CN113616797B - Low-water-solubility polyphenol drug carrier and preparation method and application thereof - Google Patents
Low-water-solubility polyphenol drug carrier and preparation method and application thereof Download PDFInfo
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- CN113616797B CN113616797B CN202110885476.8A CN202110885476A CN113616797B CN 113616797 B CN113616797 B CN 113616797B CN 202110885476 A CN202110885476 A CN 202110885476A CN 113616797 B CN113616797 B CN 113616797B
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- 150000008442 polyphenolic compounds Chemical class 0.000 title claims abstract description 58
- 235000013824 polyphenols Nutrition 0.000 title claims abstract description 58
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 239000003937 drug carrier Substances 0.000 title abstract description 24
- KJXSIXMJHKAJOD-LSDHHAIUSA-N (+)-dihydromyricetin Chemical compound C1([C@@H]2[C@H](C(C3=C(O)C=C(O)C=C3O2)=O)O)=CC(O)=C(O)C(O)=C1 KJXSIXMJHKAJOD-LSDHHAIUSA-N 0.000 claims abstract description 122
- 239000003814 drug Substances 0.000 claims abstract description 93
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 74
- 229940079593 drug Drugs 0.000 claims abstract description 62
- KQILIWXGGKGKNX-UHFFFAOYSA-N dihydromyricetin Natural products OC1C(=C(Oc2cc(O)cc(O)c12)c3cc(O)c(O)c(O)c3)O KQILIWXGGKGKNX-UHFFFAOYSA-N 0.000 claims abstract description 61
- 239000004094 surface-active agent Substances 0.000 claims abstract description 49
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims abstract description 34
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims abstract description 34
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- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 claims abstract description 27
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- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 6
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- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 6
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 6
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 6
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 6
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- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 6
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- OCZVHBZNPVABKX-UHFFFAOYSA-N 1,1-diphenyl-2-(2,4,6-trinitrophenyl)hydrazine;ethanol Chemical compound CCO.[O-][N+](=O)C1=CC([N+](=O)[O-])=CC([N+]([O-])=O)=C1NN(C=1C=CC=CC=1)C1=CC=CC=C1 OCZVHBZNPVABKX-UHFFFAOYSA-N 0.000 description 3
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- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
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- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Communicable Diseases (AREA)
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- Gastroenterology & Hepatology (AREA)
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Abstract
The invention relates to the technical field of medicament preparation, and provides a low-water-solubility polyphenol medicament carrier, a preparation method and application thereof, in order to solve the problems that the medicament carrier in the prior art is short in slow release time and cannot realize early-stage quick release and later-stage slow release. The drug carrier capable of slowly releasing the low water-solubility polyphenol drugs is prepared from monoglyceride (GMO), sorbitan oleate (Span 80), ethyl oleate and water, and is an aggregate based on a surfactant, so that the low water-solubility polyphenol drugs can be released continuously. For the whole release period, the drug release time can reach at least 38 hours, the slow release effect is achieved, and the taking times of the dihydromyricetin can be reduced. And the accumulated release rate of the carrier to the low water-solubility polyphenol medicines can reach more than 92 percent.
Description
Technical Field
The invention relates to the technical field of medicament preparation, in particular to a low-water-solubility polyphenol medicament carrier, and a preparation method and application thereof.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
Dihydromyricetin (DMY), a woody vine plant extracted from Ampelopsis genus of Vitaceae family, also useful fructus Hoveniae extract, wherein the main active ingredient is flavonoid, and the substance has various peculiar effects of scavenging free radical, resisting oxidation, resisting thrombosis, resisting tumor, and relieving inflammation; the dihydromyricetin is a special flavonoid compound, and has the general characteristics of the flavonoid compound, and also has the effects of relieving alcoholism, preventing alcoholic liver and fatty liver, inhibiting liver cell deterioration, reducing the incidence rate of liver cancer and the like. Is good product for protecting liver, relieving hangover.
Dihydromyricetin is a polyphenol drug with low water solubility, has various pharmacological actions and biological activities, such as the like, but has poor solubility in aqueous solution, so that the dihydromyricetin is difficult to be absorbed and utilized by small intestine when being orally taken, which severely limits the application of the dihydromyricetin in practical application. In order to overcome the drawbacks of low water-solubility polyphenols such as dihydromyricetin, many formulations and carriers have been studied in recent years to ameliorate the drawbacks of such drugs, such as liposomes, microemulsions, lyotropic crystals, hydrogels, etc.
A surfactant is an amphiphilic compound having a hydrophilic head and a hydrophobic tail, the hydrophobic tails of the molecules associating with each other to form micelles, and when the concentration of surfactant exceeds a certain value, i.e. exceeds a critical micelle concentration, surfactant-based aggregates spontaneously form in aqueous solution. The aggregate has a lipophilic region for entrapping a low water-solubility drug therein, and can solubilize a hydrophobic drug. And the aggregate structure has viscoelasticity, can protect the medicine, and can realize slow release of the medicine.
