WO2024051848A1 - 用于防治神经系统病变的药物组合物及其应用 - Google Patents
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Definitions
- the invention belongs to the technical field of biomedicine, and specifically relates to a pharmaceutical composition for preventing and treating neurological diseases and its application.
- Cerebrovascular disease generally refers to various diseases of cerebral blood vessels, including cerebral atherosclerosis, thrombosis, stenosis, occlusion, cerebral arteritis, cerebral artery injury, cerebral aneurysm, intracranial vascular malformation, and cerebral aneurysm. Ischemic or hemorrhagic accidents of brain tissue caused by venous fistulas, etc., lead to disability or death of patients, and the incidence rate accounts for 1/4-1/2 of the total neurological hospitalization cases.
- Cerebral stroke is an acute cerebrovascular disease. It is a group of diseases that causes brain tissue damage due to sudden rupture of blood vessels in the brain or the inability of blood to flow into the brain due to blood vessel obstruction, including ischemic and hemorrhagic stroke.
- Adults in my country The primary cause of death and disability in people, the incidence rate of stroke among urban and rural residents in my country is 650/100,000. There are more than 5 million new strokes in the country every year, and its mortality rate accounts for 22.45% of the total causes of death. More than 1.5 million people die every year, five The recurrence rate within a year is 50%, and lifelong disability accounts for 80%. Its incidence is rapidly increasing at an annual rate of 8.7%, and it doubles every 10 years among people over 55 years old.
- Clinically used stroke treatment drugs mainly include: thrombolytic drugs, anti-platelet aggregation drugs, fiber-reducing drugs, anticoagulant drugs and neuroprotective drugs.
- Thrombolytic drugs include alteplase, urokinase, etc., which have a certain effect on patients in the early stage of the disease, but they also have the risk of bleeding.
- the use of drugs needs to be evaluated by a doctor, meets the indications and excludes contraindications before use, and the dosage and effective time Studies such as window are still immature and need further exploration and research; anti-platelet aggregation drugs include aspirin, hydroclopidogrel, dipyridamole, etc., and some patients taking aspirin, clopidogrel, etc.
- Fibrin-reducing drugs and anticoagulant drugs are mainly used for acute ultra-early treatment measures, mainly used to dissolve thrombosis and prevent the recurrence of thrombosis; neuroprotective drugs are used to intervene in the waterfall cascade effect of the penumbra, but there are safety risks
- a variety of drugs have shown effects on nerve cells and peripheral nerve cells in vitro such as cell repair and nutritional support.
- it is administered through conventional administration routes (muscular injection, intravenous injection, oral administration, mucosal administration, etc.) and cannot pass the blood-brain barrier (blood barrier), which limits its role in nerve repair, nutritional support, etc.
- blood-brain barrier blood barrier
- Patent applications disclose technical content related to nerve repair protein extracts and nerve repair protein compositions with repair effects.
- the aforementioned applications and contents are essential to this application. Few technical references and components.
- the object of the present invention is to provide a pharmaceutical composition for use in preparing drugs for preventing and treating neurological lesions, wherein the pharmaceutical composition for preventing and treating neurological lesions contains nerve repair drugs and/or blood circulation improving drugs and anti-inflammatory drugs. drug.
- the nerve repair drugs and/or blood circulation improving drugs are selected from the group consisting of mouse nerve growth factor, monosialoganglioside (GM1), cerebrospinalis carnosine, methylcobalamin, and adenosylcobalamin.
- Vitamin B complex butylphthalide, cinpazide maleate, edaravone, edaravone dexbornillol, citicoline, citicoline sodium, gangliosides, oxiracetam , Piracetam, Aniracetam, Nerve Growth Factor, Citicoline, Neurotropin, Oryzanol, Vitamin B1, Vitamin B6, Vitamin B12, Vitamin C, Vitamin E, Compound Cerebroside, Brain Any one of protein, nervonic acid or their combination.
- the anti-inflammatory drug is selected from dexamethasone, methylprednisolone, prednisolone, methylprednisolone (methylprednisolone), cortisone, hydrocortisone, prednisone, Prednisolone or any combination thereof.
- the pharmaceutical composition for preventing and treating neurological lesions consists of a pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid and a pharmaceutical composition for a single acupoint injection.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 15ug-90ug of mouse nerve growth factor, 0.5mg-1.0mg of methylcobalamin, adenosylcobalamin or vitamin B 12 or citicoline. Any one 0.25mg-1.0mg, cerebrospinal glycoside carnosine or monosialoganglioside (GM1) or any one compound cerebrospinal ganglioside 2ml-8ml or ganglioside 20-40mg and dexamethasone 2mg -5mg composition.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 30ug-90ug of mouse nerve growth factor, 0.5mg-1.0mg of methylcobalamin, adenosylcobalamin or vitamin B 12 or citicoline. Any one 0.25mg-1.0mg, cerebrospinal glycoside carnosine or monosialoganglioside (GM1) or any one compound cerebroside ganglioside 4ml-6ml or ganglioside 20-40mg and dexamethasone 2mg -5mg composition.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 30ug of mouse nerve growth factor, 0.5mg of methylcobalamin, 0.5mg of adenosylcobalamin, cerebrospinal carnosine or monosialoganglioside ( GM1) or any compound cerebropeptide ganglioside 2ml-8ml or ganglioside 20-40mg and dexamethasone 5mg.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 30ug of mouse nerve growth factor, 0.5mg of methylcobalamin, 0.5mg of adenosylcobalamin, cerebrospinal carnosine or monosialoganglioside ( GM1) or any compound cerebropeptide ganglioside 4ml-6ml or ganglioside 20-40mg and dexamethasone 2mg.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 90ug of mouse nerve growth factor, 1.0 mg of methylcobalamin, 0.5 mg of adenosylcobalamin, cerebrospinal carnosine or monosialoganglioside ( GM1) or any compound cerebropeptide ganglioside 2ml-8ml or ganglioside 20-40mg and dexamethasone 5mg.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 60ug of mouse nerve growth factor, 1.0 mg of methylcobalamin, 0.5 mg of adenosylcobalamin, cerebrospinal carnosine or monosialoganglioside (GM1) or any compound cerebropeptide ganglioside 2ml-8ml or ganglioside 20-40mg and dexamethasone 3mg.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 30 ug of mouse nerve growth factor, 0.5 mg of methylcobalamin, 0.5 mg of adenosylcobalamin, 4 ml of cerebrospinal fluid and 5 mg of dexamethasone.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 0.5-1.0 mg of methylcobalamin, 0.1-0.5 mg of adenosylcobalamin and 2-5 mg of dexamethasone.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid optionally contains 100-300 mg of any one or combination of nerve repair cell protein extracts and/or nerve repair protein compositions with repair effects. , preferably 150-200mg.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid optionally contains 2-10 mg of naloxone hydrochloride, preferably 5-8 mg.
- the pharmaceutical composition for single acupoint injection is composed of mouse nerve growth factor It consists of 30ug-90ug, methylcobalamin 0.5mg-1.0mg, adenosylcobalamin 0.5mg-1.0mg, dexamethasone 2mg-5mg and lidocaine hydrochloride 1ml, wherein the concentration of lidocaine hydrochloride is selected from 0.8%, Any one of 1%, 1.5% and 2%.
- the pharmaceutical composition for single acupoint injection consists of 30ug of mouse nerve growth factor, 0.5mg of methylcobalamin, 0.5mg of adenosylcobalamin, 2mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein , the concentration of lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5%, and 2%.
- the pharmaceutical composition for single acupoint injection consists of 30ug of mouse nerve growth factor, 0.5mg of methylcobalamin, 1.0mg of adenosylcobalamin, 5mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein , the concentration of lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5%, and 2%.
- the pharmaceutical composition for single acupoint injection consists of 90ug of mouse nerve growth factor, 1.0mg of methylcobalamin, 0.5mg of adenosylcobalamin, 5mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein , the concentration of lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5%, and 2%.
- the pharmaceutical composition for single acupoint injection consists of 60ug of mouse nerve growth factor, 1.0mg of methylcobalamin, 0.5mg of adenosylcobalamin, 3mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein , the concentration of lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5%, and 2%.
- the pharmaceutical composition for a single acupoint injection optionally contains 100-300 mg of any one of the nerve repair cell protein extract and/or the nerve repair protein composition with repair effect, or any other thereof. combination.
- the pharmaceutical composition for single acupoint injection is used on an ad hoc basis.
- the Hegu acupoint, Shousanli, Shouwuli, Zusanli, Yanglingquan, Yinlingquan, Sanyinjiao and Yangjiao acupoints on the affected side of the limb are selected, and the Hegu acupoint and Zusanli acupoint on the healthy side are selected. Perform acupoint injections.
- the pharmaceutical composition for single acupoint injection is injected once a day into the acupoint, and the treatment course is 7 days.
- each acupoint injection treatment lasts for 2-6 courses, preferably 4-5 courses.
- the intrathecal injection of cerebrospinal fluid is selected from any one of lumbar puncture, implantable intrathecal drug infusion system, puncture injection through Ommaya capsule, or a combination thereof.
- the pharmaceutical composition for preventing and treating neurological lesions optionally Contains pharmaceutical compositions for single intravenous injection.
- the pharmaceutical composition for a single intravenous injection has the same components and proportions as the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid.
- a pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid a pharmaceutical composition for a single intravenous injection, and a single acupoint injection of drugs are administered sequentially or simultaneously.
- cerebrospinal fluid is injected intrathecally or intravenously twice a week, with two weeks as a course of treatment and four weeks of treatment.
- the pharmaceutical composition for preventing and treating neurological lesions is optionally used in combination with any one of physical therapy, rehabilitation training, or a combination thereof.
- the physical therapy is selected from the group consisting of electrical stimulation, external treatment and massage, ointment therapy, external application therapy, acupuncture, skin acupuncture, electroacupuncture, pricking and cupping, low-frequency electrotherapy, and star therapy. Any one or combination of ganglion block therapy, auricular acupoint therapy, hyperbaric oxygen therapy, minimally invasive acupoint catgut embedding.
- the rehabilitation training is selected from manual functional training to improve the elasticity and tension of muscles and fascia to stimulate the proprioceptors of paralyzed muscles to accelerate functional reconstruction, passive movement according to the degree of paralysis, and fascial release. any one or combination thereof.
- the neurological disease is selected from the group consisting of stroke, brain trauma and sequelae, spinal cord injury and sequelae, cerebrovascular disease and sequelae, motor neuron disease, cerebral palsy, Parkinson's disease, dementia, spinal cord Post-inflammatory sequelae, sequelae of meningitis, sequelae of encephalitis, brain dysplasia, brain atrophy, ataxia, multiple sclerosis, neuromyelitis optica, multiple system atrophy, persistent vegetative state, carbon monoxide poisoning delayed encephalopathy, cranial nerve damage Any one or combination of diseases, brain tumors and postoperative neurological dysfunction, intraspinal tumors and postoperative neurological dysfunction, neuropathic pain, neurological damage secondary to cervical, thoracolumbar and spinal lesions, and brain damage secondary to epilepsy .
