CN113171341B - Berberine hydrochloride microemulsion, preparation method thereof and application thereof in antibacterial drugs - Google Patents

Berberine hydrochloride microemulsion, preparation method thereof and application thereof in antibacterial drugs Download PDF

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CN113171341B
CN113171341B CN202110441881.0A CN202110441881A CN113171341B CN 113171341 B CN113171341 B CN 113171341B CN 202110441881 A CN202110441881 A CN 202110441881A CN 113171341 B CN113171341 B CN 113171341B
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berberine hydrochloride
microemulsion
mixture
preparation
skin
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CN113171341A (en
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傅茂润
刘峰
韩聪
杜雅珉
焦文晓
甄文娜
刘金鹏
袁丽雪
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Qilu University of Technology
Shandong Analysis and Test Center
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Qilu University of Technology
Shandong Analysis and Test Center
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    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/02—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing liquids as carriers, diluents or solvents
    • A01N25/04—Dispersions, emulsions, suspoemulsions, suspension concentrates or gels
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • 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
    • A61P1/12—Antidiarrhoeals
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D1/00—Detergent compositions based essentially on surface-active compounds; Use of these compounds as a detergent
    • C11D1/66—Non-ionic compounds
    • C11D1/825—Mixtures of compounds all of which are non-ionic
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
    • C11D3/16—Organic compounds
    • C11D3/20—Organic compounds containing oxygen
    • C11D3/2003—Alcohols; Phenols
    • C11D3/2065—Polyhydric alcohols
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
    • C11D3/16—Organic compounds
    • C11D3/38—Products with no well-defined composition, e.g. natural products
    • C11D3/382—Vegetable products, e.g. soya meal, wood flour, sawdust
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
    • C11D3/48—Medical, disinfecting agents, disinfecting, antibacterial, germicidal or antimicrobial compositions
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D1/00—Detergent compositions based essentially on surface-active compounds; Use of these compounds as a detergent
    • C11D1/66—Non-ionic compounds
    • C11D1/667—Neutral esters, e.g. sorbitan esters
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D1/00—Detergent compositions based essentially on surface-active compounds; Use of these compounds as a detergent
    • C11D1/66—Non-ionic compounds
    • C11D1/74—Carboxylates or sulfonates esters of polyoxyalkylene glycols
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention relates to the field of berberine hydrochloride drug carriers, and particularly provides a berberine hydrochloride microemulsion, a preparation method thereof and application thereof in antibacterial drugs. The berberine hydrochloride microemulsion carrier comprises RH60, span80, EG and PSO. Weighing RH60, span80 and EG by mass, stirring and uniformly mixing at a certain temperature to form a first mixture, accurately weighing the first mixture and PSO according to a certain weight ratio, placing the components in a container, and stirring and uniformly mixing at a certain temperature to form a second mixture. And dropwise adding the water phase into the container, and uniformly mixing to obtain a third mixture, namely the target sample. The microemulsion drug carrier can play a role in synergy with berberine hydrochloride, and can reduce the dosage of berberine hydrochloride.

Description

Berberine hydrochloride microemulsion, preparation method thereof and application thereof in antibacterial drugs
Technical Field
The invention belongs to the technical field of berberine hydrochloride drug carriers, and particularly relates to a berberine hydrochloride microemulsion, a preparation method of the microemulsion and application of the microemulsion in antibacterial drugs, food cleaning agents and skin external preparations.
Background
The information in this background section is only for enhancement of 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 that is already known to a person of ordinary skill in the art.
