Application of 6 '-O-caffeoyl arbutin in preparation of medicine for treating dementia

Abstract

The invention relates to application of 6 '-O-caffeoyl arbutin in preparation of a medicine for treating dementia, and belongs to the technical field of biological medicine. The 6 '-O-caffeoyl arbutin disclosed by the invention has a remarkable dementia treatment value, the action mechanism accurately fits the core pathological process of dementia, a neuroprotective effect is played by relieving oxidative stress and inhibiting inflammatory reaction, oxidative stress related indexes such as superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) can be effectively adjusted, and the dementia treatment effect is improved. The release of lactic dehydrogenase (LDH) and malondialdehyde (MDA) and the level of damage-induced nitric oxide synthase (I NOS) are reduced, so that the NMDA-induced PC12 cell damage is protected.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of biological medicine, and particularly relates to application of 6'-O-coffeoyl arbutin in preparation of a medicine for treating dementia. BACKGROUND

[0002] Dementia is a syndrome characterized by progressive cognitive decline and impairment of daily life ability, and is related to multiple pathological mechanisms such as mitochondrial dysfunction, abnormal aggregation of alpha-synuclein, inflammatory response and nerve cell damage, and seriously affects the quality of life of patients. At present, the core drugs for treating dementia in the clinic are mainly symptomatic treatment, mainly including cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists, which are the mainstream drug regimen for treating dementia at the present stage.

[0003] 6'-O-coffeoyl arbutin is a natural polyphenolic compound with anti-inflammatory and antioxidant activity. At present, the research on this compound is mainly concentrated in the fields of cosmetics and medicine. In the field of cosmetics, it is mainly used in the research and development of whitening and anti-aging related products. The research direction in the field of medicine is mainly liver protection, uric acid reduction, improvement of atopic dermatitis, etc. At present, there is no related report on the treatment of dementia by 6'-O-coffeoyl arbutin. SUMMARY

[0004] The purpose of the present application is to provide a new drug application scheme for treating dementia in view of the current situation that the clinical treatment of dementia in the prior art relies on cholinesterase inhibitors and NMDA receptor antagonists. To this end, the present application provides application of 6'-O-coffeoyl arbutin in preparation of a medicine for treating dementia.

[0005] The present application provides application of 6'-O-coffeoyl arbutin in preparation of a medicine for treating dementia, and the chemical structural formula of the 6'-O-coffeoyl arbutin is shown as formula 1. Formula 1.

[0006] Preferably, the treatment of dementia includes improvement of cognitive dysfunction. The dementia includes Parkinson dementia or Alzheimer's disease.

[0007] Preferably, the cause of the dementia includes abnormal aggregation of alpha-synuclein. The medicine achieves the treatment of dementia by inhibiting the release of pro-inflammatory factors and repairing cell damage of activated microglia cells. The repairing of cell damage includes repairing at least one damage of neurons, astrocytes and oligodendrocytes.

[0008] The application also provides a use of 6'-O-caffeoyl arbutin in the preparation of a drug for treating Parkinson's disease, wherein a chemical structural formula of the 6'-O-caffeoyl arbutin is shown as formula 1.

[0009] Preferably, the Parkinson's disease includes Parkinson's dementia.

[0010] Preferably, the drug comprises 6'-O-caffeoyl arbutin and a pharmaceutically acceptable adjuvant; The 6'-O-caffeoyl arbutin has a weight percentage content of 0.9% to 99% in the drug.

[0011] Preferably, the pharmaceutically acceptable adjuvant comprises a lipophilic solubilizing adjuvant or a water-soluble solubilizing adjuvant.

[0012] Preferably, the lipophilic solubilizing adjuvant comprises one or more of soybean oil, corn oil, medium-chain triglyceride, glycerol monooleate, glycerol monolinoleate, caprylic capric acid monodiglyceride, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer, poloxamer, polyethylene glycol 400, polyethylene glycol 1000, and polyethylene glycol 4000. The water-soluble solubilizing adjuvant comprises one or more of polyvinylpyrrolidone K12, polyvinylpyrrolidone K15, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, polyvinylpyrrolidone K90, polyethylene glycol 400, polyethylene glycol 4000, sulfobutyl betadex sodium, and hydroxypropyl betadex.

[0013] Preferably, the dosage form of the drug comprises an oral dosage form, an injection dosage form, a mucosal administration dosage form, a cavity administration dosage form, or a topical dosage form. The oral dosage form comprises a powder, a tablet, a granule, a capsule, a solution, an emulsion, or a suspension. The injection dosage form comprises an injection solution or a sterile powder for injection. The mucosal administration dosage form comprises eye drops, nose drops, an eye ointment, a gargle, a sublingual tablet, a sticking tablet, or a film patch. The cavity administration dosage form comprises an aerosol, a spray, a powder spray, drops, or drop pills. The cavity comprises a respiratory tract. The topical dosage form comprises a gel.

[0014] Preferably, when the drug is an oral dosage form, the pharmaceutically acceptable adjuvant comprises a lipophilic solubilizing adjuvant. When the drug is an injection dosage form, the pharmaceutically acceptable adjuvant comprises a water-soluble solubilizing adjuvant. The water-soluble solubilizing adjuvant includes polyethylene glycol 400 and polyvinylpyrrolidone K12.

[0015] Advantages: The application provides application of 6'-O-coffeoyl arbutin in preparation of a medicine for treating dementia, and a chemical structural formula of the 6'-O-coffeoyl arbutin is shown in formula 1. The 6'-O-coffeoyl arbutin has significant therapeutic value for dementia, a mechanism of action thereof is accurate and consistent with a core pathological process of dementia, the 6'-O-coffeoyl arbutin plays a neuroprotective role by reducing oxidative stress and inhibiting inflammatory reactions, can effectively regulate oxidative stress-related indexes such as superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), reduces release of lactate dehydrogenase (LDH) and malondialdehyde (MDA) and a level of injury-induced nitric oxide synthase (INOS), thereby protecting NMDA-induced PC12 cell damage, and is different from an existing mode of action of simply relieving symptoms, and can more intervene in disease progression from a pathological aspect. It is verified through examples of the application that the 6'-O-coffeoyl arbutin can significantly improve spatial cognitive ability and memory function of a MPTP-induced Parkinson model mouse, relieve movement and emotional abnormalities of the mouse, effectively adjust escape latency, target quadrant residence time and platform crossing times of a scopolamine-induced dementia model mouse, comprehensively improve spatial memory and behavioral ability of the model animal, and has clear and comprehensive treatment effect, and has more application advantages and popularization value compared with existing therapeutic drugs. BRIEF DESCRIPTION OF DRAWINGS

[0016] In order to more clearly illustrate the technical solutions in the embodiments of the application or the prior art, the following will briefly introduce the drawings needed to be used in the embodiments.

[0017] Figure 1 is a result graph of inflammation detection of 6'-O-coffeoyl arbutin on LPS-induced BV2 cell damage; wherein, Figure 1 CA in the figure is a 6'-O-coffeoyl arbutin treatment group; Figure 1 A in the figure is interleukin-1 β ( Il-1β ) result graph, Figure 1 B in the figure is interleukin-6 Il-6 ) result graph, Figure 1 C in the figure is tumor necrosis factor-α Tnf-α ) result graph, Figure 1 D in the figure is inducible nitric oxide synthase I nos ) result graph; meanings of significance marks in the figure are as follows: compared with a blank control group, # represents P<0.05, ## represents P<0.01, compared with a model control group, P<0.05, P < 0.01; Figure 2 Fig. I is a graph of oxidative index and inflammation detection results of 6'-O-caffeoyl arbutin on NMDA-induced PC12 cell damage; wherein, Control is a blank control group, NMDA-2 mM is a model control group, and CA is a 6'-O-caffeoyl arbutin treatment group; Figure 2 A in Fig. is a glutathione detection result graph, Figure 2 B in Fig. is a superoxide dismutase detection result graph, Figure 2 C in Fig. is a malondialdehyde detection result graph, Figure 2 D in Fig. is a catalase detection result graph; the significance indicators in the graph have the following meanings: # represents P < 0.05, and ## represents P < 0.01 compared with the blank control group, and P < 0.05, P < 0.01; Figure 3 Fig. II is a graph of oxidative index and inflammation detection results of 6'-O-caffeoyl arbutin on NMDA-induced PC12 cell damage; wherein, Control is a blank control group, NMDA-2 mM is a model control group, and CA is a 6'-O-caffeoyl arbutin treatment group; Figure 2 A in Fig. is a lactate dehydrogenase detection result graph, Figure 2 B in Fig. is a nitric oxide detection result graph, Figure 2 C in Fig. is a total nitric oxide synthase detection result graph, Figure 2 D in Fig. is an injury-induced nitric oxide synthase detection result graph; the significance indicators in the graph have the following meanings: # represents P < 0.05, and ## represents P < 0.01 compared with the blank control group, and P < 0.05, P < 0.01; Figure 4 Fig. is a graph of spatial cognitive and memory capacity detection results of 6'-O-caffeoyl arbutin on MPTP-induced Parkinson's model mice; Figure 4 CA in Fig. is a 6'-O-caffeoyl arbutin treatment group; Figure 4 A in Fig. is a Y maze trajectory graph, Figure 4 B in Fig. is a Y maze new and different arm exploration distance statistical graph, Figure 4 C in Fig. is a Y maze new and different arm exploration frequency statistical graph, Figure 4 D in Fig. is a Y maze new and different arm visit time statistical graph, Figure 4 E in Fig. is a new object recognition index statistical graph, Figure 4 F in Fig. is a new object recognition index trajectory graph, Figure 4G in the figure is the track graph of the open field experiment, Figure 4 H in the figure is the total distance statistics graph of the open field, Figure 4 I in the figure is the total average moving speed statistics graph of the open field, Figure 4 J in the figure is the central region access time statistics graph of the open field, Figure 4 K in the figure is the central region access frequency statistics graph of the open field; the significance identification in the figure has the following meanings: compared with the blank control group, # represents P<0.05, ## represents P<0.01, compared with the model control group, represents P<0.05, represents P<0.01; Figure 5 is the detection result graph of the memory ability of 6'-O-caffeoyl arbutin on the scopolamine-induced dementia model mice; wherein, Figure 5 CA in the figure is the 6'-O-caffeoyl arbutin treatment group; Figure 5 A in the figure is the latency extension statistics graph of escape, Figure 5 B in the figure is the time statistics graph of staying in the target quadrant, Figure 5 C in the figure is the number of times of crossing the platform; the significance identification in the figure has the following meanings: compared with the blank control group, # represents P<0.05, ## represents P<0.01, compared with the model control group, represents P<0.05, represents P<0.01. DETAILED DESCRIPTION

[0018] The application provides application of 6'-O-caffeoyl arbutin in preparation of a medicine for treating dementia, and a chemical structural formula of the 6'-O-caffeoyl arbutin is shown as formula 1. , formula 1.

[0019] As an embodiment, the 6'-O-coffeoyl arbutin has significant therapeutic value for dementia, the mechanism of action is precisely matched with the core pathological process of dementia, and the neuroprotective effect is achieved by reducing oxidative stress and inhibiting inflammatory response. The 6'-O-coffeoyl arbutin can effectively regulate oxidative stress-related indicators such as superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), reduce the release of lactate dehydrogenase (LDH) and malondialdehyde (MDA), and lower the level of inducible nitric oxide synthase (INOS), thereby protecting NMDA-induced PC12 cell damage. Unlike the existing drugs that only have a symptomatic relief mode of action, the 6'-O-coffeoyl arbutin can intervene in the disease progression from a pathological level. As an embodiment, the 6'-O-coffeoyl arbutin and the modeling agent NMDA are tested for their non-inhibitory effect on PC12 cells by MTT method, and then the relevant indicators are detected. It is found that the 6'-O-coffeoyl arbutin protects NMDA-induced PC12 cell damage by reducing oxidative stress and inflammation.

[0020] As an embodiment, the treatment of dementia includes improving cognitive dysfunction. The dementia includes Parkinson's dementia or Alzheimer's disease. As an embodiment, the cognitive dysfunction includes cognitive dysfunction caused by Parkinson's disease and / or Alzheimer's disease. As an embodiment, the improvement of cognitive dysfunction includes the improvement of spatial cognitive ability, new object recognition memory function, spatial memory ability, and behavioral ability, as well as the relief of movement and emotional abnormalities. As an embodiment, the 6'-O-coffeoyl arbutin has a significant improvement effect on spatial cognition, memory function, movement, and emotional abnormalities of model mice after 13 days of continuous intravenous injection or 60 days of oral administration.

[0021] As an embodiment, the cause of dementia includes abnormal aggregation of alpha-synuclein. The drug achieves the treatment of dementia by inhibiting the release of pro-inflammatory factors by microglial cell activation and repairing cell damage. The repairing of cell damage includes repairing at least one damage in neurons, astrocytes, and oligodendrocytes.

[0022] As an embodiment, the 6'-O-caffeoyl arbutin of the present application can effectively protect the lipopolysaccharide-induced BV2 cell (an in vitro model of glial cells) damage by regulating the expression of inflammation-related genes. As an embodiment, the inflammation-related genes include at least one of interleukin-1β (Il-1β) gene, interleukin-6 (Il-6) gene, tumor necrosis factor-α (Tnf-α) gene and inducible nitric oxide synthase (iNOS) gene. As an embodiment, the 6'-O-caffeoyl arbutin of the present application can effectively protect the NMDA-induced PC12 cell (an in vitro model of neurons) damage by regulating the oxidative stress and inflammation-related indicators. As an embodiment, the oxidative stress and inflammation-related indicators include at least one of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), lactate dehydrogenase (LDH), malondialdehyde (MDA), total nitric oxide synthase (T NOS) and inducible nitric oxide synthase (I NOS).

[0023] The present application also provides the use of 6'-O-caffeoyl arbutin in the preparation of a medicament for treating Parkinson's disease, wherein the chemical structure of the 6'-O-caffeoyl arbutin is shown as Formula 1.

[0024] As an embodiment, the Parkinson's disease of the present application includes Parkinson's dementia. As an embodiment, the Parkinson's dementia of the present application is treated by improving cognitive dysfunction. As an embodiment, the improvement of cognitive dysfunction of the present application includes the improvement of spatial cognitive ability, new object recognition memory function, spatial memory ability and behavior ability, and the alleviation of movement and emotional abnormalities. As an embodiment, the 6'-O-caffeoyl arbutin of the present application can significantly improve the spatial cognitive ability and memory function of MPTP-induced Parkinson's model mice, alleviate their movement and emotional abnormalities, effectively adjust the escape latency, target quadrant residence time and platform crossing frequency of scopolamine-induced dementia model mice, and comprehensively improve the spatial memory and behavior ability of the model animals, so that the treatment effect is clear and comprehensive, and the application advantage and popularization value are higher than those of the existing treatment drugs.

