CN113842496B - Wound surface liquid dressing and preparation method thereof - Google Patents

Wound surface liquid dressing and preparation method thereof Download PDF

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CN113842496B
CN113842496B CN202111141512.6A CN202111141512A CN113842496B CN 113842496 B CN113842496 B CN 113842496B CN 202111141512 A CN202111141512 A CN 202111141512A CN 113842496 B CN113842496 B CN 113842496B
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wound
liquid
dressing
liquid dressing
film
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CN113842496A (en
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刘兰香
张弘
陈赤清
毛业富
刘义稳
战祥
宁然
谢山宇
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Wufeng Chicheng Biotech Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/0066—Medicaments; Biocides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0019—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0057—Ingredients of undetermined constitution or reaction products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents

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Abstract

The invention discloses a liquid dressing liquid for wound surface and a preparation method thereof, wherein the liquid dressing comprises bleached lac, plasticizer and dioctadecyl gallate (GA-C) 28 ) And a solvent system, the liquid dressing of the invention consisting of GA-C 28 To move aliveThe nature component is natural nontoxic degradable bleached lac as a film forming substrate to prepare the spray type GA-C 28 The bleached lac wound liquid dressing has the advantages of rapid film formation on the surface of the skin, good film air permeability and liquid absorbability, certain deformation resistance, good anti-inflammation and healing effects on the wound, high healing speed of the wound, high healing rate, accordance with the relevant national requirements, satisfaction of the requirements on wound liquid dressings in daily life and medical treatment, and good application prospect. The preparation method of the liquid dressing is simple to operate, mild in process conditions and suitable for industrial large-scale production.

Description

Wound surface liquid dressing and preparation method thereof
Technical Field
The invention relates to a liquid dressing and a preparation method thereof, in particular to a preparation method of a wound surface liquid dressing in a shape of Chinese character 'ji', belonging to the technical field of medicine preparation.
Background
Superficial skin injuries such as slight scratches, cuts, contusions and burns of the skin are very common in daily life, and the most commonly used method of care is by means of adhesive application. The wound surface liquid dressing is a novel band-aid which can disinfect wounds, promote wound healing, and replace a common band-aid when wounds such as cuts, abrasions, cracks, rhagades and the like appear, and belongs to a biological film-forming type disinfectant. The wound surface liquid dressing is sprayed or smeared to form a protective film on a wound, combines the continuous disinfection function and the protection function of the wound surface into a whole, and has good sterilization performance. Compared with the conventional liquid band-aids, they are better in waterproof property and air permeability, free from the restriction of the size and position of the wound, beautiful and convenient to use, and thus are receiving more and more attention in daily life and medical care.
An ideal dressing should satisfy 3 conditions simultaneously, one is that the proper water vapor transmission rate (MVTR) can provide a moist environment for the wound surface and can prevent water; secondly, effectively stopping bacteria and preventing external bacteria from polluting the wound surface; thirdly, the safety is high, secondary damage can not be caused, a microenvironment suitable for cell growth and migration can be provided, and conditions such as skin healing and the like can be promoted. At present, the wound surface liquid dressings on the market are various in types, and raw materials are classified into hydrated colloids, alginates, gels, traditional celluloses, chitosan and the like. For example, the xiaolin (japanese famous brand) band-aid currently on the market with a better tombstone is a wound liquid dressing which adopts low-nitrogen nitrocellulose as a film-forming material, and the product also contains castor oil, camphor, ethyl acetate, benzyl alcohol, isopropyl palmitate and other components. At present, wound liquid dressings used in daily life or reported in literature have the defects of complex formula, undefined active ingredients, mostly synthetic or semi-synthetic chemicals as film forming matrixes, difficulty in simultaneously meeting the defects of good waterproofness and air permeability and the like.
Bleached lac, gallic acid and octacosanol are all chemicals derived from insect secretions.
Octacosanol (Octacosanol, n-CH) 3 (CH 2 ) 26 CH 2 OH) is a saturated higher aliphatic alcohol, is derived from the secretion of the wax insect, and has been widely studied and applied to functional foods for its physiological activities such as cholesterol reduction, physical fitness enhancement, anti-tumor, and cytoprotective effects. Meanwhile, the ultra-long alkyl straight chain structure of octacosanol endows the octacosanol with ultra-strong hydrophobicity, and the hydroxyl provides a structurally modified active site for the octacosanol, so that the octacosanol is an excellent active substance of a potential biological functional material. Another important natural polyphenol compound, gallic acid, is obtained from gallnut, and is widely used in the fields of medicine, food, biology, chemical industry and the like because of having a plurality of important physiological activities such as anti-inflammation, antioxidation, anti-free radical, anti-tumor and the like. In addition, the hydroxyl (phenol) on the benzene ring structure of gallic acid has high binding affinity with proteins in tissue biomolecules, and is a natural biomolecule adhesive. Thus, gallic acid and Octacosanol (Octacosanol, n-CH) are used 3 (CH 2 ) 26 CH 2 OH) as raw material to synthesize the dioctadecyl gallate (C) through esterification reaction 35 H 62 O 5 ,GA-C 28 ) The excellent performance of the two can be combined into one to endow GA-C with 28 More excellent physiological activity.
The bleached lac is natural resin obtained by extracting lac insect secretion and bleaching, has the characteristics of easy degradation, biological non-toxicity, good viscosity, water resistance, oil resistance and the like, and is a potential natural excellent film forming substance. The wound surface liquid dressing has very important significance in wound treatment or repair, and is beneficial to compression hemostasis, wound protection from physical contact injury, microbial infection invasion such as bacteria prevention, body healing promotion and the like. Therefore, the invention takes the bleached lac as the film-forming substrate of the wound liquid dressing for the first time, and adds the novel compound GA-C 28 The spraying type composite wound surface liquid dressing with strong adhesion, excellent water resistance and good air permeability is prepared by screening a solvent system, a plasticizer, a formula ratio and the like which can be quickly dried, and is applied to a mouse wound surface model for effect evaluation so as to meet the requirements of daily life and medical treatment on the wound surface liquid dressing.
Disclosure of Invention
The invention aims to provide a wound surface liquid dressing and a preparation method thereof, aiming at the technical defects that the existing liquid adhesive bandage has a complex formula, undefined active ingredients, most film-forming matrixes are synthetic or semi-synthetic chemicals, and the formed adhesive bandage film cannot simultaneously meet the requirements of better water resistance and air permeability.
In order to achieve the object of the present invention, the present invention provides, in one aspect, a wound dressing comprising dioctadecyl gallate GA-C 28 And a solvent system.
Wherein the liquid dressing contains 1-5g of GA-C per 2L of solvent system 28 Preferably, it contains 1.0 to 3.0g of GA-C 28 More preferably, it contains 1.0 to 2.0g of GA-C 28 More preferably, it contains 2.0g of GA-C 28 。
In particular, it is possible to use,
in particular, the solvent system is a fast drying solvent system, being a compound of ethanol and ethyl acetate.