- the object of the present invention is to provide a pharmaceutical composition for preventing and treating neurological lesions, which contains nerve repairing drugs and/or blood circulation improving drugs and anti-inflammatory drugs.
- the nerve repair drugs and/or blood circulation improving drugs are selected from the group consisting of mouse nerve growth factor, monosialoganglioside (GM1), cerebrospinalis carnosine, methylcobalamin, and adenosylcobalamin.
- Vitamin B complex Vitamin B complex, butylphthalide, cinpazide maleate, edaravone, edaravone dexbornillol, citicoline Alkali, citicoline sodium, ganglioside, oxiracetam, piracetam, aniracetam, nerve growth factor, citicoline, neurotropin, oryzanol, vitamin B1, vitamin B6, Any one or a combination of vitamin B12, vitamin C, vitamin E, compound cerebroside, cerebroprotein, and nervonic acid.
- the anti-inflammatory drug is selected from dexamethasone, methylprednisolone, prednisolone, methylprednisolone (methylprednisolone), cortisone, hydrocortisone, prednisone, Prednisolone or any combination thereof.
- the pharmaceutical composition for preventing and treating neurological lesions consists of a pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid and a pharmaceutical composition for a single acupoint injection.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 15ug-90ug of mouse nerve growth factor, 0.5mg-1.0mg of methylcobalamin, adenosylcobalamin or vitamin B 12 or citicoline. Any one 0.25mg-1.0mg, cerebrospinal glycoside carnosine or monosialoganglioside (GM1) or any one compound cerebroside ganglioside 2ml-8ml or ganglioside 20-40mg and dexamethasone 2mg -5mg composition.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 30ug-90ug of mouse nerve growth factor, 0.5mg-1.0mg of methylcobalamin, adenosylcobalamin or vitamin B 12 or citicoline. Any one 0.25mg-1.0mg, cerebrospinal glycoside carnosine or monosialoganglioside (GM1) or any one compound cerebroside ganglioside 4ml-6ml or ganglioside 20-40mg and dexamethasone 2mg -5mg composition.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 30ug of mouse nerve growth factor, 0.5mg of methylcobalamin, 0.5mg of adenosylcobalamin, cerebrospinal carnosine or monosialoganglioside ( GM1) or any compound cerebropeptide ganglioside 2ml-8ml or ganglioside 20-40mg and dexamethasone 5mg.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 30ug of mouse nerve growth factor, 0.5mg of methylcobalamin, 0.5mg of adenosylcobalamin, cerebrospinal carnosine or monosialoganglioside ( GM1) or any compound cerebropeptide ganglioside 4ml-6ml or ganglioside 20-40mg and dexamethasone 2mg.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 90ug of mouse nerve growth factor, 1.0 mg of methylcobalamin, 0.5 mg of adenosylcobalamin, cerebrospinal carnosine or monosialoganglioside ( GM1) or any compound cerebropeptide ganglioside 2ml-8ml or ganglioside 20-40mg and dexamethasone 5mg.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 60ug of mouse nerve growth factor, 1.0 mg of methylcobalamin, 0.5 mg of adenosylcobalamin, cerebrospinal carnosine or monosialoganglioside (GM1) or any compound cerebropeptide ganglioside 2ml-8ml or ganglioside 20-40mg and dexamethasone 3mg.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 30 ug of mouse nerve growth factor, 0.5 mg of methylcobalamin, 0.5 mg of adenosylcobalamin, 4 ml of cerebrospinal fluid and 5 mg of dexamethasone.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 0.5-1.0 mg of methylcobalamin, 0.1-0.5 mg of adenosylcobalamin and 2-5 mg of dexamethasone.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid optionally contains 100-300 mg of any one or combination of nerve repair cell protein extracts and/or nerve repair protein compositions with repair effects. , preferably 150-200mg.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid optionally contains 2-10 mg of naloxone hydrochloride, preferably 5-8 mg.
- the pharmaceutical composition for single acupoint injection consists of mouse nerve growth factor 30ug-90ug, methylcobalamin 0.5mg-1.0mg, adenosylcobalamin 0.5mg-1.0mg, dexamethasone 2mg- It consists of 5 mg and 1 ml of lidocaine hydrochloride, wherein the concentration of lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5% and 2%.
- the pharmaceutical composition for single acupoint injection consists of 30ug of mouse nerve growth factor, 0.5mg of methylcobalamin, 0.5mg of adenosylcobalamin, 2mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein , the concentration of lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5%, and 2%.
- the pharmaceutical composition for single acupoint injection consists of 30ug of mouse nerve growth factor, 0.5mg of methylcobalamin, 1.0mg of adenosylcobalamin, 5mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein , the concentration of lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5%, and 2%.
- the pharmaceutical composition for single acupoint injection consists of 90ug of mouse nerve growth factor, 1.0mg of methylcobalamin, 0.5mg of adenosylcobalamin, 5mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein , the concentration of lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5%, and 2%.
- the pharmaceutical composition for single acupoint injection consists of 60ug of mouse nerve growth factor, 1.0mg of methylcobalamin, 0.5mg of adenosylcobalamin, 3mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein , the concentration of lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5%, and 2%.
- the pharmaceutical composition for single acupoint injection optionally contains 100-300 mg of nerve repair cell protein extract and/or nerve repair protein composition with repair effect. any one or combination thereof.
- the pharmaceutical composition for single acupoint injection is used on an ad hoc basis.
- the Hegu acupoint, Shousanli, Shouwuli, Zusanli, Yanglingquan, Yinlingquan, Sanyinjiao and Yangjiao acupoints on the affected side of the limb are selected, and the Hegu acupoint and Zusanli acupoint on the healthy side are selected. Perform acupoint injections.
- the pharmaceutical composition for single acupoint injection is injected once a day into the acupoint, and the treatment course is 7 days.
- each acupoint injection treatment lasts for 2-6 courses, preferably 4-5 courses.
- the intrathecal injection of cerebrospinal fluid is selected from any one of lumbar puncture, implantable intrathecal drug infusion system, puncture injection through Ommaya capsule, or a combination thereof.
- the pharmaceutical composition for preventing and treating neurological lesions optionally contains a pharmaceutical composition for single intravenous injection.
- the pharmaceutical composition for a single intravenous injection has the same components and proportions as the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid.
- a pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid a pharmaceutical composition for a single intravenous injection, and a single acupoint injection of drugs are administered sequentially or simultaneously.
- cerebrospinal fluid is injected intrathecally or intravenously twice a week, with two weeks as a course of treatment and four weeks of treatment.
- the pharmaceutical composition for preventing and treating neurological lesions is optionally used in combination with any one of physical therapy, rehabilitation training, or a combination thereof.
- the physical therapy is selected from the group consisting of electrical stimulation, external treatment and massage, ointment therapy, external application therapy, acupuncture, skin acupuncture, electroacupuncture, pricking and cupping, low-frequency electrotherapy, and star therapy. Any one or combination of ganglion block therapy, auricular acupoint therapy, hyperbaric oxygen therapy, minimally invasive acupoint catgut embedding.
- the rehabilitation training is selected from manual functional training to improve the elasticity and tension of muscles and fascia to stimulate the proprioceptors of paralyzed muscles to accelerate functional reconstruction, passive movement according to the degree of paralysis, and fascial release. any one or combination thereof.
- the neurological disease is selected from the group consisting of stroke, brain trauma and sequelae, spinal cord injury and sequelae, cerebrovascular disease and sequelae, motor neuron disease, cerebral palsy, Parkinson's disease, Dementia, sequelae of myelitis, sequelae of meningitis, sequelae of encephalitis, brain dysplasia, cerebral atrophy, ataxia, multiple sclerosis, neuromyelitis optica, multiple system atrophy, persistent vegetative state, carbon monoxide poisoning, delayed encephalopathy, cranial encephalopathy Any of neurological damaging diseases, brain tumors and postoperative neurological dysfunction, intraspinal tumors and postoperative neurological dysfunction, neuropathic pain, neurological damage secondary to cervical, thoracolumbar and spinal lesions, and brain damage secondary to epilepsy or combination thereof.
- Another object of the present invention is to provide a treatment plan for preventing and treating neurological lesions, which treatment plan includes a pharmaceutical composition for preventing and treating neurological lesions containing nerve repairing drugs and/or improving blood circulation drugs and anti-inflammatory drugs.
- the nerve repair drugs and/or blood circulation improving drugs are selected from the group consisting of mouse nerve growth factor, monosialoganglioside (GM1), cerebrospinalis carnosine, methylcobalamin, and adenosylcobalamin.
- Vitamin B complex butylphthalide, cinpazide maleate, edaravone, edaravone dexbornillol, citicoline, citicoline sodium, gangliosides, oxiracetam , Piracetam, Aniracetam, Nerve Growth Factor, Citicoline, Neurotropin, Oryzanol, Vitamin B1, Vitamin B6, Vitamin B12, Vitamin C, Vitamin E, Compound Cerebroside, Brain Any one of protein, nervonic acid or their combination.
- the anti-inflammatory drug is selected from dexamethasone, methylprednisolone, prednisolone, methylprednisolone (methylprednisolone), cortisone, hydrocortisone, prednisone, Prednisolone or any combination thereof.
- the pharmaceutical composition for preventing and treating neurological lesions consists of a pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid and a pharmaceutical composition for a single acupoint injection.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 15ug-90ug of mouse nerve growth factor, 0.5mg-1.0mg of methylcobalamin, adenosylcobalamin or vitamin B 12 or citicoline. Any one 0.25mg-1.0mg, cerebrospinal glycoside carnosine or monosialoganglioside (GM1) or any one compound cerebrospinal ganglioside 2ml-8ml or ganglioside 20-40mg and dexamethasone 2mg -5mg composition.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 30ug-90ug of mouse nerve growth factor, 0.5mg-1.0mg of methylcobalamin, adenosylcobalamin or vitamin B 12 or citicoline. Any one 0.25mg-1.0mg, cerebrospinal glycoside carnosine or monosialoganglioside (GM1) or any one compound cerebrospinal ganglioside 4ml-6ml or ganglioside 20-40mg and dexamethasone 2mg -5mg composition.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid is grown from mouse nerves.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 30ug of mouse nerve growth factor, 0.5mg of methylcobalamin, 0.5mg of adenosylcobalamin, cerebrospinal carnosine or monosialoganglioside ( GM1) or any compound cerebropeptide ganglioside 4ml-6ml or ganglioside 20-40mg and dexamethasone 2mg.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 90ug of mouse nerve growth factor, 1.0 mg of methylcobalamin, 0.5 mg of adenosylcobalamin, cerebrospinal carnosine or monosialoganglioside ( GM1) or any compound cerebropeptide ganglioside 2ml-8ml or ganglioside 20-40mg and dexamethasone 5mg.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 60ug of mouse nerve growth factor, 1.0 mg of methylcobalamin, 0.5 mg of adenosylcobalamin, cerebrospinal carnosine or monosialoganglioside (GM1) or any compound cerebropeptide ganglioside 2ml-8ml or ganglioside 20-40mg and dexamethasone 3mg.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 30ug of mouse nerve growth factor, 0.5mg of methylcobalamin, 0.5mg of adenosylcobalamin, 4ml of cerebrospinal fluid and 5mg of dexamethasone.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 0.5-1.0 mg of methylcobalamin, 0.1-0.5 mg of adenosylcobalamin and 2-5 mg of dexamethasone.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid optionally contains 100-300 mg of any one or combination of nerve repair cell protein extracts and/or nerve repair protein compositions with repair effects. , preferably 150-200mg.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid optionally contains 2-10 mg of naloxone hydrochloride, preferably 5-8 mg.