Berberine hydrochloride is an isoquinoline alkaloid extracted from plants, also known as berberine. It is usually a yellow crystalline needle-like powder; no odor, extremely bitter taste; slightly soluble in water and ethanol. The existing research shows that the berberine hydrochloride has wide pharmacological actions including antibiosis, anti-inflammation, anti-tumor, arrhythmia resistance and insulin resistance, and is mainly used for intestinal infection, bacillary dysentery and the like in clinic. The berberine hydrochloride has poor intestinal absorption, and gastrointestinal tract reactions such as upper abdominal discomfort, inappetence, abdominal pain, diarrhea or constipation and the like easily occur after long-term application of a large dose, so that the frequency of medication of patients is frequent, the tolerance and the efficacy are poor, and the clinical application of the berberine hydrochloride is greatly limited. The berberine hydrochloride is embedded in the drug carrier, so that the defects can be effectively overcome, and the beneficial effect of the berberine hydrochloride can be exerted. At present, commercially available berberine hydrochloride preparations are mainly tablets and capsules, and with the development of preparation technology, the following carriers and dosage forms are developed in succession: orally disintegrating tablet, effervescent tablet, cyclodextrin clathrate, liposome, microcapsule, gel, microemulsion, and lyotropic liquid crystal.
Researchers find that the compatibility of certain medicines and preparations can generate synergistic action, so that the dosage of the medicines can be greatly reduced, and the toxic and side effects of the medicines are reduced. In the study of yoga in Jiangnan university, micelle is used for encapsulating anticancer drug DOX, and the half inhibition concentration (IC 50 value) of a drug-loaded micelle sample on cancer cells is obviously reduced compared with an anticancer drug solution under the same drug concentration. The adoption of a proper carrier for carrying out the entrapment on the medicine is expected to reduce the dosage of the indissolvable medicine and improve the side effect caused by the medicine which cannot be absorbed.
Disclosure of Invention
Based on the research background, the invention aims to construct a carrier with synergistic effect on berberine hydrochloride, enhance the treatment effect on diarrhea and other gastrointestinal diseases, and have significant research significance and application value on bacteriostasis, fresh-keeping effect and the like of fresh food surfaces (if vegetable raw materials, fresh-cut fruits and vegetables and clean vegetables) susceptible to food-borne pathogenic bacteria. In order to achieve the technical purpose, the invention provides the following technical scheme:
in a first aspect, the invention provides a berberine hydrochloride microemulsion, and provides an oil-in-water microemulsion, in order to realize the synergistic interaction, peony seed oil with certain antioxidant activity is adopted in the microemulsion.
The peony seed oil is edible and can be added into skin care products, the safety performance is good, the peony seed oil can cover the bad smell of berberine hydrochloride to a certain degree, and the compliance of medicine entrance is increased.
Based on the medicine and the oil phase, the invention also researches the components such as surfactant, cosurfactant and the like needed in the microemulsion. The microemulsion preparation provided by the invention is stable, the preparation and the medicament generate a synergistic effect, and the oxidation resistance and the antibacterial performance of the microemulsion preparation are obviously improved.
In a second aspect, the invention provides a preparation method of the berberine hydrochloride microemulsion preparation.
In the research of the preparation method, the mixing sequence and the temperature of the surfactant, the cosurfactant and the oil phase have obvious influence on the stability effect of the microemulsion preparation.
In addition, the oil-in-water microemulsion preparation is more suitable to be developed into an external preparation, such as a preparation for inhibiting bacteria on the surface of skin or the surface of fruits and vegetables.
In the existing research, berberine hydrochloride is commonly used for treating intestinal infection such as gastroenteritis and bacillary dysentery, eye conjunctivitis and suppurative otitis media. The berberine hydrochloride microemulsion provided by the invention can also be used for treating gastroenteritis, bacillary dysentery and other intestinal infections, conjunctivitis, suppurative otitis media and the like. According to the verification result of the invention, the berberine hydrochloride microemulsion preparation shows a synergistic antibacterial effect. According to the existing research results, berberine hydrochloride has good inhibitory effect on including dysentery bacillus, typhoid bacillus, pertussis bacillus, diphtheria bacillus staphylococcus aureus, hemolytic streptococcus, pneumococcus and amoeba protozoon, so the third aspect of the invention also provides the application of the berberine hydrochloride microemulsion in preparing antibacterial drugs.
In addition, the raw materials and the dosage of the berberine hydrochloride microemulsion provided by the first aspect of the invention are safe dosage, and the berberine hydrochloride microemulsion not only can be developed into an oral liquid preparation, but also can be used as an external preparation to exert the sterilization effect and the antioxidation effect.
Therefore, the invention also provides a food cleaning agent and a skin external preparation, and provides the application of the berberine hydrochloride microemulsion in the fields of food sterilization or skin sterilization and oxidation resistance.