[0025] As an embodiment, the weight percentage content of the 6'-O-caffeoyl arbutin of the present application in the medicament is greater than 0 and less than or equal to 100% of any value. As an embodiment, the medicament of the present application comprises 6'-O-caffeoyl arbutin and a pharmaceutically acceptable excipient; the weight percentage content of the 6'-O-caffeoyl arbutin in the medicament is 0.9% to 99%.

[0026] As an embodiment, the pharmaceutically acceptable adjuvant of the present application comprises a lipophilic solubilizing adjuvant or a water-soluble solubilizing adjuvant. As an embodiment, the lipophilic solubilizing adjuvant or the water-soluble solubilizing adjuvant of the present application can significantly improve the solubility of 6'-O-caffeoyl arbutin in the preparation, which is significantly improved from 0.2 mg / mL without using the solubilizing adjuvant to 2.2 mg / mL-545 mg / mL.

[0027] As an embodiment, the lipophilic solubilizing adjuvant of the present application comprises one or more of soybean oil, corn oil, medium-chain triglyceride, glyceryl monooleate, glyceryl monolinoleate, caprylic capric acid monoditriglyceride, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer, poloxamer, polyethylene glycol 400, polyethylene glycol 1000, and polyethylene glycol 4000; and the water-soluble solubilizing adjuvant comprises one or more of polyvinylpyrrolidone K12, polyvinylpyrrolidone K15, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, polyvinylpyrrolidone K90, polyethylene glycol 400, polyethylene glycol 4000, sulfobutyl betadex sodium, and hydroxypropyl betadex. As an embodiment, the polyoxyethylene hydrogenated castor oil of the present application includes but is not limited to polyoxyethylene (40) hydrogenated castor oil. As an embodiment, the polyoxyethylene castor oil of the present application includes but is not limited to polyoxyethylene (35) castor oil. As an embodiment, the polyethylene glycol 400 of the present application improves the solubility of the drug by changing the polarity of the solvent system. The polyvinylpyrrolidone K12 of the present application, as a high molecular polymer, mainly plays a role by forming a soluble complex with drug molecules or inhibiting crystallization. The combined use of the two can achieve a synergistic solubilizing effect, and reduce the use amount to achieve the solubilizing effect of individual use.

[0028] As an embodiment, the dosage form of the drug of the present application comprises an oral dosage form, an injection dosage form, a mucosal administration dosage form, a cavity administration dosage form, or a topical dosage form. The oral dosage form comprises a powder, a tablet, a granule, a capsule, a solution, an emulsion, or a suspension. The injection dosage form comprises an injection solution or a sterile powder for injection. The mucosal administration dosage form comprises eye drops, nose drops, eye ointment, gargle, sublingual tablets, adhesive tablets, or film patches. The cavity administration dosage form comprises an aerosol, a spray, a powder mist, drops, or drop pills. The cavity comprises the respiratory tract. The topical dosage form comprises a gel. The tablet comprises an effervescent tablet.

[0029] As an embodiment, the capsule includes a self-emulsifying microemulsion soft capsule. As an embodiment, the self-emulsifying microemulsion soft capsule is prepared by mixing an oil phase and an aqueous phase. As an embodiment, the oil phase of the present application includes, but is not limited to, one or more of medium-chain triglycerides, glycerol monooleate, soybean oil, corn oil, caprylic capric acid monodiglyceride, and glycerol monolinoleate. As an embodiment, the aqueous phase of the present application includes, but is not limited to, one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, and water. As an embodiment, the 6'-O-caffeoyl arbutin of the present application is added after mixing the oil phase and the aqueous phase, or is dissolved in one of the phases and then mixed.

[0030] As an embodiment, the emulsion includes a self-emulsifying microemulsion oral solution. As an embodiment, the self-emulsifying microemulsion oral solution is prepared by mixing an oil phase and an aqueous phase. As an embodiment, the oil phase of the present application includes, but is not limited to, one or more of medium-chain triglycerides, caprylic capric acid monodiglyceride, and glycerol monolinoleate. As an embodiment, the aqueous phase of the present application includes, but is not limited to, one or more of polyoxyethylene hydrogenated castor oil, 96% volume concentration aqueous ethanol solution, and anhydrous ethanol. As an embodiment, the 6'-O-caffeoyl arbutin of the present application is added after mixing the oil phase and the aqueous phase, or is dissolved in one of the phases and then mixed.

[0031] As an embodiment, the administration mode of the injection form of the present application includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, or intracavitary injection.

[0032] As an embodiment, the present application promotes the dissolution of 6'-O-caffeoyl arbutin by the lipophilic solubilizing adjuvant or the water-soluble solubilizing adjuvant.

[0033] As an embodiment, when the drug is in the form of an oral dosage form, the pharmaceutically acceptable adjuvant includes a lipophilic solubilizing adjuvant; When the drug is in the form of an injection, the pharmaceutically acceptable adjuvant includes a water-soluble solubilizing adjuvant; The water-soluble solubilizing adjuvant includes polyethylene glycol 400 and polyvinylpyrrolidone K12.

[0034] As an embodiment, when the drug is in the form of an oral dosage form, the present application constructs a high-oil-content lipid system using a lipophilic solubilizing adjuvant, or prepares 6'-O-caffeoyl arbutin into an amorphous solid dispersion or a micellar system using a polyethylene glycol solvent; As an embodiment, when the drug is in the form of an injection, the present application uses a water-soluble solubilizing adjuvant to solubilize by inclusion, micelles, or formation of soluble complexes; the water-soluble solubilizing adjuvant includes polyethylene glycol 400 and polyvinylpyrrolidone K12.

[0035] As an embodiment, when the dosage form of the drug is a self-emulsifying microemulsion soft capsule, the drug of the present application can be composed of 6'-O-caffeoyl arbutin, medium-chain triglyceride, glycerol monooleate, polyoxyethylene (40) hydrogenated castor oil, and water; the mass ratio of the 6'-O-caffeoyl arbutin, medium-chain triglyceride, glycerol monooleate, polyoxyethylene (40) hydrogenated castor oil, and water can be 1:10:12:67:10.

[0036] As an embodiment, when the dosage form of the drug is a self-emulsifying microemulsion soft capsule, the drug of the present application can be composed of 6'-O-caffeoyl arbutin, medium-chain triglyceride, glycerol monooleate, polyoxyethylene (40) hydrogenated castor oil, and water; the mass ratio of the 6'-O-caffeoyl arbutin, medium-chain triglyceride, glycerol monooleate, polyoxyethylene (40) hydrogenated castor oil, and water can be 15:12:12:51:10.

[0037] As an embodiment, when the dosage form of the drug is a self-emulsifying microemulsion soft capsule, the drug of the present application can be composed of 6'-O-caffeoyl arbutin, medium-chain triglyceride, glycerol monooleate, polyoxyethylene (40) hydrogenated castor oil, and water; the mass ratio of the 6'-O-caffeoyl arbutin, medium-chain triglyceride, glycerol monooleate, polyoxyethylene (40) hydrogenated castor oil, and water can be 20:12:12:46:10.

[0038] As an embodiment, when the dosage form of the drug is a self-emulsifying microemulsion soft capsule, the drug of the present application can be composed of 6'-O-caffeoyl arbutin, medium-chain triglyceride, glycerol monooleate, polyoxyethylene (40) hydrogenated castor oil, and water; the mass ratio of the 6'-O-caffeoyl arbutin, medium-chain triglyceride, glycerol monooleate, polyoxyethylene (40) hydrogenated castor oil, and water can be 40:12:12:40:10.

[0039] As an embodiment, when the dosage form of the drug is a self-emulsifying microemulsion soft capsule, the drug of the present application can be composed of 6'-O-caffeoyl arbutin, medium-chain triglyceride, glycerol monooleate, polyoxyethylene (35) castor oil, and water; the mass ratio of the 6'-O-caffeoyl arbutin, medium-chain triglyceride, glycerol monooleate, polyoxyethylene (35) castor oil, and water can be 90:10:12:68:10.

[0040] As an implementation form, when the dosage form of the medicine is a self-emulsifying microemulsion soft capsule, the medicine of the present application can be composed of 6'-O-caffeoyl arbutin, soybean oil (refined), glycerol monooleate, polyoxyethylene hydrogenated castor oil and water; the mass ratio of the 6'-O-caffeoyl arbutin, soybean oil (refined), glycerol monooleate, polyoxyethylene hydrogenated castor oil and water can be 50:10:12:68:10.

[0041] As an implementation form, when the dosage form of the medicine is a self-emulsifying microemulsion soft capsule, the medicine of the present application can be composed of 6'-O-caffeoyl arbutin, corn oil, glycerol monooleate, polyoxyethylene hydrogenated castor oil and water; the mass ratio of the 6'-O-caffeoyl arbutin, corn oil, glycerol monooleate, polyoxyethylene hydrogenated castor oil and water can be 50:10:12:68:10.

[0042] As an implementation form, when the dosage form of the medicine is a self-emulsifying microemulsion soft capsule, the medicine of the present application can be composed of 6'-O-caffeoyl arbutin, corn oil, glycerol monooleate, polyoxyethylene hydrogenated castor oil and water; the mass ratio of the 6'-O-caffeoyl arbutin, corn oil, glycerol monooleate, polyoxyethylene hydrogenated castor oil and water can be 50:10:12:68:10.

[0043] As an implementation form, when the dosage form of the medicine is a self-emulsifying microemulsion soft capsule, the medicine of the present application can be composed of 6'-O-caffeoyl arbutin, corn oil, glycerol monooleate, polyoxyethylene hydrogenated castor oil and water; the mass ratio of the 6'-O-caffeoyl arbutin, corn oil, glycerol monooleate, polyoxyethylene hydrogenated castor oil and water can be 50:10:12:68:10.

[0044] As an implementation form, when the dosage form of the medicine is a self-emulsifying microemulsion soft capsule, the medicine of the present application can be composed of 6'-O-caffeoyl arbutin, corn oil, glycerol monooleate, polyoxyethylene hydrogenated castor oil and water; the mass ratio of the 6'-O-caffeoyl arbutin, corn oil, glycerol monooleate, polyoxyethylene hydrogenated castor oil and water can be 50:10:12:68:10.

[0045] As an embodiment, when the dosage form of the drug of the present application is a tablet, the drug of the present application can consist of 6'-O-caffeoyl arbutin, lactose, copovidone, crospovidone, and sodium stearyl fumarate; and the mass ratio of the 6'-O-caffeoyl arbutin, lactose, copovidone, crospovidone, and sodium stearyl fumarate can be 200:438:292:50:20.

[0046] As an embodiment, when the dosage form of the drug of the present application is a tablet, the drug of the present application can consist of 6'-O-caffeoyl arbutin, lactose, copovidone, crospovidone, and sodium stearyl fumarate; and the mass ratio of the 6'-O-caffeoyl arbutin, lactose, copovidone, crospovidone, and sodium stearyl fumarate can be 200:438:292:50:20.

[0047] As an embodiment, when the dosage form of the drug of the present application is a tablet, the drug of the present application can consist of 6'-O-caffeoyl arbutin, lactose, copovidone, crospovidone, and sodium stearyl fumarate; and the mass ratio of the 6'-O-caffeoyl arbutin, lactose, copovidone, crospovidone, and sodium stearyl fumarate can be 200:438:292:50:20.

[0048] As an embodiment, when the dosage form of the drug of the present application is a tablet, the drug of the present application can consist of 6'-O-caffeoyl arbutin, lactose, copovidone, crospovidone, and sodium stearyl fumarate; and the mass ratio of the 6'-O-caffeoyl arbutin, lactose, copovidone, crospovidone, and sodium stearyl fumarate can be 200:438:292:50:20.

[0049] As an embodiment, when the dosage form of the drug of the present application is a tablet, the drug of the present application can consist of 6'-O-caffeoyl arbutin, lactose, copovidone, crospovidone, and sodium stearyl fumarate; and the mass ratio of the 6'-O-caffeoyl arbutin, lactose, copovidone, crospovidone, and sodium stearyl fumarate can be 200:438:292:50:20.

[0050] As an embodiment, when the dosage form of the drug of the present application is a tablet of a cyclodextrin inclusion compound, the drug of the present application can be composed of 6'-O-caffeoyl arbutin, sulfobutyl betadex sodium, corn starch, sodium carboxymethyl cellulose, sodium carboxymethyl starch, and magnesium stearate; and the mass ratio of the 6'-O-caffeoyl arbutin, sulfobutyl betadex sodium, corn starch, sodium carboxymethyl cellulose, sodium carboxymethyl starch, and magnesium stearate can be 1:6:60:20:10:9.

[0051] As an embodiment, when the dosage form of the drug of the present application is a tablet of a cyclodextrin inclusion compound, the drug of the present application can be composed of 6'-O-caffeoyl arbutin, sulfobutyl betadex sodium, corn starch, sodium carboxymethyl cellulose, sodium carboxymethyl starch, and magnesium stearate; and the mass ratio of the 6'-O-caffeoyl arbutin, sulfobutyl betadex sodium, corn starch, sodium carboxymethyl cellulose, sodium carboxymethyl starch, and magnesium stearate can be 1:6:60:20:10:9.

[0052] As an embodiment, when the dosage form of the drug of the present application is an eye drop or a nose drop, the drug of the present application can be composed of 6'-O-caffeoyl arbutin, polyethylene glycol 400, sodium carboxymethyl cellulose, and water; and the mass ratio of the 6'-O-caffeoyl arbutin, polyethylene glycol 400, sodium carboxymethyl cellulose, and water can be 0.2:1:0.5:10.

[0053] As an embodiment, when the dosage form of the drug of the present application is an eye drop or a nose drop, the drug of the present application can be composed of 6'-O-caffeoyl arbutin, polyethylene glycol 400, sodium carboxymethyl cellulose, and water; and the mass ratio of the 6'-O-caffeoyl arbutin, polyethylene glycol 400, sodium carboxymethyl cellulose, and water can be 0.2:1:0.5:10.

[0054] As an embodiment, when the dosage form of the drug of the present application is an eye drop or a nose drop, the drug of the present application can be composed of 6'-O-caffeoyl arbutin, polyethylene glycol 400, sodium carboxymethyl cellulose, and water; and the mass ratio of the 6'-O-caffeoyl arbutin, polyethylene glycol 400, sodium carboxymethyl cellulose, and water can be 0.2:1:0.5:10.

