CN113967192A - Pharmaceutical composition for accelerating wound healing, preparation method and application thereof - Google Patents
Pharmaceutical composition for accelerating wound healing, preparation method and application thereof Download PDFInfo
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- CN113967192A CN113967192A CN202111321959.1A CN202111321959A CN113967192A CN 113967192 A CN113967192 A CN 113967192A CN 202111321959 A CN202111321959 A CN 202111321959A CN 113967192 A CN113967192 A CN 113967192A
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- pharmaceutical composition
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- phytosterol
- liposome
- wound healing
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 73
- 230000029663 wound healing Effects 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 63
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- 235000012000 cholesterol Nutrition 0.000 claims abstract description 27
- 229920002125 Sokalan® Polymers 0.000 claims abstract description 25
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims abstract description 20
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 20
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- OILXMJHPFNGGTO-NRHJOKMGSA-N Brassicasterol Natural products O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@](C)([C@H]([C@@H](/C=C/[C@H](C(C)C)C)C)CC4)CC3)CC=2)CC1 OILXMJHPFNGGTO-NRHJOKMGSA-N 0.000 claims description 4
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- BTEISVKTSQLKST-UHFFFAOYSA-N Haliclonasterol Natural products CC(C=CC(C)C(C)(C)C)C1CCC2C3=CC=C4CC(O)CCC4(C)C3CCC12C BTEISVKTSQLKST-UHFFFAOYSA-N 0.000 claims description 4
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Images
Classifications
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
Abstract
The invention relates to a pharmaceutical composition for accelerating wound healing, a preparation method and application thereof. The pharmaceutical composition for accelerating wound healing comprises phytosterol, soybean lecithin, cholesterol, carbomer, sodium hydroxide and sterile water. The pharmaceutical composition can keep the wound moist, resist inflammation and inhibit bacteria, reduce the inflammation degree of the wound and accelerate the wound healing.
Description
[ technical field ] A method for producing a semiconductor device
The invention belongs to the field of phytosterol liposome. More specifically, the invention relates to a pharmaceutical composition for accelerating wound healing, a preparation method of the pharmaceutical composition, and application of the pharmaceutical composition.
[ background of the invention ]
Healthy skin plays a key role in maintaining defense and preventing infection, fluid imbalance and thermal imbalance, and when skin is wounded, it heals through a series of physiological processes, including inflammation, tissue formation and remodeling (Gurtner G C, Werner S, Barrandon Y, et al. Wound Repair and Regeneration [ J ] Nature,2008,453(7193): 314-. In the early stage of the healing process, inflammation is an essential stage, cells at the wound site amplify inflammatory response to produce repair, but inflammation is found in an experimental model of repair to delay healing and cause scar increase (striking S A, Krieg T, Davidson J M. inflammation in wound repair: molecular and cellular mechanisms [ J ] Journal of Investigative surgery, 2007,127(3): 514) and 525), and the wound healing speed is 2 times higher in a wet environment than in a dry environment, and the effects of reducing the scar incidence rate and the wound infection rate and the like are also found. In order to heal the wound as soon as possible, reduce the risk of disease caused by the long-term exposure of the wound and reduce the generation of scars to the greatest extent, the wound needs to use an external medicine, but the absorption effect of the existing product is not obvious, the wound is extremely sensitive, irritative substances bring pain, and excessive stimulation can generate adverse effects on the wound, so that the smearing substance which has small irritation on the skin, can continuously diminish inflammation and inhibit bacteria and keeps local moisture is urgently needed to accelerate the healing of the wound.