- the pharmaceutical composition for single acupoint injection consists of mouse nerve growth factor 30ug-90ug, methylcobalamin 0.5mg-1.0mg, adenosylcobalamin 0.5mg-1.0mg, dexamethasone 2mg- It consists of 5 mg and 1 ml of lidocaine hydrochloride, wherein the concentration of lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5% and 2%.
- the pharmaceutical composition for a single acupoint injection consists of 30ug of mouse nerve growth factor, 0.5mg of methylcobalamin, 0.5mg of adenosylcobalamin, 2mg of dexamethasone and 1ml of lidocaine hydrochloride.
- the concentration of lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5%, and 2%.
- the pharmaceutical composition for single acupoint injection consists of 30ug of mouse nerve growth factor, 0.5mg of methylcobalamin, 1.0mg of adenosylcobalamin, 5mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein , the concentration of lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5%, and 2%.
- the pharmaceutical composition for single acupoint injection consists of 90ug of mouse nerve growth factor, 1.0mg of methylcobalamin, 0.5mg of adenosylcobalamin, 5mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein , the concentration of lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5%, and 2%.
- the pharmaceutical composition for single acupoint injection consists of 60ug of mouse nerve growth factor, 1.0mg of methylcobalamin, 0.5mg of adenosylcobalamin, 3mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein , the concentration of lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5%, and 2%.
- the pharmaceutical composition for a single acupoint injection optionally contains 100-300 mg of any one of the nerve repair cell protein extract and/or the nerve repair protein composition with repair effect, or any other thereof. combination.
- the pharmaceutical composition for single acupoint injection is used on an ad hoc basis.
- the Hegu acupoint, Shousanli, Shouwuli, Zusanli, Yanglingquan, Yinlingquan, Sanyinjiao and Yangjiao acupoints on the affected side of the limb are selected, and the Hegu acupoint and Zusanli acupoint on the healthy side are selected. Perform acupoint injections.
- the pharmaceutical composition for single acupoint injection is injected once a day into the acupoint, and the treatment course is 7 days.
- each acupoint injection treatment lasts for 2-6 courses, preferably 4-5 courses.
- the intrathecal injection of cerebrospinal fluid is selected from any one of lumbar puncture, implantable intrathecal drug infusion system, puncture injection through Ommaya capsule, or a combination thereof.
- the pharmaceutical composition for preventing and treating neurological lesions optionally contains a pharmaceutical composition for single intravenous injection.
- the pharmaceutical composition for a single intravenous injection has the same components and proportions as the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid.
- a pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid a pharmaceutical composition for a single intravenous injection, and a single acupoint injection of drugs are administered sequentially or simultaneously.
- cerebrospinal fluid is injected intrathecally or intravenously twice a week, with two weeks as a course of treatment and four weeks of treatment.
- the pharmaceutical composition for preventing and treating neurological lesions is optionally used in combination with any one of physical therapy, rehabilitation training, or a combination thereof.
- the physical therapy is selected from the group consisting of electrical stimulation, external therapy and massage, ointment therapy, external application therapy, acupuncture, skin acupuncture, electroacupuncture, pricking and cupping, low-frequency electrotherapy, and star therapy. Any one or combination of ganglion block therapy, auricular acupoint therapy, hyperbaric oxygen therapy, minimally invasive acupoint catgut embedding.
- the rehabilitation training is selected from manual functional training to improve the elasticity and tension of muscles and fascia to stimulate the proprioceptors of paralyzed muscles to accelerate functional reconstruction, passive movement according to the degree of paralysis, and fascial release. any one or combination thereof.
- the neurological disease is selected from the group consisting of stroke, brain trauma and sequelae, spinal cord injury and sequelae, cerebrovascular disease and sequelae, motor neuron disease, cerebral palsy, Parkinson's disease, dementia, spinal cord Post-inflammatory sequelae, sequelae of meningitis, sequelae of encephalitis, brain dysplasia, brain atrophy, ataxia, multiple sclerosis, neuromyelitis optica, multiple system atrophy, persistent vegetative state, carbon monoxide poisoning delayed encephalopathy, cranial nerve damage Any one or combination of diseases, brain tumors and postoperative neurological dysfunction, intraspinal tumors and postoperative neurological dysfunction, neuropathic pain, neurological damage secondary to cervical, thoracolumbar and spinal lesions, and brain damage secondary to epilepsy .
- the nerve repair cell protein extract or nerve repair cell protein composition with repair effect described in the present invention is prepared with reference to patent applications (CN2023100429139, PCT/CN2023/073566, CN2023100429143, PCT/CN2023/073582). have to.
- the preparation method of the nerve repair cell protein extract with nerve repair effect includes the following steps:
- S-1 Mesenchymal passaged stem cells with a density of 5.0 ⁇ 10 6 /mL-5.0 ⁇ 10 7 /mL were placed in DMEM/F12 40-50%, RPMI1640 40-50%, bovine serum albumin (BSA) )0.1-2%, epidermal growth factor (EGF) 1-15ug/mL, fibroblast growth factor (FGF) 1-15ug/mL, insulin transferrin 1-15ug/mL, compound amino acid (18AA) 0.01- 0.1% and 2-10 ⁇ mol/L stress medium, and then culture it at 37.0°C ⁇ 0.5°C, 5% ⁇ 1.0% CO2 for 2h-6h, separate, wash, and collect the cells, where , the stressor is selected from any one of compounds 1-16 or a combination thereof;
- BSA bovine serum albumin
- S-2 Disperse the collected cells in the solvent at a density of 5.0 ⁇ 10 6 /mL-5.0 ⁇ 10 7 /mL, and then place them at 2°C-8°C for ultrasonic treatment to prepare a cell lysis solution , wherein the solvent is selected from any one selected from physiological saline, 5% glucose solution, phosphate buffered saline (PBS), TBPS buffer, TBST buffer, Tris buffer or a combination thereof;
- PBS phosphate buffered saline
- TBPS buffer TBST buffer
- Tris buffer Tris buffer
- step S-3 After separating the cell lysate prepared in step S-2, the obtained separation liquid is filtered through 0.45um and 0.22um filters in sequence.
- the culture medium of step S-1 contains DMEM/F12 42-45%, RPMI1640 42-45%, bovine serum albumin (BSA) 0.5-1.5%, epidermal cell growth factor (EGF) 5 -10ug/mL, fibroblast growth factor (FGF) 5-10ug/mL, insulin transferrin 5-10ug/mL, compound amino acid (18AA) 0.02-0.05% and 3-8 ⁇ mol/L stressors.
- BSA bovine serum albumin
- the culture medium of step S-1 contains DMEM/F12 45%, RPMI1640 45%, bovine serum albumin (BSA) 0.5%, epidermal growth factor (EGF) 10ug/mL, fibroblasts Growth factor (FGF) 10ug/mL, insulin transferrin 10ug/mL, compound amino acid (18AA) 0.05% and 4-6 ⁇ mol/L stressors.
- BSA bovine serum albumin
- the density of mesenchymal passage stem cells in step S-1 is 8.0 ⁇ 10 6 -2.0 ⁇ 10 7 cells/mL, preferably 8.0 ⁇ 10 6 -1.0 ⁇ 10 7 cells/mL.
- the mesenchymal passage stem cells in step S-1 are cultured in the culture medium for 3h-5h, preferably 3.5h-4.5h.
- the solvent for washing cells in step S-1 is selected from any one of physiological saline, 5% glucose solution, phosphate buffer (PBS), TBPS buffer, TBST buffer, and Tris buffer. Or a combination thereof, the number of cell washings is 2-5 times, preferably 3-4 times.
- the separation described in step S-1 is selected from any one of centrifugation, filtration or a combination thereof, wherein the centrifugation conditions are 1000-2000rpm*3-15min, preferably 1200rpm-1500rpm* 5-10min.
- the ultrasonic conditions of step S-2 are: working at 2°C-8°C, 25kHZ, 360W for 3 seconds, followed by a gap of 1 second, and ultrasonic treatment for 1-5 minutes.
- the separation described in step S-3 is selected from any one of 2000-8000rpm*10-30min centrifugation, multi-stage centrifugation, multi-stage filtration or a combination thereof, preferably 3000-7000rpm*15-25min .
- the multi-stage centrifugation in step S-3 is 3000-4000rpm*3-5min, 5000-6000rpm*3-5min and 7000rpm*5-8min.
- the filter membrane pore size of the multi-stage filtration is selected from any one of 80um, 50um, 30um, 10um, and 5um.
- the cell protein extract prepared in step S-3 is frozen and stored, preferably at -40°C to -20°C.
- the cell protein extract prepared in step S-3 is enzymatically hydrolyzed by either a nuclease or a totipotent nuclease and then separated and purified.
- the culture of mesenchymal passaged stem cells or the culture of primary mesenchymal stem cells adopts the culture methods in this field.
- the culture of mesenchymal passage stem cells includes the following steps: adding primary mesenchymal stem cells to the passage medium at an initial density of 5.0 ⁇ 10 5 -5.0 ⁇ 10 6 /ml. , and then place it in the culture medium at 37.0°C ⁇ 0.5°C and 5% ⁇ 1.0% CO2 for 10-15 days. Every 2-3 days, after observing that the subculture medium turns yellow, replace half of the subculture medium. , the subculture medium contains DMEM/F12 medium with 10% FBS, 100 U/ml penicillin and 100ug/ml streptomycin.
- the culture of primary mesenchymal stem cells includes the following steps:
- the preparation method of the neural repair protein composition according to the present invention includes Including the following steps:
- step (2) Under the conditions of 2°C-8°C, configure the enzymatic hydrolyzate prepared in step (1) with an elution solvent to 5-15mg/ml, and then pass it through the chromatographic column with an elution flow rate of 0.1-1ml/min. Monitor and collect the elution fraction with a UV wavelength of 280nm, and the elution solvent consists of 50mmol/L phosphate buffer (pH 6.8) containing 300mmol/L sodium chloride.
- the nuclease is selected from any one of RNA nuclease, DNA nuclease or a combination thereof.
- any one or a combination of 25 U/mL-30 U/mL nuclease or totipotent nuclease is added to the cell protein extract of the present invention, and placed at 37°C ⁇ 1°C. Carry out enzymatic hydrolysis for 20min-30min to prepare enzymatic hydrolysis solution.
- the molecular weight of the nerve repair protein composition is 20kDa-250kDa, preferably 35kDa-200kDa.