The beneficial effects of one or more technical schemes are as follows:
1. the invention firstly provides a microemulsion preparation of berberine hydrochloride, the preparation process of the microemulsion preparation is simple and convenient, the average grain diameter of a microemulsion carrier is below 60nm, the grain diameter distribution is uniform, the structure is stable, and the prepared microemulsion can keep the stability for a long time (more than 60 days). The medicine is expected to achieve better absorption effect when entering the body, and the stability is good, thus being beneficial to industrial production and storage.
2. The microemulsion carrier provided by the invention has a synergistic interaction effect on berberine hydrochloride, and the verification proves that the antioxidant and bacteriostatic effects of the medicament in the form of the microemulsion preparation are improved. Based on the efficacy, the berberine hydrochloride microemulsion preparation can reduce the dosage of berberine hydrochloride during clinical medication, and is expected to reduce the side effect caused by the existing medication mode.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention.
FIG. 1 is a pseudo-ternary phase diagram of the RH 60-Span 80-EG/PSO/H2O system;
FIG. 2 is the variation of the particle size of the blank microemulsion and the microemulsion sample after loading berberine hydrochloride;
FIG. 3 is a graph of particle size versus time for different microemulsion samples;
FIG. 4 shows the DPPH.removing capacity of different samples;
FIG. 5 shows the effect of various samples on the inhibition of Staphylococcus aureus;
FIG. 6 is a graph of DPPH.scavenging capacity for different drugs in solution and microemulsion (1 for drug solution, 2 for drug microemulsion).
Detailed Description
It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
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 according to the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
As described in the background art, berberine hydrochloride is poorly absorbed from the intestinal tract and long-term high dose administration may result in severe gastrointestinal side effects. In order to solve the technical problems, the invention provides a berberine hydrochloride microemulsion preparation which can realize a synergistic effect with berberine hydrochloride and effectively improve the oxidation resistance and the antibacterial performance of the medicament.
The invention provides berberine hydrochloride microemulsion, which comprises berberine hydrochloride, a non-ionic surfactant, a cosurfactant, a water phase and an oil phase, and is characterized in that the oil phase is peony seed oil.
Conventional microemulsion formulations typically include four components-a surfactant, a co-surfactant, an oil phase, and an aqueous phase. Wherein the oil phase is injectable oil such as soybean oil, oleum Sesami, and oleum Camelliae. The technical scheme of the invention aims to improve the drug effect of berberine hydrochloride by the coating effect of the carrier and realize the synergistic effect. Based on the thought, the invention firstly conceives that the vegetable oil with pharmacodynamic activity is adopted as the oil phase, wherein the peony seed oil is the woody nut vegetable oil extracted from peony seeds, has good antioxidant effect, belongs to edible oil, is often added into skin care products, and is safe to use.
In order to provide a stable microemulsion preparation, the invention further researches the types and the proportions of the surfactant and the cosurfactant. The nonionic surfactant comprises one or a mixture of more of tween 80, tween 60, tween 40, span80, span 60, span 20, sucrose stearate, tristearin, hydrogenated castor oil or tristearin; the cosurfactant is an alcohol preparation, and comprises one or more of ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol, isoamyl alcohol, hexanol, octanol, glycerol, 1, 2-propylene glycol and ethylhexyl glycerol.
In a more effective embodiment, the surfactant comprises hydrogenated castor oil, specifically hydrogenated castor oil polyoxyethylene ether CO40 or hydrogenated castor oil polyethylene glycol ether RH60.
In a more effective embodiment, the surfactant further comprises span80 or span 20.
The invention further provides a combination of the surfactants, namely the surfactant is a combination of hydrogenated castor oil polyglycol ether RH60 and span 80; in this series of embodiments, the co-surfactant employs ethylhexylglycerin. In an embodiment of the first aspect of the present invention, the raw materials of the berberine hydrochloride microemulsion include berberine hydrochloride, hydrogenated castor oil polyethylene glycol ether RH60, span80, ethylhexylglycerin and water.