Liposomes (Liposomes) are mostly artificial biofilms composed of phospholipids and cholesterol, and have biocompatibility and degradability, so that they have a remarkable absorption effect, and also have the effects of moisturizing and nutrition supplementation. However, the liposome has low encapsulation efficiency on the functional substances, poor stability and poor rigidity, and is easy to damage in storage, and the technical problems are not reasonably solved, so that the liposome is not widely applied. Phytosterols can be used as a replacement for most cholesterol as a constituent of liposomes because they have similar properties to cholesterol, are also amphiphilic molecules, and have a significant anti-inflammatory effect that can effectively inhibit the development of inflammation. The addition of the phytosterol can avoid the defect that the liposome is used on gel, and other effective substances are not required to be wrapped in the liposome, so that the entrapment rate and the effective utilization rate of the phytosterol liposome are improved.
The present inventors have concluded the present invention by summarizing the disadvantages of strong skin irritation, poor absorption, low encapsulation efficiency of liposomes, poor stability and poor rigidity of gels, and by a large number of experimental studies and analyses based on the summary of the prior art.
[ summary of the invention ]
[ problem to be solved ]
The invention aims to provide a pharmaceutical composition for accelerating wound healing.
It is another object of the present invention to provide a method for preparing a pharmaceutical composition for accelerating wound healing.
It is another object of the present invention to provide the use of a pharmaceutical composition for accelerating wound healing.
[ solution ]
The invention is realized by the following technical scheme.
The invention relates to a pharmaceutical composition for accelerating wound healing.
The pharmaceutical composition for accelerating wound healing comprises the following components: in parts by weight
According to a preferred embodiment of the present invention, the pharmaceutical composition for accelerating wound healing comprises the following components: in parts by weight
According to another preferred embodiment of the invention, the phytosterol is one or more phytosterols selected from the group consisting of beta-sitosterol, stigmasterol, campesterol and brassicasterol.
According to another preferred embodiment of the invention, the carbomer is carbopol 934 or polyacrylic acid 934.
According to another preferred embodiment of the present invention, the concentration of the aqueous sodium hydroxide solution is 1.6 to 2.4 mol/L.
The invention also relates to a preparation method of the pharmaceutical composition for accelerating wound healing, which is characterized by comprising the following preparation steps:
A. liposome preparation
Dissolving 0.3-1.0 part by weight of phytosterol, 1.0-2.0 parts by weight of soybean lecithin and 0.01-0.5 part by weight of cholesterol in a mixture of chloroform and methanol according to a volume ratio of 1.5-2.5: 1, uniformly mixing, carrying out rotary evaporation for 1-2 hours in a rotary evaporator under the conditions of temperature of 40-50 ℃ and rotation speed of 30-50 rpm, adding a phosphate buffer solution with pH 7.4 and concentration of 8-12 mmol/L, stirring for 10-30 minutes by using a magnetic stirrer, carrying out suction filtration for 1-3 times by using a 0.22 mu m microporous filter membrane under the conditions of temperature of 5-10 ℃ and pressure of 0.3-0.5 MPa, and carrying out ultrasonic oscillation treatment for 10-20 minutes on the obtained plasmid under the conditions of temperature of 2-5 ℃ and frequency of 10-20 KHz to obtain the phytosterol liposome;
B. gel preparation
Dissolving 0.3-3.0 parts by weight of carbomer in 94.0-99.0 parts by weight of sterile water, swelling for 1-3 hours, and adjusting the pH value to 6-7 by using a sodium hydroxide solution with the concentration of 1.6-2.4 mol/L to obtain gel;
C. mixing
And D, uniformly mixing the phytosterol liposome obtained in the step A and the gel obtained in the step B to obtain the pharmaceutical composition for accelerating wound healing.
The invention also relates to a pharmaceutical composition prepared by the preparation method. The content of the phytosterol liposome gel in the pharmaceutical composition is 1.5-6.5% by weight.
The invention also relates to application of the pharmaceutical composition in preparing a medicament for accelerating wound healing.
According to another preferred embodiment of the invention, the amount of the pharmaceutical composition to be applied to the skin per day is unlimited.
According to another preferred embodiment of the invention, the skin applied is normal skin or damaged skin.
The present invention will be described in more detail below.