[0055] As an embodiment, when the dosage form of the drug of the present application is an eye drop or a nose drop, the drug of the present application can be composed of 6'-O-caffeoyl arbutin, polyethylene glycol 400, sodium carboxymethyl cellulose, and water; and the mass ratio of the 6'-O-caffeoyl arbutin, polyethylene glycol 400, sodium carboxymethyl cellulose, and water can be 0.2:1:0.5:10.

[0056] As an embodiment, when the dosage form of the drug of the present application is an eye drop or a nose drop, the drug of the present application can consist of 6'-O-caffeoyl arbutin, hydroxypropyl betadex, sodium carboxymethyl cellulose, and water; and the mass ratio of the 6'-O-caffeoyl arbutin, hydroxypropyl betadex, sodium carboxymethyl cellulose, and water can be 0.2:1:0.5:10.

[0057] As an embodiment, when the dosage form of the drug of the present application is a powder, the drug of the present application can consist of 6'-O-caffeoyl arbutin and dextrin; and the mass ratio of the 6'-O-caffeoyl arbutin and dextrin can be 99:1.

[0058] As an embodiment, when the dosage form of the drug of the present application is a granule, the drug of the present application can consist of 6'-O-caffeoyl arbutin, sucrose powder, sodium carboxymethyl cellulose, and talc; and the mass ratio of the 6'-O-caffeoyl arbutin, sucrose powder, sodium carboxymethyl cellulose, and talc can be 20:40:12:15.

[0059] As an embodiment, when the dosage form of the drug of the present application is a hard capsule, the drug of the present application can consist of 6'-O-caffeoyl arbutin and corn starch; and the mass ratio of the 6'-O-caffeoyl arbutin and corn starch can be 88:12.

[0060] As an embodiment, when the dosage form of the drug of the present application is a sublingual tablet, the drug of the present application can consist of 6'-O-caffeoyl arbutin, polyvinylpyrrolidone K30, poloxamer 188, citric acid, and saccharin sodium; and the mass ratio of the 6'-O-caffeoyl arbutin, polyvinylpyrrolidone K30, poloxamer 188, citric acid, and saccharin sodium can be 15:70:3:2:10.

[0061] As an embodiment, when the dosage form of the drug of the present application is a sublingual tablet, the drug of the present application, per 100 mg of a tablet, can consist of 6'-O-caffeoyl arbutin, gelatin, mannitol, sodium deoxycholate, aspartame, and peppermint flavor; and the mass ratio of the 6'-O-caffeoyl arbutin, gelatin, mannitol, sodium deoxycholate, aspartame, and peppermint flavor can be 10:50:30:2:1:0.5, and an appropriate amount of purified water is contained.

[0062] As an embodiment, when the dosage form of the medicine of the present application is injection, the medicine of the present application can be composed of 6'-O-caffeoyl arbutin, polyethylene glycol 400, mannitol, sodium citrate buffer salt and water for injection, per 2 mL; the mass ratio of the 6'-O-caffeoyl arbutin, polyethylene glycol 400 and mannitol is 50:400:100, and the sodium citrate buffer salt is contained in an appropriate amount, and the water for injection is added to 4.0 mL.

[0063] As an embodiment, when the dosage form of the medicine of the present application is injection, the medicine of the present application can be composed of 6'-O-caffeoyl arbutin and polyethylene glycol 4000, per bottle; the mass ratio of the 6'-O-caffeoyl arbutin and polyethylene glycol 4000 can be 100:400.

[0064] As an embodiment, when the dosage form of the medicine of the present application is injection, the medicine of the present application can be composed of 6'-O-caffeoyl arbutin, polyethylene glycol 4000, an isotonicity adjusting agent, an antioxidant, a pH adjusting agent and water for injection, per bottle; the mass ratio of the 6'-O-caffeoyl arbutin and polyethylene glycol 4000 is 20:200, and the isotonicity adjusting agent, the antioxidant and the pH adjusting agent are contained in an appropriate amount, and the water for injection is 2 mL.

[0065] As an embodiment, when the dosage form of the medicine of the present application is injection, the medicine of the present application can be composed of 6'-O-caffeoyl arbutin, polyethylene glycol 400, polyvinylpyrrolidone K12, polyvinylpyrrolidone K15, polyvinylpyrrolidone K17, sodium citrate buffer salt and water for injection, per 2 mL; the mass ratio of the 6'-O-caffeoyl arbutin, polyethylene glycol 400 and polyvinylpyrrolidone (K12 or K15 or K17) is 50:200:20, and the sodium citrate buffer salt is contained in an appropriate amount, and the water for injection is added to 2.0 mL.

[0066] As an embodiment, when the dosage form of the medicine of the present application is injection, the medicine of the present application can be composed of 6'-O-caffeoyl arbutin, polyethylene glycol 400, polyvinylpyrrolidone (K12 or K15 or K17), sodium citrate buffer salt and water for injection, per 2 mL; the mass ratio of the 6'-O-caffeoyl arbutin, polyethylene glycol 400 and polyvinylpyrrolidone (K12 or K15 or K17) is 50:100:40, and the sodium citrate buffer salt is contained in an appropriate amount, and the water for injection is added to 2.0 mL.

[0067] As an embodiment, when the dosage form of the medicine according to the present application is an injection, the medicine according to the present application can be composed of 6'-O-caffeoyl arbutin, polyethylene glycol 4000, polyvinylpyrrolidone (K12 or K15 or K17), sodium citrate buffer salt, and water for injection, in the amount of 2 mL per vial, wherein the mass ratio of the 6'-O-caffeoyl arbutin, polyethylene glycol 4000, and polyvinylpyrrolidone (K12 or K15 or K17) is 50:90:60, and the sodium citrate buffer salt is contained in an appropriate amount, and the water for injection is added to 2.0 mL.

[0068] As an embodiment, when the dosage form of the medicine according to the present application is an injection, the medicine according to the present application can be composed of 6'-O-caffeoyl arbutin, polyethylene glycol 4000, polyvinylpyrrolidone (K12 or K15 or K17), sodium citrate buffer salt, and water for injection, in the amount of 2 mL per vial, wherein the mass ratio of the 6'-O-caffeoyl arbutin, polyethylene glycol 4000, and polyvinylpyrrolidone (K12 or K15 or K17) is 50:90:60, and the sodium citrate buffer salt is contained in an appropriate amount, and the water for injection is added to 2.0 mL.

[0069] As an embodiment, when the dosage form of the medicine according to the present application is an injection, the medicine according to the present application can be composed of 6'-O-caffeoyl arbutin, polyethylene glycol 4000, polyvinylpyrrolidone (K12 or K15 or K17), sodium citrate buffer salt, and water for injection, in the amount of 2 mL per vial, wherein the mass ratio of the 6'-O-caffeoyl arbutin, polyethylene glycol 4000, and polyvinylpyrrolidone (K12 or K15 or K17) is 50:90:60, and the sodium citrate buffer salt is contained in an appropriate amount, and the water for injection is added to 2.0 mL.

[0070] As an embodiment, when the dosage form of the medicine according to the present application is an injection, the medicine according to the present application can be composed of 6'-O-caffeoyl arbutin, polyethylene glycol 4000, polyvinylpyrrolidone (K12 or K15 or K17), sodium citrate buffer salt, and water for injection, in the amount of 2 mL per vial, wherein the mass ratio of the 6'-O-caffeoyl arbutin, polyethylene glycol 4000, and polyvinylpyrrolidone (K12 or K15 or K17) is 50:90:60, and the sodium citrate buffer salt is contained in an appropriate amount, and the water for injection is added to 2.0 mL.

[0071] As an embodiment, when the dosage form of the medicine according to the present application is an injection, the medicine according to the present application can be composed of 6'-O-caffeoyl arbutin, polyethylene glycol 4000, polyvinylpyrrolidone (K12 or K15 or K17), sodium citrate buffer salt, and water for injection, in the amount of 2 mL per vial, wherein the mass ratio of the 6'-O-caffeoyl arbutin, polyethylene glycol 4000, and polyvinylpyrrolidone (K12 or K15 or K17) is 50:90:60, and the sodium citrate buffer salt is contained in an appropriate amount, and the water for injection is added to 2.0 mL.

[0072] As an implementation form, when the dosage form of the medicine of the present application is an injection, the medicine of the present application can be composed of 6'-O-caffeoyl arbutin, hydroxypropyl betadex and water for injection; the mass ratio of the 6'-O-caffeoyl arbutin and the hydroxypropyl betadex can be 50:80, and the water for injection is appropriately contained.

[0073] As an implementation form, when the dosage form of the medicine of the present application is an inhalation powder / rectal administration agent, the medicine of the present application can be composed of 6'-O-caffeoyl arbutin and polyvinylpyrrolidone (K12 or K15 or K17 or K25, K30, K90); the mass ratio of the 6'-O-caffeoyl arbutin and the polyvinylpyrrolidone (K12 or K15 or K17 or K25, K30, K90) can be 45:80.

[0074] As an implementation form, when the dosage form of the medicine of the present application is a dry suspension, the medicine of the present application can be composed of 6'-O-caffeoyl arbutin, gum arabic, Tween-60 and glucose powder; the mass ratio of the 6'-O-caffeoyl arbutin, gum arabic, Tween-60 and glucose powder can be 50:20:8:22.

[0075] As an implementation form, when the dosage form of the medicine of the present application is a gel, the medicine of the present application can be composed of 6'-O-caffeoyl arbutin, distilled water, glycerol, ethyl cellulose and gelatin; the mass ratio of the 6'-O-caffeoyl arbutin, distilled water, glycerol, ethyl cellulose and gelatin can be 65:20:6:5.5:3.5.

[0076] In order to further illustrate the present application, the application of 6'-O-caffeoyl arbutin provided by the present application in the preparation of a medicine for treating dementia is described in detail below in combination with the drawings and examples, but they cannot be understood as limiting the protection scope of the present application.

[0077] The sources of the test raw materials used in the examples of the present application are as follows: Test medicine: 6'-O-caffeoyl arbutin, provided by Yunnan University, produced by Yunnan University, product batch number 20240713; Cells: rat adrenal medulla pheochromocytoma cells (PC12) were purchased from the American Type Culture Collection (Manassas, Virginia, USA), and the PC12 cells were cultured with 1640 culture medium containing 10 % (v / v) FBS and 1 % (v / v) penicillin and streptomycin mixed double-antibody preparation, and when the cells reached the exponential growth phase, the operation of subculture and cryopreservation was performed; Animals: C57BL / 6 mice (SPF level); source: Yunnan University Experimental Animal Center; production license number: SCXK (Yunnan) K2021-0001; use license number: SYXK (Yunnan) K2021-0001; gender: male; body weight: 18-20 g; Instrument: animal gas anesthesia machine (Rivodent company, model CDS 9000); multifunctional enzyme label instrument (SpectraMax190) American Molecular Devices company; Reagents: cell proliferation and toxicity detection kit (CCK-8, Meilunbio, MA0218-5); methyl-D-aspartic acid (NMDA, Aldrich, N129532); lactate dehydrogenase (LDH) kit (colorimetric method) A020-1-2; total superoxide dismutase (T-SOD) test box (hydroxylamine method) A001-1-2; catalase (CAT) assay kit A007-1-1; reduced glutathione (GSH) assay kit A006-1-1; total nitric oxide synthase (NOS) test box [NOS (T-NOS)] (colorimetric method) A014-2-2; Pharmaceutical excipients: soybean oil, corn oil, medium-chain triglyceride, glycerol monooleate, glycerol monolinoleate, caprylic capric acid monodiglyceride, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyvinyl pyrrolidone, cross-linked polyvinyl pyrrolidone, polyvinyl pyrrolidone-vinyl acetate copolymer, poloxamer, polyethylene glycol 400, polyethylene glycol 1000, polyethylene glycol 4000, polyvinyl pyrrolidone K12, polyvinyl pyrrolidone K15, polyvinyl pyrrolidone K17, polyvinyl pyrrolidone K25, polyvinyl pyrrolidone K30, polyvinyl pyrrolidone K90, polyethylene glycol 400, polyethylene glycol 4000, sulfobutyl betadex sodium, hydroxypropyl betadex, corn starch, potato starch, sodium carboxymethyl cellulose, sodium carboxymethyl starch, magnesium stearate, β-cyclodextrin, sucrose powder, talc, poloxamer, gelatin, glucose powder, benzyl alcohol, gum arabic, Tween-60, glycerol, distilled water, ethyl cellulose, all purchased from the market.

[0078] The application will be further described below in conjunction with examples: Example 1 Verification of the in vitro neuroprotective activity of 6'-O-caffeoyl arbutin 1. BV2 cell model The experiment was divided into different groups: blank control group, in which the cells were incubated in DMEM medium for 16 h; lipopolysaccharide model group, in which the cells were cultured in DMEM medium for 16 h, and then lipopolysaccharide (0.5 μg / mL) was added for 24 h; positive drug edaravone group, in which the cells were cultured in DMEM medium for 16 h, and then edaravone (15 μM) and lipopolysaccharide (0.5 μg / mL) were added for 24 h; 6'-O-caffeoyl arbutin group (5 μM, 10 μM or 15 μM), BV2 cells were incubated in DMEM medium for 24 h, and then treated with lipopolysaccharide (0.5 μg / mL) and different concentrations of samples for 24 h. After the expiration, rinse once with PBS, add RNA extraction reagent, extract total RNA, and convert to cDNA, and use qRT-PCR to determine the expression level of inflammatory genes, and obtain the experimental results as shown in Figure 1 .

[0079] According to the results shown in Figure 1 , 6'-O-caffeoyl arbutin has a good antagonistic effect on the inflammatory response of BV2 cells caused by lipopolysaccharide, specifically reducing the expression levels of inflammatory genes interleukin-1 β ( Il-1β ), interleukin-6 Il-6 , tumor necrosis factor-α Tnf-α , and inducible nitric oxide synthase I nos (P<0.01). The above results show that 6'-O-caffeoyl arbutin can effectively protect lipopolysaccharide-induced BV2 cell (in vitro model of glial cells) damage by regulating the expression of inflammation-related genes.