- the protein composition obtained in step (2) is frozen and stored, preferably at -40°C to -20°C.
- a freeze-drying protective agent is added to the protein composition collected in step (2) and freeze-dried to prepare a protein composition freeze-dried preparation, wherein the freeze-drying protective agent is selected from the group consisting of mannitol, Sorbitol, dextran, glycerol, sucrose, trehalose, glucose, lactose, maltose, dextran, tricaprylin (HES), polyethylene glycol, ethylene glycol, phosphate, acetate, citric acid Any one of salt, sorbitol, starch or a combination thereof.
- the freeze-dried preparation contains 0.5-8%, preferably 1-5%, of a freeze-dried protective agent in terms of mass percentage.
- a protein stabilizer is optionally added to the protein composition collected in step (2), wherein the protein stabilizer is selected from any one of albumin, zinc salts, and aluminum salts.
- the pH of the freeze-dried preparation is 6-8, preferably pH 7-7.5.
- the freeze-dried preparation is reconstituted with physiological saline or 5% glucose solution before use, and then used by any one of intravenous injection, intrathecal injection, lumbar puncture or a combination thereof.
- the percentage when the present invention relates to the percentage between liquid and liquid, the percentage is volume/volume percentage; when the present invention relates to the percentage between liquid and solid, the percentage is volume/weight percentage; the present invention When referring to percentages between solids and liquids, the percentages are weight/volume; the remainder are weight/weight.
- the present invention uses the stroke rating scale in Table 1 and the Barthel Index (Modified Barthel Index, MBI) in Table 2 as the rating scale.
- MBI Modified Barthel Index
- the highest score is 45 points and the lowest score is 0 points.
- ⁇ 20 means extremely severe functional impairment and complete dependence on life; 20-40 means needing a lot of help; 40-60 means needing help; >60 means basic self-care.
- the present invention has the following beneficial effects:
- the present invention scientifically selects the components and proportions of the pharmaceutical composition, and adopts any one of cerebrospinal fluid injection (including intrathecal injection, intracerebroventricular administration, etc.), acupoint injection, intravenous injection, or other combinations.
- Cerebrospinal fluid injection allows drugs to directly enter the subarachnoid space or intraventricular space of the brain and spinal cord, reach the brain and spinal cord parenchyma and nerve injury sites through cerebrospinal fluid circulation, and directly supply nerve repair drugs or nerve damage to neurons and glial cells.
- Nutrients can eliminate drug absorption disorders caused by the blood-brain barrier, significantly increase the peak concentration of drugs in central nervous system tissues, and effectively treat neurological deficits or neurological dysfunction.
- the pharmaceutical composition has synergistic effects, rapid onset of action, and ease of administration. It has the advantages of small dosage, high bioavailability, basically no side effects and basically no recurrence rate, and can significantly improve the treatment prognosis and quality of life of patients.
- the culture of primary mesenchymal stem cells includes the following steps:
- Passage culture of primary mesenchymal stem cells (culture of mesenchymal stem cells): Add primary mesenchymal stem cells at an initial density of 5.0 ⁇ 10 5 -5.0 ⁇ 10 6 /ml into a solution containing 10% FBS and 100U /ml penicillin and 100ug/ml streptomycin in DMEM/F12 culture medium, and then culture it at 37.0°C ⁇ 0.5°C, 5% ⁇ 1.0% CO2 for 10-15 days, with an interval of 2-3 days , after observing that the medium turns yellow, replace the medium by half.
- step (2) Disperse the cells collected in step (1) in physiological saline at a density of 1.0 ⁇ 10 7 cells/mL, ultrasonicate for 3s, 1s gap, and 2min under the conditions of 2-8°C, 25kHz, 360W to obtain cells. Lysis solution;
- step (3) Centrifuge the cell lysate prepared in step (2) at 7000rpm*20min, and filter the obtained centrifuge through 0.45um and 0.22um filters in sequence to obtain the cell protein extract.
- the preparation of the nerve repair protein composition of the present invention includes the following steps:
- the elution flow rate is 0.1-1ml/min, monitor and collect the elution fraction with a UV wavelength of 280nm, and obtain, among which, the elution fraction Desolvation consists of 50mmol/L phosphate buffer (pH 6.8) containing 300mmol/L sodium chloride.
- step (3) Add mannitol to the cell protein composition prepared in step (2), stir, mix evenly, and freeze-dry.
- the resulting freeze-dried preparation contains 2.15% mannitol (m/m).
- group 1 Thirty patients with ischemic stroke were selected and divided into group 1 (5 patients), group 2 (20 patients) and group 3 (5 patients). There were no statistically significant differences in age, disease type, gender, etc. among the subjects in each group (P>0.05).
- Patient inclusion criteria Meet the diagnostic criteria for ischemic stroke, 20 to 70 years old, relatively stable condition, informed consent to accept this clinical study; good compliance.
- Patient exclusion criteria (1) Patients with recurrent cerebral infarction had an mRS score of ⁇ 2 before the onset; (2) Head computed tomography (CT) showed intracranial hemorrhagic diseases (such as hemorrhagic stroke, epidural hematoma, cranial hematoma, etc.) Internal hematoma, intraventricular hemorrhage, subarachnoid hemorrhage, etc.); (3) Cerebral infarction accompanied by disturbance of consciousness (NIHSS score 1a item ⁇ 1 point), transient ischemic attack, cerebral arteritis, brain tumor, brain trauma, craniocerebral Patients with internal infections and brain parasitic diseases; (4) Suspected or confirmed history of alcohol and drug abuse; (5) Pregnant, lactating women or those who plan to become pregnant in the near future and who are unwilling to take contraceptive measures; (6) The expected survival time is shorter than 3 months; (7) Those who have participated in other clinical trials within 3 months before enrollment; (8) Patients who the researcher believes
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 30ug of mouse nerve growth factor, 0.5mg of methylcobalamin, 0.5mg of adenosylcobalamin, 4ml of cerebrospinal fluid and 5mg of dexamethasone. Intrathecal injection of cerebrospinal fluid is performed twice a week, with a two-week course of treatment lasting four weeks.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 30ug of mouse nerve growth factor, 0.5mg of methylcobalamin, 0.5mg of adenosylcobalamin, 4ml of cerebrospinal fluid and 5mg of dexamethasone. Intrathecal injection of cerebrospinal fluid is performed twice a week, with a two-week course of treatment lasting four weeks.
- the pharmaceutical composition for a single acupoint injection consists of 60ug of mouse nerve growth factor, 0.5mg of methylcobalamin, 0.5mg of adenosylcobalamin, 5mg of dexamethasone and 1ml of lidocaine hydrochloride. Hegu, Shousanli, Shouwuli, Zusanli, Yanglingquan, Yinlingquan, Sanyinjiao and Yangjiao acupoints on the lateral limb were selected, and Hegu and Zusanli acupoints on the healthy side were selected for acupoint injection. Acupuncture points are injected once a day, with a two-week course of treatment lasting four weeks.
- the pharmaceutical composition for a single intrathecal injection of cerebrospinal fluid consists of 30ug of mouse nerve growth factor, 0.5mg of methylcobalamin, 0.5mg of adenosylcobalamin, 4ml of cerebrospinal fluid and 5mg of dexamethasone. Intrathecal injection of cerebrospinal fluid is performed twice a week, with a two-week course of treatment lasting four weeks.
- the pharmaceutical composition for a single acupoint injection consists of 60ug of mouse nerve growth factor, 0.5mg of methylcobalamin, 0.5mg of adenosylcobalamin, 5mg of dexamethasone and 1ml of lidocaine hydrochloride.
- Acupoint injections were performed at Hegu, Shousanli, Shouwuli, Zusanli, Yanglingquan, Yinlingquan, Sanyinjiao and Yangjiao acupoints on the affected limb and Hegu and Zusanli acupoints on the healthy side.
- Acupuncture points are injected once a day, and one course of treatment lasts for four weeks.
- Group 1 On the day of treatment, about 60% of patients took effect. The effective rate of one course of treatment is 60% and the effective rate is 40%. The effective rate of the second course of treatment is 80% and the effective rate is 60%.
- Group 2 On the day of treatment, about 70% of patients took effect. The effective rate of one course of treatment is 80% and the effective rate is 50%. The effective rate of the second course of treatment is 90% and the effective rate is 60%.
- Group 3 On the day of treatment, about 80% of patients took effect. The effective rate of one course of treatment is 100% and the effective rate is 60%. The effective rate of the second course of treatment is 100% and the effective rate is 80%.
