WO2024051844A1 - Composition pharmaceutique pour la prévention et le traitement de la paralysie du nerf facial en phase aiguë et son utilisation - Google Patents
Composition pharmaceutique pour la prévention et le traitement de la paralysie du nerf facial en phase aiguë et son utilisation Download PDFInfo
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- WO2024051844A1 WO2024051844A1 PCT/CN2023/117896 CN2023117896W WO2024051844A1 WO 2024051844 A1 WO2024051844 A1 WO 2024051844A1 CN 2023117896 W CN2023117896 W CN 2023117896W WO 2024051844 A1 WO2024051844 A1 WO 2024051844A1
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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 acute phase facial nerve paralysis, its preparation method and its application.
- Facial nerve palsy also known as facial neuritis, Bell's palsy, dystonia, mouth and eye deviation, etc.
- Facial nerve edema and/or myelin edema often occur in the early stage of pathology, and facial nerve injury Pressure or local circulation disorder may cause axonal degeneration in the late stage, most notably in the stylomastoid foramen and the facial nerve canal.
- facial nerve paralysis is divided into acute phase (within 15 days of onset), recovery phase (16 days to 6 months of onset), and sequelae phase (more than 6 months of onset).
- Treatment methods for facial nerve paralysis include medication (dehydration drugs or anti-edema drugs, antiviral drugs, B vitamins, glucocorticoids, etc.), acupuncture, physical therapy, facial rehabilitation training, etc. Mild and moderate patients can significantly improve their symptoms after 2 weeks to 2 months of treatment, with effective and clinical cure rates of 60%-70%. However, more than 30% of moderate and severe patients have sequelae. To date, there are no specific drugs for the treatment of acute facial nerve paralysis. For this reason, there is a need to develop pharmaceutical compositions that can safely and effectively treat facial nerve paralysis in the acute phase.
- 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 preventing and treating acute phase facial nerve paralysis, which composition contains dehydration drugs, antiviral drugs, anti-inflammatory drugs, nerve repair drugs and/or blood improvement drugs. Any one or combination of circulating drugs.
- the dehydrating drug is selected from any one of mannitol, sorbitol, aescin, sodium aescin, 50% hypertonic glucose solution or a combination thereof.
- the antiviral drug is selected from the group consisting of acyclovir, valacyclovir, dibazole, Rhinoceros Jiedu, Virusin, favipiravir, Paxlovid, and monogravir (Molnupiravir), oseltamivir, remdesivir, remdesivir (GS-5734), indinavir, saquinavir, lopinavir, ritonavir (Ritonavir), a Zanavir, darunavir, tipranavir, flusanavir, enzatovir, pretovir, abacavir, elvitegravir, maribabavir, raltegravir, Any of bavirin, amantadine, oseltamivir, zanamivir, peramivir, lanamivir, ganciclovir, baloxavir, or nelfinavir or combination
- the anti-inflammatory drug is selected from dexamethasone, methylprednisolone, prednisolone, methylprednisolone (methylprednisolone), cortisone, hydrocortisone, prednisone, Prednisolone or any combination thereof.
- 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, 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, cerebroprotein , any one or combination thereof.
- GM1 monosialoganglioside
- cerebrospinalis carnosine methylcobalamin
- adenosylcobalamin Vitamin B complex
- butylphthalide cinpazide maleate
- edaravone edar
- the pharmaceutical composition for preventing and treating acute phase facial nerve paralysis contains mannitol, sodium aescinate, acyclovir or valacyclovir, dexamethasone, prednisone, and cytophosphate Any one of sodium choline, ginkgo leaves, mouse nerve growth factor, methylcobalamin, adenosylcobalamin or a combination thereof.
- the pharmaceutical composition for preventing and treating acute facial nerve paralysis consists of a pharmaceutical composition for oral administration and a pharmaceutical composition for acupoint injection.
- the pharmaceutical composition for single oral administration contains 125-250 ml of mannitol, 0.5 mg of methylcobalamin, 5 mg of anti-inflammatory drugs, 30 mg of fasudil, 30 ug of mouse nerve growth factor, and 15 ml of ginkgo leaf extract.
- the anti-inflammatory drug is selected from any one of dexamethasone, sodium aescinate, methylprednisolone or a combination thereof.
- the dosage regimen of the oral pharmaceutical composition is:
- the pharmaceutical composition for single oral administration contains 125-250 ml of mannitol, 10-20 mg of sodium aescin, 0.3-0.4 g of acyclovir or valacyclovir, dexamethasone or prednisone.