Solvents are classified into 4 classes depending on the evaporation rate: (this classification compares the evaporation rate of the solvent at atmospheric temperature, based on butyl acetate BAC); 1) quick-drying solvent: faster than BAC by more than 3 times; 2) medium-dry solvent: faster than BAC by about 1.5 times; 3) slow drying solvent: the evaporation rate is between EAC and amyl alcohol; 4) very slow drying solvent: drying slower than the EAC evaporation rate is called.
In particular, the volume ratio of ethanol to ethyl acetate in the solvent system is (60-80): 20-40), preferably (60-75): 25-30, and more preferably 75: 25.
In particular, the ethanol is absolute ethanol.
Wherein, the GA-C 28 Is prepared by the esterification reaction of gallic acid and n-octacosanol.
In particular, the esterification reaction temperature is 95-110 ℃, preferably 100 ℃; the esterification reaction time is 20-30 h.
In particular, the molar ratio of the gallic acid to the n-octacosanol is 2-4.5: 1, preferably 3: 1.
especially, in the esterification reaction process, after the gallic acid and the n-octacosanol are dissolved in a reaction solvent, a catalyst concentrated sulfuric acid is added, the mixture is heated, and the GA-C is prepared by the esterification reaction under the action of the catalyst 28 。
In particular, the esterification solvent is selected from 1, 4-dioxane, cyclohexane, toluene or xylene, preferably 1, 4-dioxane.
Particularly, the method further comprises the steps of carrying out reduced pressure distillation treatment on the reaction mixed solution after the esterification reaction, removing the solvent, and carrying out purification treatment of silica gel column chromatography, wherein in the purification treatment process, the eluent is a mixed solution of ethyl acetate, petroleum ether and formic acid, and the ratio of ethyl acetate: petroleum ether: formic acid 6:4:0.03 (V/V).
In particular, the liquid dressing also comprises bleached lac and a plasticizer.
Wherein the plasticizer is selected from polyethylene glycol 1000, polyethylene glycol 2000, polyethylene glycol 4000 or polyethylene glycol 10000, preferably polyethylene glycol 1000 and polyethylene glycol 2000, and more preferably polyethylene glycol 2000.
In particular, each 2L of solvent system in the liquid dressing comprises 150-250g of bleached lac, 30-70g of plasticizer and GA-C 28 1-5g。
In particular, each 2L of solvent system in the liquid dressing comprises 180-220g of bleached shellac, PEG2K 40-60g and GA-C 28 1.0-3.0g。
In particular, the liquid dressing comprises 180g of bleached lac, PEG2K 50g and GA-C in each 2L of solvent system 28 1.0-2.0g。
In particular, the liquid dressing comprises 180g of bleached lac, PEG2K 50g and GA-C in each 2L of solvent system 28 2.0g。
The invention also provides a preparation method of the wound surface liquid dressing, which is characterized by comprising the following steps: ,
1) preparing the following raw materials in parts by weight
150-250 parts of bleached lac, 30-70 parts of plasticizer and GA-C 28 1-5
2) Under the stirring state, bleaching lac, plasticizer and GA-C 28 Adding the mixture into a first solvent, heating, stirring and uniformly mixing, wherein the first solvent is absolute ethyl alcohol;
3) adding a second solvent of ethyl acetate, stirring to dissolve the raw materials, and then cooling to obtain the liquid dressing.
Wherein, in the step 1), the plasticizer is selected from polyethylene glycol 1000(PEG1K), polyethylene glycol 2000(PEG2K), polyethylene glycol 4000(PEG4K) or polyethylene glycol 10000(PEG10K), preferably polyethylene glycol 1000 and polyethylene glycol 2000, and more preferably polyethylene glycol 2000(PEG 2K).
In particular, GA-C as described in step 1) 28 Is prepared by the esterification reaction of gallic acid and n-octacosanol.
Particularly, the raw materials are in proportion as follows: bleached lac 180-220, PEG2K 40-60, GA-C 28 1.0-3.0; preferably: bleached lac 180, PEG2K 50, GA-C 28 1.0-2.0; more preferably bleached shellac 180, PEG2K 50, GA-C 28 2.0。
In particular, the heating temperature in the step 2) is 35-50 ℃, and preferably 45 ℃; the stirring and mixing time is 2-4h, preferably 2.5 h.
In particular, the temperature in step 3) is maintained between 35 and 50 ℃ and preferably at 45 ℃ during the addition of ethyl acetate.
In particular, the volume ratio of the absolute ethyl alcohol in the step 2) to the ethyl acetate in the step 3) is (60-80): (20-40), preferably (60-75): (25-30), and more preferably 75: 25.
Particularly, the total solvent of the liquid dressing is formed by the first solvent absolute ethyl alcohol in the step 2) and the second solvent ethyl acetate in the step 3), wherein the ratio of the total volume of the total solvent to the raw materials is as follows: 150 g of bleached lac, 30-70g of plasticizer and GA-C are dissolved in 2L of total solvent (i.e. solvent consisting of absolute ethyl alcohol and ethyl acetate) 28 1-5 g; preferably 180-220g of dissolving and bleaching lac, 40-60g of PEG2K 40 and GA-C 28 1.0-3.0 g; more preferably 180g of dissolved bleached lac, 50g of PEG2K 50, and GA-C 28 1.0-2.0 g; more preferably 180g of dissolved bleached lac, 50g of PEG2K 50, and GA-C 28 2.0g。
That is, the following raw materials by weight are added into each 2L of solvent system consisting of absolute ethyl alcohol and ethyl acetate: 150-250g of bleached lac, 30-70g of plasticizer and GA-C 28 1-5 g; preferably bleached lac 180-220g, PEG2K 40-60g, GA-C 28 1.0-3.0 g; more preferably 180g of dissolved bleached lac, 50g of PEG2K 50, and GA-C 28 1.0-2.0 g; more preferably 180g of dissolved bleached lac, 50g of PEG2K 50, and GA-C 28 2.0g。
The wound surface liquid dressing of the invention takes the bleached lac which is naturally sourced as the film forming substrate, and has the advantages of safety and good biocompatibilityThe film has better air permeability and waterproofness; meanwhile, the active component GA-C of the wound surface liquid dressing of the invention 28 The active ingredient is also obtained by one-step synthesis of natural products of gallic acid and octacosanol, and has the advantages of anti-inflammation, antibiosis, better affinity with protein and the like.
The wound surface liquid dressing of the invention firstly mixes the bleached lac and the novel compound GA-C 28 The two-in-one process is characterized in that ethanol-ethyl acetate is used as a solvent system, PEG20000 is added as a plasticizer, the formula only contains five substances, and the effects of the substances in the formula are relatively clear. Compared with the commercialized liquid dressing or the liquid dressing reported in the existing literature, the liquid dressing has the advantages of novel active ingredients and film-forming matrix, simple formula, good anti-inflammatory and healing effects on wounds, accordance with the relevant requirements of the national standard, satisfaction of the requirements on wound surface liquid dressings in daily life and medical treatment, and good application prospect.