However, the inventors have found that the sustained release time of the carrier drug containing the surfactant is short and the cumulative release rate is low. In addition, the existing low-water-solubility polyphenol drug carrier has a drug release rate of only 20-30% in the previous 500min, but in actual use, some drugs need to have a higher release rate in the early stage, and the later stage is used as consolidation reinforcement to need to be released continuously and slowly, and the existing drug carrier can not meet the use requirement.
Disclosure of Invention
The invention provides a low-water-solubility polyphenol drug carrier, a preparation method and application thereof, and aims to solve the problems that the drug carrier in the prior art is short in slow release time and cannot realize early-stage rapid release and later-stage slow release. The drug carrier capable of slowly releasing the low water-solubility polyphenol drugs is prepared from monoglyceride (GMO), sorbitan oleate (Span 80), ethyl oleate and water, and is an aggregate based on a surfactant, so that the low water-solubility polyphenol drugs can be released continuously. In addition, the release rate of the carrier within 500min reaches 50-70%, which is favorable for quick action and slow release in the later period, and is used for strengthening the action effect. For the whole release period, the drug release time can reach at least 38 hours, the slow release effect is achieved, and the taking times of the dihydromyricetin can be reduced. And the accumulated release rate of the carrier to the low water-solubility polyphenol medicines can reach more than 92 percent.
Specifically, the invention is realized by the following technical scheme:
in a first aspect of the invention, a low water-solubility polyphenol drug carrier is provided, wherein the carrier takes a glycerate monoester aggregate as a matrix, the aggregate comprises a surfactant, ethyl oleate and water, and the surfactant is the glycerate monoester and the sorbitan oleate.
In a second aspect, the invention provides a method for preparing a low water-solubility polyphenol drug carrier, comprising the following steps: mixing monoglyceride, sorbitan oleate, ethyl oleate and water.
In a third aspect, the invention provides an application of a low water-solubility polyphenol drug carrier in preparing antioxidant drugs, antibacterial drugs, anticancer drugs, liver protecting drugs and blood lipid regulating drugs.
In a fourth aspect of the invention, there is provided a carrier medicament comprising a low water solubility polyphenol medicament carrier.
In a fifth aspect of the present invention, there is provided a carrier medicament comprising a low water-soluble polyphenol medicament carrier and a low water-soluble polyphenol medicament.
In a sixth aspect of the invention, there is provided an antioxidant drug comprising a low water-solubility polyphenol drug carrier.
The technical scheme has the following beneficial effects:
1) The GMO, span80, ethyl oleate and water are utilized to prepare a drug carrier capable of slowly releasing the low water-solubility polyphenol drugs, and the drug carrier is an aggregate based on a surfactant, so that the low water-solubility polyphenol drugs, especially the dihydromyricetin, can be released continuously.
2) The prepared medicine carrier has the slow release effect on the release time of dihydromyricetin at least 38 hours. Can reduce the administration frequency of dihydromyricetin. And the accumulated release rate of the carrier to the dihydromyricetin can reach more than 92 percent.
3) The release rate of the drug carrier within 500min reaches 50-70%, which is helpful for quick action and slow release in later period, and is used for strengthening effect. In addition, the prepared carrier can change the in-vitro release rate of the medicine by adjusting the temperature. Experimental data show that the release of the carrier to the dihydromyricetin can reach 53h at room temperature and can reach 38h at the simulated human body temperature.
4) The medicine carrier prepared by the technical scheme of the invention has good antioxidant activity.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention. Embodiments of the present invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 is GMO-Span80 (1:1)/EtOL/H at 25 ℃ 2 Quasi-ternary phase diagram of O system.
Fig. 2 (a) storage modulus G' (solid) and loss modulus G "(hollow) of drug loaded samples A1, A2, A3 as a function of shear stress at 25 ℃. (b) Frequency scan curves (G "hollow, G' solid) for drug loaded samples A1, A2, A3 at 25 ℃. (c) Shear viscosity as a function of shear rate for drug loaded samples A1, A2, A3 at 25 ℃.
FIG. 3 is a standard curve of dihydromyricetin, and an inset shows the absorption spectrum of dihydromyricetin.
FIG. 4 is an in vitro release profile of dihydromyricetin in samples (a) A1, A2, A3, (B) B1, B2, B3, (C) C1, C2, C3 at 37 ℃.
FIG. 5 is an in vitro release profile of dihydromyricetin in samples (a) A1, A2, A3, (B) B1, B2, B3, (C) C1, C2, C3, (d) A1, A5, C5, E1 at 25 ℃.
FIG. 6 is a graph showing the DPPH radical scavenging activity of drug-loaded samples A1, A2, A3, and the graph showing the DPPH radical scavenging activity of dihydromyricetin ethanol solution.
Detailed Description
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions or under conditions recommended by the manufacturer.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments in accordance with the present disclosure. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.
The invention provides a low-water-solubility polyphenol drug carrier, a preparation method and application thereof, and aims to solve the problems that the drug carrier in the prior art is short in slow release time and cannot realize early-stage rapid release and later-stage slow release. The drug carrier capable of slowly releasing the low water-solubility polyphenol drugs is prepared from monoglyceride (GMO), sorbitan oleate (Span 80), ethyl oleate and water, and is an aggregate based on a surfactant, so that the low water-solubility polyphenol drugs can be released continuously. In addition, the release rate of the carrier within 500min reaches 50-60%, which is favorable for quick action and slow release in the later period and is used for strengthening the action effect. For the whole release period, the drug release time can reach at least 38 hours, the slow release effect is achieved, and the taking times of the dihydromyricetin can be reduced. And the accumulated release rate of the carrier to the low water-solubility polyphenol medicines can reach more than 92 percent.