The invention relates to a pharmaceutical composition for accelerating wound healing.
The pharmaceutical composition for accelerating wound healing comprises the following components: in parts by weight
The phytosterol has the basic effects that the phytosterol forms liposome with soybean lecithin and cholesterol to enhance the oxidation resistance of the liposome and improve the physical rigidity, and in addition, the phytosterol has excellent anti-inflammatory effect, so that other anti-inflammatory substances do not need to be added into the liposome, the stimulation to the skin is reduced, and the entrapment rate is also improved.
The phytosterol used in the present invention is one or more phytosterols selected from the group consisting of beta-sitosterol, stigmasterol, campesterol and brassicasterol, which are all products currently marketed, such as beta-sitosterol, stigmasterol, sold by Shaanxi Haas Schff Biotechnology, Inc.
The main function of the soybean lecithin in the pharmaceutical composition for accelerating wound healing is that the soybean lecithin and liposome form a bilayer structure, namely, the outer layer is a hydrophilic layer, and the inner layer is a hydrophobic layer.
The soybean lecithin used in the present invention is a product currently marketed, for example, by soyabean lecithin available from technical development ltd of the soybean industry of great lianhua.
The essential role of cholesterol in a pharmaceutical composition for accelerating wound healing is that it constitutes a liposome with soybean lecithin and phytosterol, increases the structural diversity of the liposome, improves the absorption efficiency of phytosterol on the skin, and synergistically promotes the growth of wound cells with phytosterol.
The cholesterol used in the present invention is a currently marketed product, such as cholesterol sold by Angel chemical technology, Inc., Anhui.
The basic role of carbomer in pharmaceutical compositions for accelerating wound healing is that it forms a gel matrix with water, suspending liposomes in a carrier gel.
The carbomer used in the present invention is carbopol 934 or polyacrylic acid 934, both of which are currently marketed products, such as carbopol 934 sold by pharmaceutical excipients, Inc., of Zihong, N.C. of Guizhou province.
In the present invention, the basic function of sodium hydroxide in the pharmaceutical composition for accelerating wound healing of the present invention is to adjust the gel ph thereof. The concentration of the sodium hydroxide solution used in the invention is 1.6-2.4 mol/L. The sodium hydroxide used in the present invention is a product currently marketed, for example, sodium hydroxide sold by the company Sammerfei.
In the invention, when the contents of cholesterol, soybean lecithin agent, carbomer, sodium hydroxide and sterile water are in the range, if the content of the phytosterol is lower than 0.3 weight part, the content of the phytosterol is too low, the physical rigidity and the oxidation resistance of the prepared liposome are not high, and the anti-inflammatory effect of the pharmaceutical composition on wounds is also low; if the content of the phytosterol is more than 1.0 part by weight, the absorption inhibition effect of a human body can be generated, and a part of the phytosterol is in a free state without forming a liposome with lecithin; therefore, it is reasonable that the content of the phytosterol is 0.3-1.0 part by weight, preferably 0.4-0.8 part by weight;
likewise, when the contents of phytosterol, cholesterol, carbomer, sodium hydroxide and sterile water are within the ranges, if the content of soybean lecithin is less than 1.0 part by weight, a sufficient amount of liposomes cannot be formed, adversely affecting the wound healing effect; if the content of the soybean lecithin agent is higher than 2.0 parts by weight, the cholesterol and the phytosterol are not combined in a sufficient amount, so that waste is caused; therefore, the content of the soybean lecithin agent is proper to be 1.0 to 2.0 parts by weight, and preferably 1.2 to 1.8 parts by weight;
when the contents of the phytosterol, the soybean lecithin, the carbomer, the sodium hydroxide and the sterile water are in the range, if the content of the cholesterol is lower than 0.01 part by weight, the growth promoting effect of the phytosterol on cells cannot be effectively activated; if the content of cholesterol is higher than 0.5 part by weight, the rigidity and oxidation resistance of the liposome are reduced, and the effect is influenced; therefore, the content of cholesterol is suitably 0.01 to 0.5 parts by weight, preferably 0.08 to 0.45 parts by weight;