- Disone tablets 1-5mg Citicoline sodium tablets 0.2-0.5mg, Ginkgo biloba leaves 0.1-0.2g, mouse nerve growth factor 30-90ug, methylcobalamin 0.5-1.0mg, adenosylcobalamin 0.1-0.5mg, Dexamethasone 2-5 mg of any one or combination thereof.
- the dosage regimen of the oral pharmaceutical composition is:
- Oral prednisone acetate tablets (5 mg/time, 2 times/day, for one week), followed by oral prednisone acetate tablets (5 mg/time, once/day, for one week);
- the oral pharmaceutical composition is selected from simultaneous administration or sequential administration or a combination thereof.
- the pharmaceutical composition for a single acupoint injection is composed of mouse nerve growth factor, methylcobalamin, and vitamin B1 in a mass ratio of 0.03:0.5:200.
- 30ug of mouse nerve growth factor, methylcobalamin 0.5 mg of amine and 200 mg of vitamin B1 are mixed into 5 ml of medicinal solution and then injected into the acupoint.
- the pharmaceutical composition for single acupoint injection contains any one of 30ug of mouse nerve growth factor, 0.5mg of methylcobalamin, 200mg of vitamin B 1 or a combination thereof.
- the pharmaceutical composition for a single acupoint injection consists of 30-90ug of mouse nerve growth factor, 0.5-1.0 mg of methylcobalamin, 0.1-0.5 mg of adenosylcobalamin, and 2-5 mg of dexamethasone.
- the pharmaceutical composition for single acupoint injection is composed of mouse nerve growth factor It consists of 30ug, methylcobalamin 0.5mg, adenosylcobalamin 0.5mg, dexamethasone 2mg and lidocaine hydrochloride 1ml, wherein the concentration of lidocaine hydrochloride is selected from any of 0.8%, 1%, 1.5% and 2%. A sort of.
- the pharmaceutical composition for a single acupoint injection consists of 30ug of mouse nerve growth factor, 0.5mg 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 a 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 a single acupoint injection consists of 60ug of mouse nerve growth factor, 0.8mg 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 Yangbai point, temple point, Sibai point, Yingxiang point, Juliiao point, Dicang point and Jieche point on the affected side of the face are selected for acupoint injection.
- 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.
- Another object of the present invention is to provide a pharmaceutical composition for use in the preparation of drugs for preventing and treating acute facial nerve paralysis, wherein the pharmaceutical composition for preventing and treating acute facial nerve paralysis contains dehydrating drugs and antiviral drugs. , any one or combination of anti-inflammatory drugs, nerve repair drugs and/or blood circulation improving drugs.
- the dehydrating drug is selected from any one of mannitol, sorbitol, aescin, sodium aescin, 50% hypertonic glucose solution or a combination thereof.
- the antiviral drug is selected from the group consisting of acyclovir, valacyclovir, diba Azole, Rhinoceros Jiedu, Virusin, favipiravir, Paxlovid, Molnupiravir, Oseltamivir, Remdesivir, Remdesivir (GS-5734), Indene Dinavir, saquinavir, lopinavir, ritonavir (Ritonavir), atazanavir, darunavir, tipranavir, flusanavir, enzatovir, pritovir Abacavir, elvitegravir, maribavirin, raltegravir, ribavirin, amantadine, oseltamivir, zanamivir, peramivir, lanimivir Any one of ganciclovir, baloxavir, nelfinavir or a combination thereof.
- the anti-inflammatory drug is selected from dexamethasone, methylprednisolone, prednisolone, methylprednisolone (methylprednisolone), cortisone, hydrocortisone, prednisone, Prednisolone or any combination thereof.
- 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, 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, cerebroprotein , any one or combination thereof.
- GM1 monosialoganglioside
- cerebrospinalis carnosine methylcobalamin
- adenosylcobalamin Vitamin B complex
- butylphthalide cinpazide maleate
- edaravone edar
- the pharmaceutical composition for preventing and treating acute phase facial nerve paralysis contains mannitol, sodium aescinate, acyclovir or valacyclovir, dexamethasone, prednisone, and cytophosphate Any one of sodium choline, ginkgo leaves, mouse nerve growth factor, methylcobalamin, adenosylcobalamin or a combination thereof.
