CN117679522A - Pharmaceutical composition for preventing and treating nervous system lesions and application thereof - Google Patents

Pharmaceutical composition for preventing and treating nervous system lesions and application thereof Download PDF

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Publication number
CN117679522A
CN117679522A CN202311159266.6A CN202311159266A CN117679522A CN 117679522 A CN117679522 A CN 117679522A CN 202311159266 A CN202311159266 A CN 202311159266A CN 117679522 A CN117679522 A CN 117679522A
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China
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pharmaceutical composition
nerve
brain
injection
medicine
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陈琳
王宇
高文勇
李建军
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Beijing Darwin Cell Biotechnology Co ltd
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Beijing Darwin Cell Biotechnology Co ltd
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H39/00—Devices for locating or stimulating specific reflex points of the body for physical therapy, e.g. acupuncture
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    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
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    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
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Abstract

The invention relates to application of a pharmaceutical composition in preparing medicines for preventing and treating nervous system diseases, wherein the pharmaceutical composition for preventing and treating nervous system diseases contains a nerve repairing medicine and/or a blood circulation improving medicine and an anti-inflammatory medicine. The invention scientifically screens the components and the proportion of the pharmaceutical composition, adopts any one or the combination of cerebrospinal fluid injection (including intrathecal injection, intraventricular injection and the like), acupoint injection and intravenous injection, and leads the medicine to directly enter subarachnoid space or cerebral chamber of brain and spinal cord, reach the parenchyma of brain and spinal cord and nerve injury part through cerebrospinal fluid circulation, directly supply nerve repair medicine or nerve nutrient substance to neurons and glial cells, eliminate medicine absorption disorder caused by blood brain barrier, obviously improve the medicine peak concentration in central nervous system tissue and effectively treat nerve function deficiency or nerve dysfunction.

Description

Pharmaceutical composition for preventing and treating nervous system lesions and application thereof
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a pharmaceutical composition for preventing and treating nervous system lesions and application thereof.
Background
Cerebrovascular disease (cerebrovascular disease) refers broadly to various diseases of cerebral vessels, including cerebral atherosclerosis, thrombosis, stenosis, occlusion, cerebral arteritis, cerebral arterial injury, cerebral aneurysm, intracranial vascular deformity, cerebral arteriovenous fistula, etc., and ischemic or hemorrhagic accidents of brain tissues caused by the cerebral arterial aneurysm, intracranial vascular deformity, cerebral arteriovenous fistula, etc., leading to disability or death of patients, and the incidence rate accounts for 1/4-1/2 of the total hospitalized cases of the nervous system.
Cerebral stroke (cerebral stroke) is an acute cerebrovascular disease, a group of diseases which cause damage to brain tissues due to sudden rupture of cerebral blood vessels or failure of blood to flow into the brain due to vessel occlusion, including ischemic and hemorrhagic strokes, a leading cause of fatal disability in adults in our country.
The clinically used cerebral apoplexy treatment medicine mainly comprises thrombolytic medicine, anti-platelet aggregation medicine, fiber-reducing medicine, anticoagulant medicine, neuroprotective medicine and the like. Thrombolytic drugs including alteplase, urokinase and the like have certain curative effects on patients in early onset of disease, but also have bleeding risks, the administration needs to be evaluated by doctors, the drugs meet the indication and can be used only after contraindications are removed, and the researches of dosage, effective time window and the like are still immature and remain to be further explored and studied; the anti-platelet aggregation medicines comprise aspirin, clopidogrel, dipyridamole and the like, and the probability of recurrent vascular events of patients taking part of aspirin, clopidogrel and the like is still high; the treatment of the fiber-reducing medicine and the anticoagulation medicine is mainly used for acute super-early treatment measures and is mainly used for dissolving thrombus and preventing recurrence of thrombus; neuroprotective agents are used to interfere with the cascade effect of the penumbra, but present a safety hazard.
Patients with neurological dysfunction or neurological dysfunction caused by brain or spinal cord nerve injury, nervous system injury, craniocerebral injury, neurodegenerative disease, stroke, cardiovascular and cerebrovascular diseases and the like increase year by year, so that the incidence rate of the global nervous system diseases rises year by year, the human health is seriously affected, the social burden is increased, and the effective therapeutic drugs are not available.
The various medicines show that nerve cells and peripheral nerve cells have effects of cell repair, nutrition support and the like in vitro. However, it cannot be administered by the conventional administration route (intramuscular injection, intravenous injection, oral administration, mucosal administration, etc.) and is not limited to exert effects of nerve repair, nutritional support, etc. by the blood brain barrier (blood barrier). For this reason, research and development of a pharmaceutical composition with more safe and effective nerve repair efficacy is required to meet clinical demands.
Patent applications (CN 2023100429139, PCT/CN2023/073566, CN2023100429143, PCT/CN 2023/073582) disclose technical content about a neural repair protein extract and a neural repair protein composition having repair efficacy, which are essential technical references and components of the present application.
Disclosure of Invention
The invention aims to provide an application of a pharmaceutical composition in preparing medicines for preventing and treating nervous system diseases, wherein the pharmaceutical composition for preventing and treating nervous system diseases contains a nerve repair medicine and/or a blood circulation improving medicine and an anti-inflammatory medicine.
In a preferred embodiment of the present invention, the nerve repair drug and/or the blood circulation improving drug is selected from any one or a combination of murine nerve growth factor, monosialoganglioside (GM 1), cerebroside carnosine, mecobalamin, adenosyl cobalamin, compound vitamin B, butylphthalide, cinepazide maleate, edaravone dexamphetamine, citicoline, sodium citicoline, ganglioside, oxiracetam, piracetam, aniracetam, nerve growth factor, citicoline, neurotolepin, oryzanol, vitamin B1, vitamin B6, vitamin B12, vitamin C, vitamin E, compound brain peptide ganglioside, brain protein, and nervonic acid.
In a preferred embodiment of the present invention, the anti-inflammatory drug is selected from any one of dexamethasone, methylprednisolone, prednisone, methylprednisolone (methylprednisolone), cortisone, hydrocortisone, prednisone, prednisolone, or a combination thereof.
In a preferred technical scheme of the invention, the pharmaceutical composition for preventing and treating nervous system lesions consists of a pharmaceutical composition for single intrathecal injection of cerebrospinal fluid and a pharmaceutical composition for single acupoint injection.
In the preferred technical scheme of the invention, the single intrathecal injection of the pharmaceutical composition consists of 15ug-90ug of mouse nerve growth factor, 0.5mg-1.0mg of mecobalamin, adenosylcobalamin or vitamin B 12 Or any one of 0.25mg-1.0mg of citicoline, brain glycoside carnosine or monosialoganglioside (GM 1) or any one of 2ml-8ml of compound brain peptide ganglioside or ganglioside 20-40mg and dexamethasone 2mg-5 mg.
In the preferred technical scheme of the invention, the single intrathecal injection of cerebrospinal fluid is used for preparing the medicineThe composition comprises mouse nerve growth factor 30ug-90ug, mecobalamin 0.5mg-1.0mg, and adenosylcobalamin or vitamin B 12 Or any one of 0.25mg-1.0mg of citicoline, cerebroside carnosine or monosialoganglioside (GM 1) or any one of 4ml-6ml of compound cerebropeptidyl ganglioside or ganglioside 20-40mg and dexamethasone 2mg-5 mg.