Compared with the prior art, the invention has the following advantages and benefits:
1. the natural product bleached lac is taken as a film forming substrate, and the film forming substrate is novel and has the advantages of safety, good biocompatibility, good film air permeability, good water resistance and the like;
2. active ingredient GA-C 28 The active ingredients have the advantages of anti-inflammation, antibiosis, better affinity with protein and the like;
3. the formula is simple, only five substances are contained, the effect of each substance in the formula is relatively clear, and no toxic or side effect exists;
4. the invention can quickly form a film on the surface of skin under the condition of spraying, and the formed film has bacteriostasis, air permeability, good liquid absorbability and certain deformation resistance;
5. the invention has better anti-inflammatory and healing effects on wounds, meets the relevant requirements of national standards, meets the requirements on wound surface liquid dressing in daily life and medical treatment, and has better application prospect.
Drawings
FIG. 1 is a graph showing the measurement of the liquid viscosity and the film thickness of bleached lac at different addition levels;
FIG. 2 is a graph of the tensile strength and deformation rate analysis of different plasticizers for a wound fluid dressing film;
FIG. 3 is a graph showing the effect of PEG2000 addition on the viscosity of a wound fluid dressing, the tensile strength of a formed film, and the deformation rate;
FIG. 4 is a graph of the effect of a solvent system on the time to film formation and surface drying of a composite wound surface liquid dressing;
FIG. 5 shows different GA-C 28 The water vapor transmission rate of the formed film under the addition amount;
fig. 6 is the particle size of the prepared wound liquid dressing;
FIG. 7A is an SEM (50 μm) view of a film after film formation of a wound liquid dressing of the present invention;
FIG. 7B is an SEM (5 μm) view of a film after film formation of the wound liquid dressing of the present invention;
FIG. 8A is an AFM (atomic force microscope) test profile after film formation of a wound liquid dressing;
FIG. 8B is a three-dimensional view of AFM after film formation of a wound liquid dressing;
FIG. 8C is a cross-sectional view of the wound fluid dressing after film formation;
FIG. 9 is a water contact angle test chart after the wound liquid dressing is filmed;
FIG. 10 is the healing rate of each group of mice at different times;
FIG. 11 shows the photographs of wound healing and pathological sections of skin of each group of mice at different times.
Detailed Description
The invention will be further described with reference to specific embodiments, and the advantages and features of the invention will become apparent as the description proceeds. These examples are illustrative only and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
Experiment raw material, reagent and instrument
Bleached lac and gallic acid monohydrate (provided by resource insect institute of China forestry science research institute); octacosanol (provided by resource insect institute of China forestry science research institute);
gallic acid n-dioctadecyl ester (GA-C) 28 Provided by national institute of forestry science and research resources insect institute); polyethylene glycol 1000, 2000, 4000, 10000(PEG1K, PEG2K, PEG4K, PEG 10K); polyvinylpyrrolidone K30(PVP, national pharmaceutical group chemicals limited); polyvinyl alcohol-224 (PVA, Shanghai Aladdin Biotechnology Ltd., AR); ethanol, ethyl acetate, sodium chloride, calcium chloride (AR, west julong technologies, ltd, Sichuan); german SOS brand liquid woundplast spray (product 01 for short);
TENSOR 27 Fourier transform infrared spectrometer (Bruker, Germany); TMS-Pro Property Analyzer (FTC Co., USA); NDJ-8S rotational viscometer (Shanghai Jingke industries, Ltd.); (ii) a Nanotrac Wave II dynamic light scattering instrument (mcgkok, usa); sigma 300 scanning electron microscope (carl zeiss (shanghai) management ltd); 5500AFM atomic force microscopy (Bruker, Germany); attention Theta Flex water contact apparatus (Baiohlin technologies, Sweden).
EXAMPLE 1A Synthesis of Compound GA-C 28
1. The gallic acid monohydrate (2.26g, 12.0mmol) and n-octacosanol (1.65g, 4.0mmol) were weighed out accurately and added to a two-necked bottle with a water separator and a thermometer, wherein the molar ratio of gallic acid to n-octacosanol was 3: 1;
in the embodiment of the invention, the molar ratio of the gallic acid to the n-octacosanol is 3: 1 for example, other molar ratios are (2-4.5): 1 are also suitable for use in the present invention.
2. Accurately measuring 20.0mL (usually 15.0-35.0mL) of 1, 4-dioxane solvent, and adding into a two-mouth bottle;
usually, the ratio of the amount of the solvent to the amount of the octacosanol is 9-22:1, namely, the liquid-solid ratio of the solvent to the octacosanol is 9-22:1, namely, the ratio of the volume of the solvent to the mass of the octacosanol is 9-22:1, and 9-22ml of the solvent is used for dissolving every 1g of the octacosanol; the liquid-solid ratio of the dosage of the solvent to the gallic acid is 6.6-15.5:1, namely the liquid-solid ratio of the solvent to the gallic acid is 6.6-15.5:1, namely the ratio of the volume of the solvent to the mass of the gallic acid monohydrate is 6.6-15.5:1, and every 1g of the gallic acid monohydrate is dissolved by 6.6-15.5ml of the solvent;
in particular, when the liquid-solid ratio of the solvent dosage to the octacosanol is 12.1 and the liquid-solid ratio of the solvent dosage to the gallic acid is 8.8, namely the dosage of the solvent is 20.0mL, the highest yield of the target product can be obtained.
3. Accurately measuring 0.89mL (usually 0.44-1.08mL) of concentrated sulfuric acid serving as a catalyst, and adding the concentrated sulfuric acid into a two-mouth bottle;
the purpose and function of adding the solvent in sequence are to dissolve the two reaction raw materials, so that the two reaction raw materials are subjected to chemical reaction under the condition of proper concentration, and then the function of adding concentrated sulfuric acid is to initiate and promote the reaction, and the concentrated sulfuric acid is the catalyst of the esterification reaction. The use amount of the concentrated sulfuric acid is less than that of octacosanol which is one of reaction raw materials, no target product is generated, and the yield of the target product is too low due to the increase of quinone by-products when the use amount is too large, so that the use amount of the concentrated sulfuric acid is optimal according to the result of a single-factor experiment and the use amount of the concentrated sulfuric acid when the highest yield of the target product is obtained.
The selective density of the concentrated sulfuric acid is 1.84g/cm 3 And the mass fraction is 98.3 percent of concentrated sulfuric acid.
The using amount (by mass) of the concentrated sulfuric acid is 10.0-120.0% of the mass of the octacosanol, and the mass ratio of the concentrated sulfuric acid to the octacosanol is (10-120): 100. the dosage range of the concentrated sulfuric acid is 0.089-1.08mL/g of concentrated sulfuric acid. When the dosage of the concentrated sulfuric acid is 100.0 percent of the octacosanol, namely the dosage of the concentrated sulfuric acid is 0.89mL, the highest yield of the target product can be obtained.