- the pharmaceutical composition for preventing and treating acute facial nerve paralysis consists of a pharmaceutical composition for oral administration and a pharmaceutical composition for acupoint injection.
- the pharmaceutical composition for single oral administration contains 125-250 ml of mannitol, 0.5 mg of methylcobalamin, 5 mg of anti-inflammatory drugs, 30 mg of fasudil, 30 ug of mouse nerve growth factor, and 15 ml of ginkgo leaf extract.
- the anti-inflammatory drug is selected from any one of dexamethasone, sodium aescinate, methylprednisolone or a combination thereof.
- the dosage regimen of the oral pharmaceutical composition is:
- the pharmaceutical composition for single oral administration contains 125-250 ml of mannitol, 10-20 mg of sodium aescin, 0.3-0.4 g of acyclovir or valacyclovir, dexamethasone or prednisone.
- Disone tablets 1-5mg Citicoline sodium tablets 0.2-0.5mg, Ginkgo biloba leaves 0.1-0.2g, mouse nerve growth factor 30-90ug, methylcobalamin 0.5-1.0mg, adenosylcobalamin 0.1-0.5mg, Dexamethasone 2-5 mg of any one or combination thereof.
- the dosage regimen of the oral pharmaceutical composition is:
- Oral prednisone acetate tablets (5 mg/time, 2 times/day, for one week), followed by oral prednisone acetate tablets (5 mg/time, once/day, for one week);
- the oral pharmaceutical composition is selected from simultaneous administration or sequential administration or a combination thereof.
- the pharmaceutical composition for a single acupoint injection is composed of mouse nerve growth factor, methylcobalamin, and vitamin B1 in a mass ratio of 0.03:0.5:200.
- 30ug of mouse nerve growth factor, methylcobalamin 0.5 mg of amine and 200 mg of vitamin B1 are mixed into 5 ml of medicinal solution and then injected into the acupoint.
- the pharmaceutical composition for single acupoint injection contains any one of 30ug of mouse nerve growth factor, 0.5mg of methylcobalamin, 200mg of vitamin B 1 or a combination thereof.
- the pharmaceutical composition for a single acupoint injection consists of 30-90ug of mouse nerve growth factor, 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 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 a single acupoint injection consists of 30ug of mouse nerve growth factor, 0.5mg of methylcobalamin, 0.5mg of adenosylcobalamin, 5mg 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 a 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 a single acupoint injection consists of 60ug of mouse nerve growth factor, 0.8mg 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 Yangbai point, temple point, Sibai point, Yingxiang point, Juliiao point, Dicang point and Jieche point on the affected side of the face are selected for acupoint injection.
- the pharmaceutical composition for a 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.
- Another object of the present invention is to provide a treatment plan for treating acute phase facial nerve paralysis.
- the treatment plan includes using the pharmaceutical composition for preventing and treating acute phase facial nerve paralysis of the present invention.
- the pharmaceutical composition for paralysis contains any one or a combination of dehydration drugs, antiviral drugs, anti-inflammatory drugs, nerve repair drugs and/or blood circulation improving drugs.
- the dehydrating drug is selected from any one of mannitol, sorbitol, aescin, sodium aescin, 50% hypertonic glucose solution or a combination thereof.
- the antiviral drug is selected from the group consisting of acyclovir, valacyclovir, dibazole, Rhinoceros Jiedu, Virusin, favipiravir, Paxlovid, and monogravir (Molnupiravir), oseltamivir, remdesivir, remdesivir (GS-5734), indinavir, saquinavir, lopinavir, ritonavir (Ritonavir), a Zanavir, darunavir, tipranavir, flusanavir, enzatovir, pretovir, abacavir, elvitegravir, maribabavir, Raltegravir, ribavirin, amantadine, oseltamivir, zanamivir, peramivir, lanamivir, ganciclovir, baloxavir, nefir Any one or combination of acyclovir, valacycl
- the anti-inflammatory drug is selected from dexamethasone, methylprednisolone, prednisolone, methylprednisolone (methylprednisolone), cortisone, hydrocortisone, prednisone, Prednisolone or any combination thereof.
- 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, 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, cerebroprotein , any one or combination thereof.
- GM1 monosialoganglioside
- cerebrospinalis carnosine methylcobalamin
- adenosylcobalamin Vitamin B complex
- butylphthalide cinpazide maleate
- edaravone edar
- the pharmaceutical composition for preventing and treating acute phase facial nerve paralysis contains mannitol, sodium aescinate, acyclovir or valacyclovir, dexamethasone, prednisone, and cytophosphate Any one of sodium choline, ginkgo leaves, mouse nerve growth factor, methylcobalamin, adenosylcobalamin or a combination thereof.