In the preferred technical scheme of the invention, the single intrathecal injection pharmaceutical composition consists of 30ug of mouse nerve growth factor, 0.5mg of mecobalamin, 0.5mg of adenosylcobalamin, 2ml-8ml of any one of brain carnosine or monosialoganglioside (GM 1) or compound brain peptide ganglioside or 20-40mg of ganglioside and 5mg of dexamethasone.
In the preferred technical scheme of the invention, the single intrathecal injection pharmaceutical composition consists of any one of 4ml-6ml or ganglioside 20-40mg and dexamethasone 2mg, wherein the one of the 4ml-6ml comprises mouse nerve growth factor 30ug, mecobalamin 0.5mg, adenosylcobalamin 0.5mg, cerebroside carnosine or monosialoganglioside (GM 1) or compound brain peptide ganglioside.
In the preferred technical scheme of the invention, the single intrathecal injection pharmaceutical composition consists of 90ug of mouse nerve growth factor, 1.0mg of mecobalamin, 0.5mg of adenosylcobalamin, 2ml-8ml of any one of brain carnosine or monosialoganglioside (GM 1) or compound brain peptide ganglioside or 20-40mg of ganglioside and 5mg of dexamethasone.
In the preferred technical scheme of the invention, the pharmaceutical composition for single intrathecal injection consists of any 2ml-8ml of mouse nerve growth factor 60ug, mecobalamin 1.0mg, adenosylcobalamin 0.5mg, cerebroside carnosine or monosialoganglioside (GM 1) or compound brain peptide ganglioside or ganglioside 20-40mg and dexamethasone 3 mg.
In a preferred embodiment of the invention, the single intrathecal injection of pharmaceutical composition consists of 30ug of murine nerve growth factor, 0.5mg of mecobalamin, 0.5mg of adenosylcobalamin, 4ml of cerebroside carnosine and 5mg of dexamethasone.
In the preferred technical scheme of the invention, the single intrathecal injection of the pharmaceutical composition consists of 0.5-1.0mg of mecobalamin, 0.1-0.5mg of adenosylcobalamin and 2-5mg of dexamethasone.
In a preferred embodiment of the present invention, the pharmaceutical composition for single intrathecal injection of cerebrospinal fluid optionally contains 100-300mg of any one or a combination of a neural repair cell protein extract and/or a neural repair protein composition having a repair efficacy, preferably 150-200mg.
In a preferred embodiment of the invention, the pharmaceutical composition for single intrathecal injection of cerebrospinal fluid optionally contains 2-10mg naloxone hydrochloride, preferably 5-8mg.
In the preferred technical scheme of the invention, the pharmaceutical composition for single acupoint injection consists of 30ug-90ug of mouse nerve growth factor, 0.5mg-1.0mg of mecobalamin, 0.5mg-1.0mg of adenosylcobalamin, 2mg-5mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein the concentration of the lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5% and 2%.
In a preferred technical scheme of the invention, the pharmaceutical composition for single acupoint injection consists of 30ug of mouse nerve growth factor, 0.5mg of mecobalamin, 0.5mg of adenosylcobalamin, 2mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein the concentration of the lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5% and 2%.
In a preferred technical scheme of the invention, the pharmaceutical composition for single acupoint injection consists of 30ug of mouse nerve growth factor, 0.5mg of mecobalamin, 1.0mg of adenosylcobalamin, 5mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein the concentration of the lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5% and 2%.
In a preferred technical scheme of the invention, the pharmaceutical composition for single acupoint injection consists of 90ug of mouse nerve growth factor, 1.0mg of mecobalamin, 0.5mg of adenosylcobalamin, 5mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein the concentration of the lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5% and 2%.
In a preferred technical scheme of the invention, the pharmaceutical composition for single acupoint injection consists of 60ug of mouse nerve growth factor, 1.0mg of mecobalamin, 0.5mg of adenosylcobalamin, 3mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein the concentration of the lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5% and 2%.
In a preferred embodiment of the present invention, the pharmaceutical composition for single acupoint injection optionally contains 100-300mg of any one or combination of a neural repair cell protein extract and/or a neural repair protein composition having a repair effect.
In the preferred technical scheme of the invention, the pharmaceutical composition for single acupoint injection is clinically matched.
In the preferred technical scheme of the invention, the Hegu acupoint, the hand three interior, the hand five interior, the foot three interior, the yanling spring, the yin ling spring, the Sanyinjiao acupoint and the yang Jian-side Hegu acupoint and the foot three interior acupoint are selected for acupoint injection.
In the preferred technical scheme of the invention, the medicine composition for single acupoint injection is injected once per acupoint every day, and 7 days is a treatment course.
In the preferred technical scheme of the invention, each acupoint injection treatment is carried out for 2-6 treatment courses, preferably 4-5 treatment courses.
In a preferred embodiment of the present invention, the intrathecal injection of cerebrospinal fluid is selected from any one of lumbar puncture and implantable intrathecal drug infusion system, or a combination thereof, by Ommaya capsule puncture injection.
In a preferred embodiment of the present invention, the pharmaceutical composition for preventing and treating nervous system disorders optionally contains a pharmaceutical composition for single intravenous injection.
In a preferred embodiment of the present invention, the pharmaceutical composition for single intravenous injection has the same components and proportions as the pharmaceutical composition for single intrathecal injection.
In the preferred technical scheme of the invention, the single cerebrospinal fluid intrathecal injection pharmaceutical composition, the single intravenous injection pharmaceutical composition and the single acupoint injection pharmaceutical are sequentially or simultaneously used.
In a preferred embodiment of the invention, the cerebrospinal fluid is injected intrathecally or intravenously 2 times per week, and two weeks are a course of treatment for four weeks.
In a preferred embodiment of the present invention, the pharmaceutical composition for preventing and treating nervous system disorders is optionally used in combination with any one of physical therapy, rehabilitation training or a combination thereof.
In a preferred embodiment of the present invention, the physical therapy is selected from any one or a combination of electrical stimulation, external therapy and massage, massage therapy, external therapy, acupuncture, skin acupuncture, electro acupuncture, puncture cupping, low frequency electrical therapy, stellate ganglion blocking therapy, auricular point therapy, hyperbaric oxygen therapy, and minimally invasive point catgut implantation.
In a preferred technical scheme of the invention, the rehabilitation training is selected from any one or combination of bare-handed functional training, improving the elasticity and tension of muscles and fascia, enabling paralyzed muscle proprioceptors to be stimulated to accelerate functional reconstruction, and performing passive exercise and fascia release according to the paralyzed degree.
In a preferred embodiment of the present invention, the nervous system disorder is selected from any one or a combination of cerebral apoplexy, brain trauma and sequelae, spinal cord injury and sequelae, cerebrovascular disease and sequelae, motor neuron disease, cerebral palsy, parkinson's disease, dementia, myelitis sequelae, meningitis sequelae, encephalitis sequelae, brain dysplasia, brain atrophy, ataxia, multiple sclerosis, neuromyelitis optica, multiple system atrophy, sustained plant survival status, carbon monoxide poisoning delayed encephalopathy, cranial nerve injury disease, brain tumor and post-operative nerve dysfunction, intrathecal tumor and post-operative nerve dysfunction, neuropathic pain, nerve injury secondary to cervical, thoracic and lumbar vertebra lesions, and brain injury secondary to epilepsy.