A large number of test results show that in the nonionic surfactant and the cosurfactant, hydrogenated castor oil polyglycol ether (RH 60), span80 (Span 80) and Ethylhexyl Glycerol (EG) are mixed according to a certain proportion, and after Peony Seed Oil (PSO) is added, water is added under continuous stirring, so that a uniform, transparent and long-term stable microemulsion carrier can be obtained; further, the weight ratio of the hydrogenated castor oil polyglycol ether (RH 60), span80 (Span 80) and Ethylhexyl Glycerol (EG) is 0.5-2.
In the berberine hydrochloride microemulsion, the weight ratio of berberine hydrochloride, hydrogenated castor oil polyethylene glycol ether RH60 (RH 60), span80 (Span 80), ethylhexyl Glycerol (EG), peony seed oil and water is 0.05-0.15: 1.5-2.5: 0.5 to 1.5: 0.5-1.5: 0.5-1.5: 90 to 99 percent.
In a further preferable scheme, the weight ratio of the berberine hydrochloride, the hydrogenated castor oil polyethylene glycol ether RH60 (RH 60), the Span80 (Span 80), the Ethylhexyl Glycerin (EG), the peony seed oil and the water is 0.08-0.12: 1.5-2.0: 0.5 to 1.0:0.5 to 1.0:0.5 to 1.0:92 to 97; further, the weight ratio is 0.07-0.11: 1.7-2.0: 0.7 to 1.0:0.7 to 1.0:0.7 to 1.0:93 to 96; in a specific embodiment, the weight ratio is 0.1:1.96:0.98:0.98:0.98:95.
in a second aspect of the present invention, a preparation method of the berberine hydrochloride microemulsion described in the first aspect is provided, wherein the preparation method comprises the following steps: and mixing the surfactant and the cosurfactant to obtain a first mixture, mixing the first mixture and the peony seed oil to obtain a second mixture, uniformly mixing the second mixture and berberine hydrochloride to obtain a third mixture, and adding water into the third mixture to obtain the berberine hydrochloride microemulsion.
The berberine hydrochloride microemulsion mainly aims to solve the technical problems of unsatisfactory water solubility and poor intestinal absorption effect of berberine hydrochloride. Aiming at the technical problem, the preparation of the oil-in-water microemulsion preparation is beneficial to improving the affinity of intestinal tracts to medicines and improving the absorption effect, and the preparation state is not easy to change once the preparation is diluted in a body, so that the preparation can keep good stability. Therefore, in the preparation method, firstly, the surfactant is mixed with the oil phase, and then the water is added, so that the O/W type microemulsion preparation is prepared.
In addition, the oil-in-water microemulsion preparation is more suitable to be developed into an external preparation, such as a preparation for inhibiting bacteria on the surface of skin or the surface of fruits and vegetables.
Furthermore, in the research process of the invention, the mixing temperature of the components has a more obvious influence on the stabilizing effect of the microemulsion preparation. The mixing temperature of the surfactant and the co-surfactant is preferably 30 to 80 ℃, and more preferably 45 to 55 ℃, specifically, for example, 46 ℃, 47 ℃, 48 ℃, 49 ℃, or 50 ℃, 51 ℃, 52 ℃ or the like. The first mixture is mixed with peony seed oil, and the second mixture is mixed with berberine hydrochloride at 20-30 deg.C, such as 22 deg.C, 23 deg.C, 24 deg.C, 25 deg.C, 26 deg.C or 27 deg.C, and can be mixed at room temperature (25 deg.C) by one skilled in the art.
Wherein, the second mixture and the berberine hydrochloride need a period of mixing time, and the prolonged mixing time is beneficial to obtaining a microemulsion preparation with smaller granularity and more uniformity, and the proper mixing time is 10-14 h according to the verification.
In addition, the water is added into the third mixture in a dropwise manner, and the required amount of water is slowly added into the third mixture, and the microemulsion is obtained by matching and stirring in the dropwise process.
In the third aspect of the invention, the berberine hydrochloride microemulsion is applied to the preparation of antibacterial drugs.
The antibacterial drug can be used for treating diseases caused by dysentery bacillus, typhoid bacillus, bordetella pertussis, diphtheria bacillus, staphylococcus aureus, hemolytic streptococcus, pneumococcus or amoeba.