[0080] 2. PC12 cell model The experiment was divided into different groups: control group, in which the cells were incubated in 1640 medium for 24 h; NMDA model group, in which the cells were cultured in 1640 medium for 24 h, and then NMDA (2 mM) was added for 6 h; 6'-O-caffeoyl arbutin group (5 μM, 10 μM or 15 μM), PC12 cells were incubated in 1640 medium for 24 h, and then treated with different concentrations of samples for 24 h. Then NMDA was added for 6 h (final concentration 2 mM), and after the expiration, the cell lysate was collected, and the oxidation and inflammation indicators were determined, and the experimental results are shown in Figure 2 and Figure 3 .

[0081] According to the results shown in Figure 2 and Figure 3The results show that 6'-O-caffeoyl arbutin has a good antagonistic effect on NMDA-induced PC12 cell oxidative and antioxidant imbalance and inflammatory response, specifically, increasing the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) (P<0.05 / 0.01), while reducing the release of lactate dehydrogenase (LDH) and malondialdehyde (MDA), increasing the level of T NOS (total nitric oxide synthase), and reducing the level of I NOS (injury-induced nitric oxide synthase) (P<0.01). The above results show that 6'-O-caffeoyl arbutin can effectively protect NMDA-induced PC12 cell (neuron in vitro model) damage by regulating oxidative stress and inflammation-related indicators.

[0082] Example 2 In vivo pharmacodynamic verification of 6'-O-caffeoyl arbutin on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Parkinson's model mice by intraperitoneal injection 1. Test animals: C57BL / 6, 9~10-week-old male mice, body weight: 20~24g.

[0083] 2. Grouping and administration The above mice were randomly divided into 6 groups, 10 in each group (n=10). The specific administration is as follows: ① Normal control group: 0.1 mL / 10g of physiological saline was injected into the tail vein once a day for 13 days; ② Model control group: 0.1 mL / 10g of physiological saline was injected into the tail vein once a day for 1~2 days. Modeling was performed on days 4~9, specifically, MPTP was injected intraperitoneally on day 4 at 15mg / kg, on day 5 at 20mg / kg, on day 6 at 30mg / kg, and on days 7~9 at 30mg / kg, for a total of 6 days of modeling. 0.1 mL / 10g of physiological saline was injected into the tail vein on days 10~13; ③ Positive control group (L-dopa group, referred to as L-DOPA-20): L-DOPA 20mg / kg (Sigma, C17197076) was administered by tail vein injection once a day, starting 3 days in advance (days 1~3), and MPTP modeling was performed intraperitoneally 1h after administration on days 4~9 (same as the model group), and the administration was continued until day 13; ④ 6'-O-caffeoyl arbutin low-dose treatment group (referred to as CA-5): 6'-O-caffeoyl arbutin 5mg / kg was administered by tail vein injection once a day. Consistent with the positive control group, administration was started 3 days in advance (days 1~3), and MPTP modeling was performed intraperitoneally 1h after administration on days 4~9 (same as the model group), and the administration was continued until day 13; ⑤6’-O-caffeoyl arbutin middle dose treatment group (CA-10): 10 mg / kg, and the rest of the operations were the same as the low dose group; ⑥6’-O-caffeoyl arbutin high dose treatment group (CA-20): 20 mg / kg, and the rest of the operations were the same as the low dose group.

[0084] 3. Model construction The model group, positive drug control group and three dose groups of CA were from the 4th day. After 1 h of giving the corresponding drug, the model was made by intraperitoneal injection of MPTP, and the normal control group of mice was injected with the corresponding volume of normal saline, and the modeling lasted to the 9th day.

[0085] 4. Behavioral detection All the above mice were sequentially carried out Y maze experiment, new object recognition experiment and open field experiment, and the related behavioral indexes were recorded.

[0086] ① Y maze experiment Y maze test was used to evaluate spatial working memory on the 14th day. The device was composed of three identical arms (40 cm x 10 cm x 5 cm) at an angle of 120 degrees.

[0087] First, the mice were placed in the test room for 1 h of adaptation. In the first training, the new arm was blocked, and the mice were allowed to explore in the remaining two arms (the starting arm and the other arm) for 10 min. After a 24 h interval, the second training was carried out, and the mice could freely enter all three arms and explore for 5 min.

[0088] All test sessions were recorded using the VisuTrack system (Shanghai Biyan Biotechnology Co., Ltd.). The percentage of time spent by the mice in the new arm during the test phase (as an index of spatial memory) and the total distance of movement (as an index of autonomous activity) were analyzed.

[0089] ② New object recognition experiment New object recognition test was used to evaluate the recognition memory ability after the last administration on the 15th day. The test consisted of three stages: adaptation, training and testing.

[0090] Adaptation: 24 h before training, each mouse was placed individually in an open field (60 cm x 60 cm x 40 cm) and allowed to explore freely for 10 min.

[0091] Training: the next day, two identical objects (A and A1) were placed in the left and right corners of the field, respectively. Each mouse was placed in the field with its back to the objects and allowed to explore for 5 min.

[0092] Testing period: After a 24-hour interval, one of the familiar objects (A1) was replaced with a new object (C). The mice were then placed back in the testing area for another 5 minutes. Exploratory behavior was defined as the mouse sniffing or touching the object with its nose within a range of less than 2 cm.

[0093] Between rounds of testing, the testing area and objects were thoroughly cleaned with 75% ethanol to eliminate olfactory cues. All testing procedures were recorded and analyzed using the VisuTrack automated tracking system (Shanghai Bio-Technology Co., Ltd.). The time spent by mice exploring familiar objects (Tf) and new objects (Tn) was recorded, and the discrimination index was calculated using the following formula: Discrimination Index = (Tn - Tf) / (Tn + Tf) × 100%.

[0094] ③Open field experiment The open field experiment was conducted on day 16 to assess spontaneous activity in the animals. Mice were transferred to the experimental laboratory for environmental acclimatization. Two hours later, the mice were placed in the center of an open box (50cm × 50cm) and allowed to explore the environment voluntarily for 310 seconds. Movement paths and behaviors were recorded and analyzed using the Weisu Orbital Animal Behavior Analysis System developed by Shanghai Xinsoft Co., Ltd. Total movement distance, movement speed, and movement time were calculated.

[0095] The behavioral test results are shown in the figure below. According to... Figure 4 A~ Figure 4 As shown in the result D, we can see that: In the Y-maze experiment, the model mice showed a significant decrease in the distance they moved in the new arm, the number of explorations, and the time they stayed in the maze. However, after intervention with 6'-O-caffeoylarbutin, all the indicators rebounded significantly, indicating that it can improve the spatial cognitive ability of the dementia model.

[0096] In the new object recognition experiment, according to Figure 4 E and Figure 4 The F-values ​​in the model group showed a significant decrease in the discrimination index, while the drug-treated group showed a significant recovery and improved cognitive and memory functions.

[0097] Open field experiment results Figure 4 G~ Figure 4 The K values ​​in the study showed that MPTP treatment significantly reduced the total distance traveled, average speed, number of central region entries, and dwell time in the model animals. These indicators were significantly improved in the drug-treated group, indicating that 6'-O-caffeoylarbutin can alleviate motor and emotional abnormalities in the dementia model. These results demonstrate that 6'-O-caffeoylarbutin can improve spatial cognition and cognitive memory function in Parkinson's dementia model mice, alleviate motor and emotional abnormalities, and exert neuroprotective and dementia therapeutic effects in vivo. This further provides in vivo experimental evidence for its use in the preparation of drugs for treating dementia (including Parkinson's dementia).

[0098] Example 3 In vivo pharmacodynamic verification of 6'-O-caffeoyl arbutin on scopolamine-induced dementia model 1. Test animals: C57BL / 6, 9~10-week-old male mice, body weight: 20~24 g.

[0099] 2. Grouping and administration The mice were divided into a normal control group, a model group, a positive control donepezil group (1 mg / kg), and three 6'-O-caffeoyl arbutin dose groups (10, 40, and 160 mg / kg), with 10 mice in each group.

[0100] ① Normal control group: 0.1 mL / 10 g of normal saline was given once a day, and no scopolamine was given throughout the 60-day period; ② Model group: 0.1 mL / 10 g of normal saline was given once a day for 60 days, and scopolamine modeling was performed by intraperitoneal injection starting from the 31st day and continuing until the 60th day; ③ Positive control group (donepezil group): donepezil 1 mg / kg was given by gavage once a day, and scopolamine modeling was performed by intraperitoneal injection of 1 mg / kg 1 h after administration starting from the 31st day and continuing until the 60th day; ④ 6'-O-caffeoyl arbutin low-dose treatment group (referred to as CA-10): 6'-O-caffeoyl arbutin 10 mg / kg was given by gavage once a day, and scopolamine modeling was performed by intraperitoneal injection of 1 mg / kg 1 h after administration starting from the 31st day and continuing until the 60th day; ⑤ 6'-O-caffeoyl arbutin medium-dose treatment group (referred to as CA-40): the dose was 40 mg / kg, and the rest of the operations were the same as those of the low-dose group; ⑥ 6'-O-caffeoyl arbutin high-dose treatment group (referred to as CA-160): 160 mg / kg, and the rest of the operations were the same as those of the low-dose group.

[0101] 3. Model construction The model group, the positive drug control group, and the three dose groups of CA started from the 31st day. Scopolamine modeling (Sigma, 6533-68-2) was performed by intraperitoneal injection of 1 mg / kg 1 h after administration of the corresponding drugs, and the normal control group of mice was injected with the corresponding volume of normal saline, and the modeling was continued until the 60th day.

[0102] 4. Behavioral detection The water maze experiment was performed 30 min after the last modeling, and the relevant behavioral indicators were recorded.

[0103] The water maze online detection system consists of a stainless steel spray cylindrical pool and an image acquisition and analysis system. The pool is 100 cm in diameter and 38 cm in height. The platform is 6 cm in diameter and 14 cm in height. The pool is evenly divided into four quadrants (NE, SE, SW, NW) according to the four directions of southeast, southwest, northwest and northeast. The arc midpoint of the quadrant pool wall is the optional animal entry point, and the platform can be placed in the center of any quadrant. The image acquisition and analysis system records animal swimming track data for index extraction and analysis. At the beginning of the experiment, the mouse is placed in the pool to swim freely for 2 min to familiarize itself with the maze environment. The experiment lasts for 5 days, and each day is scheduled at a fixed time period, with 4 training sessions per time period. At the beginning of the training, the platform is placed in the NW quadrant, and the mouse is placed in the pool from any of the four starting points with its face facing the pool wall. The free video recording system records the time for the mouse to find the platform and the swimming path. The mouse is placed in the water from four different starting points for 4 training sessions, and the time for the mouse to find the platform within 120 s is recorded as the escape latency. The number of times the mouse crosses the platform area and the residence time in the target quadrant are recorded. The test results are obtained as shown in Figure 5 .

[0104] According to the results shown in Figure 5 , the model mouse has a prolonged escape latency, and the residence time in the target quadrant and the number of times crossing the platform are significantly shortened. Compared with normal mice, the difference is statistically significant (P<0.01), and after the intervention of 6'-O-caffeoyl arbutin, the three indicators are significantly adjusted, indicating that it can improve the spatial memory and behavior of the scopolamine-induced dementia model.

[0105] Example 4 Preparation of 6'-O-caffeoyl arbutin self-emulsifying microemulsion soft capsule The present embodiment aims to provide a 6'-O-caffeoyl arbutin self-emulsifying microemulsion soft capsule, solve the problem of poor water solubility of 6'-O-caffeoyl arbutin, and meet the preparation and clinical administration needs of the dosage form. The preparation prescription table of the 6'-O-caffeoyl arbutin self-emulsifying microemulsion soft capsule is shown in Table 1.

[0106] Table 1 Preparation prescription table of 6'-O-caffeoyl arbutin drug

[0107] Preparation method: 1. Preparation of oil phase The medium-chain triglyceride and the monoolein are weighed according to the ratio, mixed, and heated to 50℃ for uniform mixing.

[0108] 2. Preparation of water phase The polyoxyethylene (40) hydrogenated castor oil and water are weighed according to the ratio, mixed, and heated to 50℃ for uniform mixing.

[0109] 3. Mixing Mix the oil phase and the water phase (at a temperature of 50°C) using an overhead stirrer set at a speed of 200-300 rpm.

[0110] 4. Adding 6'-O-Caffeoyl Arbutin Add 6'-O-Caffeoyl Arbutin to the mixture prepared in step 3 in the proportion specified, and stir to dissolve and disperse.

[0111] 5. Soft capsule filling Fill the liquid prepared in step 4 into soft capsules.

[0112] The present application prepares 6'-O-Caffeoyl Arbutin into a self-emulsifying microemulsion, and the weight percentage of 6'-O-Caffeoyl Arbutin in the drug is 1%. The prescription provided makes the solubility of 6'-O-Caffeoyl Arbutin reach 10 mg / ml, thereby increasing the solubility of the drug.

[0113] Example 5 Preparation of 6'-O-Caffeoyl Arbutin self-emulsifying microemulsion soft capsules The present example aims to provide a 6'-O-Caffeoyl Arbutin self-emulsifying microemulsion soft capsule to solve the problem of poor water solubility of 6'-O-Caffeoyl Arbutin, and meet the preparation and clinical administration needs of the dosage form. The preparation prescription table of the 6'-O-Caffeoyl Arbutin self-emulsifying microemulsion soft capsule is shown in Table 2.

[0114] Table 2 Preparation prescription table of 6'-O-Caffeoyl Arbutin drug

[0115] Preparation method: 1. Preparation of oil phase Weigh the medium-chain triglyceride and glycerol monooleate in the specified proportion, mix, and heat to 50°C to mix evenly.

[0116] 2. Preparation of water phase Weigh the polyoxyethylene (40) hydrogenated castor oil and water in the specified proportion, mix, and heat to 50°C to mix evenly.

[0117] 3. Mixing Mix the oil phase and the water phase (at a temperature of 50°C) using an overhead stirrer set at a speed of 200-300 rpm.

[0118] 4. Adding 6'-O-Caffeoyl Arbutin Add 6'-O-Caffeoyl Arbutin to the mixture prepared in step 3 in the proportion specified, and stir to dissolve and disperse.

[0119] 5. Soft capsule filling The liquid prepared in step 4 is filled into soft capsules.

[0120] The present application prepares 6'-O-caffeoyl arbutin into self-emulsifying microemulsion, the weight percentage of 6'-O-caffeoyl arbutin in the medicine is 15%, the provided prescription makes the solubility of 6'-O-caffeoyl arbutin reach 150 mg / ml, and the solubility of the medicine is increased.