The invention aims to provide a pharmaceutical composition for preventing and treating nervous system diseases, which contains a nerve repair drug, a blood circulation improving drug and an anti-inflammatory drug.
In a preferred embodiment of the present invention, the nerve repair drug and/or the blood circulation improving drug is selected from any one or a combination of murine nerve growth factor, monosialoganglioside (GM 1), cerebroside carnosine, mecobalamin, adenosyl cobalamin, compound vitamin B, butylphthalide, cinepazide maleate, edaravone dexamphetamine, citicoline, sodium citicoline, ganglioside, oxiracetam, piracetam, aniracetam, nerve growth factor, citicoline, neurotolepin, oryzanol, vitamin B1, vitamin B6, vitamin B12, vitamin C, vitamin E, compound brain peptide ganglioside, brain protein, and nervonic acid.
In a preferred embodiment of the present invention, the anti-inflammatory drug is selected from any one of dexamethasone, methylprednisolone, prednisone, methylprednisolone (methylprednisolone), cortisone, hydrocortisone, prednisone, prednisolone, or a combination thereof.
In a preferred technical scheme of the invention, the pharmaceutical composition for preventing and treating nervous system lesions consists of a pharmaceutical composition for single intrathecal injection of cerebrospinal fluid and a pharmaceutical composition for single acupoint injection.
In the preferred technical scheme of the invention, the single intrathecal injection of the pharmaceutical composition consists of 15ug-90ug of mouse nerve growth factor, 0.5mg-1.0mg of mecobalamin, adenosylcobalamin or vitamin B 12 Or any one of 0.25mg-1.0mg of citicoline, brain glycoside carnosine or monosialoganglioside (GM 1) or any one of 2ml-8ml of compound brain peptide ganglioside or ganglioside 20-40mg and dexamethasone 2mg-5 mg.
In the preferred technical scheme of the invention, the single intrathecal injection of the pharmaceutical composition consists of 30ug-90ug of mouse nerve growth factor, 0.5mg-1.0mg of mecobalamin, adenosylcobalamin or vitamin B 12 Or any one of 0.25mg-1.0mg of citicoline, cerebroside carnosine or monosialoganglioside (GM 1) or any one of 4ml-6ml of compound cerebropeptidyl ganglioside or ganglioside 20-40mg and dexamethasone 2mg-5 mg.
In the preferred technical scheme of the invention, the single intrathecal injection pharmaceutical composition consists of 30ug of mouse nerve growth factor, 0.5mg of mecobalamin, 0.5mg of adenosylcobalamin, 2ml-8ml of any one of brain carnosine or monosialoganglioside (GM 1) or compound brain peptide ganglioside or 20-40mg of ganglioside and 5mg of dexamethasone.
In the preferred technical scheme of the invention, the single intrathecal injection pharmaceutical composition consists of any one of 4ml-6ml or ganglioside 20-40mg and dexamethasone 2mg, wherein the one of the 4ml-6ml comprises mouse nerve growth factor 30ug, mecobalamin 0.5mg, adenosylcobalamin 0.5mg, cerebroside carnosine or monosialoganglioside (GM 1) or compound brain peptide ganglioside.
In the preferred technical scheme of the invention, the single intrathecal injection pharmaceutical composition consists of 90ug of mouse nerve growth factor, 1.0mg of mecobalamin, 0.5mg of adenosylcobalamin, 2ml-8ml of any one of brain carnosine or monosialoganglioside (GM 1) or compound brain peptide ganglioside or 20-40mg of ganglioside and 5mg of dexamethasone.
In the preferred technical scheme of the invention, the pharmaceutical composition for single intrathecal injection consists of any 2ml-8ml of mouse nerve growth factor 60ug, mecobalamin 1.0mg, adenosylcobalamin 0.5mg, cerebroside carnosine or monosialoganglioside (GM 1) or compound brain peptide ganglioside or ganglioside 20-40mg and dexamethasone 3 mg.
In a preferred embodiment of the invention, the single intrathecal injection of pharmaceutical composition consists of 30ug of murine nerve growth factor, 0.5mg of mecobalamin, 0.5mg of adenosylcobalamin, 4ml of cerebroside carnosine and 5mg of dexamethasone.
In the preferred technical scheme of the invention, the single intrathecal injection of the pharmaceutical composition consists of 0.5-1.0mg of mecobalamin, 0.1-0.5mg of adenosylcobalamin and 2-5mg of dexamethasone.
In a preferred embodiment of the present invention, the pharmaceutical composition for single intrathecal injection of cerebrospinal fluid optionally contains 100-300mg of any one or a combination of a neural repair cell protein extract and/or a neural repair protein composition having a repair efficacy, preferably 150-200mg.
In a preferred embodiment of the invention, the pharmaceutical composition for single intrathecal injection of cerebrospinal fluid optionally contains 2-10mg naloxone hydrochloride, preferably 5-8mg.
In the preferred technical scheme of the invention, the pharmaceutical composition for single acupoint injection consists of 30ug-90ug of mouse nerve growth factor, 0.5mg-1.0mg of mecobalamin, 0.5mg-1.0mg of adenosylcobalamin, 2mg-5mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein the concentration of the lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5% and 2%.
In a preferred technical scheme of the invention, the pharmaceutical composition for single acupoint injection consists of 30ug of mouse nerve growth factor, 0.5mg of mecobalamin, 0.5mg of adenosylcobalamin, 2mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein the concentration of the lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5% and 2%.
In a preferred technical scheme of the invention, the pharmaceutical composition for single acupoint injection consists of 30ug of mouse nerve growth factor, 0.5mg of mecobalamin, 1.0mg of adenosylcobalamin, 5mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein the concentration of the lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5% and 2%.
In a preferred technical scheme of the invention, the pharmaceutical composition for single acupoint injection consists of 90ug of mouse nerve growth factor, 1.0mg of mecobalamin, 0.5mg of adenosylcobalamin, 5mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein the concentration of the lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5% and 2%.
In a preferred technical scheme of the invention, the pharmaceutical composition for single acupoint injection consists of 60ug of mouse nerve growth factor, 1.0mg of mecobalamin, 0.5mg of adenosylcobalamin, 3mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein the concentration of the lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5% and 2%.
In a preferred embodiment of the present invention, the pharmaceutical composition for single acupoint injection optionally contains 100-300mg of any one or combination of a neural repair cell protein extract and/or a neural repair protein composition having a repair effect.
In the preferred technical scheme of the invention, the pharmaceutical composition for single acupoint injection is clinically matched.
In the preferred technical scheme of the invention, the Hegu acupoint, the hand three interior, the hand five interior, the foot three interior, the yanling spring, the yin ling spring, the Sanyinjiao acupoint and the yang Jian-side Hegu acupoint and the foot three interior acupoint are selected for acupoint injection.
In the preferred technical scheme of the invention, the medicine composition for single acupoint injection is injected once per acupoint every day, and 7 days is a treatment course.
In the preferred technical scheme of the invention, each acupoint injection treatment is carried out for 2-6 treatment courses, preferably 4-5 treatment courses.
In a preferred embodiment of the present invention, the intrathecal injection of cerebrospinal fluid is selected from any one of lumbar puncture and implantable intrathecal drug infusion system, or a combination thereof, by Ommaya capsule puncture injection.