when the contents of phytosterol, soybean lecithin, cholesterol, sodium hydroxide and sterile water are within the above range, if the content of carbomer is less than 0.3 part by weight, the thickening effect is insufficient, and gel cannot be formed; if the amount of carbomer is greater than 3.0 parts by weight, the composition is too viscous to form a gel; therefore, the amount of carbomer is suitably from 0.3 to 3.0 parts by weight, preferably from 1.0 to 2.2 parts by weight;
when the contents of the phytosterol, the soybean lecithin, the cholesterol, the carbomer and the sterile water are in the range, if the content of the sodium hydroxide is less than 0.001 part by weight, a system cannot form a neutral condition, and the carbomer cannot form gel; if the content of the sodium hydroxide is higher than 0.10 part by weight, the alkalinity is too strong, and the formed gel has irritation to wounds; therefore, the content of sodium hydroxide is preferably 0.001 to 0.10 parts by weight, more preferably 0.008 to 0.08 parts by weight.
Preferably, the composition of the phytosterol liposome gel is as follows: in parts by weight
The invention also relates to a preparation method of the pharmaceutical composition for accelerating wound healing.
The preparation method comprises the following preparation steps:
A. liposome preparation
Dissolving 0.3-1.0 part by weight of phytosterol, 1.0-2.0 parts by weight of soybean lecithin and 0.01-0.5 part by weight of cholesterol in a mixture of chloroform and methanol according to a volume ratio of 1.5-2.5: 1, uniformly mixing, carrying out rotary evaporation for 1-2 hours in a rotary evaporator under the conditions of temperature of 40-50 ℃ and rotation speed of 30-50 rpm, adding a phosphate buffer solution with pH 7.4 and concentration of 8-12 mmol/L, stirring for 10-30 minutes by using a magnetic stirrer, carrying out suction filtration for 1-3 times by using a 0.22 mu m microporous filter membrane under the conditions of temperature of 5-10 ℃ and pressure of 0.3-0.5 MPa, and carrying out ultrasonic oscillation treatment for 10-20 minutes on the obtained plasmid under the conditions of temperature of 2-5 ℃ and frequency of 10-20 KHz to obtain the phytosterol liposome;
the solution of phytosterol, soya lecithin and cholesterol in the mixed solvent is rotary evaporated in a rotary evaporator with the main purpose of removing excess mixed solvent by evaporation.
During rotary evaporation, when the rotating speed of a rotary evaporator is 30-50 rpm and the rotary evaporation time is 1-2 hours, if the rotary evaporation temperature is lower than 40 ℃, the evaporation effect cannot be achieved; if the rotary evaporation temperature is higher than 50 ℃, the evaporation is too fast, and the liposome content in the solution is lost; therefore, the rotary evaporation temperature is reasonable to be 40-50 ℃; when the rotary evaporation temperature is 40-50 ℃ and the rotary evaporation time is 1-2 hours, if the rotating speed of the rotary evaporator is lower than 30rpm, the evaporation effect cannot be achieved; if the rotating speed of the rotary evaporator is higher than 50rpm, the solution can be spilled; therefore, the rotating speed of the rotary evaporator is proper to be 30-50 rpm; when the rotary evaporation temperature is 40-50 ℃ and the rotary evaporator rotating speed is 30-50 rpm, if the rotary evaporation time is shorter than 1 hour, the mixed solvent cannot be evaporated and removed; if the rotary steaming time is longer than 2 hours, the rotary steaming time is too long; therefore, the rotary evaporation time is suitably 1 to 2 hours;
the main function of this step using phosphate buffer is to flush the liposome components and hydrate the liposomes. The main function of the suction filtration by using a 0.22 mu m microporous filter membrane is to remove microorganisms and filter the organic solution. Here, it is not preferable that the conditions for the suction filtration using the microfiltration membrane exceed the above range because the temperature affects the liposome structure; if the pressure is less than 0.3MPa, the suction filtration effect cannot be achieved; when the pressure is more than 0.5MPa, the liposome can be extracted.