- the pharmaceutical composition for preventing and treating acute facial nerve paralysis consists of a pharmaceutical composition for oral administration and a pharmaceutical composition for acupoint injection.
- the pharmaceutical composition for single oral administration contains 125-250 ml of mannitol, 0.5 mg of methylcobalamin, 5 mg of anti-inflammatory drugs, 30 mg of fasudil, 30 ug of mouse nerve growth factor, and 15 ml of ginkgo leaf extract.
- the anti-inflammatory drug is selected from any one of dexamethasone, sodium aescinate, methylprednisolone or a combination thereof.
- the dosage regimen of the oral pharmaceutical composition is:
- the pharmaceutical composition for single oral administration contains 125-250 ml of mannitol, 10-20 mg of sodium aescin, 0.3-0.4 g of acyclovir or valacyclovir, dexamethasone or prednisone.
- Dipine tablets 1-5mg Citicoline sodium tablets 0.2-0.5mg, Ginkgo biloba leaves 0.1-0.2g, mouse nerve growth factor 30-90ug, methylcobalamin 0.5-1.0mg, adenosylcobalamin 0.1-0.5mg, dexamethasone 2-5mg any one or combination thereof.
- the dosage regimen of the oral pharmaceutical composition is:
- Oral prednisone acetate tablets (5 mg/time, 2 times/day, for one week), followed by oral prednisone acetate tablets (5 mg/time, once/day, for one week);
- the oral pharmaceutical composition is selected from simultaneous administration or sequential administration or a combination thereof.
- the pharmaceutical composition for a single acupoint injection is composed of mouse nerve growth factor, methylcobalamin, and vitamin B1 in a mass ratio of 0.03:0.5:200.
- 30ug of mouse nerve growth factor, methylcobalamin 0.5 mg of amine and 200 mg of vitamin B1 are mixed into 5 ml of medicinal solution and then injected into the acupoint.
- the pharmaceutical composition for single acupoint injection contains any one of 30ug of mouse nerve growth factor, 0.5mg of methylcobalamin, 200mg of vitamin B 1 or a combination thereof.
- the pharmaceutical composition for a single acupoint injection consists of 30-90ug of mouse nerve growth factor, 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 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 a single acupoint injection consists of 30ug of mouse nerve growth factor, 0.5mg 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 a 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 a single acupoint injection consists of 60ug of mouse nerve growth factor, 0.8mg 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 Yangbai point, temple point, Sibai point, Yingxiang point, Juliiao point, Dicang point and Jieche point on the affected side of the face are selected for acupoint injection.
- 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 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 percentages are volume/volume percentages; when the present invention relates to the percentages between liquids and solids, the percentages are volume/volume percentages. / weight percentage; when the present invention relates to the percentage between solid and liquid, the percentage is weight/volume percentage; the rest is weight/weight percentage.
- This invention locates and selects acupoints in accordance with the acupoints specified in the National Standard of the People's Republic of China "Acupoint Names and Positioning" (GB/T 12345-2006) issued by the State Bureau of Technical Supervision.
- the clinical score uses the House-Brakmann facial nerve function grading efficacy evaluation form.
- the present invention has the following beneficial effects:
- the present invention scientifically combines marketed drugs for the treatment of acute phase facial paralysis, and adopts simultaneous administration and/or sequential administration to treat the affected side, which is beneficial to reducing edema in early stage facial paralysis, eliminating inflammation in the facial paralysis area, nourishing and repairing nerves damaged by facial paralysis. Damage myelin and axons.
- the dehydration drugs in the pharmaceutical composition are used to eliminate edema of facial paralysis in the acute phase, reduce or even eliminate facial nerve damage caused by acute edema, which is beneficial to the treatment, rehabilitation and prognosis of facial paralysis in the acute phase; the antiviral drugs are used to fight viruses and eliminate the causes of facial paralysis.
- anti-inflammatory drugs are used to remove inflammatory factors of facial paralysis, which is beneficial to the removal of inflammation and edema in facial paralysis, and is beneficial to the treatment, rehabilitation and prognosis of facial paralysis in the acute phase; nerve repair drugs and/or drugs to improve blood circulation It is used to improve blood circulation disorders caused by facial paralysis edema, viruses, inflammation, etc., and repair facial nerve damage caused by facial paralysis edema, viruses, inflammation, etc., which is beneficial to the treatment, rehabilitation and prognosis of facial paralysis in the acute phase.