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Abstract
本发明涉及一种药物组合物用于制备防治神经系统病变的药物中的应用,所述用于防治神经系统病变的药物组合物含有神经修复药物和/改善血液循环药物和消炎药物。本发明科学筛选药物组合物的组分及配比,并采用脑脊液注射给药(包括鞘内注射给药、脑室内给药等)、穴位注射给药、静脉注射给药的任一种或其组合,脑脊液注射给药使得药物直接进入脑与脊髓的蛛网膜下腔或脑室内,通过脑脊液循环而到达脑与脊髓实质内及神经损伤部位,直接向神经元和神经胶质细胞供应神经修复药物或神经营养物质,消除血脑屏障导致的药物吸收障碍,显著提高中枢神经系统组织中药物峰浓度,有效治疗神经功能缺失或神经功能障碍。
Description
本发明属于生物医药技术领域,具体涉及一种用于防治神经系统病变的药物组合物及其应用。
脑血管病(cerebrovascular disease)泛指脑部血管的各种疾病,包括脑动脉粥样硬化、血栓形成、狭窄、闭塞、脑动脉炎、脑动脉损伤、脑动脉瘤、颅内血管畸形、脑动静脉瘘等,所引起的脑组织的缺血或出血性意外,导致患者的致残或死亡,发病率占神经系统总住院病例的1/4-1/2。
脑卒中(cerebral stroke)是一种急性脑血管疾病,由于脑部血管突然破裂或因血管阻塞导致血液不能流入大脑而引起脑组织损伤的一组疾病,包括缺血性和出血性卒中,我国成年人致死致残的首要原因,我国城乡居民脑卒中发病率为650人/10万,全国每年新发脑卒中超过500万人,其死亡率占死因总数22.45%,每年死亡超过150万人,五年内复发率50%,终身致残占80%,其发病率正以每年8.7%的速度快速增长,且在超过55岁的人群中每10年递增1倍。
临床使用的脑卒中治疗药物主要包括:溶栓药物、抗血小板聚集药物、降纤药物、抗凝药物和神经保护药物等。溶栓药物包括阿替普酶、尿激酶等,对发病早期患者有一定的疗效,但也有出血风险,用药需要经过医生的评估,符合适应症且排除禁忌症才可使用,且剂量、有效时间窗等研究仍然不成熟,有待于进一步探索研究;抗血小板聚集药物包括阿司匹林,氢氯吡格雷,双嘧达莫等,部分服用阿司匹林、氯吡格雷等的患者再发血管事件几率仍很高;降纤药物与抗凝药物治疗主要是用于急性超早期的治疗措施,主要用于溶解血栓和预防血栓的再发生;神经保护药物用于干预半暗带的瀑布级联效应,但存在安全隐患
因脑或脊髓神经损伤、神经系统损伤、颅脑损伤、神经退行性病变、卒中、心脑血管疾病等疾病,所导致的神经系统功能缺失或神经功能障碍患者逐年增多,由此导致全球神经系统疾病的发病率逐年攀升,且严重影响人类健康,增加社会负担,但又缺少有效的治疗药物。
多种药物在体外呈现神经细胞和周围神经细胞具有细胞修复、营养支持等效果。但其通过常规给药途径(肌肉注射、静脉注射、口服给药、粘膜给药等)给药,无法通过血脑屏障(blood barrier)而限制其发挥神经修复、营养支持等作用。为此,需要研究开发更为安全有效的神经修复功效的药物组合物,以满足临床需求。
专利申请(CN2023100429139、PCT/CN2023/073566、CN2023100429143、PCT/CN2023/073582)公开了有关具有修复功效的神经修复蛋白提取物及神经修复蛋白组合物的技术内容,前述申请及内容作为本申请必不可少的技术参考和组成部分。
发明内容
本发明的目的在于提供一种药物组合物用于制备防治神经系统病变的药物中的应用,其中,所述用于防治神经系统病变的药物组合物含有神经修复药物和/改善血液循环药物和消炎药物。
本发明的优选技术方案中,所述的神经修复药物和/改善血液循环药物选自鼠神经生长因子、单唾液酸神经节苷脂(GM1)、脑苷肌肽、甲钴胺、腺苷钴胺、复合维生素B、丁苯酞、马来酸桂哌齐特、依达拉奉、依达拉奉右莰醇、胞磷胆碱、胞磷胆碱钠、神经节苷脂、奥拉西坦、吡拉西坦、茴拉西坦、神经生长因子、胞二磷胆碱、神经妥乐平、谷维素、维生素B1、维生素B6、维生素B12、维生素C、维生素E、复方脑肽节苷脂、脑蛋白、神经酸的任一种或其组合。
本发明的优选技术方案中,所述消炎药物选自地塞米松、甲基强的松龙、强力松、甲强龙(甲泼尼龙)、可的松、氢化可的松、泼尼松、泼尼松龙的任一种或其组合。
本发明的优选技术方案中,所述用于防治神经系统病变的药物组合物由单次脑脊液鞘内注射用的药物组合物和单次穴位注射用的药物组合物组成。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物由鼠神经生长因子15ug-90ug、甲钴胺0.5mg-1.0mg、腺苷钴胺或维生素B12或胞磷胆碱的任一种0.25mg-1.0mg、脑苷肌肽或单唾液酸神经节苷脂(GM1)或复方脑肽节苷脂的任一种2ml-8ml或神经节苷脂20-40mg和地塞米松2mg-5mg组成。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物由鼠神经生长因子30ug-90ug、甲钴胺0.5mg-1.0mg、腺苷钴胺或维生素B12或胞磷胆碱的任一种0.25mg-1.0mg、脑苷肌肽或单唾液酸神经节苷脂(GM1)或复方脑肽节苷脂的任一种4ml-6ml或神经节苷脂20-40mg和地塞米松2mg-5mg组成。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、腺苷钴胺0.5mg、脑苷肌肽或单唾液酸神经节苷脂(GM1)或复方脑肽节苷脂的任一种2ml-8ml或神经节苷脂20-40mg和地塞米松5mg组成。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、腺苷钴胺0.5mg、脑苷肌肽或单唾液酸神经节苷脂(GM1)或复方脑肽节苷脂的任一种4ml-6ml或神经节苷脂20-40mg和地塞米松2mg组成。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物由鼠神经生长因子90ug、甲钴胺1.0mg、腺苷钴胺0.5mg、脑苷肌肽或单唾液酸神经节苷脂(GM1)或复方脑肽节苷脂的任一种2ml-8ml或神经节苷脂20-40mg和地塞米松5mg组成。
本发明的优选技术方案中,单次脑脊液鞘内注射用的药物组合物由鼠神经生长因子60ug、甲钴胺1.0mg、腺苷钴胺0.5mg、脑苷肌肽或单唾液酸神经节苷脂(GM1)或复方脑肽节苷脂的任一种2ml-8ml或神经节苷脂20-40mg和地塞米松3mg组成。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、腺苷钴胺0.5mg、脑苷肌肽4ml和地塞米松5mg组成。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物由甲钴胺0.5-1.0mg、腺苷钴胺0.1-0.5mg和地塞米松2-5mg组成。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物任选地含有100-300mg具有修复功效的神经修复细胞蛋白提取物和/或神经修复蛋白组合物的任一种或其组合,优选为150-200mg。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物任选地含有2-10mg盐酸纳洛酮,优选为5-8mg。
本发明的优选技术方案中,单次穴位注射用的药物组合物由鼠神经生长因子
30ug-90ug、甲钴胺0.5mg-1.0mg、腺苷钴胺0.5mg-1.0mg、地塞米松2mg-5mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,单次穴位注射用的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、腺苷钴胺0.5mg,地塞米松2mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,单次穴位注射用的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、腺苷钴胺1.0mg,地塞米松5mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,单次穴位注射用的药物组合物由鼠神经生长因子90ug、甲钴胺1.0mg、腺苷钴胺0.5mg,地塞米松5mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,单次穴位注射用的药物组合物由鼠神经生长因子60ug、甲钴胺1.0mg、腺苷钴胺0.5mg,地塞米松3mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,所述单次穴位注射用的药物组合物任选地含有100-300mg具有修复功效的神经修复细胞蛋白提取物和/或神经修复蛋白组合物的任一种或其组合。
本发明的优选技术方案中,所述单次穴位注射用的药物组合物临配临用。
本发明的优选技术方案中,选取患侧肢体的合谷穴、手三里、手五里、足三里、阳陵泉、阴陵泉、三阴交和阳交穴并选取健侧的合谷穴和足三里穴进行穴位注射。
本发明的优选技术方案中,单次穴位注射用的药物组合物每天穴位注射一次,7天为疗程。
本发明的优选技术方案中,每次穴位注射治疗2-6个疗程,优选为4-5个疗程。
本发明的优选技术方案中,所述的脑脊液鞘内注射选自腰椎穿刺、植入性鞘内药物输注系统,经Ommaya囊穿刺注射的任一种或其组合。
本发明的优选技术方案中,所述用于防治神经系统病变的药物组合物任选地
含有单次静脉注射用的药物组合物。
本发明的优选技术方案中,单次静脉注射用的药物组合物具有与单次脑脊液鞘内注射用的药物组合物相同的组分及配比。
本发明的优选技术方案中,单次脑脊液鞘内注射用的药物组合物、单次静脉注射用的药物组合物与单次穴位注射药物序贯用药或同时用药。
本发明的优选技术方案中,每周脑脊液鞘内注射或静脉注射2次,两周为一个疗程,治疗四周。
本发明的优选技术方案中,所述用于防治神经系统病变的药物组合物任选地与物理疗法、康复训练的任一种或其组合联用。
本发明的优选技术方案中,所述的物理疗法选自电刺激、外治与推拿、膏摩疗法、外敷疗法、针灸、皮肤针法、电针法、刺络拔罐法、低频电疗法、星状神经节阻滞疗法、耳穴疗法、高压氧疗法、微创穴位埋线的任一种或其组合。
本发明的优选技术方案中,所述的康复训练选自徒手功能训练改善肌肉及筋膜的弹性及张力使瘫痪的肌肉本体感受器受到刺激加快功能重建、根据瘫痪程度进行被动运动、筋膜松解的任一种或其组合。
本发明的优选技术方案中,所述神经系统病变选自脑卒中、脑外伤及后遗症、脊髓损伤及后遗症、脑血管病及后遗症、运动神经元病、脑性瘫痪、帕金森病、痴呆、脊髓炎后遗症、脑膜炎后遗症、脑炎后遗症、脑发育不良、脑萎缩、共济失调、多发性硬化、视神经脊髓炎、多系统萎缩、持续植物生存状态、一氧化碳中毒迟发性脑病、颅神经损害性疾病、脑肿瘤及术后神经功能障碍、椎管内肿瘤及术后神经功能障碍、神经病理性疼痛、颈胸腰椎病变继发的神经损害、癫痫继发的脑损害中的任一种或其组合。
本发明的目的在于提供一种用于防治神经系统病变的药物组合物,所述用于防治神经系统病变的药物组合物含有神经修复药物和/改善血液循环药物和消炎药物。
本发明的优选技术方案中,所述的神经修复药物和/改善血液循环药物选自鼠神经生长因子、单唾液酸神经节苷脂(GM1)、脑苷肌肽、甲钴胺、腺苷钴胺、复合维生素B、丁苯酞、马来酸桂哌齐特、依达拉奉、依达拉奉右莰醇、胞磷胆