Specifically, the invention is realized by the following technical scheme:
in a first aspect of the invention, a low water-solubility polyphenol drug carrier is provided, wherein the carrier takes a monoglyceride aggregate as a matrix, the aggregate comprises a surfactant, ethyl oleate (EtOL) and water, and the surfactant is monoglyceride and sorbitan oleate.
Some embodiments of the invention produce GMO-Span80/EtOL/H 2 An aggregate carrier constituted by the O system. When the aggregate based on the surfactant is used as a carrier, a raw material which is green and low in toxicity and harmless to organisms is required to be selected, and the monoglyceride glyceride is a nonionic surfactant and has good emulsifying property. Because of its better biocompatibility, it is widely used in the industries of medicine, cosmetics, textile industry, etc. And monoglyceride has the characteristic of biodegradability and is often used as an auxiliary material of a drug delivery system.
Span80 (Span 80) is named as sorbitan oleate, is a yellow viscous liquid, belongs to a nonionic surfactant, is a good emulsifier, and is widely applied to the production of foods, cosmetics, medicines, textiles and the like. Ethyl oleate is a substance with good food safety, is widely applied to food additives, and is often used as a raw material for preparing drug carriers.
In one or more embodiments of the present invention, the dihydromyricetin carrier comprises 2.8-68 parts by mass of surfactant, 0-25.2 parts by mass of ethyl oleate, 32-78 parts by mass of water, and the mass of ethyl oleate is not zero.
In order to further improve the slow release effect of the carrier and realize the effect of early-stage quick release and later-stage slow release, the mass ratio of the surfactant to the ethyl oleate is 4-6:4-6, preferably 6:4, 5:5 and 4:6.
The ratio of monoglyceride to sorbitan oleate affects the stability and sustained release of the carrier, and in some embodiments, the mass ratio of monoglyceride to sorbitan oleate is 1:0.5 to 1.5, preferably 1:1.
In one or more embodiments of the invention, the water is double distilled water;
preferably, the low water-solubility polyphenol drug carrier further comprises a low water-solubility polyphenol drug.
In a second aspect, the invention provides a method for preparing a low water-solubility polyphenol drug carrier, comprising the following steps: mixing monoglyceride, sorbitan oleate, ethyl oleate and water.
Because the reduction includes multiple esters, in order to enhance the mixing effect, avoiding the adverse effect of agglomeration or uneven mixing on the carrier, in some embodiments, the low water-solubility polyphenol drug mixes the monoglyceride, sorbitan oleate and ethyl oleate at temperature I, adds water, and mixes at temperature II;
preferably, the temperature I is 60-70 ℃;
preferably, the temperature II is 25 ℃.
The mixing is carried out under the water bath condition for heat preservation;
preferably, water is added dropwise;
preferably, the moisture is added multiple times;
preferably, the water addition amount is 1-3 parts by mass each time, and the water addition interval is 5min.
In this carrier system, if all water is added at once, it is easy to be unfavorable for the mixing of the monoglyceride, and the ethyl oleate. And because the water is added at two temperatures before and after the water is added, enough water is added at one time, the carrier system is influenced in terms of mixing, uniform temperature change and reaction uniformity, and the slow release effect or stability of the carrier is further reduced.
Preferably, the preparation method further comprises the step of adding low water-solubility polyphenol drugs, mixing the low water-solubility polyphenol drugs with sorbitan oleate, and then adding monoglyceride, ethyl oleate and water for mixing.
In a third aspect, the invention provides an application of a low water-solubility polyphenol drug carrier in preparing antioxidant drugs, antibacterial drugs, anticancer drugs, liver protecting drugs and blood lipid regulating drugs.
In a fourth aspect of the invention, there is provided a carrier medicament comprising a low water solubility polyphenol medicament carrier.
In a fifth aspect of the present invention, there is provided a carrier medicament comprising a low water-soluble polyphenol medicament carrier and a low water-soluble polyphenol medicament.
Preferably, the low water-solubility polyphenol medicine is dihydromyricetin;
preferably, the mass of the low water-solubility polyphenol medicine is 0.26mg/g based on the total mass of the carrier medicine.
In a sixth aspect of the invention, there is provided an antioxidant drug comprising a low water-solubility polyphenol drug carrier.
The invention will now be described in further detail with reference to the following specific examples, which should be construed as illustrative rather than limiting.
Instrument and reagent
TABLE 1 reagents used in the embodiment of the invention
TABLE 2 instruments used in the embodiments of the invention
Drawing of phase diagram
The mixed phase with the mass ratio of the monoglyceride to Span80 being 1:1 is taken as a surfactant phase, the ethyl oleate is taken as an oil phase, the mass ratio of the surfactant to the oil phase is weighed according to the change from 10:0 to 0:10 and placed in a colorimetric tube, the colorimetric tube is placed in a water bath at 65 ℃ for fully stirring and mixing, and then double distilled water is added dropwise and fully mixed with a gradient of increasing the water content by 2 wt%. The evenly mixed mixture is placed in a constant-temperature water bath at 25 ℃ for balancing, and after balancing is finished, experimental phenomena are observed and recorded. The equilibrium time is suitably extended near the phase boundary. The phase boundaries were preliminarily judged by observing the color, transparency, viscosity, etc. of the sample.