4. Mixing, and performing esterification reaction at 100 deg.C (usually 95-110 deg.C) under stirring; after esterification reaction for 24 hours (usually 20-30 hours), cooling the reaction mixture to room temperature, carrying out reduced pressure distillation, and removing the solvent to obtain a solid crude product;
5. separating and purifying the crude solid product by silica gel column chromatography, wherein the eluent of the silica gel column chromatography isThe method is a mixed solution of ethyl acetate, petroleum ether and formic acid, wherein the weight ratio of ethyl acetate: petroleum ether: formic acid 6:4:0.03 (V/V), yielding the desired product n-dioctadecyl gallate (C) as a white powder 35 H 62 O 5 ,GA-C 28 ，1.13g)。
White powder target product GA-C 28 The yield of (b) was 50.1%.
Target product GA-C 28 Can be seen in the infrared analysis of (2), at 3547cm -1 The absorption peak of hydroxyl on benzene ring is mainly at 2989-2850cm -1 Absorption peaks at 1700cm of methylene and methyl radicals -1 Is the carbonyl absorption peak on the ester group, 1540cm -1 The main point is the absorption peak of the benzene ring skeleton.
1 H NMR(600MHz,DMSO)：δ7.59(s,2H,C3,7-H),4.67(s,2H,C8-H),2.18(dd,J＝14.5,6.8Hz,2H,C9-H),2.03-1.46(m,50H,C10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34-H),1.34(t,J＝6.8Hz,3H,C35-H)。
MS(ESI-TOF)m/z Calcd for C 35 H 62 O 5 [M-H] - 561,Found 561。
Example 1
Weighing certain mass of bleached lac, plasticizer PEG1k, and GA-C 28 (ii) a Under the stirring condition, bleaching lac, PEG1K and GA-C 28 Adding to 15.0mL of anhydrous ethanol, stirring and heating the mixture to 45 deg.C (usually 35-50 deg.C), and stirring and mixing for 2.5h (usually 2-4h) while maintaining the temperature at 45 deg.C; then 5.0mL of ethyl acetate was added to completely dissolve the solid; naturally cooling the mixed solution to room temperature to obtain the wound surface liquid dressing;
In this example, the amount of PEG1k as a plasticizer was controlled to 0.40g, GA-C 28 The addition amount of (A) was 0.03g, the addition amounts of bleached lac were 1.00, 1.40, 1.80, 2.20, 2.60g, respectively, and 5 wound surface liquid dressing samples (named samples 1-5) were prepared, each treatment being repeated 3 times.
The viscosity of the wound liquid dressing prepared in example 1 was measured using an NDJ-8S rotational viscometer (shanghaiengaku industries ltd): 10.0mL of each of 5 liquid dressings prepared in example 1 is accurately measured, a rotor No. 0 is selected, the rotating speed is set to be 60rpm, when the test value is stable, the value is read, the viscosity value of the liquid dressing is obtained, and the measurement result is shown in figure 1.
5 liquid dressings prepared in example 1 are accurately measured, 5.0mL of each liquid dressing is accurately measured, the liquid dressings are respectively paved on culture dishes with the diameter of 9.0cm, the surface drying is carried out for 3 hours at room temperature, then the liquid dressings are dried in an oven at 50 ℃ for 24 hours to form a film, the thickness of the film is measured, and the test result is shown in figure 1.
As shown in fig. 1, when the addition amounts of the bleached lac were 1.00g and 1.40g, respectively, the viscosity of the prepared liquid mixing system was low (the instrument could not measure accurately), the liquid fluidity was strong, and the film could not be formed on smooth surfaces (such as glass plate and skin); the viscosity of the liquid and the thickness of the formed film are gradually increased along with the increase of the addition amount of the bleached lac, when the addition amount of the bleached lac is 1.80-2.60g, the viscosity of the liquid is in the range of 3.08-4.25 mPa.s, the thickness of the film obtained by the liquid is in the range of 0.064-0.095mm, and the two indexes can meet the requirements of the wound surface liquid dressing. However, when the addition amount of the bleached lac is more than 2.60g, the obtained liquid has poor stability, and the uniformity of the prepared film is influenced by the overlong standing time, so that the addition amount of the bleached lac of the composite liquid dressing is preferably 1.80-2.20 g.
Example 2
Weighing certain mass of bleached lac, plasticizer PEG1k, and GA-C 28 (ii) a Under the stirring condition, bleaching lac, PEG1K and GA-C 28 Adding to 15.0mL of anhydrous ethanol, stirring and heating the mixture to 45 deg.C (usually 35-50 deg.C), and stirring and mixing for 2.5h (usually 2-4h) while maintaining the temperature at 45 deg.C; then 5.0mL of ethyl acetate was added to completely dissolve the solid; naturally cooling the mixed solution to room temperature to obtain the wound surface liquid dressing;
in this example, the amount of added bleached lac was controlled to be 1.80g, GA-C 28 Was added at 0.03g, plasticizer was added at 0.40g, and PEG1k, PEG2k, PEG4k, PEG10k, PVA, PVP were selected as plasticizers, respectively, to prepare 6 liquid dressing samples, each treatment being repeated 3 times. The sample without added plasticizer was set as a blank.
6 liquid dressings prepared in example 2 were accurately measured, 5.0mL each, and each was spread on a petri dish having a diameter of 9.0cm, dried for 3 hours at room temperature, and then dried in an oven at 50 ℃ for 24 hours to form a film, and then the tensile strength and deformation rate of the film were measured using a TMS-Pro physical property analyzer (FTC, Inc., USA), and the measurement results are shown in FIG. 2.
As shown in fig. 2, the film obtained from the blank (i.e., without plasticizer) sample was very brittle with a deformation rate of only 0.85%. To improve the brittleness of the film, this example examined the effect of 6 common plasticizers on wound fluid dressing films. Wherein, the plasticizer PVA commonly used in medical materials is not dissolved in the liquid system; the brittleness of the film formed by adding the plasticizer PVP into the system does not decrease and reversely rises; compared with a blank control, the tensile strength of the film prepared by adding PEG with different molecular weights is reduced, the deformation rate is improved, and the PEG plays a role in plasticizing the film formed by the system.
The deformation rates of the films added with PEG1K and PEG2K reach 75.72 percent and 104 percent respectively, and PEG4K and PEG1K with the same addition amount are added into the system, a small amount of solid is precipitated after the system is cooled to room temperature, and the film forming uniformity is poor. In addition, the melting points of the films formed by adding PEG1K and PEG2K are 47.5 ℃ and 51.5 ℃, and PEG2K with higher melting point is preferably selected as a plasticizer for comprehensive practical application.
Example 3 Effect of the amount of plasticizer PEG2K added
Weighing certain mass of bleached lac, plasticizer PEG2k, and GA-C 28 (ii) a Under the stirring condition, bleaching lac, PEG2k and GA-C 28 Adding into 15.0mL of absolute ethyl alcohol, stirring and heating the mixture to 45 ℃, and stirring and mixing for 2.5h under the condition of keeping the temperature at 45 ℃; then 5.0mL of ethyl acetate was added to completely dissolve the solid; naturally cooling the mixed solution to room temperature to obtain the wound surface liquid dressing;
in this example, the amount of added bleached lac was controlled to be 1.80g, GA-C 28 Was added at 0.03g and plasticizer PEG2K was added at 0,0.20,0.40,0.60,0.80,1.20,1.60 and 2.00g, respectively, to prepare 8 liquid dressing samples, each treatment being repeated 3 times.