碱、胞磷胆碱钠、神经节苷脂、奥拉西坦、吡拉西坦、茴拉西坦、神经生长因子、胞二磷胆碱、神经妥乐平、谷维素、维生素B1、维生素B6、维生素B12、维生素C、维生素E、复方脑肽节苷脂、脑蛋白、神经酸的任一种或其组合。
本发明的优选技术方案中,所述消炎药物选自地塞米松、甲基强的松龙、强力松、甲强龙(甲泼尼龙)、可的松、氢化可的松、泼尼松、泼尼松龙的任一种或其组合。
本发明的优选技术方案中,所述用于防治神经系统病变的药物组合物由单次脑脊液鞘内注射用的药物组合物和单次穴位注射用的药物组合物组成。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物由鼠神经生长因子15ug-90ug、甲钴胺0.5mg-1.0mg、腺苷钴胺或维生素B12或胞磷胆碱的任一种0.25mg-1.0mg、脑苷肌肽或单唾液酸神经节苷脂(GM1)或复方脑肽节苷脂的任一种2ml-8ml或神经节苷脂20-40mg和地塞米松2mg-5mg组成。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物由鼠神经生长因子30ug-90ug、甲钴胺0.5mg-1.0mg、腺苷钴胺或维生素B12或胞磷胆碱的任一种0.25mg-1.0mg、脑苷肌肽或单唾液酸神经节苷脂(GM1)或复方脑肽节苷脂的任一种4ml-6ml或神经节苷脂20-40mg和地塞米松2mg-5mg组成。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、腺苷钴胺0.5mg、脑苷肌肽或单唾液酸神经节苷脂(GM1)或复方脑肽节苷脂的任一种2ml-8ml或神经节苷脂20-40mg和地塞米松5mg组成。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、腺苷钴胺0.5mg、脑苷肌肽或单唾液酸神经节苷脂(GM1)或复方脑肽节苷脂的任一种4ml-6ml或神经节苷脂20-40mg和地塞米松2mg组成。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物由鼠神经生长因子90ug、甲钴胺1.0mg、腺苷钴胺0.5mg、脑苷肌肽或单唾液酸神经节苷脂(GM1)或复方脑肽节苷脂的任一种2ml-8ml或神经节苷脂20-40mg和地塞米松5mg组成。
本发明的优选技术方案中,单次脑脊液鞘内注射用的药物组合物由鼠神经生长因子60ug、甲钴胺1.0mg、腺苷钴胺0.5mg、脑苷肌肽或单唾液酸神经节苷脂
(GM1)或复方脑肽节苷脂的任一种2ml-8ml或神经节苷脂20-40mg和地塞米松3mg组成。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、腺苷钴胺0.5mg、脑苷肌肽4ml和地塞米松5mg组成。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物由甲钴胺0.5-1.0mg、腺苷钴胺0.1-0.5mg和地塞米松2-5mg组成。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物任选地含有100-300mg具有修复功效的神经修复细胞蛋白提取物和/或神经修复蛋白组合物的任一种或其组合,优选为150-200mg。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物任选地含有2-10mg盐酸纳洛酮,优选为5-8mg。
本发明的优选技术方案中,单次穴位注射用的药物组合物由鼠神经生长因子30ug-90ug、甲钴胺0.5mg-1.0mg、腺苷钴胺0.5mg-1.0mg、地塞米松2mg-5mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,单次穴位注射用的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、腺苷钴胺0.5mg,地塞米松2mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,单次穴位注射用的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、腺苷钴胺1.0mg,地塞米松5mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,单次穴位注射用的药物组合物由鼠神经生长因子90ug、甲钴胺1.0mg、腺苷钴胺0.5mg,地塞米松5mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,单次穴位注射用的药物组合物由鼠神经生长因子60ug、甲钴胺1.0mg、腺苷钴胺0.5mg,地塞米松3mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,所述单次穴位注射用的药物组合物任选地含有100-300mg具有修复功效的神经修复细胞蛋白提取物和/或神经修复蛋白组合物
的任一种或其组合。
本发明的优选技术方案中,所述单次穴位注射用的药物组合物临配临用。
本发明的优选技术方案中,选取患侧肢体的合谷穴、手三里、手五里、足三里、阳陵泉、阴陵泉、三阴交和阳交穴并选取健侧的合谷穴和足三里穴进行穴位注射。
本发明的优选技术方案中,单次穴位注射用的药物组合物每天穴位注射一次,7天为疗程。
本发明的优选技术方案中,每次穴位注射治疗2-6个疗程,优选为4-5个疗程。
本发明的优选技术方案中,所述的脑脊液鞘内注射选自腰椎穿刺、植入性鞘内药物输注系统,经Ommaya囊穿刺注射的任一种或其组合。
本发明的优选技术方案中,所述用于防治神经系统病变的药物组合物任选地含有单次静脉注射用的药物组合物。
本发明的优选技术方案中,单次静脉注射用的药物组合物具有与单次脑脊液鞘内注射用的药物组合物相同的组分及配比。
本发明的优选技术方案中,单次脑脊液鞘内注射用的药物组合物、单次静脉注射用的药物组合物与单次穴位注射药物序贯用药或同时用药。
本发明的优选技术方案中,每周脑脊液鞘内注射或静脉注射2次,两周为一个疗程,治疗四周。
本发明的优选技术方案中,所述用于防治神经系统病变的药物组合物任选地与物理疗法、康复训练的任一种或其组合联用。
本发明的优选技术方案中,所述的物理疗法选自电刺激、外治与推拿、膏摩疗法、外敷疗法、针灸、皮肤针法、电针法、刺络拔罐法、低频电疗法、星状神经节阻滞疗法、耳穴疗法、高压氧疗法、微创穴位埋线的任一种或其组合。
本发明的优选技术方案中,所述的康复训练选自徒手功能训练改善肌肉及筋膜的弹性及张力使瘫痪的肌肉本体感受器受到刺激加快功能重建、根据瘫痪程度进行被动运动、筋膜松解的任一种或其组合。
本发明的优选技术方案中,所述神经系统病变选自脑卒中、脑外伤及后遗症、脊髓损伤及后遗症、脑血管病及后遗症、运动神经元病、脑性瘫痪、帕金森病、
痴呆、脊髓炎后遗症、脑膜炎后遗症、脑炎后遗症、脑发育不良、脑萎缩、共济失调、多发性硬化、视神经脊髓炎、多系统萎缩、持续植物生存状态、一氧化碳中毒迟发性脑病、颅神经损害性疾病、脑肿瘤及术后神经功能障碍、椎管内肿瘤及术后神经功能障碍、神经病理性疼痛、颈胸腰椎病变继发的神经损害、癫痫继发的脑损害中的任一种或其组合。
本发明的另一目的在于提供一种防治神经系统病变的治疗方案,所述治疗方案包括用于防治神经系统病变的药物组合物含有神经修复药物和/改善血液循环药物和消炎药物。
本发明的优选技术方案中,所述的神经修复药物和/改善血液循环药物选自鼠神经生长因子、单唾液酸神经节苷脂(GM1)、脑苷肌肽、甲钴胺、腺苷钴胺、复合维生素B、丁苯酞、马来酸桂哌齐特、依达拉奉、依达拉奉右莰醇、胞磷胆碱、胞磷胆碱钠、神经节苷脂、奥拉西坦、吡拉西坦、茴拉西坦、神经生长因子、胞二磷胆碱、神经妥乐平、谷维素、维生素B1、维生素B6、维生素B12、维生素C、维生素E、复方脑肽节苷脂、脑蛋白、神经酸的任一种或其组合。
本发明的优选技术方案中,所述消炎药物选自地塞米松、甲基强的松龙、强力松、甲强龙(甲泼尼龙)、可的松、氢化可的松、泼尼松、泼尼松龙的任一种或其组合。
本发明的优选技术方案中,所述用于防治神经系统病变的药物组合物由单次脑脊液鞘内注射用的药物组合物和单次穴位注射用的药物组合物组成。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物由鼠神经生长因子15ug-90ug、甲钴胺0.5mg-1.0mg、腺苷钴胺或维生素B12或胞磷胆碱的任一种0.25mg-1.0mg、脑苷肌肽或单唾液酸神经节苷脂(GM1)或复方脑肽节苷脂的任一种2ml-8ml或神经节苷脂20-40mg和地塞米松2mg-5mg组成。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物由鼠神经生长因子30ug-90ug、甲钴胺0.5mg-1.0mg、腺苷钴胺或维生素B12或胞磷胆碱的任一种0.25mg-1.0mg、脑苷肌肽或单唾液酸神经节苷脂(GM1)或复方脑肽节苷脂的任一种4ml-6ml或神经节苷脂20-40mg和地塞米松2mg-5mg组成。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物由鼠神经生长
因子30ug、甲钴胺0.5mg、腺苷钴胺0.5mg、脑苷肌肽或单唾液酸神经节苷脂(GM1)或复方脑肽节苷脂的任一种2ml-8ml或神经节苷脂20-40mg和地塞米松5mg组成。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、腺苷钴胺0.5mg、脑苷肌肽或单唾液酸神经节苷脂(GM1)或复方脑肽节苷脂的任一种4ml-6ml或神经节苷脂20-40mg和地塞米松2mg组成。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物由鼠神经生长因子90ug、甲钴胺1.0mg、腺苷钴胺0.5mg、脑苷肌肽或单唾液酸神经节苷脂(GM1)或复方脑肽节苷脂的任一种2ml-8ml或神经节苷脂20-40mg和地塞米松5mg组成。
本发明的优选技术方案中,单次脑脊液鞘内注射用的药物组合物由鼠神经生长因子60ug、甲钴胺1.0mg、腺苷钴胺0.5mg、脑苷肌肽或单唾液酸神经节苷脂(GM1)或复方脑肽节苷脂的任一种2ml-8ml或神经节苷脂20-40mg和地塞米松3mg组成。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、腺苷钴胺0.5mg、脑苷肌肽4ml和地塞米松5mg组成。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物由甲钴胺0.5-1.0mg、腺苷钴胺0.1-0.5mg和地塞米松2-5mg组成。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物任选地含有100-300mg具有修复功效的神经修复细胞蛋白提取物和/或神经修复蛋白组合物的任一种或其组合,优选为150-200mg。
本发明的优选技术方案中,单次脑脊液鞘内注射的药物组合物任选地含有2-10mg盐酸纳洛酮,优选为5-8mg。
本发明的优选技术方案中,单次穴位注射用的药物组合物由鼠神经生长因子30ug-90ug、甲钴胺0.5mg-1.0mg、腺苷钴胺0.5mg-1.0mg、地塞米松2mg-5mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,单次穴位注射用的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、腺苷钴胺0.5mg,地塞米松2mg和盐酸利多卡因1ml组成,其