- the present invention uses acupoint injection to deliver any one or a combination of nerve repair drugs, blood circulation improving drugs, neurotrophic drugs, anti-inflammatory drugs, antiviral drugs, using acupoints to achieve precise treatment and scientific treatment, improve curative effect and Reduce the incidence of sequelae, reduce medication dosage, reduce facial disability rate, significantly improve treatment efficiency and reduce or even avoid side effects. It has the characteristics of quick onset, improved recovery rate, reduced recurrence rate, reduced treatment pain, shortened treatment cycle, no adverse reactions, etc. Advantages: Reduce patient treatment burden and national medical insurance burden.
- 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;
- step (3) Add the required amount of mannitol to the cell protein extract prepared in step (3), stir, mix evenly, and freeze-dry.
- the resulting freeze-dried preparation contains 5% mannitol (m/m).
- Test Example 1 Study on the therapeutic effect of the pharmaceutical composition of the present invention for acute facial paralysis
- Group 1 60 patients in the acute phase were selected and divided into group 1 (10 patients), group 2 (40 patients), and group 3 (10 patients).
- Patient inclusion criteria Meet the diagnostic criteria of facial neuritis in traditional Chinese medicine and Western medicine. Patients are all unilateral acute onset, with obvious symptoms appearing within a few hours or 1-3 days; 20-70 years old; onset within 15 days; H-B grade above level II ; Informed consent to accept this trial; patients with good compliance, non-coma, first onset of illness or previous history of facial paralysis, but no sequelae.
- Contraindications Those with complete rupture or loss of the facial nerve; those with infection or skin damage at the injection site; those who are pregnant or breastfeeding, as it may affect the health of the fetus or baby; those who are allergic to drugs, which may cause allergic reactions or other adverse reactions; those with mental disorders or Those who are unable to cooperate with rehabilitation or corrective training.
- the treatment plan of Group 1 (7 days each, 4 courses of treatment) included oral administration and acupoint injection.
- Acupoint injection administration plan :
- the pharmaceutical composition for a single acupoint injection is composed of 30ug of mouse nerve growth factor, 0.5mg of methylcobalamin, and 200mg of vitamin B1. It is formulated into 5ml of medicinal solution for immediate use. Select the Yangbai point, temple, and four white points on the affected side of the face. Acupoint injections are performed at the acupoint, Yingxiang acupoint, Juliao acupoint, Dicang acupoint and Jieche acupoint, once a day.
- the treatment plan for the 2 groups (7 days each, 4 courses of treatment) included oral administration and acupoint injection.
- Oral prednisone acetate tablets (5 mg/time, 2 times/day, for one week), followed by oral prednisone acetate tablets (5 mg/time, once/day, for one week);
- Acupoint injection administration plan :
- the pharmaceutical composition for a single acupoint injection consists of 30ug of mouse nerve growth factor, 0.5mg of methylcobalamin, 0.5mg of adenosylcobalamin, 5mg of dexamethasone and 1ml of lidocaine hydrochloride.
- Acupoint injection is performed at Yangbai point, Taiyang point, Sibai point, Yingxiang point, Juliiao point, Dicang point and Jieche point, once a day.
- the treatment plan for the 3 groups (7 days each, 4 courses of treatment) included oral administration and acupoint injection.
- Oral prednisone acetate tablets (5 mg/time, 2 times/day, for one week), followed by oral prednisone acetate tablets (5 mg/time, once/day, for one week);
- Acupoint injection administration plan :
- the pharmaceutical composition for a single acupoint injection consists of 30ug of mouse nerve growth factor, 0.5mg of methylcobalamin, 0.5mg of adenosylcobalamin, 5mg of dexamethasone and 1ml of lidocaine hydrochloride.
- Acupoint injections are performed at the Yangbai point, temple point, Sibai point, Yingxiang point, Juliiao point, Dicang point and Jieche point on the side face, once a day.
- Group 1 It takes effect on the same day of treatment, and more than 70% of patients have significant relief of ear pain, more than 40% of patients have improved facial muscles, and their mouths are not crooked and their faces are not rigid.
- the effective rate after 7 days of treatment is 70% and the effective rate is 40%.