In addition, the raw materials and the dosage of the berberine hydrochloride microemulsion provided by the first aspect of the invention are safe dosages, and the berberine hydrochloride microemulsion can be developed into an oral liquid preparation and can also be used for external sterilization and antioxidation.
Therefore, the invention also provides a food cleaning agent and a skin external preparation, and provides the application of the berberine hydrochloride microemulsion in the fields of food sterilization or skin sterilization and oxidation resistance.
In a fourth aspect of the invention, a food cleaning agent is provided, and the food cleaning agent comprises the berberine hydrochloride microemulsion of the first aspect, or raw materials in the microemulsion.
Preferably, the food cleaning agent can be used for cleaning fruits, vegetables and clean vegetables, and also comprises food utensils, wherein the food utensils are any one of tableware, food contact tools, equipment, containers and food packaging materials.
In a preferred embodiment, the cleaning method includes, but is not limited to, soaking or running water cleaning.
In the fifth aspect of the invention, a skin external preparation is provided, and the skin external lotion comprises the berberine hydrochloride microemulsion of the first aspect, or the raw materials in the microemulsion.
Preferably, the skin external preparation is an ointment, a cream, a gel, a aqua or a lotion; specific examples include skin lotion, skin cream, sunscreen cream, skin external medicine, etc.
In order to make the technical scheme of the present invention more clearly understood by those skilled in the art, the technical scheme of the present invention will be described in detail below with reference to specific examples and comparative examples, wherein the reagents in the following examples are all commercially available products.
Example 1
The preparation and performance research of the berberine acid microemulsion of the invention comprises the following research processes:
1. experimental setup
1. Preparation of the phase diagram
RH60, span80 and EG were weighed at a weight ratio of 2. The weight ratio of mix to PSO was accurately weighed from 0 to 10, and the components were placed in a colorimetric tube with a stopper and mixed well in a thermostatic water bath at 25 ℃. And continuously dropwise adding the water phase into the colorimetric tube, uniformly stirring by using a magnetic stirrer, and placing in a thermostatic water bath at 25 ℃ to achieve phase equilibrium. Phase boundaries are judged by visual inspection of aggregate clarity, hardness, viscosity, fluidity, etc.
2. Preparation of samples
Preparation of blank sample: the mass ratio of fixed texture/PSO was 8/2, RH 60/Span80/EG =2/1/1, and the water content of the sample was 95wt%. Firstly, weighing RH60, span80 and EG with corresponding mass, and stirring and mixing uniformly at 50 ℃; then, PSO with corresponding mass is weighed in the mixture and mixed evenly at 25 ℃. Weighing water with corresponding mass, and fully and uniformly mixing at 25 ℃.
Preparation of drug-loaded samples: the mass ratio of mix/PSO was fixed at 8/2, RH 60/Span80/EG =2/1/1, and the water content of the sample was 95wt%. First, a proper amount of berberine hydrochloride is weighed into a mixture of RH60, span80, EG and PSO, and stirred for 12 hours at 25 ℃ to fully mix the berberine hydrochloride and the mixture. Then weighing water with corresponding mass, and fully and uniformly mixing.
3. Dynamic Light Scattering (DLS)
The dynamic light scattering of the samples was determined using a Brookhaven NanoBrook instrument. The average particle size and PDI of the samples were measured at 25 ℃. The sample needs to be filtered through a 0.22 μm filter before measurement.
4. Scavenging DPPH (1, 1-diphenyl-2-trinitrophenylhydrazine radical) free radical
0.25mL of berberine hydrochloride microemulsion samples with different mass concentrations are added into 1.5mL of 0.1mmol/L DPPH absolute ethanol solution, and the mixture is placed for different times in a dark place. Determination of the absorbance A at 517nm 1 0.25mL of purified water was used as a blank control (A) instead of the sample 0 ) (ii) a Using 0.25mL sample and 1.5mL absolute ethyl alcohol mixed solution as sample contrast (A) 2 ). Each sample was repeated 3 times per mass concentration and averaged.