In a preferred embodiment of the present invention, the pharmaceutical composition for preventing and treating nervous system disorders optionally contains a pharmaceutical composition for single intravenous injection.
In a preferred embodiment of the present invention, the pharmaceutical composition for single intravenous injection has the same components and proportions as the pharmaceutical composition for single intrathecal injection.
In the preferred technical scheme of the invention, the single cerebrospinal fluid intrathecal injection pharmaceutical composition, the single intravenous injection pharmaceutical composition and the single acupoint injection pharmaceutical are sequentially or simultaneously used.
In a preferred embodiment of the invention, the cerebrospinal fluid is injected intrathecally or intravenously 2 times per week, and two weeks are a course of treatment for four weeks.
In a preferred embodiment of the present invention, the pharmaceutical composition for preventing and treating nervous system disorders is optionally used in combination with any one of physical therapy, rehabilitation training or a combination thereof.
In a preferred embodiment of the present invention, the physical therapy is selected from any one or a combination of electrical stimulation, external therapy and massage, massage therapy, external therapy, acupuncture, skin acupuncture, electro acupuncture, puncture cupping, low frequency electrical therapy, stellate ganglion blocking therapy, auricular point therapy, hyperbaric oxygen therapy, and minimally invasive point catgut implantation.
In a preferred technical scheme of the invention, the rehabilitation training is selected from any one or combination of bare-handed functional training, improving the elasticity and tension of muscles and fascia, enabling paralyzed muscle proprioceptors to be stimulated to accelerate functional reconstruction, and performing passive exercise and fascia release according to the paralyzed degree.
In a preferred embodiment of the present invention, the nervous system disorder is selected from any one or a combination of cerebral apoplexy, brain trauma and sequelae, spinal cord injury and sequelae, cerebrovascular disease and sequelae, motor neuron disease, cerebral palsy, parkinson's disease, dementia, myelitis sequelae, meningitis sequelae, encephalitis sequelae, brain dysplasia, brain atrophy, ataxia, multiple sclerosis, neuromyelitis optica, multiple system atrophy, sustained plant survival status, carbon monoxide poisoning delayed encephalopathy, cranial nerve injury disease, brain tumor and post-operative nerve dysfunction, intrathecal tumor and post-operative nerve dysfunction, neuropathic pain, nerve injury secondary to cervical, thoracic and lumbar vertebra lesions, and brain injury secondary to epilepsy.
It is another object of the present invention to provide a therapeutic regimen for the prevention and treatment of a neurological disorder, which includes a pharmaceutical composition for the prevention and treatment of a neurological disorder containing a nerve repair drug and/or a blood circulation improving drug and an anti-inflammatory drug.
In a preferred embodiment of the present invention, the nerve repair drug and/or the blood circulation improving drug is selected from any one or a combination of murine nerve growth factor, monosialoganglioside (GM 1), cerebroside carnosine, mecobalamin, adenosyl cobalamin, compound vitamin B, butylphthalide, cinepazide maleate, edaravone dexamphetamine, citicoline, sodium citicoline, ganglioside, oxiracetam, piracetam, aniracetam, nerve growth factor, citicoline, neurotolepin, oryzanol, vitamin B1, vitamin B6, vitamin B12, vitamin C, vitamin E, compound brain peptide ganglioside, brain protein, and nervonic acid.
In a preferred embodiment of the present invention, the anti-inflammatory drug is selected from any one of dexamethasone, methylprednisolone, prednisone, methylprednisolone (methylprednisolone), cortisone, hydrocortisone, prednisone, prednisolone, or a combination thereof.
In a preferred technical scheme of the invention, the pharmaceutical composition for preventing and treating nervous system lesions consists of a pharmaceutical composition for single intrathecal injection of cerebrospinal fluid and a pharmaceutical composition for single acupoint injection.
In the preferred technical scheme of the invention, the single intrathecal injection of the pharmaceutical composition consists of 15ug-90ug of mouse nerve growth factor, 0.5mg-1.0mg of mecobalamin, adenosylcobalamin or vitaminsElement B 12 Or any one of 0.25mg-1.0mg of citicoline, brain glycoside carnosine or monosialoganglioside (GM 1) or any one of 2ml-8ml of compound brain peptide ganglioside or ganglioside 20-40mg and dexamethasone 2mg-5 mg.
In the preferred technical scheme of the invention, the single intrathecal injection of the pharmaceutical composition consists of 30ug-90ug of mouse nerve growth factor, 0.5mg-1.0mg of mecobalamin, adenosylcobalamin or vitamin B 12 Or any one of 0.25mg-1.0mg of citicoline, cerebroside carnosine or monosialoganglioside (GM 1) or any one of 4ml-6ml of compound cerebropeptidyl ganglioside or ganglioside 20-40mg and dexamethasone 2mg-5 mg.
In the preferred technical scheme of the invention, the single intrathecal injection pharmaceutical composition consists of 30ug of mouse nerve growth factor, 0.5mg of mecobalamin, 0.5mg of adenosylcobalamin, 2ml-8ml of any one of brain carnosine or monosialoganglioside (GM 1) or compound brain peptide ganglioside or 20-40mg of ganglioside and 5mg of dexamethasone.
In the preferred technical scheme of the invention, the single intrathecal injection pharmaceutical composition consists of any one of 4ml-6ml or ganglioside 20-40mg and dexamethasone 2mg, wherein the one of the 4ml-6ml comprises mouse nerve growth factor 30ug, mecobalamin 0.5mg, adenosylcobalamin 0.5mg, cerebroside carnosine or monosialoganglioside (GM 1) or compound brain peptide ganglioside.
In the preferred technical scheme of the invention, the single intrathecal injection pharmaceutical composition consists of 90ug of mouse nerve growth factor, 1.0mg of mecobalamin, 0.5mg of adenosylcobalamin, 2ml-8ml of any one of brain carnosine or monosialoganglioside (GM 1) or compound brain peptide ganglioside or 20-40mg of ganglioside and 5mg of dexamethasone.
In the preferred technical scheme of the invention, the pharmaceutical composition for single intrathecal injection consists of any 2ml-8ml of mouse nerve growth factor 60ug, mecobalamin 1.0mg, adenosylcobalamin 0.5mg, cerebroside carnosine or monosialoganglioside (GM 1) or compound brain peptide ganglioside or ganglioside 20-40mg and dexamethasone 3 mg.
In a preferred embodiment of the invention, the single intrathecal injection of pharmaceutical composition consists of 30ug of murine nerve growth factor, 0.5mg of mecobalamin, 0.5mg of adenosylcobalamin, 4ml of cerebroside carnosine and 5mg of dexamethasone.
In the preferred technical scheme of the invention, the single intrathecal injection of the pharmaceutical composition consists of 0.5-1.0mg of mecobalamin, 0.1-0.5mg of adenosylcobalamin and 2-5mg of dexamethasone.
In a preferred embodiment of the present invention, the pharmaceutical composition for single intrathecal injection of cerebrospinal fluid optionally contains 100-300mg of any one or a combination of a neural repair cell protein extract and/or a neural repair protein composition having a repair efficacy, preferably 150-200mg.
In a preferred embodiment of the invention, the pharmaceutical composition for single intrathecal injection of cerebrospinal fluid optionally contains 2-10mg naloxone hydrochloride, preferably 5-8mg.