[0121] Example 6 Preparation of 6'-O-caffeoyl arbutin self-emulsifying microemulsion soft capsule The present application provides a 6'-O-caffeoyl arbutin self-emulsifying microemulsion soft capsule, solves the problem of poor water solubility of 6'-O-caffeoyl arbutin, and meets the preparation and clinical administration requirements of the dosage form. The preparation prescription table of the 6'-O-caffeoyl arbutin self-emulsifying microemulsion soft capsule is shown in Table 3.

[0122] Table 3 Preparation prescription table of 6'-O-caffeoyl arbutin medicine

[0123] Preparation method: 1. Preparation of oil phase The medium-chain triglyceride and the monoolein are weighed according to the ratio, mixed, and heated to 50 DEG C for uniform mixing.

[0124] 2. Preparation of water phase The polyoxyethylene (40) hydrogenated castor oil and water are weighed according to the ratio, mixed, and heated to 50 DEG C for uniform mixing.

[0125] 3. Mixing An overhead stirrer is used, and the stirring speed is set to 200-300 rpm. The oil phase and the water phase are mixed at a temperature of 50 DEG C.

[0126] 4. Addition of 6'-O-caffeoyl arbutin The 6'-O-caffeoyl arbutin is added to the liquid after step 3. mixing according to the ratio, and is stirred, dissolved and dispersed.

[0127] 5. Soft capsule filling The liquid prepared in step 4 is filled into soft capsules.

[0128] The present application prepares 6'-O-caffeoyl arbutin into self-emulsifying microemulsion, the weight percentage of 6'-O-caffeoyl arbutin in the medicine is 20%, the provided prescription makes the solubility of 6'-O-caffeoyl arbutin reach 200 mg / ml, and the solubility of the medicine is increased.

[0129] Example 7 Preparation of 6'-O-caffeoyl arbutin self-emulsifying microemulsion soft capsule The present embodiment aims to provide a 6'-O-cafeoyl arbutin self-emulsifying microemulsion soft capsule, solve the problem of poor water solubility of 6'-O-cafeoyl arbutin, and meet the preparation and clinical administration needs of the dosage form. The preparation prescription table of the 6'-O-cafeoyl arbutin self-emulsifying microemulsion soft capsule is shown in Table 4.

[0130] Table 4 6'-O-cafeoyl arbutin drug preparation prescription table

[0131] Preparation method: 1. Preparation of oil phase The medium-chain triglyceride and the glyceryl monooleate are weighed according to the ratio, mixed, and heated to 50°C for uniform mixing.

[0132] 2. Preparation of water phase The polyoxyethylene (40) hydrogenated castor oil and water are weighed according to the ratio, mixed, and heated to 50°C for uniform mixing.

[0133] 3. Mixing An overhead stirrer is used, and the stirring speed is set to 200-300 rpm. The oil phase and the water phase are mixed at a temperature of 50°C.

[0134] 4. Addition of 6'-O-cafeoyl arbutin The 6'-O-cafeoyl arbutin is added to the liquid after step 3. mixing according to the ratio, and stirred, dissolved, and dispersed.

[0135] 5. Soft capsule filling The liquid prepared in step 4 is filled into a soft capsule.

[0136] The present application prepares 6'-O-cafeoyl arbutin into a self-emulsifying microemulsion, and the weight percentage content of 6'-O-cafeoyl arbutin in the drug is 33.3%. The prescription provided makes the solubility of 6'-O-cafeoyl arbutin reach 333 mg / ml, increasing the solubility of the drug.

[0137] Example 8 Preparation of 6'-O-cafeoyl arbutin self-emulsifying microemulsion soft capsule The present embodiment aims to provide a 6'-O-cafeoyl arbutin self-emulsifying microemulsion soft capsule, solve the problem of poor water solubility of 6'-O-cafeoyl arbutin, and meet the preparation and clinical administration needs of the dosage form. The preparation prescription table of the 6'-O-cafeoyl arbutin self-emulsifying microemulsion soft capsule is shown in Table 5.

[0138] Table 5 6'-O-cafeoyl arbutin drug preparation prescription table

[0139] Preparation method: 1. Preparation of oil phase The medium-chain triglyceride, glyceryl monooleate were weighed according to the proportion, mixed, and heated to 50°C for uniform mixing.

[0140] 2. Preparation of water phase Polyoxyethylene (35) castor oil, water were weighed according to the proportion, mixed, and heated to 50°C for uniform mixing.

[0141] 3. Mixing An overhead stirrer was used, and the stirring speed was set to 200-300 rpm. The oil phase and the water phase were mixed at a temperature of 50°C.

[0142] 4. Addition of 6'-O-cafeoyl arbutin 6'-O-cafeoyl arbutin was added to the liquid prepared in step 3. according to the proportion, and stirred, dissolved and dispersed.

[0143] 5. Soft capsule filling The liquid prepared in step 4. was filled into soft capsules.

[0144] The present application prepares 6'-O-cafeoyl arbutin into a self-emulsifying microemulsion, and the weight percentage of 6'-O-cafeoyl arbutin in the drug is 47.4%. The provided prescription makes the solubility of 6'-O-cafeoyl arbutin reach 473 mg / ml, thereby increasing the solubility of the drug.

[0145] Example 9 Preparation of 6'-O-cafeoyl arbutin self-emulsifying microemulsion soft capsules The present example aims to provide a 6'-O-cafeoyl arbutin self-emulsifying microemulsion soft capsule, solve the problem of poor water solubility of 6'-O-cafeoyl arbutin, and meet the preparation and clinical administration needs of the dosage form. The specific preparation prescription table is shown in Table 6.

[0146] Table 6 6'-O-cafeoyl arbutin drug preparation prescription table

[0147] Preparation method: 1. Preparation of oil phase Refined soybean oil, glyceryl monooleate were weighed according to the proportion, mixed, and heated to 50°C for uniform mixing.

[0148] 2. Preparation of water phase Polyoxyethylene hydrogenated castor oil, water were weighed according to the proportion, mixed, and heated to 50°C for uniform mixing.

[0149] 3. Mixing Mix the oil phase and the water phase (at a temperature of 50°C) using an overhead stirrer set at a speed of 200-300 rpm.

[0150] 4. Add 6'-O-Caffeoyl Arbutin Add 6'-O-Caffeoyl Arbutin to the liquid prepared in step 3. according to the ratio, and stir to dissolve and disperse.

[0151] 5. Soft capsule filling Fill the liquid prepared in step 4. into soft capsules.

[0152] The present application prepares 6'-O-Caffeoyl Arbutin into a self-emulsifying microemulsion, and the weight percentage of 6'-O-Caffeoyl Arbutin in the drug is 33.3%. The provided prescription makes the solubility of 6'-O-Caffeoyl Arbutin reach 333 mg / ml, thereby increasing the solubility of the drug.

[0153] Example 10 Preparation of 6'-O-Caffeoyl Arbutin self-emulsifying microemulsion soft capsules The present embodiment aims to provide a 6'-O-Caffeoyl Arbutin self-emulsifying microemulsion soft capsule, solve the problem of poor water solubility of 6'-O-Caffeoyl Arbutin, and meet the preparation and clinical administration needs of the dosage form. The specific preparation prescription table is shown in Table 7.

[0154] Table 7 Preparation prescription table of 6'-O-Caffeoyl Arbutin drug

[0155] Preparation method: 1. Preparation of oil phase Weigh the corn oil and glyceryl monooleate according to the ratio, mix, and heat to 50°C to mix evenly.

[0156] 2. Preparation of water phase Weigh the polyoxyethylene hydrogenated castor oil and water according to the ratio, mix, and heat to 50°C to mix evenly.

[0157] 3. Mixing Mix the oil phase and the water phase (at a temperature of 50°C) using an overhead stirrer set at a speed of 200-300 rpm.

[0158] 4. Add 6'-O-Caffeoyl Arbutin Add 6'-O-Caffeoyl Arbutin to the liquid prepared in step 3. according to the ratio, and stir to dissolve and disperse.

[0159] 5. Soft capsule filling Fill the liquid prepared in step 4. into soft capsules.

[0160] The application prepares 6'-O-cafeoyl arbutin into self-emulsifying microemulsion, the weight percentage content of 6'-O-cafeoyl arbutin in the medicine is 33.3%, and the provided prescription makes the solubility of 6'-O-cafeoyl arbutin reach 333 mg / ml, thereby increasing the solubility of the medicine.

[0161] Example 11 Preparation of 6'-O-cafeoyl arbutin self-emulsifying microemulsion soft capsule The embodiment aims to provide a 6'-O-cafeoyl arbutin self-emulsifying microemulsion soft capsule, solve the problem of poor water solubility of 6'-O-cafeoyl arbutin, and meet the preparation and clinical administration requirements of the dosage form, and the specific preparation prescription table is shown in Table 8.

[0162] Table 8 Preparation prescription table of 6'-O-cafeoyl arbutin medicine

[0163] Preparation method: 1. Preparation of oil phase The medium-chain triglyceride, caprylic acid capric acid monodiglyceride and tridiglyceride are weighed according to the proportion, mixed, and heated to 50 DEG C and uniformly mixed.

[0164] 2. Preparation of water phase The polyoxyethylene hydrogenated castor oil and water are weighed according to the proportion, mixed, and heated to 50 DEG C and uniformly mixed.

[0165] 3. Mixing An overhead stirrer is used, the stirring speed is set to 200-300 rpm, and the oil phase and the water phase are mixed (at a temperature of 50 DEG C).

[0166] 4. Adding 6'-O-cafeoyl arbutin 6'-O-cafeoyl arbutin is added to the liquid after step 3. mixing according to the proportion, and is stirred, dissolved and dispersed.

[0167] 5. Soft capsule filling The liquid prepared in step 4 is filled into a soft capsule.

[0168] The application prepares 6'-O-cafeoyl arbutin into self-emulsifying microemulsion, the weight percentage content of 6'-O-cafeoyl arbutin in the medicine is 46.5%, and the provided prescription makes the solubility of 6'-O-cafeoyl arbutin reach 465 mg / ml, thereby increasing the solubility of the medicine.

[0169] Example 12 Preparation of 6'-O-cafeoyl arbutin self-emulsifying microemulsion oral liquid The embodiment aims to provide a 6'-O-cafeoyl arbutin self-emulsifying microemulsion oral solution, solve the problem of poor solubility of 6'-O-cafeoyl arbutin in water, and meet the preparation and clinical drug delivery needs of the dosage form. The specific preparation prescription table is shown in Table 9.

[0170] Table 9 6'-O-cafeoyl arbutin drug preparation prescription table

[0171] Preparation method: 1. Preparation of oil phase The medium-chain triglyceride, caprylic capric acid monodiglyceride and tridiglyceride were weighed according to the ratio, mixed, and heated to 50°C for uniform mixing.

[0172] 2. Preparation of water phase The polyoxyethylene hydrogenated castor oil and 96% ethanol were weighed according to the ratio, mixed, and heated to 50°C for uniform mixing.

[0173] 3. Mixing An overhead stirrer was used, and the stirring speed was set to 200-300 rpm. The oil phase and the water phase were mixed at a temperature of 50°C.

[0174] 4. Adding 6'-O-cafeoyl arbutin 6'-O-cafeoyl arbutin was added to the liquid after step 3. mixing according to the ratio, and was stirred, dissolved and dispersed.

[0175] 5. Filling The liquid prepared in step 4 was filled into an oral solution bottle.

[0176] The present application prepares 6'-O-cafeoyl arbutin into a self-emulsifying microemulsion, and the weight percentage content of 6'-O-cafeoyl arbutin in the drug is 54.5%. The prescription provided makes the solubility of 6'-O-cafeoyl arbutin reach 545 mg / ml, thereby increasing the solubility of the drug.

[0177] Example 13 Preparation of 6'-O-cafeoyl arbutin self-emulsifying microemulsion oral solution The embodiment aims to provide a 6'-O-cafeoyl arbutin self-emulsifying microemulsion oral solution, solve the problem of poor solubility of 6'-O-cafeoyl arbutin in water, and meet the preparation and clinical drug delivery needs of the dosage form. The specific preparation prescription table is shown in Table 9.

[0178] Table 10 6'-O-cafeoyl arbutin drug preparation prescription table

[0179] Preparation method: 1. Preparation of oil phase Weigh out medium-chain triglycerides and caprylic / capric acid mono- and triglycerides according to the specified ratio, mix them, and heat to 50°C until homogeneous.

[0180] 2. Preparation of the aqueous phase Weigh out the polyoxyethylene hydrogenated castor oil and 96% ethanol according to the specified ratio, mix them, and heat to 50°C to mix thoroughly.

[0181] 3. Mixing Use a top-mounted agitator and set the speed to 200-300 rpm to mix the oil and water phases (at a temperature of 50°C).

[0182] 4. Add 6'-O-caffeoylarbutin Add 6'-O-caffeoylarbutin to the liquid mixture from step 3 according to the specified ratio, and stir to dissolve and disperse.

[0183] 5. Fill Fill the oral liquid bottle with the liquid prepared in step 4.

[0184] This invention prepares 6'-O-caffeoylarbutin into a self-emulsifying microemulsion, with 6'-O-caffeoylarbutin comprising 38.7% by weight in the drug. The provided formulation achieves a solubility of 6'-O-caffeoylarbutin of 387 mg / ml, thereby increasing the solubility of the drug.

[0185] Example 14 Preparation of 6'-O-caffeoylarbutin self-emulsifying microemulsion oral solution This embodiment aims to provide a 6'-O-caffeoylarbutin self-emulsifying microemulsion oral solution to solve the problem of poor water solubility of 6'-O-caffeoylarbutin, and to meet the preparation and clinical administration requirements of this dosage form. The specific preparation formula is shown in Table 11.

[0186] Table 11 Formulation Table for the Preparation of 6'-O-Caffeoylarbutin Drug

[0187] Preparation method: 1. Preparation of the oil phase Weigh out medium-chain triglycerides and caprylic / capric acid mono- and triglycerides according to the specified ratio, mix them, and heat to 50°C until homogeneous.

[0188] 2. Preparation of the aqueous phase Weigh out the polyoxyethylene hydrogenated castor oil and 96% ethanol according to the specified ratio, mix them, and heat to 50°C to mix thoroughly.

[0189] 3. Mixing Use a top-mounted agitator and set the speed to 200-300 rpm to mix the oil and water phases (at a temperature of 50°C).

[0190] 4. Add 6'-O-Caffeoyl Arbutin Add 6'-O-Caffeoyl Arbutin to the mixed liquid of step 3. according to the ratio, stir to dissolve and disperse.