The DPPH-free radical scavenging operation of the berberine hydrochloride aqueous solution and the blank microemulsion is the same as that of the above.
The clearance SR is calculated according to the following formula: SR% = [ A ] 0 -(A 1 -A 2 )]/A 0 ×100％
2. Analysis of results
1. Act of phase
The weight ratio of RH 60/Span80/EG is 2; RH 60-Span 80-EG/PSO/H 2 The phase diagram of the O system at 25 ℃ is shown in FIG. 1. Two single phase regions were found: two solution phases (zone I and zone II). The region labeled "2 φ" is a two-phase region. More precisely, zone I is supplemented with 0 to 24% by weight of water and 0 to 28% by weight of waterPSO (particle swarm optimization). Zone II is charged with 48 to 100wt% water and 0 to 12wt% PSO.
2. Stability of the samples
The RH 60-Span 80-EG/PSO weight ratio is fixed to be 8/2, the water content is 95wt%, a sample is prepared, and the content of berberine hydrochloride of the drug-loaded sample is 1mg/g.
The particle size distribution of the blank microemulsion and the berberine hydrochloride microemulsion is determined by utilizing a dynamic light scattering technology, as shown in figure 2, the average particle size of a blank microemulsion sample is about 35nm, and the average particle size of the berberine hydrochloride microemulsion is about 50 nm. The introduction of berberine hydrochloride causes the particle size of the microemulsion to be slightly increased.
Next, the inventors investigated the stability of the blank microemulsion and the berberine hydrochloride microemulsion over 60 days (fig. 3). The average particle size and the PDI value were used as research indices. It can be found that the average particle size of the hollow white microemulsion and the berberine hydrochloride microemulsion is basically unchanged within 60 days and is respectively kept near 35nm and 50 nm. While the PDI values of the hollow microemulsion and the berberine hydrochloride microemulsion are slightly changed in 60 days, but are basically kept near 0.16 and 0.23 respectively, and the distribution of the samples is relatively uniform.
Combining the above results, both the blank microemulsion and berberine hydrochloride microemulsion show good structural stability.
3. Ability to scavenge DPPH & free radical
The DPPH and antioxidant properties of the blank microemulsion, the berberine hydrochloride microemulsion and the berberine hydrochloride aqueous solution are studied, and the results are shown in FIG. 4. It can be found that the berberine hydrochloride water solution has completed the DPPH.removing effect within 1 hour, and the removing rate is about 20 percent. Along with the increase of the action time, the berberine hydrochloride microemulsion has higher and higher clearance rate to DPPH & reach 20% after 6 hours, and the clearance rate to DPPH & reach 40% after 24 hours. The blank microemulsion showed a DPPH.clearance of less than 5% at different times, showing a very weak DPPH.clearance. Although the berberine hydrochloride microemulsion has lower DPPH removal capacity than the berberine hydrochloride aqueous solution in the early stage, the berberine hydrochloride microemulsion shows continuous removal capacity, and the removal rate of the berberine hydrochloride microemulsion is greater than the sum of the removal rates of the blank microemulsion and the berberine hydrochloride aqueous solution in 24 hours, which shows that the berberine hydrochloride and the microemulsion have synergistic effect on DPPH removal.
4. Inhibitory effect on Staphylococcus aureus
As shown in FIG. 5, the berberine hydrochloride aqueous solutions (a) with different concentrations (0.1, 0.5, 0.25, 0.125 mg/mL) have no obvious inhibition effect on Staphylococcus aureus, the berberine hydrochloride microemulsion (b) and the blank microemulsion (c) both have certain inhibition effect on Staphylococcus aureus, and the berberine hydrochloride microemulsion (b) has more obvious inhibition effect. When the concentration of the medicine is 0.1mg/mL, the diameters of inhibition zones of the medicine in the aqueous solution and the microemulsion are 1.05cm and 1.36cm respectively, and the diameter of the inhibition zone of the blank microemulsion is 1.23cm, which shows that the berberine hydrochloride and the microemulsion play a synergistic effect.