The 8 liquid dressings prepared in example 3 were accurately measured, 5.0mL each, and each was spread on a petri dish having a diameter of 9.0cm, dried for 3 hours at room temperature, and then dried in an oven at 50 ℃ for 24 hours to form a thin film, and then the tensile strength and deformation rate of the thin film were measured using a TMS-Pro property analyzer (FTC ltd., usa), and the measurement results are shown in fig. 3.
As shown in FIG. 3, the fluidity of the liquid mixed system decreased and the viscosity increased with the increase of the amount of PEG2K added, and the viscosity was 2.29 to 4.54 mPas, and accordingly, the deformation rate of the film formed therefrom showed a phenomenon of increasing and decreasing. When the addition amount of PEG2K is less than 0.40g, the deformation rate of the membrane is less than 1.38%, the brittleness of the membrane is high, and the membrane is easy to break and fall off on the surface of an object; when the addition amount thereof was 0.40g and 0.60g, the deformation rate of the film was 104% and 144%, respectively, and the tensile strength was 1.28 and 1.07MPa, respectively; when the addition amount is 0.80g, the deformation rate of the film is maximum, and the tensile strength is only 0.14 MPa; the water absorption of the film surface is increased along with the increase of the addition amount of PEG2K, so that stress defect points appear on the film surface, and the deformation rate of the film is sharply reduced. Therefore, the plasticizer PEG2K in the wound liquid dressing formula is properly added in an amount of 0.40-0.60g by comprehensively considering the deformation rate and tensile strength requirements of the wound liquid dressing to form a film.
Example 4 Effect of solvent System
Weighing certain mass of bleached lac, plasticizer PEG2k, and GA-C 28 (ii) a Under the stirring condition, bleaching lac, PEG2k and GA-C 28 Adding into anhydrous ethanol, stirring, heating the mixture to 45 deg.C, and stirring and mixing at 45 deg.C for 2.5 h; then adding ethyl acetate to completely dissolve the solid; naturally cooling the mixed solution to room temperature to obtain the wound surface liquid dressing;
In this example, the amount of added bleached lac was controlled to be 1.80g, GA-C 28 The addition amount of (A) is 0.03g, and the addition amount of the plasticizer PEG2K is 0.40 g; the total volume of the solvent system of absolute ethanol and ethyl acetate was 20.0ml, and the volume fractions of ethanol in the solvent system were 15%, 30%, 45%, 60%, 75% and 100%, respectively, and 6 liquid dressing samples were prepared, each treatment being repeated 3 times.
Respectively taking 0.10g of each of 6 prepared wound surface liquid dressing samples, uniformly and flatly paving the samples on a glass plate with the thickness of 2.0cm multiplied by 4.0cm, timing by a stopwatch, stopping timing when no liquid flows when the glass plate is obliquely placed to indicate that the solvent is completely volatilized, recording the surface drying time, and measuring results are shown in figure 4.
The surface drying time is an important index for measuring whether the wound surface liquid dressing can quickly form a film, and the less surface drying time means that the liquid dressing can quickly form the film in a shorter time so as to reduce wound infection. Bleaching shellac and GA-C 28 The ideal solvents are ethanol and ethyl acetate respectively, and simultaneously considering that the two solvents have certain sterilization and bacteriostasis effects and are also components added in medical products by pharmacopoeia, the research selects ethanol-ethyl acetate as a solvent quick-drying system.
When the volume fraction of the ethanol is smaller (less than or equal to 45 percent), the bleached lac cannot be completely dissolved in the solvent system, the system is unstable, solids are separated out when the bleached lac and the solvent system form a film, and the surface of the obtained film is not uniform; when the volume fractions of the ethanol are 60% and 75%, the obtained wound surface liquid dressing system is uniform and stable and has moderate viscosity; using a single ethanol (100%) as solvent system, GA-C 28 The solubility therein is limited, the resulting liquid is unstable and white solids precipitate on the surface of the resulting film.
As shown in fig. 4, when the volume fractions of ethanol are 15%, 30%, 45%, 60%, 75% and 100%, respectively, the surface dry time of the liquid dressing is 74.96s, 47.59s, 51.49s, 61.24s, 64.34s and 75.96 s; meet the quick-drying requirement of the wound liquid dressing, and the films formed by the wound liquid dressing are smooth and uniform. However, if combined with the consideration that medical 75% ethanol has good bactericidal effect, the (75% V) -ethyl acetate (25% V) solvent system selected herein is the solvent quick-drying system of the composite wound liquid dressing.
Example 5GA-C 28 Influence of addition amount
Weighing certain mass of bleached lac, plasticizer PEG2k, and GA-C 28 (ii) a Under the stirring condition, bleaching lac, PEG2k and GA-C 28 Adding to 15.0mL of absolute ethanol, stirring and addingHeating the mixture to 45 ℃, and stirring and mixing for 2.5 hours under the condition of keeping the temperature at 45 ℃; then 5.0mL of ethyl acetate was added to completely dissolve the solid; naturally cooling the mixed solution to room temperature to obtain the wound surface liquid dressing;
in the embodiment, the addition amount of the bleached lac is controlled to be 1.80g, the addition amount of the plasticizer PEG2K is controlled to be 0.40g, and the volume ratio of absolute ethyl alcohol to ethyl acetate in a solvent system is 75: 25; GA-C 28 Were added at 0,0.01,0.02,0.03,0.04,0.08 and 0.12g, respectively, and 7 liquid dressing samples were prepared, each treatment being repeated 3 times.
GA-C 28 The solubility of the dressing in an ethanol (75% V) -ethyl acetate (25% V) solvent system is limited, and when the addition amount of the dressing is more than or equal to 0.040g, solids are separated out after the composite wound liquid dressing is placed for 2 hours. Thus selecting GA-C 28 The influence of the amounts of the additives of 0.01,0.02 and 0.03g on the water vapor transmission rate of the formed film.
According to the national pharmaceutical industry standard contact wound dressing test method part 2: the permeability test is carried out by a permeable membrane dressing water vapor permeability (YY/T0471.2-2004), and the specific test method is as follows: before the test, after the film was left to stand in an environment of 25 ℃ and a relative humidity of 50% for 12 hours or more, the film having no defects was sealed with paraffin on a jar (jar diameter: 35.00mm) containing 100mL of deionized water, and weighed to have a mass W 1 The sealed jar was placed in an air-blast drying oven (temperature was maintained at 37 ℃ C., humidity was less than 20%) for 12 hours, and then weighed to have a mass W 2 The water vapor transmission rate is calculated according to the formula (1):
water vapor transmission rate ═ W 1 -W 2 )×1000×24/12 (1)
GA-C 28 The active ingredients in the wound liquid dressing have the functions of enhancing the bacteriostasis and the skin affinity of the wound liquid dressing on one hand and improving the compactness of the bleached lac-PEG composite membrane by introducing hydrophobic ultra-long carbon chains into the liquid dressing on the other hand, so that the GA-C is changed 28 Will help to regulate the water vapour transmission rate of the membrane. The water vapor transmission rate is used for measuring whether the environment humidity is idealThe water vapor transmission rate is 800-1200 g.m -2 ·d -1 The interval is the environment with ideal humidity for wound healing, and the water vapor transmission rate measurement result is shown in figure 5.
