl is 5-20:5-20:2-8:0.6-2.4: 4.2-16.8.
5. The pharmaceutical composition according to claim 4, wherein the weight ratio of compound I or the pharmaceutically acceptable salt thereof, polysorbate 80, hydroxymethylpropylcellulose, phosphate buffer and NaCl is 10:10:4:1.2: 8.4.
6. The pharmaceutical composition of claim 5, wherein the phosphate buffer is comprised of NaH2PO4、NaH2PO4:H2O and Na2HPO4The weight ratio of the three components is 1:3: 2.
7. Use of a pharmaceutical composition according to any one of claims 1 to 6 in the manufacture of a medicament for the prevention or treatment of a disease or condition involving or at risk of developing neuronal damage.
8. The use of claim 7, wherein the disease or condition involving or at risk of developing neuronal damage is ischemic stroke.
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| CN111346095A (en) * | 2020-03-14 | 2020-06-30 | 温州医科大学附属第二医院、温州医科大学附属育英儿童医院 | Pharmaceutical preparation for treating headache after neurosurgery operation |
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| WO2009126584A1 (en) * | 2008-04-07 | 2009-10-15 | Amgen Inc. | Gem-disubstituted and spirocyclic amino pyridines/pyrimidines as cell cycle inhibitors |
| WO2012064910A1 (en) * | 2010-11-12 | 2012-05-18 | Merck Sharp & Dohme Corp. | Piperidinone carboxamide azaindane cgrp receptor antagonists |
| WO2016075137A1 (en) * | 2014-11-10 | 2016-05-19 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) | Spiropyrazine derivatives as inhibitors of non-apoptotic regulated cell-death |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009126584A1 (en) * | 2008-04-07 | 2009-10-15 | Amgen Inc. | Gem-disubstituted and spirocyclic amino pyridines/pyrimidines as cell cycle inhibitors |
| WO2012064910A1 (en) * | 2010-11-12 | 2012-05-18 | Merck Sharp & Dohme Corp. | Piperidinone carboxamide azaindane cgrp receptor antagonists |
| WO2016075137A1 (en) * | 2014-11-10 | 2016-05-19 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) | Spiropyrazine derivatives as inhibitors of non-apoptotic regulated cell-death |
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| CN111346095A (en) * | 2020-03-14 | 2020-06-30 | 温州医科大学附属第二医院、温州医科大学附属育英儿童医院 | Pharmaceutical preparation for treating headache after neurosurgery operation |
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