CN113350284A - Pterostilbene nano eye drops and preparation method thereof - Google Patents
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Abstract
The invention discloses pterostilbene nanometer eye drops and a preparation method thereof, wherein the pterostilbene nanometer eye drops comprise pterostilbene serving as a main drug and are characterized by also comprising glycosyl hesperidin serving as a pharmaceutical auxiliary material, wherein the mass ratio of the pterostilbene to the glycosyl hesperidin is 1:15-1:30, and the pterostilbene nanometer eye drops are characterized by also comprising the glycosyl hesperidin (CAS registration number 161713-86-6, molecular formula C)34H44O20Is divided intoSub-amount 772.7) purity is more than or equal to 96 percent. The pterostilbene eye drops prepared by the invention have the advantages that the administration concentration can reach 1mg/ml, the micelle particle size is small, the distribution range is uniform, the medicine stability is good, the local safety of eyes is good, and meanwhile, glycosyl hesperidin has activities such as anti-inflammation and the like, so that the pterostilbene eye drops have good synergistic medicine effects of eyes on treating diabetic keratopathy and corneal neuropathy, and the pterostilbene nano eye drops have good economy.
Description
Technical Field
The invention relates to pterostilbene eye drops, in particular to high-stability pterostilbene nano eye drops and a preparation method thereof.
Background
Pterostilbene (CAS number 537-42-8) is an effective component derived from Pterostilbene, blueberry, grape and Pterocarpus marsupium, and has anticancer, antiinflammatory, antioxidant and analgesic effects. At present, a great deal of research shows that pterostilbene has a good effect in the treatment and the protection of skin diseases, particularly in the fields of oxidation resistance and the like. The pterostilbene has various pharmacological activities of preventing and treating cardiovascular diseases, resisting tumors, resisting oxidation and the like, has good medicinal value and has great development potential. The latest research shows that the pterostilbene has wide pharmacological activities of resisting oxidation and inflammation, removing free radicals and the like, and has wide application prospects in the aspect of treating diabetes and complications thereof, such as diabetic keratopathy. However, pterostilbene has the following defects, which seriously affect the development and utilization of the pterostilbene: (1) the solubility of the pterostilbene in water is about 0.03mg/ml at 20 ℃ in the water phase; (2) the molecular structure is unstable, the pterostilbene contains phenolic hydroxyl which is extremely unstable, so that the stability of the pterostilbene is extremely poor, and the pterostilbene is extremely unstable and easy to oxidize in an aqueous solution; (3) short half-life period, poor biological membrane permeability and extremely low bioavailability for oral administration and the like. The above disadvantages severely limit the clinical application of pterostilbene, especially the clinical application in ophthalmology. In clinical ophthalmic medicine treatment, water-soluble eye drops are the most widely used preparations, and more than 90% of clinical ophthalmic medicines are water-soluble eye drops. The defects of pterostilbene severely limit the development of aqueous eye drops. Therefore, there is a great need to further explore safe, economical and effective pterostilbene drugs for ocular treatment of diabetic keratopathy and corneal neuropathy.
Glycosyl hesperidin (CAS registry number 161713-86-6, molecular formula C)34H44O20Molecular weight 772.7) is a novel solubilizer widely used in the production of food, beverage and flavoring. The research of the inventor finds that glycosyl hesperidin with the concentration of 50mg/ml does not find obvious local irritation to eyes in eye drops, and indicates that the glycosyl hesperidin is suitable for ocular drug delivery.
Disclosure of Invention
The invention aims to provide an innovative pterostilbene nano eye drop, which improves the stability of pterostilbene molecules, improves the drug absorption rate after eye drop administration, improves the storage stability of the eye drop, and simultaneously improves the eye safety, and meanwhile, a carrier for constructing the pterostilbene micelle eye drop is a natural and safe small molecular substance and has the effects of resisting inflammation and the like, so that the constructed pterostilbene micelle eye drop has the synergistic drug effect of treating diabetic keratopathy and corneal neuropathy by eyes, glycosyl hesperidin is selected as a micelle nano carrier, a weak acid microenvironment in a micelle structure is provided, and the stability of the pterostilbene eye drop is improved.