The invention is further illustrated below with reference to examples.
Example 1
The ratio of the surfactant to the oil is 6:4, the mass ratio of the monoglyceride of glyceric acid to the oleic acid ester of sorbitol anhydride is 1:1, the water content is 80%, the GMO and Span80 (serving as the surfactant) are weighed and placed in a colorimetric tube, and the ethyl oleate is added into the colorimetric tube and stirred and mixed uniformly under a water bath at 65 ℃. And finally, dropwise adding double distilled water into the colorimetric tube, wherein the water content is increased at 2% intervals, uniformly stirring by using a magnetic stirrer, then balancing in a water bath at 25 ℃, observing and recording the phase state and the appearance change of the aggregate, and properly prolonging the balancing time when approaching the phase boundary. The phase boundaries are preliminarily judged by observing the color, transparency, viscosity, etc. of the aggregates. Designated as A1.
Example 2
The ratio of the surfactant to the oil is 6:4, the mass ratio of the monoglyceride of glyceric acid to the oleic acid ester of sorbitol anhydride is 1:1, the water content is 68%, the GMO and Span80 (serving as the surfactant) are weighed and placed in a colorimetric tube, and the ethyl oleate is added into the colorimetric tube and stirred and mixed uniformly under a water bath at 65 ℃. And finally, dropwise adding double distilled water into the colorimetric tube, wherein the water content is increased at 2% intervals, uniformly stirring by using a magnetic stirrer, then balancing in a water bath at 25 ℃, observing and recording the phase state and the appearance change of the aggregate, and properly prolonging the balancing time when approaching the phase boundary. The phase boundaries are preliminarily judged by observing the color, transparency, viscosity, etc. of the aggregates. Denoted B1.
Example 3
The ratio of the surfactant to the oil is 6:4, the mass ratio of the monoglyceride of glyceric acid to the oleic acid ester of sorbitol anhydride is 1:1, the water content is 56%, the GMO and Span80 (serving as the surfactant) are weighed and placed in a colorimetric tube, and the ethyl oleate is added into the colorimetric tube and stirred and mixed uniformly under a water bath at 65 ℃. And finally, dropwise adding double distilled water into the colorimetric tube, wherein the water content is increased at 2% intervals, uniformly stirring by using a magnetic stirrer, then balancing in a water bath at 25 ℃, observing and recording the phase state and the appearance change of the aggregate, and properly prolonging the balancing time when approaching the phase boundary. The phase boundaries are preliminarily judged by observing the color, transparency, viscosity, etc. of the aggregates. Designated as C1.
Example 4
The ratio of the surfactant to the oil is 5:5, the mass ratio of the monoglyceride of glyceric acid to the oleic acid ester of sorbitol anhydride is 1:1, the water content is 80%, the GMO and Span80 (serving as the surfactant) are weighed and placed in a colorimetric tube, and the ethyl oleate is added into the colorimetric tube and stirred and mixed uniformly under the water bath at 65 ℃. And finally, dropwise adding double distilled water into the colorimetric tube, wherein the water content is increased at 2% intervals, uniformly stirring by using a magnetic stirrer, then balancing in a water bath at 25 ℃, observing and recording the phase state and the appearance change of the aggregate, and properly prolonging the balancing time when approaching the phase boundary. The phase boundaries are preliminarily judged by observing the color, transparency, viscosity, etc. of the aggregates. Designated as A2.
Example 5
The ratio of the surfactant to the oil is 4:6, the mass ratio of the monoglyceride of glyceric acid to the oleic acid ester of sorbitol anhydride is 1:1, the water content is 80%, the GMO and Span80 (serving as the surfactant) are weighed and placed in a colorimetric tube, and the ethyl oleate is added into the colorimetric tube and stirred and mixed uniformly under a water bath at 65 ℃. And finally, dropwise adding double distilled water into the colorimetric tube, wherein the water content is increased at 2% intervals, uniformly stirring by using a magnetic stirrer, then balancing in a water bath at 25 ℃, observing and recording the phase state and the appearance change of the aggregate, and properly prolonging the balancing time when approaching the phase boundary. The phase boundaries are preliminarily judged by observing the color, transparency, viscosity, etc. of the aggregates. Designated as A3.
Example 6
The ratio of the surfactant to the oil is 6:4, the mass ratio of the monoglyceride of glyceric acid to the oleic acid ester of sorbitol anhydride is 1:1, the water content is 45%, the GMO and Span80 (serving as the surfactant) are weighed and placed in a colorimetric tube, and the ethyl oleate is added into the colorimetric tube and stirred and mixed uniformly under a water bath at 65 ℃. And finally, dropwise adding double distilled water into the colorimetric tube, wherein the water content is increased at 2% intervals, uniformly stirring by using a magnetic stirrer, then balancing in a water bath at 25 ℃, observing and recording the phase state and the appearance change of the aggregate, and properly prolonging the balancing time when approaching the phase boundary. The phase boundaries are preliminarily judged by observing the color, transparency, viscosity, etc. of the aggregates. Designated as C5.