- the effective rate of treatment for 15 days is 80%, and the effective rate is 70%.
- the recovery rate within 30 days of treatment exceeds 80%.
- Group 2 It takes effect on the same day of treatment, and more than 80% of patients have significant relief of ear pain, and more than 50% of patients have improved facial muscles, with their mouths crooked and their faces no longer rigid.
- the effective rate after 7 days of treatment is 80% and the effective rate is 50%.
- the effective rate of treatment for 15 days is 90%, and the effect is 80%.
- the recovery rate after 30 days of treatment is over 90%, with basically no sequelae, and the satisfaction score is 100 points.
- Patients who have not recovered can basically recover after continuing to take medication for 1-3 courses based on the patient's condition and medication history. The patients followed the doctor's instructions and paid attention to reducing or even avoiding the effects of staying up late, fatigue, external infections, colds and other factors. There was basically no recurrence and the quality of life was significantly improved.
- Test Group 3 The effect is faster and the improvement effect on facial muscle stiffness is more obvious. It takes effect on the same day of treatment, and more than 90% of patients have significant relief of ear pain, and more than 60% of patients have improved facial muscles, with their mouths crooked and their faces no longer rigid.
- the effective rate after 7 days of treatment is 90% and the effective rate is 70%. 90% effective after 15 days of treatment.
- the recovery rate within 30 days of treatment was 100%, with basically no sequelae, and the satisfaction score was 100 points.
- the patients followed the doctor's instructions and paid attention to reducing or even avoiding the effects of staying up late, fatigue, external infections, colds and other factors. There was basically no recurrence and the quality of life was significantly improved.
Abstract
La présente invention concerne une composition pharmaceutique pour la prévention et le traitement de la paralysie du nerf facial en phase aiguë, la composition comprenant un médicament choisi parmi un médicament diurétique osmotique, un médicament antiviral, un médicament anti-inflammatoire, un médicament de réparation nerveuse et/ou un médicament pour améliorer la circulation sanguine ou une combinaison de ces derniers. La composition pharmaceutique de la présente invention facilite l'amélioration de l'œdème de paralysie faciale à un stade précoce, l'élimination d'une inflammation au niveau d'un site de paralysie faciale, la fourniture de nutriments à un nerf endommagé et la réparation et l'endommagement de la gaine de myéline et de l'axone, et la réalisation d'une localisation et d'une administration ciblées ; ceci améliore remarquablement un effet thérapeutique et réduit ou même élimine les effets secondaires, et possède des avantages tels qu'un déclenchement rapide, une amélioration du taux de rémission, une réduction du taux de récurrence, une réduction du dosage de médicament, un soulagement de la douleur liée au traitement, un raccourcissement de la période de traitement, et étant exempt de réactions indésirables.
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PCT/CN2023/117896 WO2024051844A1 (fr) | 2022-09-09 | 2023-09-09 | Composition pharmaceutique pour la prévention et le traitement de la paralysie du nerf facial en phase aiguë et son utilisation |
PCT/CN2023/117900 WO2024051848A1 (fr) | 2022-09-09 | 2023-09-09 | Composition pharmaceutique pour la prévention et le traitement de lésions du système nerveux et son application |
PCT/CN2023/117899 WO2024051847A1 (fr) | 2022-09-09 | 2023-09-09 | Composition pharmaceutique pour la prévention et le traitement du syndrome de micro-piégeage du nerf facial et son utilisation |
PCT/CN2023/117894 WO2024051843A1 (fr) | 2022-09-09 | 2023-09-09 | Composition pharmaceutique pour la prévention et le traitement de la paralysie du nerf facial au stade convalescent et son utilisation |