The invention also aims to provide a preparation method of the pterostilbene micelle eye drops.
The technical idea of the invention is as follows: pterostilbene has definite pharmacological activities of oxidation resistance, inflammation resistance, diabetes resistance, neuroprotection and the like, but the application of pterostilbene in ophthalmic drug treatment is severely limited by the problems of extremely unstable molecular structure, difficult water solubility, low oral bioavailability and the like of the pterostilbene, particularly the eye drops are mainly aqueous solutions, and phenolic hydroxyl groups in the molecular structure of the pterostilbene are extremely unstable and are extremely easy to oxidize and inactivate in the aqueous solutions. The pterostilbene is prepared into the eye drops which are stable in aqueous solution and can be used for local eyes, the curative effect of the local application of the eyes can be effectively improved, the nano-drug delivery system is adopted to construct the pterostilbene into the nano eye drops, the nano-drug delivery system has the unique advantages of further improving the stability of the pterostilbene eye drops, prolonging the corneal residence time after administration and enhancing the curative effect, and the micromolecule natural product with bioactivity is adopted as a carrier for constructing the pterostilbene nano eye drops, so that the pterostilbene eye drops are effectively constructed, and the curative effect of the pterostilbene eye drops can be further enhanced because the carrier has pharmacological activity. The research of the inventor finds that no obvious local ocular irritation is found in eye drops of glycosyl hesperidin with the concentration of 50mg/ml, which indicates that the glycosyl hesperidin is suitable for ocular drug delivery; in addition, glycosyl hesperidin can spontaneously form a micelle-like nanostructure in an aqueous solution, plays a role in solubilizing pterostilbene, can protect the entrapped pterostilbene from being oxidized and inactivated due to the strong antioxidant activity of the glycosyl hesperidin, is weakly acidic, and can provide a microenvironment in a weakly acidic micelle for maintaining the stability of the pterostilbene.
The technical scheme of the invention is as follows: the pterostilbene micelle solution eye drops comprise pterostilbene as a main drug and are characterized by also comprising glycosyl hesperidin as a drug auxiliary material, wherein the mass ratio of the pterostilbene main drug to the glycosyl hesperidin is 1:15-1: 30.
The glycosyl hesperidin (CAS registry number 161713-86-6, molecular formula C)34H44O20Molecular weight 772.7) purity is more than or equal to 96 percent.
The preparation method of the eye drops comprises the following steps: dissolving pterostilbene and glycosyl hesperidin into absolute ethyl alcohol, carrying out water bath rotation at 40 ℃ and vacuum evaporation on the ethanol to form a uniform film in a container, adding distilled water to fully wash the film, carrying out water bath ultrasound to obtain a micelle solution, measuring and adjusting the mass percentage concentration of the pterostilbene to be 0.02-0.1%, adding a preservative, a pH regulator and an isoosmotic adjusting agent according to needs, and carrying out sterile filtration and subpackaging. Wherein the antiseptic, pH regulator, and isotonic regulator can be added according to conventional technique.
The particle size range of the pterostilbene micelle eye drops prepared by the preparation method of the pterostilbene micelle eye drops is 6-15 nm.
In the preparation method of the pterocarpus santalinus bunge eye drops, the used buffer solution is a phosphate buffer solution or a borate buffer solution commonly used for eye drops, and the pH value is 6.5-6.8.
The pterostilbene micelle eye drops prepared by the invention have good solubility of pterostilbene in an aqueous solution, the solubility of the pterostilbene can reach 10mg/ml, the micelle has extremely small particle size, uniform distribution range and good drug stability. The pterostilbene micelle eye drops not only improve the stability of pterostilbene in an aqueous solution state, but also obviously reduce the administration irritation, improve the absorption of a cornea to a medicament, reduce the administration concentration, prolong the action time of the medicament, and reduce the administration times, so that the compliance of a patient can be improved, and simultaneously glycosyl hesperidin has the activities of resisting inflammation and the like, so that the pterostilbene micelle eye drops have good synergistic drug effects of treating diabetic keratopathy and corneal neuropathy in an eye. Therefore, the pterostilbene nano eye drops have good economical efficiency.