[0191] 5. Filling Fill the liquid prepared in step 4. into an oral liquid bottle.

[0192] The present application prepares 6'-O-Caffeoyl Arbutin into a self-emulsifying microemulsion, the weight percentage of 6'-O-Caffeoyl Arbutin in the drug is 41.2%, and the solubility of 6'-O-Caffeoyl Arbutin reaches 412 mg / ml, which increases the solubility of the drug.

[0193] Example 15 Preparation of 6'-O-Caffeoyl Arbutin Tablets This embodiment aims to provide a 6'-O-Caffeoyl Arbutin tablet to solve the problem of poor water solubility of 6'-O-Caffeoyl Arbutin and meet the preparation and clinical administration requirements of the dosage form. The specific preparation prescription table is shown in Table 12.

[0194] Table 12 6'-O-Caffeoyl Arbutin Drug Preparation Prescription Table

[0195] Preparation method: After the above raw materials are crushed, the premix is prepared by adding excipients, and the premix is subjected to disaggregation / sieving by a vibrating sieve mill, mixed, and tableted.

[0196] The present application prepares 6'-O-Caffeoyl Arbutin into a tablet, the weight percentage of 6'-O-Caffeoyl Arbutin in the drug is 20%, and the solubility of 6'-O-Caffeoyl Arbutin reaches 10 mg / ml, which increases the solubility of the drug.

[0197] Example 16 Preparation of 6'-O-Caffeoyl Arbutin PEG Solid Dispersion Tablet This embodiment aims to provide a 6'-O-Caffeoyl Arbutin PEG solid dispersion tablet to solve the problem of poor water solubility of 6'-O-Caffeoyl Arbutin and meet the preparation and clinical administration requirements of the dosage form. The specific preparation prescription table is shown in Table 13.

[0198] Table 13 6'-O-Caffeoyl Arbutin Drug Preparation Prescription Table

[0199] Preparation method: The above raw materials are crushed, mixed with polyethylene glycol 400 and polyethylene glycol 4000 to form a solid dispersion, other excipients are added after crushing, mixed uniformly, granulated, dried, and compressed into tablets to obtain 6'-O-caffeoyl arbutin tablets.

[0200] The present application prepares 6'-O-caffeoyl arbutin into tablets, the weight percentage of 6'-O-caffeoyl arbutin in the medicine is 4.4%, and the provided prescription makes the solubility of 6'-O-caffeoyl arbutin reach 40 mg / ml, thereby increasing the solubility of the medicine.

[0201] Example 17 Preparation of 6'-O-caffeoyl arbutin polyethylene glycol solid dispersion tablets The present application provides a 6'-O-caffeoyl arbutin polyethylene glycol solid dispersion tablet, solves the problem of poor water solubility of 6'-O-caffeoyl arbutin, and meets the preparation and clinical administration requirements of the dosage form. The specific preparation prescription table is shown in Table 14.

[0202] Table 14 6'-O-caffeoyl arbutin medicine preparation prescription table

[0203] Preparation method: The above raw materials are crushed, mixed with polyethylene glycol 4000 to form a solid dispersion, other excipients are added after crushing, mixed uniformly, granulated, dried, and compressed into tablets to obtain 6'-O-caffeoyl arbutin tablets.

[0204] The present application prepares 6'-O-caffeoyl arbutin into tablets, the weight percentage of 6'-O-caffeoyl arbutin in the medicine is 3.7%, and the provided prescription makes the solubility of 6'-O-caffeoyl arbutin reach 32 mg / ml, thereby increasing the solubility of the medicine.

[0205] Example 18 Preparation of 6'-O-caffeoyl arbutin polyethylene glycol solid dispersion tablets The present application provides a 6'-O-caffeoyl arbutin polyethylene glycol solid dispersion tablet, solves the problem of poor water solubility of 6'-O-caffeoyl arbutin, and meets the preparation and clinical administration requirements of the dosage form. The specific preparation prescription table is shown in Table 15.

[0206] Table 15 6'-O-caffeoyl arbutin medicine preparation prescription table

[0207] Preparation method: The above raw materials are crushed, mixed with polyvinylpyrrolidone to prepare a solid dispersion, and then other excipients are added, mixed uniformly, granulated, dried, and compressed into tablets to obtain the 6'-O-caffeoyl arbutin tablet.

[0208] The present application prepares 6'-O-caffeoyl arbutin into tablets, and the weight percentage of 6'-O-caffeoyl arbutin in the medicine is 0.9%. The provided prescription makes the solubility of 6'-O-caffeoyl arbutin reach 9.2 mg / ml, thereby increasing the solubility of the medicine.

[0209] Example 19 Preparation of 6'-O-caffeoyl arbutin sulfobutyl betadex sodium cyclodextrin inclusion complex tablet The present application provides a 6'-O-caffeoyl arbutin sulfobutyl betadex sodium cyclodextrin inclusion complex tablet, solves the problem of poor water solubility of 6'-O-caffeoyl arbutin, and meets the preparation and clinical administration requirements of the dosage form. The specific preparation prescription table is shown in Table 16.

[0210] Table 16 6'-O-caffeoyl arbutin pharmaceutical preparation prescription table

[0211] The above raw materials are crushed, mixed with sulfobutyl betadex sodium cyclodextrin to prepare a solid inclusion complex, and then other excipients are added, mixed uniformly, granulated, dried, and compressed into tablets to obtain the 6'-O-caffeoyl arbutin tablet.

[0212] The present application prepares 6'-O-caffeoyl arbutin into tablets, and the weight percentage of 6'-O-caffeoyl arbutin in the medicine is 0.9%. The provided prescription makes the solubility of 6'-O-caffeoyl arbutin reach 9.4 mg / ml, thereby increasing the solubility of the medicine.

[0213] Example 20 Preparation of 6'-O-caffeoyl arbutin hydroxypropyl betadex inclusion complex tablet The present application provides a 6'-O-caffeoyl arbutin hydroxypropyl betadex inclusion complex tablet, solves the problem of poor water solubility of 6'-O-caffeoyl arbutin, and meets the preparation and clinical administration requirements of the dosage form. The specific preparation prescription table is shown in Table 17.

[0214] Table 17 6'-O-caffeoyl arbutin pharmaceutical preparation prescription table

[0215] The above raw materials are crushed, mixed with sulfobutyl betadex sodium cyclodextrin to prepare a solid inclusion complex, and then other excipients are added, mixed uniformly, granulated, dried, and compressed into tablets to obtain the 6'-O-caffeoyl arbutin tablet.

[0216] The present application prepares 6'-O-caffeoyl arbutin into tablets, the weight percentage of 6'-O-caffeoyl arbutin in the medicine is 0.95%, and the provided prescription makes the solubility of 6'-O-caffeoyl arbutin reach 9.4 mg / ml, thereby increasing the solubility of the medicine.

[0217] Example 21 Preparation of 6'-O-caffeoyl arbutin polyethylene glycol 400 solubilization eye drops / nasal drops The present application prepares 6'-O-caffeoyl arbutin polyethylene glycol 400 solubilization eye drops / nasal drops, solves the problem of poor water solubility of 6'-O-caffeoyl arbutin, and meets the preparation and clinical administration requirements of the dosage form.

[0218] Table 18 Prescription table for preparation of 6'-O-caffeoyl arbutin medicine

[0219] Preparation method: The above raw materials are crushed, heated and dissolved with 5% polyethylene glycol 400, and then other excipients are added and uniformly mixed to prepare eye drops / nasal drops.

[0220] The present application prepares 6'-O-caffeoyl arbutin into eye drops / nasal drops, the weight percentage of 6'-O-caffeoyl arbutin in the medicine is 1.7%, and the provided prescription makes the solubility of 6'-O-caffeoyl arbutin reach 20 mg / ml, thereby increasing the solubility of the medicine.

[0221] Example 22 Preparation of 6'-O-caffeoyl arbutin polyethylene glycol 400 solubilization eye drops / nasal drops The present application prepares 6'-O-caffeoyl arbutin polyethylene glycol 400 solubilization eye drops / nasal drops, solves the problem of poor water solubility of 6'-O-caffeoyl arbutin, and meets the preparation and clinical administration requirements of the dosage form.

[0222] Table 19 Prescription table for preparation of 6'-O-caffeoyl arbutin medicine

[0223] Preparation method: The above raw materials are crushed, heated and dissolved with 5% polyethylene glycol 400, and then other excipients are added and uniformly mixed to prepare eye drops / nasal drops.

[0224] The application prepares 6'-O-cafeoyl arbutin into eye drops / nasal drops, the weight percentage of 6'-O-cafeoyl arbutin in the medicine is 1.7%, the provided prescription makes the solubility of 6'-O-cafeoyl arbutin reach 20 mg / ml, and the solubility of the medicine is increased.

[0225] Example 23 Preparation of 6'-O-cafeoyl arbutin polyvinylpyrrolidone solubilization eye drops / nasal drops The embodiment aims to provide 6'-O-cafeoyl arbutin polyvinylpyrrolidone solubilization eye drops / nasal drops, solve the problem of poor solubility of 6'-O-cafeoyl arbutin in water, and meet the preparation and clinical drug delivery requirements of the dosage form, and the specific preparation prescription table is shown in Table 20.

[0226] Table 20 6'-O-cafeoyl arbutin drug preparation prescription table

[0227] Preparation method: The above raw materials are crushed, heated and dissolved with 5% polyvinylpyrrolidone, and then other auxiliary materials are added and uniformly mixed to prepare eye drops / nasal drops.

[0228] The application prepares 6'-O-cafeoyl arbutin into eye drops / nasal drops, the weight percentage of 6'-O-cafeoyl arbutin in the medicine is 1.7%, the provided prescription makes the solubility of 6'-O-cafeoyl arbutin reach 20 mg / ml, and the solubility of the medicine is increased.

[0229] Example 24 Preparation of 6'-O-cafeoyl arbutin hydroxypropyl betadex inclusion eye drops / nasal drops The embodiment aims to provide 6'-O-cafeoyl arbutin hydroxypropyl betadex inclusion eye drops / nasal drops, solve the problem of poor solubility of 6'-O-cafeoyl arbutin in water, and meet the preparation and clinical drug delivery requirements of the dosage form, and the specific preparation prescription table is shown in Table 21.

[0230] Table 21 6'-O-cafeoyl arbutin drug preparation prescription table

[0231] Preparation method: The above raw materials are crushed, heated and dissolved with 5% hydroxypropyl betadex, and then other auxiliary materials are added and uniformly mixed to prepare eye drops / nasal drops.

[0232] The application prepares 6'-O-cafeoyl arbutin into eye drops / nasal drops, the weight percentage of 6'-O-cafeoyl arbutin in the medicine is 1.7%, the provided prescription makes the solubility of 6'-O-cafeoyl arbutin reach 20 mg / ml, and the solubility of the medicine is increased.

[0233] Example 25 Preparation of 6'-O-cafeoyl arbutin hydroxypropyl betadex inclusion eye drops / nasal drops The embodiment aims to provide 6'-O-cafeoyl arbutin hydroxypropyl betadex inclusion eye drops / nasal drops, solve the problem of poor water solubility of 6'-O-cafeoyl arbutin, and meet the preparation and clinical drug delivery requirements of the dosage form, and the specific preparation prescription table is shown in Table 22.

[0234] Table 22 6'-O-cafeoyl arbutin drug preparation prescription table

[0235] Preparation method: The above raw materials are crushed, dissolved by heating with 5% hydroxypropyl betadex, and then other auxiliary materials are added and uniformly mixed to prepare eye drops / nasal drops.

[0236] The application prepares 6'-O-cafeoyl arbutin into eye drops / nasal drops, the weight percentage of 6'-O-cafeoyl arbutin in the medicine is 1.7%, the provided prescription makes the solubility of 6'-O-cafeoyl arbutin reach 20 mg / ml, and the solubility of the medicine is increased.

[0237] Example 26 Preparation of 6'-O-cafeoyl arbutin powder The embodiment aims to provide 6'-O-cafeoyl arbutin powder, solve the problem of poor water solubility of 6'-O-cafeoyl arbutin, and meet the preparation and clinical drug delivery requirements of the dosage form, and the specific preparation prescription table is shown in Table 23.

[0238] Table 23 6'-O-cafeoyl arbutin drug preparation prescription table

[0239] The above raw materials are crushed, mixed uniformly, and packaged to obtain 6'-O-cafeoyl arbutin powder.

[0240] The application prepares 6'-O-cafeoyl arbutin into powder, the weight percentage of 6'-O-cafeoyl arbutin in the medicine is 99%, the provided prescription makes the solubility of 6'-O-cafeoyl arbutin reach 2.8 mg / ml, and the solubility of the medicine is increased.

[0241] Example 27 Preparation of 6'-O-caffeoylarbutin granules This embodiment aims to provide a 6'-O-caffeoylarbutin granule formulation to solve the problem of poor water solubility of 6'-O-caffeoylarbutin, and to meet the preparation and clinical administration requirements of this dosage form. The specific preparation formula is shown in Table 24.

[0242] Table 24 Formulation Table for the Preparation of 6'-O-Caffeoyl Arbutin

[0243] The above raw materials are crushed, mixed evenly, made into granules, dried, and packaged to obtain 6'-O-caffeoylarbutin granules.

[0244] This invention prepares 6'-O-caffeoylarbutin into granules, with 6'-O-caffeoylarbutin comprising 23% by weight in the drug. The provided formulation achieves a solubility of 5.6 mg / ml for 6'-O-caffeoylarbutin, thereby increasing the drug's solubility.

[0245] Example 28 Preparation of 6'-O-caffeoylarbutin hard capsules This embodiment aims to provide a hard capsule formulation of 6'-O-caffeoylarbutin to solve the problem of poor water solubility of 6'-O-caffeoylarbutin, and to meet the preparation and clinical administration requirements of this dosage form. The specific preparation formula is shown in Table 25.

[0246] Table 25 Formulation Table for the Preparation of 6'-O-Caffeoyl Arbutin

[0247] The above raw materials are crushed, mixed evenly, and the resulting mixture is filled into hard gelatin capsules and packaged to obtain 6'-O-caffeoylarbutin capsules.

[0248] This invention prepares 6'-O-caffeoylarbutin into capsules, with 6'-O-caffeoylarbutin comprising 88% by weight in the drug. The provided formulation achieves a solubility of 2.2 mg / ml for 6'-O-caffeoylarbutin, thereby increasing the drug's solubility.