In the preferred technical scheme of the invention, the pharmaceutical composition for single acupoint injection consists of 30ug-90ug of mouse nerve growth factor, 0.5mg-1.0mg of mecobalamin, 0.5mg-1.0mg of adenosylcobalamin, 2mg-5mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein the concentration of the lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5% and 2%.
In a preferred technical scheme of the invention, the pharmaceutical composition for single acupoint injection consists of 30ug of mouse nerve growth factor, 0.5mg of mecobalamin, 0.5mg of adenosylcobalamin, 2mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein the concentration of the lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5% and 2%.
In a preferred technical scheme of the invention, the pharmaceutical composition for single acupoint injection consists of 30ug of mouse nerve growth factor, 0.5mg of mecobalamin, 1.0mg of adenosylcobalamin, 5mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein the concentration of the lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5% and 2%.
In a preferred technical scheme of the invention, the pharmaceutical composition for single acupoint injection consists of 90ug of mouse nerve growth factor, 1.0mg of mecobalamin, 0.5mg of adenosylcobalamin, 5mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein the concentration of the lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5% and 2%.
In a preferred technical scheme of the invention, the pharmaceutical composition for single acupoint injection consists of 60ug of mouse nerve growth factor, 1.0mg of mecobalamin, 0.5mg of adenosylcobalamin, 3mg of dexamethasone and 1ml of lidocaine hydrochloride, wherein the concentration of the lidocaine hydrochloride is selected from any one of 0.8%, 1%, 1.5% and 2%.
In a preferred embodiment of the present invention, the pharmaceutical composition for single acupoint injection optionally contains 100-300mg of any one or combination of a neural repair cell protein extract and/or a neural repair protein composition having a repair effect.
In the preferred technical scheme of the invention, the pharmaceutical composition for single acupoint injection is clinically matched.
In the preferred technical scheme of the invention, the Hegu acupoint, the hand three interior, the hand five interior, the foot three interior, the yanling spring, the yin ling spring, the Sanyinjiao acupoint and the yang Jian-side Hegu acupoint and the foot three interior acupoint are selected for acupoint injection.
In the preferred technical scheme of the invention, the medicine composition for single acupoint injection is injected once per acupoint every day, and 7 days is a treatment course.
In the preferred technical scheme of the invention, each acupoint injection treatment is carried out for 2-6 treatment courses, preferably 4-5 treatment courses.
In a preferred embodiment of the present invention, the intrathecal injection of cerebrospinal fluid is selected from any one of lumbar puncture and implantable intrathecal drug infusion system, or a combination thereof, by Ommaya capsule puncture injection.
In a preferred embodiment of the present invention, the pharmaceutical composition for preventing and treating nervous system disorders optionally contains a pharmaceutical composition for single intravenous injection.
In a preferred embodiment of the present invention, the pharmaceutical composition for single intravenous injection has the same components and proportions as the pharmaceutical composition for single intrathecal injection.
In the preferred technical scheme of the invention, the single cerebrospinal fluid intrathecal injection pharmaceutical composition, the single intravenous injection pharmaceutical composition and the single acupoint injection pharmaceutical are sequentially or simultaneously used.
In a preferred embodiment of the invention, the cerebrospinal fluid is injected intrathecally or intravenously 2 times per week, and two weeks are a course of treatment for four weeks.
In a preferred embodiment of the present invention, the pharmaceutical composition for preventing and treating nervous system disorders is optionally used in combination with any one of physical therapy, rehabilitation training or a combination thereof.
In a preferred embodiment of the present invention, the physical therapy is selected from any one or a combination of electrical stimulation, external therapy and massage, massage therapy, external therapy, acupuncture, skin acupuncture, electro acupuncture, puncture cupping, low frequency electrical therapy, stellate ganglion blocking therapy, auricular point therapy, hyperbaric oxygen therapy, and minimally invasive point catgut implantation.
In a preferred technical scheme of the invention, the rehabilitation training is selected from any one or combination of bare-handed functional training, improving the elasticity and tension of muscles and fascia, enabling paralyzed muscle proprioceptors to be stimulated to accelerate functional reconstruction, and performing passive exercise and fascia release according to the paralyzed degree.
In a preferred embodiment of the present invention, the nervous system disorder is selected from any one or a combination of cerebral apoplexy, brain trauma and sequelae, spinal cord injury and sequelae, cerebrovascular disease and sequelae, motor neuron disease, cerebral palsy, parkinson's disease, dementia, myelitis sequelae, meningitis sequelae, encephalitis sequelae, brain dysplasia, brain atrophy, ataxia, multiple sclerosis, neuromyelitis optica, multiple system atrophy, sustained plant survival status, carbon monoxide poisoning delayed encephalopathy, cranial nerve injury disease, brain tumor and post-operative nerve dysfunction, intrathecal tumor and post-operative nerve dysfunction, neuropathic pain, nerve injury secondary to cervical, thoracic and lumbar vertebra lesions, and brain injury secondary to epilepsy.
For clarity of presentation of the present invention, the neural repair cell protein extract or neural repair cell protein composition with repair efficacy according to the present invention was prepared with reference to patent applications (CN 2023100429139, PCT/CN2023/073566, CN2023100429143, PCT/CN 2023/073582).
In a preferred technical scheme of the invention, the preparation method of the nerve repair cell protein extract with the nerve repair effect comprises the following steps:
s-1 the density was set at 5.0X10 6 personal/mL-5.0X10 7 The mesenchymal stem cells of each/mL are placed in a culture medium containing DMEM/F12-50%, 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 (18 AA) 0.01-0.1% and 2-10 mu mol/L stressor, and then placed in a medium containing 37.0+/-0.5 ℃ and 5% +/-1.0% CO 2 After 2h-6h of culture under the condition, separating, washing and collecting cells, wherein the stressor is selected from any one of compounds 1-16 or a combination thereof;
s-2: the cells were collected at a density of 5.0X10 6 personal/mL-5.0X10 7 Dispersing the cells/mL in a solvent, and then carrying out ultrasonic treatment at the temperature of 2-8 ℃ to prepare a cell lysate, wherein the solvent is selected from any one or a combination of physiological saline, 5% glucose solution, phosphate Buffer (PBS), TBPS buffer, TBST buffer and Tris buffer;
S-3, separating the cell lysate prepared in the step S-2, and filtering the obtained separating liquid with 0.45um and 0.22um filter membranes in sequence to obtain the cell lysate.
In the preferred technical scheme of the invention, the culture medium in the step S-1 contains stress substances of DMEM/F12-45%, RPMI1640 42-45%, bovine Serum Albumin (BSA) 0.5-1.5%, epidermal Growth Factor (EGF) 5-10ug/mL, fibroblast Growth Factor (FGF) 5-10ug/mL, insulin transferrin 5-10ug/mL, compound amino acid (18 AA) 0.02-0.05% and 3-8 mu mol/L.
In a preferred technical scheme of the invention, the culture medium in the step S-1 contains DMEM/F12, RPMI1640 45, bovine Serum Albumin (BSA) 0.5, epidermal Growth Factor (EGF) 10ug/mL, fibroblast Growth Factor (FGF) 10ug/mL, insulin transferrin 10ug/mL, compound amino acid (18 AA) 0.05% and stressors of 4-6 mu mol/L.