Detailed Description
The present invention will be described in further detail below with reference to specific examples.
Example 1:
placing 10mg pterostilbene and 150mg glycosyl hesperidin into a 100mL round-bottom flask, adding 50mL absolute ethyl alcohol, fully dissolving, carrying out water bath rotation at 40 ℃ and vacuum evaporation of the absolute ethyl alcohol to obtain a uniformly dispersed film of the drug and the copolymer, then adding distilled water, fully washing the film, and carrying out water bath ultrasound at 300w power for 10min to obtain a micelle solution. And (3) filtering the micelle solution with a 0.22-micron microporous filter membrane, adding a preservative benzalkonium chloride and an isotonic regulator sodium chloride, adjusting the pH to 6.5, diluting to 10ml, performing sterile filtration, and packaging. The average particle size of the pterostilbene micelle measured by a laser particle sizer is 10.1nm, the dispersion index PDI is 0.015, and the dispersion uniformity is good. The pterostilbene micelle eye drop is stored for 3 months at room temperature, and the leakage amount of pterostilbene from the micelle is less than 10%.
Example 2:
placing 10mg pterostilbene and 300mg glycosyl hesperidin into a 100mL round-bottom flask, adding 50mL absolute ethyl alcohol, fully dissolving, carrying out water bath rotation at 40 ℃ and vacuum evaporation of the absolute ethyl alcohol to obtain a uniformly dispersed film of the drug and the copolymer, then adding distilled water, fully washing the film, and carrying out water bath ultrasound at 300w power for 10min to obtain a micelle solution. And (3) filtering the micelle solution with a 0.22-micron microporous filter membrane, adding a preservative benzalkonium chloride and an isotonic regulator sodium chloride, adjusting the pH to 6.6, diluting to 10ml, performing sterile filtration, and packaging. The average particle size of the pterostilbene micelle measured by a laser particle sizer is 10.7nm, the dispersion index PDI is 0.021, and the dispersion uniformity is good. The pterostilbene micelle eye drop is stored for 2 months at room temperature, and the leakage amount of pterostilbene from the micelle is less than 10%.
Example 3:
placing 2mg pterostilbene and 30mg glycosyl hesperidin into a 100mL round-bottom flask, adding 50mL absolute ethyl alcohol, fully dissolving, carrying out water bath rotation at 40 ℃ and vacuum evaporation of the absolute ethyl alcohol to obtain a uniformly dispersed film of the drug and the copolymer, then adding distilled water, fully washing the film, and carrying out water bath ultrasound at 300w power for 10min to obtain a micelle solution. And (3) filtering the micelle solution with a 0.22-micron microporous filter membrane, adding a preservative benzalkonium chloride and an isotonic regulator sodium chloride, adjusting the pH to 6.8, diluting to 10ml, performing sterile filtration, and packaging. The average particle size of the pterostilbene micelle measured by a laser particle sizer is 10.5nm, the dispersion index PDI is 0.019, and the dispersion uniformity is good. The pterostilbene micelle eye drop is stored for 2.5 months at room temperature, and the leakage amount of pterostilbene from the micelle is less than 10%.
Example 4:
placing 2mg pterostilbene and 60mg glycosyl hesperidin into a 100mL round-bottom flask, adding 50mL absolute ethyl alcohol, fully dissolving, carrying out water bath rotation at 40 ℃ and vacuum evaporation of the absolute ethyl alcohol to obtain a uniformly dispersed film of the drug and the copolymer, then adding distilled water, fully washing the film, and carrying out water bath ultrasound at 300w power for 10min to obtain a micelle solution. And (3) filtering the micelle solution with a 0.22-micron microporous filter membrane, adding a preservative benzalkonium chloride and an isotonic regulator sodium chloride, adjusting the pH to 6.8, diluting to 10ml, performing sterile filtration, and packaging. The average particle size of the pterostilbene micelle measured by a laser particle sizer is 10.5nm, the dispersion index PDI is 0.019, and the dispersion uniformity is good. The pterostilbene micelle eye drop is stored for 2.5 months at room temperature, and the leakage amount of pterostilbene from the micelle is less than 10%.