Preparation of drug-loaded samples
Accurately weighing 0.3g of dihydromyricetin, adding into a colorimetric tube with a plug containing 3.0g of span80, and mixing by vortex for 20 minutes. Sealing, and stirring in a water bath at 60deg.C for 12 hr to dissolve dihydromyricetin. Mixing Span80 containing dihydromyricetin with GMO, proportionally adding ethyl oleate, mixing at 65deg.C, adding required amount of double distilled water in batches, magnetically stirring, mixing, and balancing in water bath at 25deg.C.
Rheological experiments
The apparatus used for measuring the rheological properties of the samples was a Discovery HR-2 rheometer, and the measuring jig was a measuring plate with a diameter of 2cm and a cone angle of 2. The measurement set water bath temperature was 25 ℃. During measurement, the head of the rheometer is lifted to a designated position, and a sample to be measured is placed in the center of the sensor. And (3) adjusting the instrument, lowering the machine head to a designated position, controlling the thickness of a sample at the center of the sensor to be 0.053mm, setting instrument parameters, balancing the sample for 5min, and starting measurement.
And (3) fixing the frequency, selecting the stress value range to be 0.1-10000Pa, and carrying out stress scanning on all sample points to determine a linear viscoelastic region. And selecting a proper stress value in the linear viscoelastic region, re-sampling, and carrying out frequency scanning on the sample, wherein the scanning frequency range is 0.03-500rad/s. Then the sample is scanned in steady state, and the shearing rate is set to be 0.1-100s -1 . The temperature deviation should be less than 0.1 ℃ at the time of measurement.
In vitro release studies of drugs
In vitro release experiments of DMY in aggregates were performed at room temperature 25℃and physiological temperature 37℃respectively using dialysis. The small intestine environment was simulated with phosphate buffer (ph=6.8). 1.0g of the drug-loaded sample was placed in a dialysis bag (1000 Da), the dialysis bag was immersed in a beaker containing 60.0ml PBS buffer, and stirred at a constant speed using a magnet at 100 rpm. At regular intervals, 3.0ml of release medium was removed while the same volume of fresh release medium was added to the beaker. The absorbance of dihydromyricetin was measured at a wavelength of 293nm by an ultraviolet spectrophotometer (X-3, shanghai Yuan-Jiedu Co., ltd.), and the release amount of the drug was calculated to calculate the cumulative release rate of the drug.
Drug cumulative release rate = drug cumulative release amount/total amount of drug in carrier x 100%
Antioxidant study
The DPPH free radical scavenging activity method is adopted, the samples are diluted into 8 different concentrations by ethanol, and the concentration of the DPPH ethanol solution is prepared into 6 multiplied by 10 -5 mol/L. 2.0ml of sample solutions with different dilution concentrations are added into 1.0ml of DPPH ethanol solution, and the mixture is uniformly mixed by a vortex mixer and reacted for 30min in a dark place. Measuring absorbance at a wavelength of 450-650nm using ultraviolet spectrophotometer, determining measurement wavelength, measuring absorbance of sample at the wavelength, and recording as A 1 An equivalent amount of DPPH ethanol solution was used as a blank, and the absorbance thereof was designated A 0 。
RSA％＝(1-A 1 /A 0 )×100％
Results and discussion
(1) Phase behavior
GMO-Span80/EtOL/H at 25℃was studied 2 Quasi-ternary phase diagram of O system. As shown in FIG. 1, six areas are shown in the phase diagram of the system, including a golden yellow viscous flow area (I), a pale milky yellow semi-fluid viscous area (II), a pale milky yellow non-fluid viscosity relatively large inelastic area (III), a pale milky yellow non-fluid viscosity relatively large elastic area (IV), an area (V) with a pale milky yellow non-fluid elastic viscosity relatively small with the increase of the water content, and an area (VI) with a pale milky yellow fluid with the increase of the water content in a sample with a large surfactant ratio.
(2) Rheology of drug loaded samples
And (3) carrying out stress scanning on the medicine carrying sample at a fixed frequency to obtain a relation diagram of the elastic modulus G ', the viscous modulus G' and the shearing stress. It can be seen from fig. 2 (a) that the magnitude of the external shear stress is changed within a certain range, the elastic modulus and the viscous modulus of the aggregate remain substantially unchanged, and this region becomes a linear viscoelastic region in which the elastic modulus of the sample is higher than the viscous modulus, indicating that the elastic properties are dominant. When the stress increases to a certain value, the elastic modulus of the sample decreases rapidly with the increase of the stress value, and the study starts the stress with the decrease of the elastic modulusThe value is called critical stress (sigma) c ) Generally, at critical stress values, the greater the modulus of elasticity, the greater the ability of the sample to resist external forces.