In a preferred embodiment of the present invention, the mesenchymal stem cells of step S-1 have a density of 8.0X10 6 -2.0×10 7 Each mL is preferably 8.0X10 6 -1.0×10 7 And each mL.
In a preferred embodiment of the invention, the mesenchymal stem cells of step S-1 are cultured in the medium for 3h to 5h, preferably 3.5h to 4.5h.
In a preferred embodiment of the present invention, the solvent used for washing the cells in step S-1 is selected from any one or a combination of physiological saline, 5% dextrose solution, phosphate Buffer (PBS), TBPS buffer, TBST buffer, tris buffer, and the like, and the number of times of washing the cells is 2 to 5 times, preferably 3 to 4 times.
In a preferred embodiment of the present invention, the separation in step S-1 is selected from any one of centrifugation and filtration or a combination thereof, wherein the centrifugation conditions are 1000-2000rpm for 3-15min, preferably 1200-1500 rpm for 5-10min.
In the preferred technical scheme of the invention, the ultrasonic conditions of the step S-2 are as follows: working for 3s at 2-8 ℃ under the conditions of 25kHZ and 360W and then spacing for 1s, and carrying out ultrasonic treatment for 1-5min.
In a preferred embodiment of the present invention, the separation in step S-3 is selected from any one or a combination of centrifugation at 2000-8000rpm for 10-30min, multistage centrifugation, multistage filtration, preferably 3000-7000rpm for 15-25min.
In a preferred embodiment of the present invention, the multistage centrifugation in step S-3 is carried out sequentially at 3000-4000rpm for 3-5min, at 5000-6000rpm for 3-5min, and at 7000rpm for 5-8min.
In a preferred technical scheme of the invention, the pore diameter of the multi-stage filtration membrane is selected from any one of 80um, 50um, 30um, 10um and 5 um.
In a preferred embodiment of the present invention, the cellular protein extract obtained in step S-3 is frozen, preferably at-40℃to-20 ℃.
In the preferred technical scheme of the invention, the cellular protein extract prepared in the step S-3 is subjected to enzymolysis by adopting any one of nuclease or totipotent nuclease and then is subjected to separation and purification.
In a preferred embodiment of the present invention, the mesenchymal stem cells are cultured or primary mesenchymal stem cells are cultured by a method of culturing in the art.
In a preferred embodiment of the present invention, the culture of the mesenchymal stem cells comprises the following steps: the primary mesenchymal stem cells are prepared according to the initial density of 5.0x10 5 -5.0×10 6 Adding the mixture/ml into a subculture medium, and placing the subculture medium at 37.0deg.C+ -0.5deg.C and 5% + -1.0% CO 2 Culturing under the condition for 10-15 days, observing yellowing of the subculture medium every 2-3 days, and half-changing the subculture medium, wherein the subculture medium contains 10% FBS, 100U/ml penicillin and 100ug/ml streptomycin DMEM/F12 medium.
In a preferred embodiment of the present invention, the culture of primary mesenchymal stem cells comprises the steps of:
1) Cleaning umbilical cord, sterilizing, dissecting tissue, collecting the tissue of HUALONG gel layer, cutting into 3mm pieces 3 Is centrifuged, washed, tissue pieces are collected, placed in DMEM/F12 medium containing 10% fetal bovine serum FBS, 100ug/ml penicillin, 100ug/ml streptomycin, and placed in 37.0.+ -. 0.5 ℃ and 5%.+ -. 1.0% CO 2 Culturing under the condition that the culture medium is half replaced every 2-3 days, and culturing until the tissue blocks climb out of the cells;
2) Shaking, collecting low-layer cells, washing with PBS, adding 0.25% trypsin, digesting for 2min-3min, adding equal volume of trypsin stopping solution, stopping digestion, gently blowing with a sucker, centrifuging at 1200-1500rpm/min for 5-8min, and collecting cells.
In order to clearly demonstrate the present invention, the preparation method of the nerve repair protein composition of the present invention includes the steps of:
(1) Adding any one or combination of nuclease or totipotent nuclease of 20U/mL-35U/mL into the nerve repair cell protein extract, and carrying out enzymolysis for 15min-40min at 37+/-1 ℃ to prepare enzymolysis liquid;
(2) Preparing the enzymolysis liquid prepared in the step (1) into 5-15mg/ml by using an eluting solvent at the temperature of 2-8 ℃, passing through a chromatographic column, monitoring and collecting an eluting fraction with the ultraviolet wavelength of 280nm at the eluting flow rate of 0.1-1ml/min, wherein the eluting solvent consists of 50mmol/L phosphate buffer (pH 6.8) and 300mmol/L sodium chloride.
In a preferred embodiment of the present invention, the nuclease is selected from any one of RNA nuclease and DNA nuclease or a combination thereof.
In the preferred technical scheme of the invention, any one or combination of 25U/mL-30U/mL nuclease or totipotent nuclease is added into the cellular protein extract, and the cellular protein extract is subjected to enzymolysis for 20min-30min at 37+/-1 ℃ to prepare an enzymolysis liquid.
In a preferred embodiment of the invention, the molecular weight of the said nerve repair protein composition is 20kDa to 250kDa, preferably 35kDa to 200kDa.
In a preferred embodiment of the present invention, the protein composition obtained in step (2) is frozen, preferably at-40℃to-20 ℃.
In a preferred technical scheme of the invention, a freeze-drying protective agent is added into the protein composition collected in the step (2), and freeze-drying is carried out to prepare a protein composition freeze-drying preparation, wherein the freeze-drying protective agent is selected from any one of mannitol, sorbitol, dextran, glycerol, sucrose, trehalose, glucose, lactose, maltose, dextran, tricaprylin (HES), polyethylene glycol, ethylene-vinyl diene, phosphate, acetate, citrate, sorbitol and starch or a combination thereof.
In a preferred technical scheme of the invention, the freeze-dried preparation contains 0.5-8% of freeze-drying protective agent, preferably 1-5% by mass.
In a preferred embodiment of the present invention, 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 salt and aluminum salt.
According to a preferred embodiment of the invention, the pH of the lyophilized preparation is between 6 and 8, preferably between 7 and 7.5.
In a preferred technical scheme of the invention, the freeze-dried preparation is reconstituted with normal saline or 5% glucose solution before use and then is used by any one or combination of intravenous injection, intrathecal injection and lumbar puncture.
Unless otherwise indicated, when the invention relates to a percentage between liquids, the percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentage between solids and liquids, the percentage being weight/volume percentage; the balance being weight/weight percent.
The present invention uses the stroke scoring scale of table 1 and the barchel index (Modified Barthel Index, MBI) of table 2 as scoring scales unless otherwise indicated.
TABLE 1 cerebral stroke score scale
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It is stated that the check can only select and fill one item by clicking a 'v' in the corresponding item.
The highest score is 45 minutes, and the lowest score is 0 minutes.
Light weight 0-15 min, medium weight 16-30 min, and heavy weight 31-45 min.
TABLE 2 Activities of Daily Living (ADL) Meter (Barthel index)
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Scoring results:
100 minutes per minute
<20 is classified as extremely serious functional defect, and life is completely dependent; 20-40 minutes requires great help for life; 40 to 60 minutes are needed to be assisted for life; >60 is divided into living basic self-care.