[0249] Example 29 Preparation of 6'-O-caffeoylarbutin sublingual lyophilized tablets This embodiment aims to provide a 6'-O-caffeoylarbutin sublingual lyophilized tablet to solve the problem of poor water solubility of 6'-O-caffeoylarbutin, and to meet the preparation and clinical administration requirements of this dosage form. The specific preparation formula is shown in Table 26.

[0250] Table 26 Formulation table of 6'-O-caffeoyl arbutin drug preparation

[0251] Preparation method: Dissolve gelatin in hot water at 60℃, stir until completely dissolved, cool to room temperature. Add mannitol, sodium deoxycholate, aspartame, stir to dissolve. Add micronized 6'-O-caffeoyl arbutin, use high-speed shearing homogenizer (10000 rpm, 5 min) to disperse uniformly, form a suspension. Add peppermint essence, stir gently. Quantitative filling of the slurry into custom molds, placed in a freeze dryer at -45℃ for 4 h, then sublimation drying (-20℃, 0.5 mbar, 24 h) and analytical drying (25℃, 0.1 mbar, 6 h). Out of the box, aluminum foil bag sealed with nitrogen packaging.

[0252] The present application prepares 6'-O-caffeoyl arbutin into freeze-dried sublingual tablets, the weight percentage of 6'-O-caffeoyl arbutin in the drug is 10.7%, and the provided prescription makes the solubility of 6'-O-caffeoyl arbutin reach 2.5 mg / ml, thereby increasing the solubility of the drug.

[0253] Example 30 Preparation of 6'-O-caffeoyl arbutin sublingual rapidly disintegrating tablets The present application provides a 6'-O-caffeoyl arbutin sublingual rapidly disintegrating tablet, solves the problem of poor water solubility of 6'-O-caffeoyl arbutin, and meets the preparation and clinical administration requirements of the dosage form. The specific preparation prescription table is shown in Table 27.

[0254] Table 27 Formulation table of 6'-O-caffeoyl arbutin drug preparation

[0255] Preparation method: Dissolve all components in 70% aqueous ethanol solution. Spray drying, inlet temperature 100℃, outlet temperature 55℃. Collect the powder and pass through a 100 mesh sieve. This powder can be directly taken sublingually, or mixed with a small amount of direct compression excipients and compressed into high-porosity rapidly disintegrating tablets.

[0256] The present application prepares 6'-O-caffeoyl arbutin into rapidly disintegrating tablets, the weight percentage of 6'-O-caffeoyl arbutin in the drug is 15%, and the provided prescription makes the solubility of 6'-O-caffeoyl arbutin reach 15 mg / ml, thereby increasing the solubility of the drug.

[0257] Example 31 Preparation of 6'-O-caffeoyl arbutin solution type injection The embodiment aims to provide a 6'-O-cafeoyl arbutin solution type injection, solve the problem of poor water solubility of 6'-O-cafeoyl arbutin, and meet the preparation and clinical administration requirements of the dosage form. The specific preparation prescription table is shown in Table 28.

[0258] Table 28 6'-O-cafeoyl arbutin pharmaceutical preparation prescription table

[0259] Preparation method: Take about 1.4 mL of water for injection in a beaker, add mannitol and sodium citrate buffer salt, and stir to dissolve. Take another beaker, add polyethylene glycol 400, add 6'-O-cafeoyl arbutin, and stir or ultrasonic to completely dissolve. Under magnetic stirring, slowly add the PEG-6'-O-cafeoyl arbutin solution to the water phase, and mix evenly. Use water for injection to constant volume to 2.0 mL. Fine adjustment of pH to 6.0~6.5 with 0.1M HCl / NaOH. The solution is filtered and sterilized through a 0.22μm polyether sulfone (PES) filter membrane. Under sterile conditions, fill in 2mL ampoules, and seal. 121℃ wet heat sterilization for 15 min. Leak detection, lamp inspection.

[0260] The present application prepares 6'-O-cafeoyl arbutin into injection, the weight percentage content of 6'-O-cafeoyl arbutin in the medicine is 1.2%, the prescription provided makes the solubility of 6'-O-cafeoyl arbutin reach 12.5mg / ml, and the solubility of the medicine is increased.

[0261] Example 32 Preparation of 6'-O-cafeoyl arbutin sterile powder for injection The embodiment aims to provide a 6'-O-cafeoyl arbutin sterile powder for injection, solve the problem of poor water solubility of 6'-O-cafeoyl arbutin, and meet the preparation and clinical administration requirements of the dosage form. The specific preparation prescription table is shown in Table 29.

[0262] Table 29 6'-O-cafeoyl arbutin pharmaceutical preparation prescription table

[0263] Preparation method: The prescription amount of sterile and non-bacterial endotoxin polyethylene glycol 40000 is melted in a 90℃ water bath. Sterile and non-bacterial endotoxin 6'-O-caffeoyl arbutin powder is added to the melted PEG, and stirred vigorously to uniformly disperse and dissolve. The mixture is quickly poured onto a pre-cooled stainless steel plate, spread into a thin layer, and allowed to quickly solidify. The solid block is broken, ground, and sieved through an 80-mesh sieve to obtain a uniform solid dispersion powder. The powder is divided into sterile vials in a sterile operation cabinet. Add a sterile rubber plug, fully press the plug, and seal with an aluminum cap.

[0264] Before use: add 5mL of water for injection, shake gently, and it will be reconstituted into a clear solution within 30 seconds.

[0265] The present application prepares 6'-O-caffeoyl arbutin as a sterile powder, with a weight percentage of 6'-O-caffeoyl arbutin in the drug of 20%. The provided prescription achieves a solubility of 6'-O-caffeoyl arbutin of 50mg / ml, increasing the solubility of the drug.

[0266] Example 33 Preparation of 6'-O-caffeoyl arbutin lyophilized injection This example aims to provide a 6'-O-caffeoyl arbutin lyophilized injection, solving the problem of poor water solubility of 6'-O-caffeoyl arbutin, and meeting the preparation and clinical administration needs of this dosage form. The specific preparation prescription table is shown in Table 30.

[0267] Table 30 Prescription table for preparation of 6'-O-caffeoyl arbutin drug

[0268] Preparation method: In container 1, heat the prescription amount of most (about 80%) of water for injection, and add the prescription amount of isotonicity adjusting agents, antioxidants, and other water-soluble components, and stir until completely dissolved. In container 2, dissolve 6'-O-caffeoyl arbutin in the prescription amount of polyethylene glycol 4000, and heat at 90℃ to aid dissolution, forming a clear solution. Slowly add the PEG-6'-O-caffeoyl arbutin solution obtained in container 2 to the water phase in container 1 with stirring, and mix well. Make up to full volume with the remaining water for injection. Adjust the pH of the solution to the specified range using a pH adjuster. Filter sterilize with 0.45μm and 0.22μm microporous filter membranes in sequence. Fill the filtrate into sterile vials under sterile conditions, half-plug, and put into a freeze dryer. Pre-freeze at -45℃ for 2h in the freeze dryer, then perform sublimation drying (-20℃, 0.5mbar, 12h; 5℃, 0.5mbar 12h) and desorption drying (30℃, 0.1mbar, 3h). Fully plug, remove from the box, and roll the cap. Finally, perform a sealability and visible foreign matter check.

[0269] The present application prepares 6'-O-caffeoyl arbutin into lyophilized injection, the weight percentage of 6'-O-caffeoyl arbutin in the medicine is 9.1%, the provided prescription makes the solubility of 6'-O-caffeoyl arbutin reach 20 mg / ml, and the solubility of the medicine is increased.

[0270] Example 34 Preparation of 6'-O-caffeoyl arbutin polyethylene glycol 400-polyvinyl pyrrolidone synergistic solubilization injection The present application provides a 6'-O-caffeoyl arbutin polyethylene glycol 400-polyvinyl pyrrolidone synergistic solubilization injection, solves the problem of poor water solubility of 6'-O-caffeoyl arbutin, and meets the preparation and clinical administration requirements of the dosage form. The specific preparation prescription table is shown in Table 31.

[0271] Table 31 6'-O-caffeoyl arbutin pharmaceutical preparation prescription table

[0272] Preparation method: About 1.4 mL of water for injection is taken in a beaker, sodium citrate buffer salt is added, stirred and dissolved, polyethylene glycol 400 and polyvinyl pyrrolidone (K12 or K15 or K17) are added, 6'-O-caffeoyl arbutin is added, heated and stirred or ultrasonic is used to make it completely dissolved, and then mixed uniformly. The volume is made up to 2.0 mL with water for injection. The pH is finely adjusted to 6.0-6.5 with 0.1M HCl / NaOH. The solution is filtered and sterilized through a 0.22μm polyether sulfone (PES) filter membrane. In a sterile condition, it is filled into 2mL ampoules, and sealed. It is sterilized at 121℃ for 15 min. Leak detection and lamp inspection are performed.

[0273] Or the filtrate is filled into a Schlenk flask in a sterile condition, half-capped, and then put into a freeze dryer. In the freeze dryer, pre-freezing is performed at-45℃ for 2h, followed by sublimation drying (-20℃, 0.5mbar, 12h; 5℃, 0.5mbar 12h) and analytical drying (30℃, 0.1mbar, 3h). Full pressure plug, case out, and cap crimping are performed. Finally, sealing and visible foreign matter inspection are performed.

[0274] The present application prepares 6'-O-caffeoyl arbutin into lyophilized injection, the weight percentage of 6'-O-caffeoyl arbutin in the medicine is 9.1%, the provided prescription makes the solubility of 6'-O-caffeoyl arbutin reach 20 mg / ml, and the solubility of the medicine is increased.

[0275] Example 35 Preparation of 6'-O-caffeoyl arbutin polyethylene glycol 400-polyvinyl pyrrolidone synergistic solubilization injection The present embodiment aims to provide a 6'-O-caffeoyl arbutin polyethylene glycol 400-polyvinylpyrrolidone synergistic solubilization injection, to solve the problem of poor water solubility of 6'-O-caffeoyl arbutin, and to meet the preparation and clinical administration needs of the dosage form. The specific preparation prescription table is shown in Table 32.

[0276] Table 32 6'-O-caffeoyl arbutin pharmaceutical preparation prescription table

[0277] Preparation method: Take about 1.4 mL of water for injection in a beaker, add sodium citrate buffer salt, stir to dissolve, add polyethylene glycol 400 and polyvinylpyrrolidone (K12 or K15 or K17), add 6'-O-caffeoyl arbutin, heat and stir or ultrasonic to completely dissolve, mix evenly. Use water for injection to constant volume to 2.0 mL. Fine adjustment of pH to 6.0~6.5 with 0.1M HCl / NaOH. The solution is filtered through a 0.22μm polyether sulfone (PES) filter membrane to remove bacteria. In a sterile condition, fill in 2mL ampoule, seal. 121℃ wet heat sterilization for 15 min. Leak detection, lamp inspection.

[0278] Or the filtrate is filled in a sterile condition in a Schlenk flask, half stoppering, into a freeze dryer. In the freeze dryer, pre-freeze at-45℃ for 2h, then perform sublimation drying (-20℃, 0.5mbar, 12h; 5℃, 0.5mbar 12h) and analytical drying (30℃, 0.1mbar, 3h). Full stoppering, out of the box, capping. Finally, perform leak tightness and visible foreign matter inspection.

[0279] The present application prepares 6'-O-caffeoyl arbutin into an injection, the weight percentage content of 6'-O-caffeoyl arbutin in the drug is 2.5%, the solubility of 6'-O-caffeoyl arbutin reaches 25mg / ml, and the solubility of the drug is increased.

[0280] Example 36 Preparation of 6'-O-caffeoyl arbutin polyethylene glycol 4000-polyvinylpyrrolidone synergistic solubilization injection The present embodiment aims to provide a 6'-O-caffeoyl arbutin polyethylene glycol 4000-polyvinylpyrrolidone synergistic solubilization injection, to solve the problem of poor water solubility of 6'-O-caffeoyl arbutin, and to meet the preparation and clinical administration needs of the dosage form. The specific preparation prescription table is shown in Table 33.

[0281] Table 33 6'-O-caffeoyl arbutin pharmaceutical preparation prescription table

[0282] Preparation method: Take about 1.4 mL of water for injection in a beaker, add sodium citrate buffer salt, stir to dissolve, add polyethylene glycol 4000 and polyvinylpyrrolidone (K12 or K15 or K17), add 6'-O-caffeoyl arbutin, heat and stir or ultrasonic to completely dissolve, mix evenly. With water for injection to 2.0 mL. Fine adjustment of pH to 6.0~6.5 with 0.1M HCl / NaOH. The solution was filtered through a 0.22 μm polyether sulfone (PES) filter membrane to remove bacteria. In a sterile condition, fill in 2 mL ampoule, seal. 121℃ wet heat sterilization for 15 min. Leak detection, lamp inspection.

[0283] Or the filtrate is filled in a sterile condition in a Schlenk flask, half-capped, into a freeze dryer. In the freeze dryer, pre-freeze at -45℃ for 2 h, then sublimation drying (-20℃, 0.5mbar, 12h; 5℃, 0.5mbar 12h) and analytical drying (30℃, 0.1mbar, 3h). Full plug, out of the box, cap. Finally, perform a seal and visible foreign matter inspection.

[0284] The present application prepares 6'-O-caffeoyl arbutin into an injection, the weight percentage of 6'-O-caffeoyl arbutin in the medicine is 25%, the provided prescription makes the solubility of 6'-O-caffeoyl arbutin reach 25mg / ml, and the solubility of the medicine is increased.

[0285] Example 37 Preparation of 6'-O-caffeoyl arbutin hydroxypropyl betadex-polyvinylpyrrolidone synergistic solubilization injection The present application is to provide a 6'-O-caffeoyl arbutin hydroxypropyl betadex-polyvinylpyrrolidone synergistic solubilization injection, to solve the problem of 6'-O-caffeoyl arbutin difficult to dissolve in water, to meet the preparation and clinical drug delivery needs of the dosage form, and the specific preparation prescription table is shown in Table 34.

[0286] Table 34 6'-O-caffeoyl arbutin pharmaceutical preparation prescription table

[0287] Preparation method: Take about 1.4 mL of water for injection in a beaker, add sodium citrate buffer salt, stir to dissolve, add hydroxypropyl betacyclodextrin and polyvinylpyrrolidone (K12 or K15 or K17), add 6'-O-caffeoyl arbutin, heat and stir or ultrasonic to completely dissolve, mix evenly. With water for injection to 2.0 mL. Fine adjustment of pH to 6.0~6.5 with 0.1M HCl / NaOH. The solution was filtered through a 0.22μm polyether sulfone (PES) filter membrane to remove bacteria. In a sterile condition, fill in 2mL ampoule, seal. 121℃ wet heat sterilization for 15 min. Leak detection, lamp inspection.