The plasmid obtained by suction filtration of the microporous membrane is subjected to ultrasonic oscillation treatment to form the liposome. Here, it is not preferable that the conditions of the ultrasonic treatment exceed the above range, and if it is less than 10KHz, the liposome cannot be molded; if it is more than 20KHz, the liposome formed is too small or cannot be shaped.
The plasmid treated by ultrasonic oscillation is phytosterol liposome.
The 0.22 μm microporous filter membrane and the ultrasonic oscillation processing equipment used in the invention are products sold in the current market, such as Nylon66 microporous filter membrane with the pore size of 0.22 μm sold by Jinteng experiment equipment Co., Ltd, of Tianjin, and GT SONIC-D ultrasonic oscillator sold by Guangdong Gute ultrasonic corporation.
B. Gel preparation
Dissolving 0.3-3.0 parts by weight of carbomer in 94.0-99.0 parts by weight of sterile water, swelling for 1-3 hours, and adjusting the pH value to 6-7 by using a sodium hydroxide solution with the concentration of 1.6-2.4 mol/L to obtain gel;
carbomers useful in the present invention are carbopol 934 or polyacrylic acid 934.
C. Mixing
And D, uniformly mixing the phytosterol liposome obtained in the step A and the gel obtained in the step B to obtain the pharmaceutical composition for accelerating wound healing.
The invention also relates to a pharmaceutical composition prepared by the preparation method, wherein the content of the phytosterol liposome gel in the pharmaceutical composition is 1.5-6.5% by weight.
The invention also relates to application of the pharmaceutical composition in preparing a medicament for accelerating wound healing.
According to the invention, the amount of the pharmaceutical composition applied to the skin per day is unlimited; if the phytosterol liposome gel is smeared on the wound to be too thin, the using effect is reduced; if the phytosterol liposome gel is coated on the wound too thickly, the phytosterol liposome gel is not beneficial to the discharge of foreign matters from the wound; therefore, it is preferable that the phytosterol liposome gel is applied to the skin in a proper amount. The skin to be applied is normal skin or injured skin.
The phytosterol liposome gel can be applied to moist wounds, has the functions of resisting inflammation and inhibiting bacteria, reducing the inflammation degree of the wounds and accelerating the healing of the wounds on one hand, can promote the cell growth by compounding the phytosterol and the cholesterol on the other hand, can keep the skin wettability by being applied to the skin without the wounds, and can increase the oxidation resistance of the skin by replacing the existing cholesterol of the skin with the phytosterol.
[ advantageous effects ]
The invention has the beneficial effects that:
1. the pharmaceutical composition can keep the wound moist, resist inflammation and inhibit bacteria, reduce the inflammation degree of the wound and accelerate the wound healing.
2. The phytosterol in the pharmaceutical composition can enhance the oxidation resistance and physical rigidity of the liposome, and increase the absorption efficiency of the liposome on the epidermis;
3. the invention combines the phytosterol and the cholesterol, can promote the growth of cells and is beneficial to the rapid healing of wounds.
[ description of the drawings ]
FIG. 1 is an appearance diagram of a pharmaceutical composition of the present invention;
FIG. 2 is a graph showing the results of a test for the effect of blank groups on the swelling of mouse auricles;
FIG. 3 is a graph showing the results of a test for the effect of a sample set of a pharmaceutical composition of the present invention on swelling of mouse pinna;
FIG. 4 is a graph showing the results of the test on the influence of the control group on the swelling of mouse auricles;
FIG. 5 is a graph showing the results of a test for the effect of model groups on swelling of mouse auricles;
FIG. 6 is a graph showing the results of the test of the pharmaceutical composition of the present invention on the skin tissue of the back of a mouse.