Example 5:
placing 5mg pterostilbene and 100mg glycosyl hesperidin into a 100mL round-bottom flask, adding 50mL absolute ethyl alcohol, fully dissolving, carrying out water bath rotation at 40 ℃ and vacuum evaporation of the absolute ethyl alcohol to obtain a uniformly dispersed film of the drug and the copolymer, then adding distilled water, fully washing the film, and carrying out water bath ultrasound at 300w power for 10min to obtain a micelle solution. And (3) filtering the micelle solution with a 0.22-micron microporous filter membrane, adding a preservative benzalkonium chloride and an isotonic regulator sodium chloride, adjusting the pH to 6.8, diluting to 10ml, performing sterile filtration, and packaging. The average particle size of the pterostilbene micelle measured by a laser particle sizer is 11.2nm, the dispersion index PDI is 0.020, and the dispersion uniformity is good. The pterostilbene micelle eye drop is stored for 2.5 months at room temperature, and the leakage amount of pterostilbene from the micelle is less than 10%.
Experimental effects example 1: the effectiveness test of the 0.1 percent pterostilbene nano eye drops.
Experimental drugs: 0.1% pterostilbene nano eye drops (prepared in example 1, set as solution 1 group).
Control drugs: 0.1% pterostilbene eye drops (set as solution 2) were prepared with a phosphate buffer containing 15% propylene glycol.
Experimental animals and experimental methods: since STZ-induced diabetic mice serve as a well-recognized model of human diabetic lesions, the contents of this section were studied using this model. A C57BL/6 mouse is selected as a male mouse, the mouse is 6-8 weeks old, and the weight of the mouse is 18-25 g (purchased from Beijing Wittingle laboratory animal technology Co., Ltd.). Animals were randomly divided into two groups, one group was injected intraperitoneally with freshly prepared citrate buffer (pH 4.5) to prepare STZ solution, 5 days of continuous injection, and blood glucose was measured for each mouse on day 8 (one week after) after the last (fifth injection) for 3 days, and blood glucose values of STZ-injected groups of more than 300mg/dL (16.7mmol/L) were considered successful in type i diabetes model. When the experiment was taken for 12 weeks, the mice were monitored for weight and blood glucose in the same manner, and mice meeting the various parameter indexes and the conditions for taking tissue material were used for the experiment. The other group was injected with citrate buffer without STZ as a normal control. The experimental results show that the STZ intraperitoneal injection modeled mice gradually show typical symptoms of diabetes such as polydipsia, polyphagia, polyuria, weight loss and the like, the blood sugar is stably maintained at a higher level, and the weight is lower than that of normal mice (table 1), which indicates that the modeling is successful.
TABLE 1 weight and blood glucose measurements at sample points in normal and diabetic model mice: (
n＝40)
After the mice are molded for 12 weeks, a corneal epithelium scraping operation is performed to establish a diabetic cornea/nerve injury model, PBS, 0.1% pterostilbene micelle eye drops (prepared in example 1 and set as a solution 1 group) and 0.1% pterostilbene eye drops (set as a solution 2 group) are respectively given to the mice, the two groups are dropped in the eye 3 times a day, slit lamps are used for observing and photographing after corneal fluorescein staining at different time points, the corneal epithelium defect area is quantitatively analyzed, and on the 7 th day, a corneal tactile measuring instrument is selected to detect the corneal nerve sensitivity of each group of diabetic mice.
As a result, it was found that: compared with the PBS control group, the solution 2 group has no obvious effect of promoting the healing of the diabetic mice after corneal injury, and has no obvious difference (P is more than or equal to 0.05) compared with the PBS control group at each time point, while the eye drop administration of the solution 1 group effectively promotes the corneal epithelium repair of the model mice, and has obvious difference (P is less than 0.05) compared with the PBS control group at each time point.