[0288] Or the filtrate is filled in a sterile condition in a Schlenk flask, half stoppering, into a freeze dryer. In the freeze dryer, pre-freeze at -45℃ for 2h, then sublimation drying (-20℃, 0.5mbar, 12h; 5℃, 0.5mbar 12h) and analytical drying (30℃, 0.1mbar, 3h). Full stoppering, out of the box, capping. Finally, perform leak detection and visible foreign matter inspection.

[0289] The present application prepares 6'-O-caffeoyl arbutin into an injection, the weight percentage of 6'-O-caffeoyl arbutin in the freeze-dried drug is 45.5%, and the provided prescription makes the solubility of 6'-O-caffeoyl arbutin reach 25mg / ml, thereby increasing the solubility of the drug.

[0290] Example 38 Preparation of 6'-O-caffeoyl arbutin sulfobutyl betacyclodextrin sodium-polyvinylpyrrolidone synergistic solubilization injection The present application provides a 6'-O-caffeoyl arbutin sulfobutyl betacyclodextrin sodium-polyvinylpyrrolidone synergistic solubilization injection, solves the problem of poor water solubility of 6'-O-caffeoyl arbutin, and meets the preparation and clinical administration requirements of the dosage form. The specific preparation prescription table is shown in Table 35.

[0291] Table 35 6'-O-caffeoyl arbutin drug preparation prescription table

[0292] Preparation method: Take about 1.4 mL of water for injection in a beaker, add sodium citrate buffer salt, stir to dissolve, add sulfobutyl betacyclodextrin sodium and polyvinylpyrrolidone (K12 or K15 or K17), add 6'-O-caffeoyl arbutin, heat and stir or ultrasonic to completely dissolve, mix evenly. With water for injection to 2.0 mL. Fine adjustment of pH to 6.0~6.5 with 0.1M HCl / NaOH. The solution is filtered through a 0.22μm polyether sulfone (PES) filter membrane to remove bacteria. In a sterile condition, fill in 2mL ampoule, fusion seal. 121℃ wet heat sterilization for 15 min. Leak detection, lamp inspection.

[0293] Or the filtrate is filled in a sterile condition in a Schlenk flask, half stoppering, into a freeze dryer. In the freeze dryer, pre-freeze at -45℃ for 2 h, then sublimation drying (-20℃, 0.5mbar, 12h; 5℃, 0.5mbar 12h) and analytical drying (30℃, 0.1mbar, 3h). Full stoppering, out of the box, capping. Finally, perform the sealability and visible foreign matter inspection.

[0294] The present application prepares 6'-O-caffeoyl arbutin into an injection, the weight percentage of 6'-O-caffeoyl arbutin in the freeze-dried drug is 45.5%, and the provided prescription makes the solubility of 6'-O-caffeoyl arbutin reach 25mg / ml, thereby increasing the solubility of the drug.

[0295] Example 39 Preparation of 6'-O-caffeoyl arbutin polyvinylpyrrolidone solubilization injection The present application provides a 6'-O-caffeoyl arbutin polyvinylpyrrolidone solubilization injection, solves the problem of poor water solubility of 6'-O-caffeoyl arbutin, and meets the preparation and clinical administration requirements of the dosage form. The specific preparation prescription table is shown in Table 36.

[0296] Table 36 6'-O-caffeoyl arbutin drug preparation prescription table

[0297] Preparation method: Take the appropriate amount of water for injection in a beaker, add polyvinylpyrrolidone (K12 or K15 or K17), add 6'-O-caffeoyl arbutin, heat and stir or ultrasonic to completely dissolve, mix evenly. With water for injection to 2.0 mL. Fine adjustment of pH to 6.0~6.5 with 0.1M HCl / NaOH. The solution is filtered through a 0.22μm polyether sulfone (PES) filter membrane to remove bacteria. In a sterile condition, fill in 2mL ampoule, fusion seal. 121℃ wet heat sterilization for 15 min. Leak detection, lamp inspection.

[0298] or the filtrate is filled into a sterile condition in a flask, half-capped, into a freeze dryer. In the freeze dryer, pre-freezing is carried out at -45℃ for 2 hours, and then sublimation drying (-20℃, 0.5mbar, 12h; 5℃, 0.5mbar 12h) and desorption drying (30℃, 0.1mbar, 3h) are carried out. Full pressure is sealed, the box is taken out, and the cap is crimped. Finally, the sealing and visible foreign matter inspection are carried out.

[0299] The present application prepares 6'-O-caffeoyl arbutin into an injection, the weight percentage content of 6'-O-caffeoyl arbutin in the freeze-dried drug is 33.3%, and the provided prescription makes the solubility of 6'-O-caffeoyl arbutin reach 25mg / ml, thereby increasing the solubility of the drug.

[0300] Example 40 Preparation of 6'-O-caffeoyl arbutin inhalation powder / rectal administration agent The present application provides a 6'-O-caffeoyl arbutin inhalation powder / rectal administration agent, solves the problem of poor water solubility of 6'-O-caffeoyl arbutin, and meets the preparation and clinical administration requirements of the dosage form. The specific preparation prescription table is shown in Table 37.

[0301] Table 37 Preparation prescription table of 6'-O-caffeoyl arbutin drug

[0302] Preparation method: An appropriate amount of water is taken in a beaker, polyvinylpyrrolidone (K12 or K15 or K17 or K25 or K30 or K90) is added, 6'-O-caffeoyl arbutin is added, heating and stirring or ultrasonic are used to completely dissolve it, and water is used to constant volume, and then it is frozen and dried in a freeze dryer. The material is discharged, crushed, and other appropriate excipients are added to prepare an inhalation powder or a rectal administration agent.

[0303] The present application prepares 6'-O-caffeoyl arbutin into a cosolute, the weight percentage content of 6'-O-caffeoyl arbutin in the drug is 36%, and the provided prescription makes the solubility of 6'-O-caffeoyl arbutin reach 35mg / ml, thereby increasing the solubility of the drug.

[0304] Example 41 Preparation of 6'-O-caffeoyl arbutin sulfobutyl betadex sodium cyclodextrin inclusion injection The present application provides a 6'-O-caffeoyl arbutin sulfobutyl betadex sodium cyclodextrin inclusion injection, solves the problem of poor water solubility of 6'-O-caffeoyl arbutin, and meets the preparation and clinical administration requirements of the dosage form. The specific preparation prescription table is shown in Table 38.

[0305] Table 38. Formulation table for the preparation of 6'-O-caffeoylarbutin.

[0306] Preparation method: Take an appropriate amount of water for injection into a beaker, add sodium sulfobutyl betacyclodextrin and 6'-O-caffeoyl arbutin, heat and stir or sonicate until completely dissolved and mixed. Make up to volume with water for injection. Finely adjust the pH to 6.0-6.5 with 0.1M HCl / NaOH. Filter the solution through a 0.22μm polyethersulfone (PES) membrane for sterilization. Aseptically fill into 2mL ampoules and seal. Sterilize by moist heat at 121℃ for 15 min. Perform leak checks and visual inspection.

[0307] Alternatively, the filtrate can be aseptically filled into vials, partially stoppered, and placed in a freeze dryer. Pre-freeze at -45°C for 2 hours, followed by sublimation drying (-20°C, 0.5 mbar, 12 hours; 5°C, 0.5 mbar, 12 hours) and desorption drying (30°C, 0.1 mbar, 3 hours). Fully stopper, remove from the freezer, and crimp cap. Finally, check for airtightness and visible foreign matter.

[0308] This invention prepares 6'-O-caffeoylarbutin into an injection. The weight percentage of 6'-O-caffeoylarbutin in the lyophilized drug is 38.5%. The provided formulation enables the solubility of 6'-O-caffeoylarbutin to reach 30 mg / ml, thereby increasing the solubility of the drug.

[0309] Example 42 Preparation of 6'-O-caffeoylarbutin hydroxypropyl betacyclodextrin inclusion complex injection This embodiment aims to provide a 6'-O-caffeoylarbutin hydroxypropyl betacyclodextrin-encapsulated injection to solve the problem of poor water solubility of 6'-O-caffeoylarbutin, and to meet the preparation and clinical administration requirements of this dosage form. The specific preparation formula is shown in Table 39.

[0310] Table 39. Formulation table for the preparation of 6'-O-caffeoylarbutin.

[0311] Preparation method: Take an appropriate amount of water for injection in a beaker, add hydroxypropyl betacyclodextrin and 6'-O-caffeoyl arbutin, heat and stir or sonicate until completely dissolved and mixed. Make up to volume with water for injection. Finely adjust the pH to 6.0-6.5 with 0.1M HCl / NaOH. Filter the solution through a 0.22μm polyethersulfone (PES) membrane for sterilization. Aseptically fill into 2mL ampoules and seal. Sterilize by moist heat at 121℃ for 15 min. Perform leak checks and visual inspection.

[0312] Alternatively, the filtrate can be aseptically filled into vials, partially stoppered, and placed in a freeze dryer. Pre-freeze at -45°C for 2 hours, followed by sublimation drying (-20°C, 0.5 mbar, 12 hours; 5°C, 0.5 mbar, 12 hours) and desorption drying (30°C, 0.1 mbar, 3 hours). Fully stopper, remove from the freezer, and crimp cap. Finally, check for airtightness and visible foreign matter.

[0313] This invention prepares 6'-O-caffeoylarbutin into an injection. The weight percentage of 6'-O-caffeoylarbutin in the lyophilized drug is 38.5%. The provided formulation enables the solubility of 6'-O-caffeoylarbutin to reach 30 mg / ml, thereby increasing the solubility of the drug.

[0314] Example 43 Preparation of 6'-O-caffeoylarbutin dry suspension This embodiment aims to provide a 6'-O-caffeoylarbutin dry suspension to solve the problem of poor water solubility of 6'-O-caffeoylarbutin, and to meet the preparation and clinical administration requirements of this dosage form. The specific preparation formula is shown in Table 40.

[0315] Table 40. Formulation table for the preparation of 6'-O-caffeoylarbutin.

[0316] The above raw materials are crushed, mixed evenly, and packaged to obtain 6'-O-caffeoylarbutin dry suspension.

[0317] This invention prepares 6'-O-caffeoylarbutin as a dry suspension, with 6'-O-caffeoylarbutin comprising 50% by weight in the lyophilized drug. The provided formulation achieves a solubility of 2.8 mg / ml for 6'-O-caffeoylarbutin, thereby increasing the drug's solubility.

[0318] Example 44 Preparation of 6'-O-caffeoylarbutin gel This embodiment aims to provide a 6'-O-caffeoylarbutin gel to solve the problem of poor water solubility of 6'-O-caffeoylarbutin, and to meet the preparation and clinical administration requirements of this dosage form. The specific preparation formula is shown in Table 41.

[0319] Table 41. Formulation table for the preparation of 6'-O-caffeoylarbutin.

[0320] Mix the above raw materials evenly and package them to obtain 6'-O-caffeoylarbutin gel.

[0321] This invention prepares 6'-O-caffeoylarbutin into a gel, with 6'-O-caffeoylarbutin comprising 65% by weight in the lyophilized drug. The provided formulation achieves a solubility of 3.2 mg / ml for 6'-O-caffeoylarbutin, thereby increasing the drug's solubility.

[0322] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

The application of 1,6'-O-caffeoylarbutin in the preparation of drugs for treating dementia, characterized in that, The chemical structure of the 6'-O-caffeoylarbutin is shown in Formula 1. Equation 1.

2. The application according to claim 1, characterized in that, The treatment for dementia includes improving cognitive impairment; The dementia mentioned includes Parkinson's dementia or Alzheimer's disease.

3. The application according to claim 1, characterized in that, The causes of the dementia include the abnormal aggregation of α-synuclein; The drug treats dementia by inhibiting the activation and release of pro-inflammatory factors by microglia and repairing cell damage; the repair of cell damage includes repair of at least one type of damage in neurons, astrocytes, and oligodendrocytes. The application of 4,6'-O-caffeoylarbutin in the preparation of drugs for treating Parkinson's disease, characterized in that, The chemical structure of the 6'-O-caffeoylarbutin is shown in Formula 1.

5. The application according to claim 4, characterized in that, The Parkinson's disease mentioned includes Parkinson's dementia.

6. The application according to claim 1 or 5, characterized in that, The drug contains 6'-O-caffeoylarbutin and pharmaceutically acceptable excipients; The 6'-O-caffeoylarbutin has a weight percentage of 0.9% to 99% in the drug.

7. The application according to claim 6, characterized in that, Pharmaceutically acceptable excipients include lipid-soluble or water-soluble excipients.

8. The application according to claim 7, characterized in that, The lipid-based solubilizing excipients include one or more of the following: soybean oil, corn oil, medium-chain triglycerides, glyceryl monooleate, glyceryl monolinoleate, caprylic / capric acid, hydrogenated castor oil, polyoxyethylene castor oil, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer, poloxamer, polyethylene glycol 400, polyethylene glycol 1000, and polyethylene glycol 4000. The water-soluble solubilizing excipients include one or more of the following: polyvinylpyrrolidone K12, polyvinylpyrrolidone K15, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, polyvinylpyrrolidone K90, polyethylene glycol 400, polyethylene glycol 4000, sodium sulfobutyl betacyclodextrin, and hydroxypropyl betacyclodextrin.

9. The application according to claim 7, characterized in that, The dosage forms of the drug include oral dosage forms, injectable dosage forms, mucosal drug delivery dosage forms, cavity drug delivery dosage forms, or external dosage forms; The oral dosage forms include powders, tablets, granules, capsules, solutions, emulsions, or suspensions; The injectable dosage form includes an injection solution or a sterile powder for injection; The mucosal drug delivery dosage forms include eye drops, nasal drops, ophthalmic ointments, mouthwashes, sublingual tablets, adhesive tablets, or patches; The cavity drug delivery dosage forms include aerosols, sprays, powders, drops, or pellets; The cavity includes the respiratory tract; The topical dosage form includes gels.

10. The application according to claim 9, characterized in that, When the drug is in an oral dosage form, the pharmaceutically acceptable excipients include lipid solubilizing excipients; When the drug is in the form of an injectable formulation, the pharmaceutically acceptable excipients include water-soluble solubilizing excipients; The water-soluble solubilizing excipients include polyethylene glycol 400 and polyvinylpyrrolidone K12.

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