As shown in FIG. 5, with blank (GA-C) 28 Addition amount of 0) compared with that of GA-C 28 The water vapor transmission rate of the membrane was improved, but with GA-C 28 Increase in the amount added the water vapor transmission rate of the resulting film was increased and then decreased, probably because of GA-C 28 The dispersibility in the system is better when the amount of the catalyst is small, and the branching effect of the ultra-long carbon chain causes that a plurality of tiny holes are generated during film forming, thereby being beneficial to the permeation of water vapor; but with GA-C 28 The addition amount is increased, so that the phenolic hydroxyl group with better binding affinity with the bleached lac in the system is also increased, the compactness of the film is increased, and the water vapor transmission rate is reduced. Taking into account the active ingredient GA-C 28 Thus the invention selects GA-C in the wound surface liquid dressing 28 The addition amount is 0.01-0.02g for further formula optimization.
Example 6 response surface optimization test and results analysis
From the single-factor experimental results of examples 1-5, it can be known that the viscosity of the wound liquid dressing and the properties of the film are greatly influenced by each single factor, and the evaluation index of the wound liquid dressing satisfying the medical standard is multidimensional, so that the invention further selects the addition amount (X) of the bleached lac to obtain the optimal formula 1 ) PEG2K addition amount (X) 2 ) And GA-C 28 Addition amount (X) 3 ) Setting Y response values for 3 factors, and performing 3-factor 3-level response surface analysis by using a Design-expert8.0.5 response Box-Behnken method to optimize the wound surface liquid dressing formula. The response values Y are respectively viscosity (Y) 1 ) Surface dry time (Y) 2 ) Tensile Strength (Y) 3 ) Deformation rate (Y) 4 ) Water vapor transmission rate (Y) 5 ) And liquid absorbency (Y) 6 ). The optimization of the wound surface liquid dressing formula is shown in table 1, and the corresponding response value is shown in table 1.
Liquid absorbability was in accordance with national pharmaceutical industry standards part 1 of the test method of contact wound dressing: liquid for treating urinary tract infectionThe liquid absorbency was tested in the liquid absorbency test (YY/T0471.1-2004), the specific test method was as follows: 8.30g of sodium chloride and 0.277g of anhydrous calcium chloride are respectively weighed and dissolved in 1.0L of deionized water to simulate human body exudate and placed in an environment at 37 ℃ for standby. The film was cut into a 2cm X2 cm shape and placed in a petri dish (diameter 3.7cm), and the mass of the film was recorded as W 3 Adding test solution (with a mass 80 times of the film mass) at 37 deg.C, transferring into a forced air drying oven, holding at 37 deg.C for 30min, holding a sample with tweezers, suspending for 30s, and weighing the film mass W 4 The liquid absorption rate was calculated according to the formula (2).
Specific absorption rate of liquid [ (W) 3 -W 4 )/W 3 ]×100％ (2)
TABLE 1 optimal formulation and index values for wound liquid dressings
Figure BDA0003284105820000121
Figure BDA0003284105820000131
As shown in table 1:
1) the viscosity is taken as an examination index, the liquid viscosity of the 24 groups of formulas is within the range of 2.20-3.60mPa & s, and is equivalent to that of the commercial 01 wound liquid dressing, and the liquid viscosity of the formulas is moderate, so that the formulas can be well adhered to the uneven surface and form a film when being sprayed actually, and the use requirements of the wound liquid dressing on different wounds are met.
2) The surface drying time is taken as an evaluation index, the film forming surface drying time of the 24 groups of formulas is distributed between 42 s and 72s, and compared with the commodity 01, the surface drying time of the liquid dressing is shorter, namely the film forming speed of the liquid dressing on the surface of a wound is faster, and the exposure time of the wound in the air is reduced, so that the secondary infection of the wound is effectively prevented.
3) The tensile strength is taken as an assessment index, except for the formulas WP11 and WP17, the tensile strength of films formed by other 22 formulas is more than 1.0 MPa; moreover, in these 22 formulations, the film formed by 15 dressings had a deformation rate greater than 70%, respectively: WP01-06, WP08-10, WP12-13, WP15-16, WP20, WP22 and WP 24. The water vapor transmission rate of the films formed by the 15 formulations was further examined on the basis of this.
The water vapor transmission rate of the film formed by the liquid dressing of 15 formulas (WP01-06, WP08-10, WP12-13, WP15-16, WP20, WP22 and WP24) is distributed in 496 and 944 g.m. -2 ·d -1 Interval in which the water vapour transmission rate is greater than 800 g.m -2 ·d -1 The formula is 3 groups of WP06, WP16 and WP20, and the liquid absorbability of the film formed by the components is further examined on the basis of the formula.
4) The results of the liquid absorbency tests of films formed from the 3 formulations (WP06, WP16 and WP20) show that the film formed from the 3 formulations tested had the best liquid absorbency of formulation WP16 (110.32%), the worst of formulation WP20 (64.02%), and the liquid absorbency of formulation WP06 was 99.35% between the two. The high liquid absorption rate means that the film has higher water absorption capacity, which is beneficial to accelerating the healing speed of the wound, and the moist surface of the wound easily causes the mass propagation of bacteria to cause secondary damage.
Therefore, the optimal compound wound liquid dressing formula is preferably selected from WP06 according to the influences of tensile strength, deformation rate, water vapor transmission rate and liquid absorbability on the wound dressing: the addition amount of bleached lac is 1.80g, the addition amount of PEG2k is 0.50g, and GA-C 28 The addition was 0.02g, and the solvent system was 20.0mL ethanol (75% V) -ethyl acetate (25% V). The formula is expanded by 100 times according to the general preparation method of the composite wound liquid dressing and the film, the viscosity of the obtained liquid is 2.65 mPa.s, the tensile strength is 1.62MPa, the deformation rate is 145.92%, and the water vapor transmission rate is 952.34 g.m -2 ·d -1 And the liquid absorption rate is 97.26%, the measured indexes are basically consistent with the indexes of WP06 in Table 1, and the RSD of each index is less than or equal to 2.1%, which shows that the formula has good reproducibility and can be prepared in large quantity.
Example 7
Weighing a certain mass of bleached lac 180g, plasticizer PEG2k 50g and GA-C respectively 28 2g of the total weight of the mixture; floating under stirringWhite lac, PEG2k, GA-C 28 Adding into 1500mL of absolute ethyl alcohol, stirring and heating the mixture to 45 ℃, and stirring and mixing for 2.5h under the condition of keeping the temperature at 45 ℃; then ethyl acetate (500mL) was added to dissolve the solid completely, ethanol (75% V) -ethyl acetate (25% V) in the solvent system; and naturally cooling the mixed solution to room temperature to obtain the wound surface liquid dressing.