PCT/CN2023/117897 WO2024051845A1 (fr) | 2022-09-09 | 2023-09-09 | Composition pharmaceutique pour prévention et traitement des séquelles de paralysie du nerf facial, et son utilisation |
PCT/CN2023/117898 WO2024051846A1 (fr) | 2022-09-09 | 2023-09-09 | Utilisation d'un appareil radiofréquence dans le traitement de la syncinésie de paralysie faciale |
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PCT/CN2023/117899 WO2024051847A1 (fr) | 2022-09-09 | 2023-09-09 | Composition pharmaceutique pour la prévention et le traitement du syndrome de micro-piégeage du nerf facial et son utilisation |
PCT/CN2023/117894 WO2024051843A1 (fr) | 2022-09-09 | 2023-09-09 | Composition pharmaceutique pour la prévention et le traitement de la paralysie du nerf facial au stade convalescent et son utilisation |
PCT/CN2023/117897 WO2024051845A1 (fr) | 2022-09-09 | 2023-09-09 | Composition pharmaceutique pour prévention et traitement des séquelles de paralysie du nerf facial, et son utilisation |
PCT/CN2023/117898 WO2024051846A1 (fr) | 2022-09-09 | 2023-09-09 | Utilisation d'un appareil radiofréquence dans le traitement de la syncinésie de paralysie faciale |
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2023
- 2023-09-09 WO PCT/CN2023/117896 patent/WO2024051844A1/fr unknown
- 2023-09-09 CN CN202311159251.XA patent/CN117679649A/zh active Pending
- 2023-09-09 WO PCT/CN2023/117900 patent/WO2024051848A1/fr unknown
- 2023-09-09 WO PCT/CN2023/117899 patent/WO2024051847A1/fr unknown
- 2023-09-09 WO PCT/CN2023/117894 patent/WO2024051843A1/fr unknown
- 2023-09-09 CN CN202311159255.8A patent/CN117679521A/zh active Pending
- 2023-09-09 CN CN202311159241.6A patent/CN117679520A/zh active Pending
- 2023-09-09 CN CN202311159233.1A patent/CN117679518A/zh active Pending
- 2023-09-09 CN CN202311159266.6A patent/CN117679522A/zh active Pending
- 2023-09-09 WO PCT/CN2023/117897 patent/WO2024051845A1/fr unknown
- 2023-09-09 CN CN202311159238.4A patent/CN117679519A/zh active Pending
- 2023-09-09 WO PCT/CN2023/117898 patent/WO2024051846A1/fr unknown
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CN102988403A (zh) * | 2012-12-06 | 2013-03-27 | 祁建春 | 用于治疗急性期面瘫的注射药物组合 |
CN113082043A (zh) * | 2021-04-20 | 2021-07-09 | 王化兰 | 一种中医穴位注射治疗面神经麻痹的药物 |
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ERHU LI: "Yiqi Tongluo Tang(益气通络汤)Combined with Western Treatment Facial Paralysis Randomized Controlled Study", JOURNAL OF PRACTICAL TRADITIONAL CHINESE INTERNAL MEDICINE, vol. 30, no. 10, 14 November 2016 (2016-11-14), pages 47 - 48, XP093148390, DOI: 10.13729/j.issn.1671-7813.2016.10.21 * |
GUAN-WEN SHANG: "Clinical Therapeutic Effect of Traditional Chinese and Western medicine on Therapy in 42 Patients with Acute Idiopathic Facial Paralysis", LIAONING JOURNAL OF TRADITIONAL CHINESE MEDICINE, vol. 36, no. 6, 18 June 2009 (2009-06-18), pages 992, XP093148383, DOI: 10.13192/j.ljtcm.2009.06.131.shanggw.090 * |
JING ZHAO, XU XIAOSHUANG; YAN YAN: "Advances in Research on Acupoint Injection in the Treatment of Idiopathic Nerve Palsy", JOURNAL OF LIAONING UNIVERSITY OF TRADITIONAL CHINESE MEDICINE, vol. 22, no. 8, 15 May 2020 (2020-05-15), pages 158 - 161, XP093148377, DOI: 10.13194/j.issn.1673-842x.2020.08.038 * |
WANGZHANG YANG: "Diagnosis, Evaluation, and Stage and grade-based Treatment for Peripheral Facial Paralysis", CHINESE JOURNAL OF INTEGRATIVE MEDICINE ON CARDIO-/CEREBROVASCULAR DISEASE, vol. 15, no. 3, 10 February 2017 (2017-02-10), pages 257 - 263, XP093148379 * |
Also Published As
Publication number | Publication date |
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CN117679522A (zh) | 2024-03-12 |
CN117679521A (zh) | 2024-03-12 |
WO2024051843A1 (fr) | 2024-03-14 |
WO2024051845A1 (fr) | 2024-03-14 |
WO2024051846A1 (fr) | 2024-03-14 |
CN117679649A (zh) | 2024-03-12 |
CN117679520A (zh) | 2024-03-12 |
WO2024051848A1 (fr) | 2024-03-14 |
CN117679519A (zh) | 2024-03-12 |
WO2024051847A1 (fr) | 2024-03-14 |
CN117679518A (zh) | 2024-03-12 |
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