The Barthel index score is 40 or more, and the recovery treatment benefit is the largest.
ADL capability defect level: 0-20 is a serious functional defect; 20-45 = severe functional defect; 50-70 = moderate functional defect; 75-95 = mild functional defect; 100 =adl self-care
Compared with the prior art, the invention has the following beneficial effects:
the invention scientifically screens the components and the proportion of the pharmaceutical composition, adopts any one or combination of cerebrospinal fluid injection administration (including intrathecal injection administration, intraventricular administration and the like), acupoint injection administration and intravenous injection administration, and the cerebrospinal fluid injection administration enables the medicine to directly enter subarachnoid cavities or cerebral chambers of brain and spinal cord, reaches the parts of brain and spinal parenchyma and nerve injury through cerebrospinal fluid circulation, directly supplies nerve repair medicine or neurotrophic substances to neurons and glial cells, eliminates the medicine absorption disorder caused by blood brain barrier, obviously improves the medicine peak concentration in central nervous system tissues, effectively treats the neurological deficit or the neurological dysfunction, and has the advantages of synergy, quick effect, small dosage, high bioavailability, basically no side effect, basically no recurrence rate and the like, and obviously improves the treatment prognosis and the life quality of patients.
Detailed Description
The following detailed description of the invention is provided in connection with specific embodiments, but is not intended to limit the scope of the invention.
Example 1Preparation of neural repair cell protein extract with repair effect
1. Culture of primary mesenchymal Stem cells
The culture of primary mesenchymal stem cells comprises the following steps:
1) Cleaning umbilical cord, sterilizing, dissecting tissue, collecting the tissue of HUALONG gel layer, cutting into 3mm pieces 3 Centrifuging, washing, collecting tissue pieces, placing in culture flask, addingAdding DMEM/F12 medium containing 10% fetal bovine serum FBS, 100ug/ml penicillin, 100ug/ml streptomycin, and placing at 37deg.C and 5% CO 2 Culturing under the condition to promote the adherence of the culture medium, observing the yellowing of the culture medium every 2-3 days, and half-changing the culture medium, and culturing for 10-12 days until the cells on the tissue block edge can climb out;
2) Slightly shaking to drop the tissue blocks, and respectively collecting the tissue blocks and lower cells, wherein the collected tissue blocks are subjected to wall-attached culture;
3) Washing the collected low-layer cells with PBS, adding a proper amount of 0.25% trypsin for digestion for 2-3 min, adding an equal volume of trypsin stopping solution for stopping digestion, lightly blowing a bottle bottom by a suction tube, centrifuging at 1500rpm for 5min, and collecting the cells.
2. Subculture of Primary mesenchymal Stem cells (culture of mesenchymal Stem cells)
Subculture of primary mesenchymal stem cells (culture of mesenchymal passage stem cells): the primary mesenchymal stem cells are prepared according to the initial density of 5.0x10 5 -5.0×10 6 Each ml was added to DMEM/F12 medium containing 10% FBS, 100U/ml penicillin and 100ug/ml streptomycin, and then placed at 37.0deg.C.+ -. 0.5 ℃ and 5%.+ -. 1% CO 2 Culturing under the condition for 10-15 days at intervals of 2-3 days, and half-changing the culture medium after observing the yellowing of the culture medium.
3. Preparation of Compounds 1-16 reference 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).
The preparation method of the nerve repair cell protein extract with the nerve repair effect comprises the following steps:
(1) Mesenchymal passaged cells were passaged at a density of 8.0X10 6 Adding into culture medium containing DMEM/F1245%, RPMI1640 45%, bovine Serum Albumin (BSA) 0.5%, epidermal Growth Factor (EGF) 10ug/mL, fibroblast Growth Factor (FGF) 10ug/mL, insulin transferrin 10ug/mL, compound amino acid (18 AA) 0.05% and 5 μmol/L of compound 16, and placing at 37deg.C and 5% CO 2 After 4h incubation, cells were collected after centrifugation at 1200rpm for 5min and washing 3 times with PBS;
(2) The cells collected in step (1) were packed at a density of 1.0X10 7 Dispersing the cells/mL in physiological saline, and performing ultrasonic treatment at 2-8deg.C, 25kHz and 360W for 3s and 1s gap for 2min to obtain cell lysate;
(3) And (3) centrifuging the cell lysate prepared in the step (2) for 20min at 7000rpm, and filtering the obtained centrifugate by a 0.45um filter membrane and a 0.22um filter membrane in sequence to obtain the cell protein extract.
Example 2Preparation of a nerve repair protein composition
The preparation of the nerve repair protein composition comprises the following steps:
(1) Adding 25U/mL omnipotent nuclease (UCF.ME UltraNuclease) into the cellular protein extract prepared in the example 1, and performing enzymolysis at 37 ℃ for 30min to obtain an enzymolysis solution;
(2) Preparing the enzymolysis liquid prepared in the step (1) into 10mg/ml by using an eluting solvent at the temperature of 2-8 ℃, sequentially passing through a high-purity silica gel liquid chromatography protective column (Wonda guard C18, 4.6X5 mm) and a high-purity silica gel liquid chromatography preparation column (SHIMSEN Ankylo C18,5 mu m, 4.6X250 mm), wherein the eluting flow rate is 0.1-1ml/min, and monitoring and collecting an eluting fraction with the ultraviolet wavelength of 280nm, wherein the eluting solvent consists of 50mmol/L phosphate buffer (pH6.8) containing 300mmol/L sodium chloride.
(3) Mannitol is added into the cellular protein composition prepared in the step (2), and after stirring and mixing uniformly, the obtained freeze-dried preparation contains 2.15% mannitol (m/m).
Test example 1The pharmaceutical composition of the invention is used for researching the curative effect of cerebral arterial thrombosis
(one) subject
30 patients with ischemic cerebral apoplexy are selected and divided into 1 group (5), 2 groups (20) and 3 groups (5). The subjects in each group were statistically not significantly different (P > 0.05) in age, disease type, sex, etc.
Patient inclusion criteria: meets the diagnosis standard of cerebral arterial thrombosis, is 20-70 years old, has relatively stable disease condition, and is informed to accept the clinical study; the compliance is good.
Patient exclusion criteria: (1) The mRS score of the patient with recurrent cerebral infarction before the occurrence is more than or equal to grade 2; (2) Intracranial Computed Tomography (CT) suggests intracranial hemorrhagic diseases (e.g., hemorrhagic stroke, epidural hematoma, intracranial hematoma, cerebral ventricular hemorrhage, subarachnoid hemorrhage, etc.); (3) Cerebral infarction with consciousness disturbance (NIHSS score 1a is greater than or equal to 1 score), transient cerebral ischemia attack, cerebral arteritis, brain tumor, brain trauma, intracranial infection, and brain parasite; (4) a history of alcohol, drug abuse is suspected or confirmed; (5) Pregnant, lactating women or those who have recently planned pregnancy and are reluctant to take contraceptive measures; (6) expected survival of less than 3 months; (7) other clinical trials were enrolled within 3 months prior to group entry; (8) Researchers consider patients not likely to participate in this clinical trial.
(II) test method
Dosing regimen of group 1:
the single intrathecal injection pharmaceutical composition consisted of 30ug of murine nerve growth factor, 0.5mg of mecobalamin, 0.5mg of adenosylcobalamin, 4ml of cerebroside carnosine and 5mg of dexamethasone. The cerebrospinal fluid is injected intrathecally for 2 times per week, and two weeks are a treatment course and four weeks of treatment.