Test example 1 wound surface liquid dressing and film characterization
1. Particle size measurement
The particle size of the wound fluid dressing of example 7 was observed using a Nanotrac Wave II dynamic light scattering instrument (mctheir ltd., usa) and the results are shown in figure 6. The results show that: the mixed system is a suspension, and the liquid particle size distribution is uniform, wherein the particle size of the primary particle is 443 +/-5 nm (figure 6).
2. Scanning electron microscope testing
The wound liquid dressing prepared in example 7 was filmed using a Sigma 300 scanning electron microscope (carl zeiss (shanghai) management ltd) for apparent morphological analysis: the film was applied to the conductive gel, spread uniformly with tweezers, and then tested, with the results shown in fig. 7A and 7B.
SEM test results show that the film surface is relatively compact, has no obvious holes (figure 7A), and can prevent exogenous pathogenic bacteria from entering; the film surface was further enlarged to reveal a small number of ravines (fig. 7B) in the film surface that facilitate the ingress and egress of water vapor, thereby providing the wound surface with ideal wound healing moisture.
3. Atomic force microscopy testing
The surface roughness of the film formed by the wound liquid dressing of example 7 was observed using a 5500AFM atomic force microscope (brueck, germany): AFM test results (figures 8A-C) show that the surface of the film is rough and can be better attached to irregular surfaces, and meanwhile, research shows that when the surface of the film has certain roughness, the adhesion of bacteria such as staphylococcus aureus and the like on the surface of the film can be prevented.
4. Water contact Angle test
The film formed by the wound liquid dressing of example 7 was observed for hydrophilicity and hydrophobicity using an attention Theta Flex water contact apparatus (Baiohlin technologies, Inc., Sweden). The hydrophilicity and hydrophobicity of the surface of the material have important influence on cell proliferation and platelet adhesion resistance, and when the water contact angle of the surface of the material is between 40 and 60 degrees, the material is suitable for both cell proliferation and platelet adhesion resistance. The water contact angle test experiment result shows that the water contact angle of the film formed by the wound surface liquid dressing with the optimal formula is 58.2 +/-1 degrees (figure 9), and the water contact angle of the film is proper.
5. Liquid absorbency test
According to the national pharmaceutical industry standard, part 1 of the test method of the contact wound dressing: liquid absorbency (YY/T0471.1-2004) the wound liquid dressing film prepared in example 7 was tested for liquid absorbency, the specific test method being as follows: 8.30g of sodium chloride and 0.277g of anhydrous calcium chloride are respectively weighed and dissolved in 1.0L of deionized water to simulate human body exudate and placed in an environment at 37 ℃ for standby. The film was cut into a 2cm × 2cm shape and placed in a petri dish (diameter: 3.7cm), and the mass of the film was recorded as W 3 Adding test solution (with a mass 80 times of the film mass) at 37 deg.C, transferring into a forced air drying oven, holding at 37 deg.C for 30min, holding a sample angle with tweezers, suspending for 30s, and weighing the film mass W 4 The liquid absorption rate was calculated according to the formula (3).
Specific absorption rate of liquid [ (W) 4 -W 3 )/W 3 ]×100％ (3)
The liquid absorbency test results are as follows: the liquid absorption rate of the film formed by the wound surface liquid dressing prepared in the example 7 is 99.35 percent, and the national pharmaceutical industry standard (YY/T0471.1-2004) is met.
6. Tensile Strength test
Tensile tests were performed using a TMS-Pro physical property analyzer (FTC Co., Ltd., USA). The wound dressing film prepared in example 7 was cut into a uniform 7mm by 15mm film for tensile testing. The width and height of each film was recorded before stretching for later calculations, and after recording the films were mounted on a jig, testing was started and data was recorded. The specific parameters of the instrument are as follows: stretching rate of 10.0mm/s, maximum stretching distance: 300mm, and at least 5 parallel samples are tested by using a breaking point positioned in the middle of the test sample as a test qualification standard.
The tensile strength test results are as follows: the tensile strength of the film formed by the wound liquid dressing prepared in example 7 is 1.56MPa, and the deformation rate is 134.66%, which indicates that the film formed by the wound liquid dressing has a certain deformation resistance.
Test example 2 wound healing test
Experimental animals: kunming mice, weighing 20-25 g, 24 mice, half male and half female, purchased from Sibefu (Beijing) Biotechnology Limited, quality certification number: SCXK (Jing) 2019-.
The use of the mice complies with the national animal welfare regulations guiding opinions on the animals being treated, the use scheme of the mice is approved by the ethical committee of the resource insect research institute of the Chinese forestry scientific research institute, and all animal experiments are carried out according to the nursing and use guide of experimental animals.
The wound surface liquid dressing of example 7 is used as an experimental group; directly using medical gauze at the wound as a blank control group; the liquid dressing prepared in comparative example 1 was sprayed on the wound as a control matrix (i.e., GA-C was not added to the control matrix) 28 And other components are the same as those in the experimental group). The experimental group, the blank control group and the matrix control group are 2 groups of female and male mice respectively, and the total number of the groups is 6. The 24 mice were randomly divided into 6 groups of 4 mice each, and the sex of the mice in each group was the same, and then the mice were subjected to modeling and wound healing experiments.
Each mouse is anesthetized by intraperitoneal injection with 0.3% sodium pentobarbital (10.0 mu L/g), the back of each mouse is unhaired by 6% sodium sulfide, preferably the back of each mouse is smooth and the skin of each mouse is not damaged, a round whole-layer skin with the diameter of about 10.0mm is cut off from the back of each mouse by a round puncher and reaches the sarcolemma deeply, and a whole-skin-layer defect model is caused. After the model is made, the mice are fed in separate cages, so that the influence of licking wounds on experimental observation is avoided, and the mice can freely drink and eat water. And (5) after the wound is dried and retracted for 2 hours, measuring the wound area, namely the wound area. The experimental group and the matrix control group applied dressings to model wounds of mice every 12 hours every day, and when the application was performed, a spray can with the dressings was continuously sprayed three times against the wounds at a position 1.0cm away from the wounds. Wounds of mice in the placebo group were bandaged with medical gauze and replaced once a day.
Observing the wound surfaces of animals on days 0,3,7 and 14 respectively, taking pictures, calculating the wound area by photoshop, recording the original wound area as S1, and the wound area on the nth day after wound as S2, calculating the wound healing rate according to a formula (4), drawing a curve of the change of the healed wound area along with time, and dying one mouse respectively on days 7 and 14 and carrying out pathological observation on the mouse.