中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,单次穴位注射用的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、腺苷钴胺1.0mg,地塞米松5mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,单次穴位注射用的药物组合物由鼠神经生长因子90ug、甲钴胺1.0mg、腺苷钴胺0.5mg,地塞米松5mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,单次穴位注射用的药物组合物由鼠神经生长因子60ug、甲钴胺1.0mg、腺苷钴胺0.5mg,地塞米松3mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,所述单次穴位注射用的药物组合物任选地含有100-300mg具有修复功效的神经修复细胞蛋白提取物和/或神经修复蛋白组合物的任一种或其组合。
本发明的优选技术方案中,所述单次穴位注射用的药物组合物临配临用。
本发明的优选技术方案中,选取患侧肢体的合谷穴、手三里、手五里、足三里、阳陵泉、阴陵泉、三阴交和阳交穴并选取健侧的合谷穴和足三里穴进行穴位注射。
本发明的优选技术方案中,单次穴位注射用的药物组合物每天穴位注射一次,7天为疗程。
本发明的优选技术方案中,每次穴位注射治疗2-6个疗程,优选为4-5个疗程。
本发明的优选技术方案中,所述的脑脊液鞘内注射选自腰椎穿刺、植入性鞘内药物输注系统,经Ommaya囊穿刺注射的任一种或其组合。
本发明的优选技术方案中,所述用于防治神经系统病变的药物组合物任选地含有单次静脉注射用的药物组合物。
本发明的优选技术方案中,单次静脉注射用的药物组合物具有与单次脑脊液鞘内注射用的药物组合物相同的组分及配比。
本发明的优选技术方案中,单次脑脊液鞘内注射用的药物组合物、单次静脉注射用的药物组合物与单次穴位注射药物序贯用药或同时用药。
本发明的优选技术方案中,每周脑脊液鞘内注射或静脉注射2次,两周为一个疗程,治疗四周。
本发明的优选技术方案中,所述用于防治神经系统病变的药物组合物任选地与物理疗法、康复训练的任一种或其组合联用。
本发明的优选技术方案中,所述的物理疗法选自电刺激、外治与推拿、膏摩疗法、外敷疗法、针灸、皮肤针法、电针法、刺络拔罐法、低频电疗法、星状神经节阻滞疗法、耳穴疗法、高压氧疗法、微创穴位埋线的任一种或其组合。
本发明的优选技术方案中,所述的康复训练选自徒手功能训练改善肌肉及筋膜的弹性及张力使瘫痪的肌肉本体感受器受到刺激加快功能重建、根据瘫痪程度进行被动运动、筋膜松解的任一种或其组合。
本发明的优选技术方案中,所述神经系统病变选自脑卒中、脑外伤及后遗症、脊髓损伤及后遗症、脑血管病及后遗症、运动神经元病、脑性瘫痪、帕金森病、痴呆、脊髓炎后遗症、脑膜炎后遗症、脑炎后遗症、脑发育不良、脑萎缩、共济失调、多发性硬化、视神经脊髓炎、多系统萎缩、持续植物生存状态、一氧化碳中毒迟发性脑病、颅神经损害性疾病、脑肿瘤及术后神经功能障碍、椎管内肿瘤及术后神经功能障碍、神经病理性疼痛、颈胸腰椎病变继发的神经损害、癫痫继发的脑损害中的任一种或其组合。
为了清楚地表述本发明,本发明所述的具有修复功效的神经修复细胞蛋白提取物或神经修复细胞蛋白组合物参照专利申请(CN2023100429139、PCT/CN2023/073566、CN2023100429143、PCT/CN2023/073582)制得。
本发明的优选技术方案中,所述具有神经修复功效的神经修复细胞蛋白提取物的制备方法,包括如下步骤:
S-1:将密度为5.0×106个/mL-5.0×107个/mL的间充质传代干细胞置于含有DMEM/F12 40-50%、RPMI1640 40-50%、牛血清蛋白(BSA)0.1-2%、表皮细胞生长因子(EGF)1-15ug/mL、成纤维细胞生长因子(FGF)1-15ug/mL、胰岛素转铁蛋白1-15ug/mL、复方氨基酸(18AA)0.01-0.1%和2-10μmol/L应激物的培养基中,再将其置于37.0℃±0.5℃、5%±1.0%CO2条件下培养2h-6h后,分离,洗涤,收集细胞,其中,所述的应激物选自化合物1-16的任一种或其组合;
S-2:将收集细胞按照密度为5.0×106个/mL-5.0×107个/mL分散于溶剂中,再将其置于2℃-8℃条件下超声处理,制得细胞裂解液,其中,所述溶剂选自选自生理盐水、5%葡萄糖溶液、磷酸盐缓冲液(PBS)、TBPS缓冲液、TBST缓冲液、Tris缓冲液的任一种或其组合;
S-3:将步骤S-2制得的细胞裂解液分离后,所得的分离液依次经0.45um、0.22um滤膜过滤,即得。
本发明的优选技术方案中,步骤S-1的培养基中含有DMEM/F12 42-45%、RPMI1640 42-45%、牛血清蛋白(BSA)0.5-1.5%、表皮细胞生长因子(EGF)5-10ug/mL、成纤维细胞生长因子(FGF)5-10ug/mL、胰岛素转铁蛋白5-10ug/mL、复方氨基酸(18AA)0.02-0.05%和3-8μmol/L的应激物。
本发明的优选技术方案中,步骤S-1的培养基中含有DMEM/F12 45%、RPMI1640 45%、牛血清蛋白(BSA)0.5%、表皮细胞生长因子(EGF)10ug/mL、成纤维细胞生长因子(FGF)10ug/mL,胰岛素转铁蛋白10ug/mL、复方氨基酸(18AA)0.05%和4-6μmol/L的应激物。
本发明的优选技术方案中,步骤S-1的间充质传代干细胞密度为8.0×106-2.0×107个/mL,优选为8.0×106-1.0×107个/mL。
本发明的优选技术方案中,步骤S-1的间充质传代干细胞在培养基中培养3h-5h,优选为3.5h-4.5h。
本发明的优选技术方案中,步骤S-1中洗涤细胞的溶剂选自生理盐水、5%葡萄糖溶液、磷酸盐缓冲液(PBS)、TBPS缓冲液、TBST缓冲液、Tris缓冲液的任一种或其组合,细胞洗涤次数为2-5次,优选为3-4次。
本发明的优选技术方案中,步骤S-1所述的分离选自离心、过滤的任一种或其组合,其中,所述离心条件为1000-2000rpm*3-15min,优选为1200rpm-1500rpm*5-10min。
本发明的优选技术方案中,步骤S-2的超声条件为:在2℃-8℃、25kHZ、360W条件下工作3s再间隙1s,超声处理1-5min。
本发明的优选技术方案中,步骤S-3所述分离选自2000-8000rpm*10-30min离心、多级离心、多级过滤的任一种或其组合,优选为3000-7000rpm*15-25min。
本发明的优选技术方案中,步骤S-3的多级离心依次为3000-4000rpm*3-5min、5000-6000rpm*3-5min和7000rpm*5-8min。
本发明的优选技术方案中,所述多级过滤的滤膜孔径选自80um、50um、30um、10um、5um的任一种。
本发明的优选技术方案中,将步骤S-3制得的细胞蛋白提取物冻存,优选冻存于-40℃至-20℃。
本发明的优选技术方案中,将步骤S-3制得的细胞蛋白提取物采用核酸酶或全能核酸酶的任一种酶解后再分离纯化。
本发明的优选技术方案中,所述间充质传代干细胞的培养或原代间充质干细胞的培养采用本领域的培养方法。
本发明的优选技术方案中,所述间充质传代干细胞的培养包括下述步骤:将原代间充质干细胞按照初始密度为5.0×105-5.0×106个/ml加入到传代培养基中,再将其置于37.0℃±0.5℃、5%±1.0%CO2条件下培养10-15天,每隔2-3天,观察传代培养基变黄后,半量更换传代培养基,其中,所述传代培养基含有10%FBS、100U/ml青霉素和100ug/ml链霉素的DMEM/F12培养基。
本发明的优选技术方案中,所述原代间充质干细胞的培养包括下述步骤:
1)将脐带清洗消毒后,组织解剖,取华通胶层组织,将其切成3mm3的小块,离心,清洗,收集组织块,将其置于含10%胎牛血清FBS、100ug/ml青霉素、100ug/ml链霉素的DMEM/F12培养基中,再将其置于37.0℃±0.5℃、5%±1.0%CO2条件下培养,每间隔2-3天半量更换培养基,培养至组织块爬出细胞;
2)振摇,收集低层细胞用PBS清洗后,加入0.25%的胰蛋白酶消化2min-3min,加入等体积的胰蛋白酶终止液停止消化,吸管轻轻吹打,1200-1500rpm/min*5-8min离心后,收集细胞,即得。
为了清楚地表述本发明,本发明所述的神经修复蛋白组合物的制备方法,包
括如下步骤:
(1)在本发明的神经修复细胞蛋白提取物中加入20U/mL-35U/mL的核酸酶或全能核酸酶的任一种或其组合,将其置于37℃±1℃条件下酶解15min-40min,制得酶解液;
(2)在2℃-8℃条件下,将步骤(1)制得的酶解液用洗脱溶剂配置成5-15mg/ml后,过色谱柱,洗脱流速为0.1-1ml/min,监测并收集紫外波长为280nm的洗脱馏分,即得,其中,洗脱溶剂由50mmol/L磷酸盐缓冲液(pH6.8)中含300mmol/L氯化钠组成。
本发明的优选技术方案中,所述核酸酶选自RNA核酸酶、DNA核酸酶的任一种或其组合。
本发明的优选技术方案中,在本发明的细胞蛋白提取物中加入25U/mL-30U/mL的核酸酶或全能核酸酶的任一种或其组合,将其置于37℃±1℃条件下酶解20min-30min,制得酶解液。
本发明的优选技术方案中,所述神经修复蛋白组合物的分子量为20kDa-250kDa,优选为35kDa-200kDa。
本发明的优选技术方案中,将步骤(2)所得蛋白组合物冻存,优选冻存于-40℃至-20℃。
本发明的优选技术方案中,在步骤(2)收集的蛋白组合物中加入冻干保护剂,冻干,制得蛋白组合物冻干制剂,其中,所述冻干保护剂选自甘露醇、山梨糖醇、右旋糖酐、甘油、蔗糖、海藻糖、葡萄糖、乳糖、麦芽糖、葡聚糖、三辛酸甘油酯(HES)、聚乙二醇、乙烯乙二烯、磷酸盐、醋酸盐、柠檬酸盐、山梨醇、淀粉中的任一种或其组合。
本发明的优选技术方案中,以质量百分比计,所述冻干制剂中含有冻干保护剂0.5-8%,优选为1-5%。
本发明的优选技术方案中,将步骤(2)收集的蛋白组合物中任选地加入蛋白稳定剂,其中,所述蛋白稳定剂选自白蛋白、锌盐、铝盐的任一种。
本发明的优选技术方案,所述冻干制剂pH6-8,优选为pH7-7.5。
本发明的优选技术方案中,所述冻干制剂临用前用生理盐水或5%葡萄糖溶液复溶后,采用静脉注射、鞘内注射、腰椎穿刺的任一种或其组合方式使用。
除非另有说明,本发明涉及液体与液体之间的百分比时,所述的百分比为体积/体积百分比;本发明涉及液体与固体之间的百分比时,所述百分比为体积/重量百分比;本发明涉及固体与液体之间的百分比时,所述百分比为重量/体积百分比;其余为重量/重量百分比。
除非另有说明,本发明使用表1脑卒中评分量表和表2的Barthel指数(Modified Barthel Index,MBI)作为评分量表。
表1脑卒中评分量表
说明:在相应项目内打“√”,每项检查只能选填一项。
最高分45分,最低分0分。
轻型:0-15分,中型:16-30分,重型:31-45分。
表2日常生活活动(ADL)量表(Barthel指数)
评分结果:
满分100分