The corneal sensitivity detection result shows that compared with the PBS control group, the solution 2 group does not significantly promote the corneal sensitivity recovery of diabetic mice, and each time point has no significant difference (P is more than or equal to 0.05) compared with the PBS control group, while the solution 1 group is eye drop-administered to effectively promote the sensitivity recovery of model mice, and each time point has significant difference (P is less than 0.05) compared with the PBS control group.
Experimental effect example 2: cytotoxicity test of 0.1% pterostilbene nanometer eye drop.
Experimental drugs: 0.1% pterostilbene nano eye drops (prepared in example 1, set as solution 1 group).
Control drugs: PBS solution
The experimental method comprises the following steps: experiments were performed using a human corneal epithelial cell line. Each well of 24-well culture plate is inoculated with 2X 104After culturing the cells in DMEM/F12(1:1) containing 10% fetal bovine serum for 48 hours, the cells were replaced with serum-free medium for downstream experiments. HCECs are prepared into single cell suspension by using culture solution containing 10% fetal calf serum, the single cell suspension is inoculated to a 96-well plate at the density of 1000-3000 cells/well, and PBS and solution 1 group are added for treatment after 24 hours of culture. After the cells are added with the solution and incubated for 4 hours and 24 hours respectively, the original culture solution is discarded, the culture solution is replaced by a serum-free culture medium containing 0.5mg/ml MTT, the incubation is continued for 4 hours, the supernatant is discarded, 150ul DMSO is added into each hole, the mixture is shaken for 10 minutes to fully dissolve the bluish purple crystals in the cells, and the light absorption value at 490nm is measured by an enzyme linked immunosorbent assay detector.
The solution 1 group cells of the present invention were found to be free of cytotoxicity after 4 hours incubation.
Experimental effect example 3: the storage stability of the 0.1 percent pterostilbene nanometer eye drops.
Experimental drugs: 0.1% pterostilbene nano eye drops (prepared in example 1, set as solution 1 group).
The experimental method comprises the following steps: preparing 0.1% pterostilbene nanometer eye drops (prepared in example 1 and set as 1 group of solution), packaging in a 2ml ampoule, storing at 25 ℃ in a dark place, periodically taking the eye drops, filtering by adopting a 0.22 mu m microporous membrane, measuring the concentration of pterostilbene drugs in the solution before and after the filtration by using a high performance liquid chromatography, and calculating the storage stability of the eye drops.
Experimental results show that the 0.1% pterostilbene nano eye drops (prepared in example 1 and set as solution 1 group) have good storage stability, the content of pterostilbene after 20 weeks of storage is over 90%, and the chemical structure changes such as oxidation and the like of the pterostilbene are preliminarily verified by adopting high performance liquid chromatography for detection and separation.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the scope of the present invention is not limited thereto. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (3)
1. A high-stability pterostilbene nanometer eye drop comprises pterostilbene as a main drug and is characterized by also comprising glycosyl hesperidin as a drug auxiliary material, wherein the mass ratio of the pterostilbene main drug to the glycosyl hesperidin is 1:15-1: 30; dissolving pterostilbene main drug and glycosyl hesperidin drug auxiliary material in absolute ethyl alcohol, uniformly forming a film in a container by water bath rotary vacuum evaporation of an organic solvent at 40 ℃, adding distilled water to fully wash the film, and performing water bath ultrasonic treatment to obtain a micellar solution, wherein the final mass percentage concentration of the pterostilbene is 0.02-0.1%, and the particle size range of the pterostilbene is 6-15 nm; and finally adding a preservative, a pH regulator and an isotonic regulator, and performing sterile filtration and subpackage.
2. The pterostilbene eye drops as claimed in claim 1, wherein the concentration of the pterostilbene main drug is 0.02-0.1%.
3. Pterostilbene eye drops according to claim 1, wherein the glycosyl hesperidin (CAS denden) is presentNotation 161713-86-6, molecular formula C34H44O20Molecular weight 772.7) purity is more than or equal to 96 percent.
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| CN114983986A (en) * | 2022-06-21 | 2022-09-02 | 温州医科大学 | Application of pterostilbene modified nitrogen-containing functionalized graphene nanocomposite in preparation of slow-release medicine for treating xerophthalmia and preparation method |
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