To further investigate the effect of oscillations on the internal structure of the sample, the frequency scan was performed on the sample with a fixed shear stress at 25 ℃. The elastic modulus versus viscous modulus versus frequency curves are shown in fig. 2 (b), where the elastic modulus is greater than the viscous modulus for all three samples over the vibration frequency range, indicating that the elastic properties are dominant. Wherein the elastic modulus of the 12/8/80 sample (representing surfactant/ethyl oleate/water=12/8/80) is substantially unchanged in the vibration frequency range of 0.03-100rad/s, and the elastic modulus of the sample tends to increase when the frequency is greater than 100 rad/s. The elastic modulus of the 10/10/80 sample is substantially unchanged in the vibration frequency range of 0.03-40rad/s, and the elastic modulus of the sample tends to decrease when the frequency is greater than 44 rad/s. The elastic modulus of the 8/12/80 sample is substantially unchanged in the vibration frequency range of 0.03-100rad/s, and the elastic modulus of the sample tends to decrease when the frequency is greater than 100 rad/s. The viscous modulus of the three samples is substantially constant over the frequency range of 0.03-40rad/s, with the viscous modulus of the samples increasing when the frequency is greater than 44 rad/s. By converting the dynamic viscoelasticity results into a relaxation spectrum, the trend of the relaxation modulus over time is obtained. As can be seen from the relaxation spectrum, the relaxation modulus of the 12/8/80 sample is higher than that of the 10/10/80 sample at the early relaxation time, and the relaxation modulus of the 10/10/80 sample is higher than that of the 12/8/80 sample at the late relaxation time.
The steady state rheological properties may account for the magnitude of the aggregate's ability to resist external shear forces, with a higher shear viscosity indicating a greater ability of the sample to resist external shear forces. The plot of shear viscosity as a function of shear rate for all sample points is given in fig. 2 (c), with shear viscosity for all three samples decreasing with increasing shear rate, exhibiting shear-thinning non-newtonian fluid properties. And as the surfactant ratio is greater, the viscosity of the sample is greater, probably due to the greater surfactant content, the greater dihydromyricetin content in the sample, resulting in an increase in the viscosity of the sample.
(3) In vitro Release test
FIG. 3 is a standard curve of dihydromyricetin, and an inset shows the absorption spectrum of dihydromyricetin. From the ultraviolet absorption spectrum of the dihydromyricetin, the maximum absorption wavelength of the dihydromyricetin is 293nm, the absorbance of the dihydromyricetin with different concentrations at the maximum absorption wavelength is measured, and the standard curve of the dihydromyricetin is obtained by fitting: abs=0.01505+35.99c (mg/mL) R 2 ＝0.9961
Wherein Abs is absorbance of dihydromyricetin at 293nm, and C is concentration of dihydromyricetin
Table 3 shows the nomenclature and composition of the samples
FIG. 5 (a) is a graph showing the release profile of a sample containing 80% water at 25℃with varying ratios of V-zone surfactant to oil. From the release time of each sample in the graph, the sustained release of dihydromyricetin can be realized by all four samples (the release time can last 58 h). In the early release period (before 8 hours), the release rate of dihydromyricetin is high, the cumulative release rate reaches 60%, and the reason for the phenomenon is probably that part of drug molecules adhered to the surface of a sample are dissolved out, so that the release rate is high; as the release time increases, the dihydromyricetin dissolved in the surfactant and oil phase escapes through the surface film material, dissolution becomes relatively difficult, the release rate slows down, the rate of rise of the cumulative release rate slows down, and eventually the release plateau is reached. It can also be seen from the release profile that the greater the surfactant content in the sample, the smaller the cumulative release rate of dihydromyricetin, which can be explained by the stability of the sample, the greater the surfactant content of the sample, the greater the stability of the sample, and the greater the interaction between dihydromyricetin and the carrier, and therefore the smaller the cumulative release rate.