Example 2
In this embodiment, a preparation method of a berberine hydrochloride microemulsion is provided, which includes the following steps:
0.02g of berberine hydrochloride, 0.392g of RH60, 0.196g of Span80, 0.196g of EG, 0.196g of peony seed oil and 19g of water are respectively weighed. Fully and uniformly mixing RH60, span80 and EG at 50 ℃ to obtain a first mixture, mixing the first mixture with peony seed oil at room temperature (25 ℃) to obtain a second mixture; adding berberine hydrochloride powder into the second mixture at room temperature, and stirring for 12 hr to obtain the third mixture. And dripping the weighed water into the third mixture, and fully and uniformly mixing to obtain the berberine hydrochloride microemulsion.
Example 3
In this embodiment, another preparation method of a berberine hydrochloride microemulsion is provided, which includes the following steps:
0.015g of berberine hydrochloride, 0.310g of RH60, 0.185g of Span, 0.150g of EG, 0.150g of peony seed oil and 17g of water are respectively weighed. Fully and uniformly mixing RH60, span80 and EG at 80 ℃ to obtain a first mixture, mixing the first mixture with peony seed oil at 20 ℃ to obtain a second mixture; adding berberine hydrochloride powder into the second mixture at room temperature, and stirring for 10 hr to obtain the third mixture. And dripping the weighed water into the third mixture, and fully and uniformly mixing to obtain the berberine hydrochloride microemulsion.
Example 4
In this embodiment, another preparation method of berberine hydrochloride microemulsion is provided, which includes the following steps:
0.032g of berberine hydrochloride, 0.410g of RH60, 0.210g of Span80, 0.210g of EG, 0.210g of peony seed oil and 21g of water are respectively weighed. Fully and uniformly mixing RH60, span80 and EG at 75 ℃ to obtain a first mixture, mixing the first mixture with peony seed oil at 30 ℃ to obtain a second mixture; adding berberine hydrochloride powder into the second mixture at 30 deg.C, and stirring for 14 hr to obtain the third mixture. And dripping the weighed water into the third mixture, and fully and uniformly mixing to obtain the berberine hydrochloride microemulsion.
Comparative example 1
In the research process of the invention, a great deal of investigation is carried out on the types and the dosages of the surfactant and the cosurfactant, and the investigation result is shown in table 1:
TABLE 1. Varying the composition of the components of the sample, the appearance of the sample at different temperatures
Figure BDA0003035343200000101
In table 1, the samples were left at different temperatures for 30 days, and the appearance of the samples at different temperatures was observed, and it can be seen that RH60 and CO40, although being surfactant components with similar structures, are turbid when the temperature of the microemulsion is changed after conventional replacement, and the stabilizing effect of the microemulsion in examples 1 to 4 cannot be obtained.
Comparative example 2
In the research process of the invention, the proportion of each component in the microemulsion is also considered, the appearance of the samples after one day and 30 days of preparation is observed by changing the content of each component in the example 1, and the samples 4 and 10 are transparent microemulsion after one day but are turbid after 30 days, which indicates that the microemulsion structure is unstable. The other sample compositions did not constitute a transparent microemulsion.
TABLE 2 appearance of samples by varying the content of each component in the samples
Figure BDA0003035343200000102
Figure BDA0003035343200000111
Comparative example 3
This comparative example was carried out by constructing samples according to the preparation method of example 1 and judging the DPPH removing ability of different drugs in solution and microemulsion by changing the types of drugs in example 1, the drug content was 0.1mg/g, the reaction time was 24 hours, and the results are shown in FIG. 6, wherein 1 in the figure represents the aqueous drug solution preparation, and 2 represents the microemulsion preparation of the above drugs.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (12)

1. The berberine hydrochloride microemulsion is characterized by consisting of berberine hydrochloride, a non-ionic surfactant, a cosurfactant, a water phase and an oil phase, wherein the oil phase is peony seed oil, the non-ionic surfactant is hydrogenated castor oil polyethylene glycol ether RH60 and span80, and the cosurfactant is ethyl hexyl glycerol; in the berberine hydrochloride microemulsion, the weight ratio of the berberine hydrochloride, the hydrogenated castor oil polyglycol ether, the span80, the ethylhexyl glycerin, the peony seed oil and the water is 0.07 to 0.11:1.7 to 2.0:0.7 to 1.0:0.7 to 1.0:0.7 to 1.0:93 to 96;
wherein hydrogenated castor oil polyglycol ether/span 80/ethylhexyl glycerol =2/1/1;
the preparation method of the berberine hydrochloride microemulsion comprises the following steps: and mixing the surfactant and the cosurfactant to obtain a first mixture, mixing the first mixture and the peony seed oil to obtain a second mixture, uniformly mixing the second mixture and berberine hydrochloride to obtain a third mixture, and adding water into the third mixture to obtain the berberine hydrochloride microemulsion.