The healing rate of the wound surface is [ (S1-S2)/S1 ]. 100% (4)
The wound healing experiment results show that 3 groups of mice have good conditions and do not have adverse reactions such as food refusal and the like in the wound healing experiment of 14 days. As shown in fig. 10, the group 3 mice did not show significant gender differences between female and male mice during wound healing. Surprisingly, the wound healing rate of the experimental group in different time periods is better than that of the matrix control group and the blank control group, the wound healing rate of the experimental group on the 3 rd day and the 7 th day reaches 36.6 percent and 71.2 percent, and is about 20 percent higher than that of the matrix control group and the blank control group on average; the healing rate of the wound surface of the experimental group on the 14 th day reaches 94.7%, which shows that the wound surface composite wound surface liquid dressing has the capability of promoting the healing of the wound.
To further observe the status of epidermal cells of mice during different wound healing processes, the wound skin of 3 groups of mice was pathologically sectioned, as shown in fig. 11. On day 7, mild keratosis appeared evident on the skin surface in all three groups, and the dermal tissue was filled with granulation tissue, indicating that the wounds of all three groups of mice were healing gradually at this stage. In addition, the surface of the slice of the experimental group is observed to have a part of inflammatory necrotic tissues, hyperplastic granulation tissues and a large amount of new capillaries and fibroblasts under the necrotic tissues; the blank control and the matrix control showed a large amount of inflammatory necrotic tissue on the surface, hyperplastic granulation tissue beneath it, mild hyperkeratosis of the epidermis, and a degree of ulceration and crust formation. Meanwhile, the bottom of the experimental granulation ulcer is basically free of inflammatory cells and is filled with mature collagen fibers. On day 14, the experimental groups developed intact skin structure and good hair follicle growth, while the other two groups had no new hair follicle tissue growth, and the placebo group had significant inflammation compared to the other two groups. Therefore, the experimental result shows that the wound healing condition of the mice of the experimental group is better than that of the matrix control group and the blank control group in the same time, and the wound surface liquid dressing has obvious effects of diminishing inflammation and promoting wound healing on the wound.
(1)GA-C 28 The optimal formula of the bleached lac wound surface liquid dressing is as follows: the addition amount of bleached lac is 180.0g, the addition amount of plasticizer PEG2K is 50.0g, and GA-C 28 The amount of (2.0 g) added, and the solvent quick-drying system was 2.0L ethanol (75% V) -ethyl acetate (25% V).
(2) The wound liquid dressing has a liquid viscosity of 2.54 mPas, a tensile strength of 1.56MPa, a deformation rate of 134.66%, and a water vapor transmission rate of 944.8g m -2 ·d -1 And the liquid absorption rate is 99.35 percent, and all indexes meet the national medicine industry standard YY/T0471-2004.
(3) Mouse animal model experiment shows that GA-C 28 The wound healing rates of bleached lac wound fluid dressings reached 36.6% and 71.2% on days 3 and 7, which were on average about 20% higher than those of the matrix control and the blank control groups; the wound healing rate of the mouse on day 14 reaches 94.7%, which indicates that the composite liquid dressing has the effects of diminishing inflammation and promoting wound healing, can meet the requirements of daily life and medical treatment on the wound liquid dressing, and has better application prospect.
The wound surface liquid dressing of the invention is prepared by using the gallic acid n-dioctadecyl ester (GA-C) 28 ) As an active ingredient, natural nontoxic degradable bleached lac is used as a film forming substrate to create a spraying type GA-C 28 The bleached lac composite wound surface liquid dressing and the application effect thereof are evaluated. Through single factor experiment and response surface, 24 groups of composite wound liquid dressing formulas are designed, and the viscosity, the surface drying time of film forming, the tensile strength, the deformation rate, the water vapor transmission rate, the liquid absorbability and the like of the composite wound liquid dressing formulas are considered, so that the optimal formula for the wound liquid dressing preparation is determined: the addition amount of bleached lac was 180.0g, the addition amount of plasticizer PEG2K was 50.0g, and GA-C 28 The amount of (2.0 g) was added, and the solvent quick-drying system was 2.0L of ethanol (75% V) -ethyl acetate (25% V). The formula can quickly form a film on the surface of skin under the condition of spraying, and the formed film has good antibacterial property, air permeability and liquid absorbability and certain anti-deformation capability. Mouse animal model experiments show that the wound healing rate of the composite wound liquid dressing on the 3 rd day and the 7 th day reaches 36.6 percent and 71.2 percent, which are averagely higher than that of a matrix control group and a blank control group by about 20 percent; the wound healing rate of the mice reaches 94.7% on day 14. Compared with the commercialized or reported liquid dressing in the prior literature, the composite wound liquid dressing prepared by the method has the advantages of novel active ingredients and film-forming matrix, simple formula, better anti-inflammation and healing effects on the wound, accordance with the relevant requirements of the national standard, capability of meeting the requirements on wound liquid dressings in daily life and medical treatment and better application prospect.
The above-described embodiments of the present invention are merely exemplary and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.

Claims (12)

1. A liquid dressing for wound surface is characterized by comprising dioctadecyl gallate and a solvent system.
2. The dressing of claim 1 further comprising bleached shellac, a plasticizer.
3. The dressing of claim 2 wherein said liquid dressing contains 1-5g n-dioctadecyl gallate per 2L of solvent system.
4. The dressing according to claim 1 or 2, wherein said n-dioctadecyl gallate is formed by esterification of gallic acid with n-octacosanol.
5. A preparation method of a wound surface liquid dressing is characterized by comprising the following steps:
1) preparing the following raw materials in parts by weight
150-250 portions of bleached lac, 30-70 portions of plasticizer and 1-5 portions of n-dioctadecyl gallate
2) Adding bleached lac, a plasticizer and dioctadecyl gallate into a first solvent under the stirring state, heating, stirring and mixing uniformly, wherein the first solvent is absolute ethyl alcohol;
3) Adding a second solvent of ethyl acetate, stirring to dissolve the raw materials, and then cooling to obtain the liquid dressing.
6. The method as set forth in claim 5, wherein the raw materials in step 1) comprise, by weight, about 220 parts of bleached lac-ma-jiao, about 40-60 parts of plasticizer, and about 1.0-3.0 parts of n-dioctadecyl gallate.
7. The method of claim 5 or 6, wherein in step 1) the plasticizer is selected from PEG1000, PEG2000 or PEG 4000.
8. The method as claimed in claim 5 or 6, wherein the volume ratio of the absolute ethanol in step 2) to the ethyl acetate in step 3) is (60-80) to (20-40).
9. The method as claimed in claim 5 or 6, wherein the volume ratio of the absolute ethanol in step 2) to the ethyl acetate in step 3) is (60-75) to (25-30).
10. The process of claim 5 or 6, wherein the volume ratio of the absolute ethanol in step 2) to the ethyl acetate in step 3) is 75: 25.
11. The method as claimed in claim 8, wherein the following raw materials are added per 2L of solvent system consisting of absolute ethyl alcohol and ethyl acetate: 150-250 g of bleached lac, 30-70 g of plasticizer and 1-5 g of n-dioctadecyl gallate.
12. The method according to claim 5 or 6, wherein the n-dioctadecyl gallate in step 1) is obtained by esterification of gallic acid with n-octacosanol.
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