FIG. 4 (a) is a graph showing the release profile of a sample containing 80% water at 37℃with varying ratios of V-zone surfactant to oil. From the release profile, it can be seen that the four samples still achieve sustained release of dihydromyricetin (release time sustainable 38 h) at simulated physiological temperature. The release rate at 37 ℃ is faster than the release profile at 25 ℃, probably due to the increased thermal movement of the molecules and the increased diffusion rate of the drug, resulting in an increased release rate and an increased cumulative release rate. The application adopts different release kinetic models to fit a release curve, the fitting result is shown in table 2, and the fitting result shows that the release curve of an 8/12/80 sample accords with a Korsmeyer-Peppas equation at 25 ℃, the early release index of the sample is more than 0.89, which indicates that the release type in the period belongs to super CaseII transport, and the release in the period is mainly controlled by the erosion action of a polymer chain; and the release index of the sample is smaller than 0.5 in the middle and later stages of release, which indicates that the release of dihydromyricetin at the stage belongs to Fickian diffusion, and the release of the sample is controlled by the erosion swelling effect of the polymer. The early and middle release phases of the 6/14/80 sample accord with the zero order kinetic equation, which shows that the release process in the period is hardly controlled by concentration diffusion and is always released at a constant rate; and the middle and later release phases accord with a first-level kinetic equation, and the release is controlled by concentration diffusion. The early release phase of the 10/10/80 sample accords with a zero-order kinetic equation, the middle release phase accords with a first-order kinetic equation, and the later release phase accords with a Korsmeyer-Peppas equation, so that the release of the sample is controlled by the concentration diffusion and polymer swelling erosion. The early release phase of the 12/8/80 sample accords with a zero order kinetic equation, which shows that the early release is hardly controlled by concentration diffusion; the middle and later release phases conform to a first-order kinetic equation, which shows that the release of the sample at the middle and later release phases belongs to the release of concentration diffusion control. The mid-release of the 12/8/80, 10/10/80 and 8/12/80 samples at 37℃were all in accordance with the Korsmeyer-Peppas equation, where the 12/8/80 samples had a release index greater than 0.45 and less than 0.89, indicating that the release at this stage was due to non-Fickian diffusion, i.e., the release at this stage was controlled by both diffusion and erosion, as compared to 25 ℃; and the release indices of the 10/10/80 and 8/12/80 samples were less than 0.45, indicating that it is a Fickian diffusion. Whereas at the latter temperature only the mid-release period of the 8/12/80 sample was in accordance with the Korsmeyer-Peppas equation and the release type was super Case ii delivery, indicating that the temperature increase changed the release from erosion control of the polymer chains to diffusion and erosion control, again explaining the phenomenon that the temperature increase resulted in an increase in the cumulative release rate and release rate. FIG. 5 (b) is a graph showing the release profile of a 68% aqueous sample at 25℃with varying ratios of surfactant to oil in the IV region. From the release profile, it can be seen that the smaller the surfactant content in the sample, the greater the cumulative release rate of dihydromyricetin. The release kinetics analysis shows that the release early phase of the 19/13/68 sample accords with a zero order kinetics equation, which shows that the release at the stage is not controlled by concentration diffusion; the release middle period of the sample accords with the Korsmeyer-Peppas equation, and the release index is smaller than 0.45, which shows that the release middle period belongs to Fickian diffusion; the later release stage accords with a first-order kinetic equation, which shows that the later release stage is controlled by concentration diffusion. The release curves of samples 16/16/68 and 13/19/68 fit the first order kinetic equation, indicating that their release is concentration diffusion controlled. And the early and middle release phases of the 9.6/22.4/68 sample accord with the Korsmeyer-Peppas equation, the early release index is more than 0.89, which indicates that the release type in the early release phase belongs to super-Case II delivery, and the release in the early release phase is mainly controlled by the erosion action of the polymer chain; while the release index in the middle of release is less than 0.45, indicating that the release in this stage is Fickian diffusion; and the later release phase accords with a first-order kinetic equation, which shows that the release at the later stage is controlled by concentration diffusion.
FIG. 4 (b) is a graph showing the release profile of a 68% aqueous sample at 37℃with varying ratios of surfactant to oil in the IV region. From the release profile, it was found that the more surfactant content of the sample, the smaller the cumulative release rate, similar to the 25 c condition, probably due to the greater the dihydromyricetin content, the stronger the interaction with the carrier, resulting in a reduced cumulative release rate. The release kinetics analysis shows that the release of the four samples accords with a first-order kinetic equation, and the fitting index is larger than 0.92, which shows that the release of the samples in the phase region is controlled by concentration diffusion at 37 ℃.
In addition, fig. 4 shows that the release rate of the carrier reaches 50-70% within 500min, which is favorable for quick action and slow release in the later period, and is used for strengthening the action effect.
FIG. 5 (c) is a graph showing the release profile of a sample containing 56% water at 25℃with varying ratios of surfactant to oil in zone III, and it can be seen that the four samples all achieved slow release of dihydromyricetin. In the early release period (before 10 hours), the release rate of dihydromyricetin is higher, the cumulative release rate reaches 70%, and the reason for the phenomenon is probably that part of drug molecules adhered to the surface of a sample are dissolved out, so that the release rate is higher; as the release time increases, the dihydromyricetin dissolved in the surfactant and oil phase escapes through the surface film material, dissolution becomes relatively difficult, the release rate slows down, the rate of rise of the cumulative release rate slows down, and eventually the release plateau is reached. The release kinetics analysis shows that the release curve of the 26.4/17.6/56 sample accords with a first order kinetic equation, which shows that the release curve is mainly controlled by concentration diffusion. The early release phase of the 22/22/56 sample accords with the Korsmeyer-Peppas equation, and the release index is greater than 0.89, which indicates that the release type in the period belongs to super-CaseII delivery, and the release in the period is mainly controlled by the erosion action of the polymer chain; the release middle term accords with a first-level kinetic equation and is controlled by concentration diffusion; the late release phase conforms to the Korsmeyer-Peppas equation, with a release index less than 0.45, indicating that the release at this stage is Fickian diffusion. The earlier stage and later stage of the release curve of the 17.6/26.4/56 sample accords with a first-order kinetic equation, which shows that the release curve is controlled by concentration diffusion; whereas the mid-release curve conforms to the Korsmeyer-Peppas equation with a release index less than 0.45, indicating a release type Fickian diffusion at this stage. 13.2/30.8/56 samples, the early stage of the release curve accords with a first-order kinetic equation, which shows that the release in the stage is mainly controlled by concentration diffusion; both the mid and late release phases conform to the Korsmeyer-Peppas equation, with release indices less than 0.45, indicating that the release at this stage is Fickian release.