2. The berberine hydrochloride microemulsion of claim 1, wherein the mixing temperature of the surfactant and the co-surfactant is 50 ℃ or 75 ℃ or 80 ℃.
3. The berberine hydrochloride microemulsion according to claim 1, wherein the first mixture is mixed with peony seed oil, and the second mixture is mixed with berberine hydrochloride at 20 to 30 ℃; the second mixture and berberine hydrochloride need a period of mixing time, and the mixing time is 10 to 14h; and adding water into the third mixture in a required amount into the third mixture in a dropwise manner, and stirring in a matched manner in the dropwise process to obtain the microemulsion.
4. The berberine hydrochloride microemulsion of claim 3, wherein the first mixture is mixed with peony seed oil and the second mixture is mixed with berberine hydrochloride at room temperature.
5. The use of the berberine hydrochloride microemulsion according to claim 1 for the preparation of an antibacterial medicament.
6. The use of claim 5, wherein the antibacterial agent is useful for the treatment of diseases caused by Staphylococcus aureus.
7. A food cleaning agent, which is characterized in that the food cleaning agent comprises the berberine hydrochloride microemulsion according to claim 1.
8. The food detergent according to claim 7, wherein the food detergent is used for cleaning fruits, vegetables, clean vegetables, and also comprises cleaning food utensils, the food utensils comprising any one of tableware, food-contact tools, equipment, containers, and food packaging materials.
9. The food cleaning agent according to claim 8, wherein the cleaning means comprises a soaking or running water cleaning means.
10. A skin external preparation, wherein the skin external lotion comprises the berberine hydrochloride microemulsion according to claim 1.
11. The external preparation for skin according to claim 10, wherein the external preparation for skin is an ointment, a cream, a gel, a lotion or a lotion.
12. The external preparation for skin according to claim 10, wherein the external preparation for skin is skin lotion, skin cream, sunscreen, or external medicine for skin.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101474407A (en) * 2009-02-04 2009-07-08 西南大学 Application of span 60 and/or span 80 in promoting absorption of coptis alkaloid
CN104825389A (en) * 2015-04-10 2015-08-12 广东药学院 Berberine hydrochloride self-microemulsion preparation having good oral bioavailability and preparation method thereof
CN104920642A (en) * 2015-07-03 2015-09-23 山东省分析测试中心 Food-grade peony seed blend oil microemulsion and preparing method thereof
CN111939128A (en) * 2020-08-19 2020-11-17 山东省分析测试中心 Temperature-sensitive lyotropic liquid crystal drug carrier and preparation method and application thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101474407A (en) * 2009-02-04 2009-07-08 西南大学 Application of span 60 and/or span 80 in promoting absorption of coptis alkaloid
CN104825389A (en) * 2015-04-10 2015-08-12 广东药学院 Berberine hydrochloride self-microemulsion preparation having good oral bioavailability and preparation method thereof
CN104920642A (en) * 2015-07-03 2015-09-23 山东省分析测试中心 Food-grade peony seed blend oil microemulsion and preparing method thereof
CN111939128A (en) * 2020-08-19 2020-11-17 山东省分析测试中心 Temperature-sensitive lyotropic liquid crystal drug carrier and preparation method and application thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
牡丹籽油纳米乳凝胶的制备及体外透皮特性研究;王小宁 等;《化工科技》;20171231;第25卷(第6期);第42-46页 *
酸黄连素纳米微乳的制备及体外抗菌活性比较;孙红武 等;《中国兽医杂志》;20071231;第43卷(第3期);第54-55页 *

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