<20分为极严重功能缺陷,生活完全需要依赖;20—40分为生活需要很大帮助;40—60分为生活需要帮助;>60分为生活基本自理。
Barthel指数得分40分以上者康复治疗的效益最大。
ADL能力缺陷程度:0—20为严重功能缺陷;20—45=严重功能缺陷;50—70=中度功能缺陷;75—95=轻度功能缺陷;100=ADL自理
与现有技术相比,本发明具有下述有益效果:
本发明科学筛选药物组合物的组分及配比,并采用脑脊液注射给药(包括鞘内注射给药、脑室内给药等)、穴位注射给药、静脉注射给药的任一种或其组合,
脑脊液注射给药使得药物直接进入脑与脊髓的蛛网膜下腔或脑室内,通过脑脊液循环而到达脑与脊髓实质内及神经损伤部位,直接向神经元和神经胶质细胞供应神经修复药物或神经营养物质,消除血脑屏障导致的药物吸收障碍,显著提高中枢神经系统组织中药物峰浓度,有效治疗神经功能缺失或神经功能障碍,所述药物组合物具有协同增效、起效快、给药量少、生物利用度高、基本无副作用和基本无复发率等优点,显著改善患者的治疗预后和生活质量。
下面结合具体实施例对本发明的详细内容做进一步解释和描述,但并不以此限制本发明的保护范围。
实施例1具有修复功效的神经修复细胞蛋白提取物的制备
1、原代间充质干细胞的培养
原代间充质干细胞的培养包括下述步骤:
1)将脐带清洗消毒后,组织解剖,取华通胶层组织,将其切成3mm3的小块,离心,清洗,收集组织块,将其置于培养瓶中,加入含10%胎牛血清FBS、100ug/ml青霉素、100ug/ml链霉素的DMEM/F12培养基,再将其置于37℃、5%CO2条件下培养,促进其贴壁,每间隔2-3天,观察培养基变黄后,半量更换培养基,培养10-12天,至组织块边上可见细胞爬出;
2)轻轻摇晃,使组织块掉落,分别收集组织块和低层细胞,其中,将收集的组织块再贴壁培养;
3)将收集的低层细胞用PBS清洗后,加入适量0.25%胰蛋白酶消化2min-3min,加入等体积的胰蛋白酶终止液停止消化,吸管轻轻吹打瓶底,1500rpm*5min离心后,收集细胞,即得。
2、原代间充质干细胞的传代培养(间充质传代干细胞的培养)
原代间充质干细胞的传代培养(间充质传代干细胞的培养):将原代间充质干细胞按照初始密度为5.0×105-5.0×106个/ml加入到含有10%FBS、100U/ml青霉素和100ug/ml链霉素的DMEM/F12培养基中,再将其置于37.0℃±0.5℃、5%±1.0%CO2条件下培养10-15天,每间隔2-3天,观察培养基变黄后,半量更换培养基。
3、化合物1-16的制备参照文献1(New limonophyllines A-C from the stem of Atalantia monophylla and cytotoxicity against cholangiocarcinoma and HepG2 cell lines,Arch.Pharm.Res.(2018)41:431–437)。
具有神经修复功效的神经修复细胞蛋白提取物的制备方法,包括如下步骤:
(1)将间充质传代细胞按照密度为8.0×106个/mL加入到含有DMEM/F12 45%、RPMI1640 45%、牛血清蛋白(BSA)0.5%、表皮细胞生长因子(EGF)10ug/mL、成纤维细胞生长因子(FGF)10ug/mL、胰岛素转铁蛋白10ug/mL、复方氨基酸(18AA)0.05%和5μmol/L的化合物16的培养基中,再将其置于37℃、5%CO2条件下培养4h后,将其置于1200rpm*5min离心,用PBS洗涤3次后,收集细胞;
(2)将步骤(1)收集的细胞按照密度为1.0×107个/mL分散于生理盐水中,在2-8℃、25kHz、360W条件下超声3s、间隙1s,超声2min,制得细胞裂解液;
(3)将步骤(2)制得的细胞裂解液置于7000rpm*20min离心,将所得的离心液依次经0.45um、0.22um滤膜过滤,即得细胞蛋白提取物。
实施例2神经修复蛋白组合物的制备
本发明神经修复蛋白组合物的制备包括如下步骤:
(1)在实施例1制得的细胞蛋白提取物中,加入25U/mL的全能核酸酶(UCF.ME UltraNuclease),将其置于37℃酶解30min后,制得酶解液;
(2)在2℃-8℃条件下,将步骤(1)制得的酶解液用洗脱溶剂配置成10mg/ml,依次过高纯硅胶液相色谱保护柱(WondaGuard C18,4.6×5mm)、高纯硅胶液相色谱制备柱(SHIMSEN Ankylo C18,5μm,4.6×250mm),洗脱流速为0.1-1ml/min,监测并收集紫外波长为280nm的洗脱馏分,即得,其中,洗脱溶剂由50mmol/L磷酸盐缓冲液(pH6.8)中含300mmol/L氯化钠组成。
(3)在步骤(2)制得的细胞蛋白组合物中加入甘露醇,搅拌,混合均匀后,冻干,所得冻干制剂中含有2.15%的甘露醇(m/m)。
试验例1本发明药物组合物用于缺血性脑卒中的治疗效果研究
(一)受试者
选取缺血性脑卒中患者30名,分为1组(5名)、2组(20名)和3组(5名)。各组受试者在年龄、疾病类型、性别等方面,统计学无显著差异(P>0.05)。
患者入组标准:符合缺血性脑卒中的诊断标准,20~70岁,病情相对稳定,知情同意接受本临床研究;依从性好。
患者排除标准:(1)复发型脑梗死患者此次发病前mRS评分≥2级;(2)头颅计算机断层扫描(CT)提示颅内出血性疾病(如出血性脑卒中、硬膜外血肿、颅内血肿、脑室出血、蛛网膜下腔出血等);(3)脑梗死伴意识障碍(NIHSS评分1a项≥1分)、短暂性脑缺血发作、脑动脉炎、脑肿瘤、脑外伤、颅内感染、脑寄生虫病患者;(4)怀疑或确有酒精、药物滥用病史;(5)妊娠、哺乳期妇女或近期计划妊娠以及不愿意采取避孕措施者;(6)预计生存期低于3个月;(7)入组前3个月内参加过其他临床试验者;(8)研究者认为不宜参加本临床试验的患者。
(二)试验方法
1组的给药方案:
单次脑脊液鞘内注射的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、腺苷钴胺0.5mg、脑苷肌肽4ml和地塞米松5mg组成。每周脑脊液鞘内注射2次,两周为一个疗程,治疗四周。
2组的给药方案:
1、单次脑脊液鞘内注射用的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、腺苷钴胺0.5mg、脑苷肌肽4ml和地塞米松5mg组成。每周脑脊液鞘内注射2次,两周为一个疗程,治疗四周。
2、单次穴位注射用的药物组合物由鼠神经生长因子60ug、甲钴胺0.5mg、腺苷钴胺0.5mg、地塞米松5mg和盐酸利多卡因1ml组成,临配临用,选取患侧肢体的合谷穴、手三里、手五里、足三里、阳陵泉、阴陵泉、三阴交和阳交穴并选取健侧的合谷穴和足三里穴进行穴位注射。每天穴位注射1次,两周为一个疗程,治疗四周。
3组的给药方案:
(1)单次脑脊液鞘内注射用的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、腺苷钴胺0.5mg、脑苷肌肽4ml和地塞米松5mg组成。每周脑脊液鞘内注射2次,两周为一个疗程,治疗四周。
(2)单次穴位注射用的药物组合物由鼠神经生长因子60ug、甲钴胺0.5mg、腺苷钴胺0.5mg、地塞米松5mg和盐酸利多卡因1ml组成,临配临用,选取患侧肢体的合谷穴、手三里、手五里、足三里、阳陵泉、阴陵泉、三阴交和阳交穴及健侧的合谷穴和足三里穴进行穴位注射。每天穴位注射1次,一周为一个疗程,治疗四周。
(3)单次脑脊液鞘内注射用实施例2制得的神经修复细胞蛋白组合物130ug,用2ml生理盐水溶解。每周脑脊液鞘内注射2次,两周为一个疗程,治疗四周。
疗效评定:使用表1的脑卒中量表和表2的Barthel指数量表(Modified Barthel Index,MBI)。
1组:治疗当天,约60%患者起效。一个疗程的有效率60%和显效率40%。第二个疗程的有效率为80%和显效率60%。
2组:治疗当天,约70%患者起效。一个疗程的有效率80%和显效率50%。第二个疗程的有效率为90%和显效率60%。
3组:治疗当天,约患者80%起效。一个疗程的有效率100%和显效率60%。第二个疗程的有效率为100%和显效率80%。
以上对本发明具体实施方式的描述并不限制本发明,本领域技术人员可以根据本发明作出各种改变或变形,只要不脱离本发明的精神,均应属于本发明权利要求保护的范围。
Claims (10)
- 一种药物组合物用于制备防治神经系统病变的药物中的应用,其中,所述用于防治神经系统病变的药物组合物含有神经修复药物和/改善血液循环药物和消炎药物;优选地,所述的神经修复药物和/改善血液循环药物选自鼠神经生长因子、单唾液酸神经节苷脂(GM1)、脑苷肌肽、甲钴胺、腺苷钴胺、复合维生素B、丁苯酞、马来酸桂哌齐特、依达拉奉、依达拉奉右莰醇、胞磷胆碱、胞磷胆碱钠、神经节苷脂、奥拉西坦、吡拉西坦、茴拉西坦、神经生长因子、胞二磷胆碱、神经妥乐平、谷维素、维生素B1、维生素B6、维生素B12、维生素C、维生素E、复方脑肽节苷脂、脑蛋白、神经酸的任一种或其组合;优选地,所述消炎药物选自地塞米松、甲基强的松龙、强力松、甲强龙(甲泼尼龙)、可的松、氢化可的松、泼尼松、泼尼松龙的任一种或其组合。
- 如权利要求1所述的应用,所述用于防治神经系统病变的药物组合物由单次脑脊液鞘内注射用的药物组合物和单次穴位注射用的药物组合物组成。
- 如权利要求1-2任一项所述的应用,单次脑脊液鞘内注射的药物组合物由鼠神经生长因子15ug-90ug、甲钴胺0.5mg-1.0mg、腺苷钴胺或维生素B12或胞磷胆碱的任一种0.25mg-1.0mg、脑苷肌肽或单唾液酸神经节苷脂(GM1)或复方脑肽节苷脂的任一种2ml-8ml或神经节苷脂20-40mg和地塞米松2mg-5mg组成。
- 如权利要求1-3任一项所述的应用,单次穴位注射用的药物组合物由鼠神经生长因子30ug-90ug、甲钴胺0.5mg-1.0mg、腺苷钴胺0.5mg-1.0mg、地塞米松2mg-5mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
- 如权利要求1-4任一项所述的应用,选取患侧肢体的合谷穴、手三里、手五里、足三里、阳陵泉、阴陵泉、三阴交和阳交穴并选取健侧的合谷穴和足三里穴进行穴位注射。
- 如权利要求1-5任一项所述的应用,每周脑脊液鞘内注射或静脉注射2次,两周为一个疗程,治疗四周。
- 如权利要求1-6任一项所述的应用,所述用于防治神经系统病变的药物组合物任选地与物理疗法、康复训练的任一种或其组合联用。
- 如权利要求1-7任一项所述的应用,所述神经系统病变选自脑卒中、脑外 伤及后遗症、脊髓损伤及后遗症、脑血管病及后遗症、运动神经元病、脑性瘫痪、帕金森病、痴呆、脊髓炎后遗症、脑膜炎后遗症、脑炎后遗症、脑发育不良、脑萎缩、共济失调、多发性硬化、视神经脊髓炎、多系统萎缩、持续植物生存状态、一氧化碳中毒迟发性脑病、颅神经损害性疾病、脑肿瘤及术后神经功能障碍、椎管内肿瘤及术后神经功能障碍、神经病理性疼痛、颈胸腰椎病变继发的神经损害、癫痫继发的脑损害中的任一种或其组合。
- 如权利要求1-8任一项所述的用于防治神经系统病变的药物组合物,所述用于防治神经系统病变的药物组合物含有神经修复药物和/改善血液循环药物和消炎药物。
- 一种防治神经系统病变的治疗方案,所述治疗方案包括所述如权利要求1-8任一项所述的用于防治神经系统病变的药物组合物含有神经修复药物和/改善血液循环药物和消炎药物。
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