FIG. 4 (c) shows the release profile of a sample containing 56% water with a different ratio of surfactant to oil in zone III at 37℃and it can be seen from the release profile that the slow release of dihydromyricetin can be achieved for all four samples. The release curves of the three samples of 26.4/17.6/56, 17.6/26.4/56 and 13.2/30.8/56 all conform to the first-order kinetic equation, and the fitting indexes of the three samples are all larger than 0.96, which indicates that the release of the three samples is mainly controlled by concentration diffusion; the early phase of the release curve of the 22/22/56 sample accords with a zero-order kinetic equation, which shows that the early phase is not controlled by concentration diffusion and is released at a constant rate all the time; the middle and later stages of release conform to the first order kinetic equation, indicating that the middle and later stages are controlled by concentration diffusion.
Since the components and composition in the carrier have a significant effect on the release behaviour of the drug. This study explored the effect of samples with different water content on the release behavior of dihydromyricetin and fig. 5 (d) shows the release profile of samples with different water content on dihydromyricetin at 25 ℃. From the figure, it can be seen that, except for the 54/36/10 samples, which exhibited abrupt release, the more water content in the remaining samples, the faster the release rate, and the greater the cumulative release rate, probably due to the increased water content, the enhanced carrier swelling effect, and the greater the release rate of dihydromyricetin from the surfactant and oil phase to the aqueous phase.
Table 4 shows the release kinetics of the entrapped dihydromyricetin samples at 37℃over different periods
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Table 5 shows the release kinetics model and fitting parameters of the entrapped dihydromyricetin sample at 25deg.C
The K-P equation is known as the Korsmeyer-Peppas equation
(4) Antioxidant experiment
The antioxidant experiment adopts DPPH free radical scavenging activity. FIG. 6 is an antioxidative koji of a drug-loaded sampleThe line, inset, is the antioxidant profile of dihydromyricetin ethanol solution. It can be seen from the figure that the scavenging efficiency for free radicals increases with increasing dihydromyricetin content in the sample. IC for all samples compared to dihydromyricetin ethanol solution 50 The value is two orders of magnitude lower than that of the dihydromyricetin ethanol solution, which shows that the aggregate of the entrapped dihydromyricetin has better antioxidant activity.
The foregoing description is only a preferred embodiment of the present invention, and the present invention is not limited thereto, but it is to be understood that modifications and equivalents of some of the technical features described in the foregoing embodiments may be made by those skilled in the art, although the present invention has been described in detail with reference to the foregoing embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (15)
1. The low water-solubility polyphenol medicine is characterized in that a carrier takes a monoglyceride aggregate as a matrix, the aggregate comprises a surfactant, ethyl oleate and water, and the surfactant is monoglyceride and sorbitan oleate;
the active ingredient of the low water-solubility polyphenol medicine is dihydromyricetin;
the dihydromyricetin carrier comprises 2.8-68 parts by mass of surfactant, 0-25.2 parts by mass of ethyl oleate, 32-78 parts by mass of water and non-zero mass of ethyl oleate;
the mass ratio of the monoglyceride to the sorbitan oleate is 1:0.5-1.5.
2. The low water-soluble polyphenol drug according to claim 1, wherein the water is double distilled water.
3. A process for the preparation of a low water-soluble polyphenol as claimed in any of claims 1 to 2 comprising: mixing monoglyceride, sorbitan oleate, ethyl oleate and water.
4. The method of preparing a low water-soluble polyphenol drug according to claim 3, wherein the monoglyceride, sorbitan oleate and ethyl oleate are mixed at temperature I, water is added, and the mixture is mixed at temperature II.
5. The method for preparing a low water-soluble polyphenol drug according to claim 3, wherein the mass ratio of the monoglyceride to the sorbitan oleate is 1:1.
6. The method for preparing a low water-soluble polyphenol according to claim 4, wherein the temperature I is 60-70 ℃.
7. The method for preparing a low water-soluble polyphenol according to claim 4, wherein the temperature ii is 25 ℃.
8. The method for preparing a low water-soluble polyphenol drug according to claim 3, wherein the mixing is carried out under water bath conditions.
9. The method for preparing a low water-soluble polyphenol drug according to claim 8, wherein water is added dropwise.
10. The method for preparing a low water-soluble polyphenol drug according to claim 8, wherein the water is added in a plurality of times.
11. The method for preparing a low water-soluble polyphenol drug according to claim 8, wherein the water content is 1 to 3 parts by mass per time.
12. The method for preparing a low water-soluble polyphenol drug according to any of claims 1 to 2, wherein the active ingredient of the low water-soluble polyphenol drug is mixed with sorbitan oleate, and then monoglyceride, ethyl oleate and water are added to be mixed.
13. Use of a low water-soluble polyphenol as claimed in any of claims 1 to 2 in the manufacture of an antioxidant medicament.
14. The medicament according to claim 1, wherein the active ingredient of the low water-soluble polyphenol medicament has a mass of 0.26mg/g based on the total mass of the medicament.
15. An antioxidant drug comprising the low water-soluble polyphenol drug according to any one of claims 1 to 2, characterized in that the drug has an antioxidant effect.
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