Dosing regimen of group 2:
1. the pharmaceutical composition for single intrathecal injection of cerebrospinal fluid consists of 30ug of mouse nerve growth factor, 0.5mg of mecobalamin, 0.5mg of adenosylcobalamine, 4ml of cerebroside carnosine and 5mg of dexamethasone. The cerebrospinal fluid is injected intrathecally for 2 times per week, and two weeks are a treatment course and four weeks of treatment.
2. The single acupoint injection pharmaceutical composition comprises 60ug of mouse nerve growth factor, 0.5mg of mecobalamin, 0.5mg of adenosyl cobalamine, 5mg of dexamethasone and 1ml of lidocaine hydrochloride, and is prepared for clinical use by selecting Hegu acupoint, ganli, yinling, sanxiong and Yanggan acupoints of affected side and selecting Hegu acupoint and Ganli acupoint of healthy side for acupoint injection. The injection is carried out for 1 time per day, two weeks are a treatment course, and four weeks are treated.
Dosing regimen of group 3:
(1) The pharmaceutical composition for single intrathecal injection of cerebrospinal fluid consists of 30ug of mouse nerve growth factor, 0.5mg of mecobalamin, 0.5mg of adenosylcobalamine, 4ml of cerebroside carnosine and 5mg of dexamethasone. The cerebrospinal fluid is injected intrathecally for 2 times per week, and two weeks are a treatment course and four weeks of treatment.
(2) The single acupoint injection pharmaceutical composition comprises mouse nerve growth factor 60ug, mecobalamin 0.5mg, adenosyl cobalamin 0.5mg, dexamethasone 5mg and lidocaine hydrochloride 1ml, and is administered by selecting the Hegu acupoint, ganli, zusanli, yanglingquan, YINLINGQU, sanyinjiao and Yanggiao acupoints and Jianli acupoint on the affected side. The injection is carried out for 1 time per day, one treatment course is one week, and the treatment is four weeks.
(3) A single intrathecal injection of 130ug of the nerve repair cell protein composition prepared in example 2 was dissolved in 2ml of physiological saline. The cerebrospinal fluid is injected intrathecally for 2 times per week, and two weeks are a treatment course and four weeks of treatment.
Efficacy assessment: the stroke scale of table 1 and the barchel index scale of table 2 (Modified Barthel Index, MBI) were used.
Group 1: on the day of treatment, about 60% of patients had an effect. The effective rate of one treatment course is 60% and the effective rate is 40%. The effective rate of the second treatment course is 80% and the effective rate is 60%.
Group 2: on the day of treatment, about 70% of patients had an effect. The effective rate of one treatment course is 80% and the obvious rate is 50%. The effective rate of the second treatment course is 90% and the effective rate is 60%.
Group 3: on the day of treatment, about 80% of patients have had efficacy. The effective rate of one treatment course is 100% and the effective rate is 60%. The effective rate of the second treatment course is 100% and the effective rate is 80%.
The above description of the embodiments of the present invention is not intended to limit the present invention, and those skilled in the art can make various changes or modifications according to the present invention without departing from the spirit of the present invention, and shall fall within the scope of the claims of the present invention.

Claims (10)

1. The application of a pharmaceutical composition in preparing medicines for preventing and treating nervous system diseases, wherein the pharmaceutical composition for preventing and treating nervous system diseases contains a nerve repair medicine and/or a blood circulation improving medicine and an anti-inflammatory medicine;
preferably, the nerve repair drug and/or blood circulation improving drug is selected from any one or combination of murine nerve growth factor, monosialoganglioside (GM 1), cerebroside carnosine, mecobalamin, adenosylcobalamine, vitamin B complex, butylphthalide, cinepazide maleate, edaravone dextroamphetamine, citicoline sodium, ganglioside, oxiracetam, piracetam, aniracetam, nerve growth factor, citicoline, neurotolepin, oryzanol, vitamin B1, vitamin B6, vitamin B12, vitamin C, vitamin E, compound cerebropeptidyl-glycoside, brain protein, and nervonic acid;
preferably, the anti-inflammatory drug is selected from any one or combination of dexamethasone, methylprednisolone, prednisone, methylprednisolone, cortisone, hydrocortisone, prednisone, prednisolone.
2. The use according to claim 1, wherein the pharmaceutical composition for preventing and treating nervous system disorders consists of a pharmaceutical composition for single intrathecal injection of cerebrospinal fluid and a pharmaceutical composition for single acupoint injection.
3. The use according to any one of claims 1-2, wherein the single intrathecal injection of cerebrospinal fluid comprises 15ug-90ug of murine nerve growth factor, 0.5mg-1.0mg of mecobalamin, adenosylcobalamin or vitamin B 12 Or any one of 0.25mg-1.0mg of citicoline, brain glycoside carnosine or monosialoganglioside (GM 1) or any one of 2ml-8ml of compound brain peptide ganglioside or ganglioside 20-40mg and dexamethasone 2mg-5 mg.
4. The use according to any one of claims 1-3, wherein the pharmaceutical composition for single point injection consists of 30ug-90ug of murine nerve growth factor, 0.5mg-1.0mg of mecobalamin, 0.5mg-1.0mg of adenosylcobalamin, 2mg-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%, 2%.
5. The use according to any one of claims 1-4, selecting the Hegu acupoint, the Sanyi, the Wuyi, the Zusanli, the Yanglingquan, the Yinlingquan, the Sanyinjiao and the Yangjiao acupoint of the affected side and selecting the Hegu acupoint and Zusanli acupoint of the healthy side for acupoint injection.
6. The use according to any one of claims 1-5, wherein the cerebrospinal fluid is injected intrathecally or intravenously 2 times per week for a course of two weeks for four weeks.
7. The use according to any one of claims 1 to 6, optionally in combination with any one of physiotherapy, rehabilitation training or a combination thereof, of a pharmaceutical composition for the prevention and treatment of neurological pathologies.
8. The use of any one of claims 1-7, wherein the neurological disorder is selected from any one or combination of stroke, brain trauma and sequelae, spinal cord injury and sequelae, cerebrovascular disease and sequelae, motor neuron disease, cerebral palsy, parkinson's disease, dementia, myelitis sequelae, meningitis sequelae, encephalitis sequelae, brain dysplasia, brain atrophy, ataxia, multiple sclerosis, neuromyelitis optica, multiple system atrophy, sustained plant survival status, delayed brain disease from carbon monoxide poisoning, cranial nerve injury disease, brain tumor and post-operative nerve dysfunction, intrathecal tumor and post-operative nerve dysfunction, neuropathic pain, nerve damage secondary to cervical, thoracic, lumbar vertebra lesions, brain damage secondary to epilepsy.
9. The pharmaceutical composition for preventing and treating a nervous system disorder according to any one of claims 1 to 8, which contains a nerve repair drug and/or a blood circulation improving drug and an anti-inflammatory drug.
10. A therapeutic regimen for the prevention and treatment of a neurological disorder, which comprises the pharmaceutical composition for the prevention and treatment of a neurological disorder according to any one of claims 1 to 8, containing a nerve repair drug and/or a blood circulation improving drug and an anti-inflammatory drug.
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