[ detailed description ] embodiments
The invention will be better understood from the following examples.
Example 1: preparation of pharmaceutical composition for accelerating wound healing
The implementation steps of this example are as follows:
A. liposome preparation
Dissolving 0.3 weight part of beta-sitosterol phytosterol, 1.0 weight part of soybean lecithin and 0.01 weight part of cholesterol in a mixture of chloroform and methanol according to a volume ratio of 2.2: 1, then carrying out rotary evaporation for 1.6 hours at the temperature of 50 ℃ and the rotation speed of 44rpm in an RE-2000 rotary evaporator sold by Shanghai Yangrong biochemical instrument factory, then adding a phosphate buffer solution with the pH value of 7.4 and the concentration of 8mmol/L, stirring for 16 minutes by using a magnetic stirrer, then carrying out suction filtration for 2 times at the temperature of 8 ℃ and the pressure of 0.5MPa by using a Nylon66 microporous filter membrane with the pore diameter of 0.22 mu m sold by Tianjin Jinteng experimental equipment Limited, and carrying out ultrasonic oscillation treatment for 10 minutes at the temperature of 2 ℃ and the frequency of 16HKz by using an SONGT-D ultrasonic oscillator sold by Guangdong Gute ultrasonic corporation to obtain a plant alcohol liposome;
B. gel preparation
Dissolving 0.3 weight part of carbomer in 98.0 weight part of sterile water, swelling for 2.2 hours, and adjusting the pH value to 6.0 by using a sodium hydroxide solution with the concentration of 1.6mol/L to obtain gel;
C. mixing
And D, uniformly mixing the phytosterol liposome obtained in the step A with the gel obtained in the step B to obtain the pharmaceutical composition for accelerating wound healing, wherein the content of the phytosterol liposome gel in the pharmaceutical composition is 1.6% by weight.
The appearance of the pharmaceutical composition taken by electron microscopy is shown in figure 1, and the success of liposome preparation can be seen from figure 1.
Example 2: preparation of pharmaceutical composition for accelerating wound healing
The implementation steps of this example are as follows:
A. liposome preparation
Dissolving 0.8 parts by weight of stigmasterol phytosterol, 1.2 parts by weight of soybean lecithin and 0.1 part by weight of cholesterol in a mixture of chloroform and methanol according to a volume ratio of 2.5: 1, then carrying out rotary evaporation for 2.0 hours at the temperature of 40 ℃ and the rotation speed of 30rpm in an RE-2000 rotary evaporator sold by Shanghai Yangrong biochemical instrument factory, then adding a pH 7.4 phosphate buffer solution with the concentration of 10mmol/L, stirring for 24 minutes by using a magnetic stirrer, then carrying out suction filtration for 1 time at the temperature of 5 ℃ and the pressure of 0.4MPa by using a Nylon66 microporous filter membrane with the pore diameter of 0.22 mu m sold by Jinteng experimental equipment Limited, Tianjin, and obtaining a plasmid, and carrying out ultrasonic oscillation treatment for 20 minutes at the temperature of 3 ℃ and the frequency of 20KHz by using an SONGT-D ultrasonic oscillator sold by Guangdong Gute ultrasonic Gmby, and obtaining a phytosterol liposome;
B. gel preparation
Dissolving 1.0 part by weight of carbomer in 94.0 parts by weight of sterile water, swelling for 1.0 hour, and adjusting the pH value to 6.3 by using a sodium hydroxide solution with the concentration of 1.8mol/L to obtain gel;
C. mixing
And D, uniformly mixing the phytosterol liposome obtained in the step A with the gel obtained in the step B to obtain the pharmaceutical composition for accelerating wound healing, wherein the content of the phytosterol liposome gel in the pharmaceutical composition is 3.2% by weight.
Example 3: preparation of pharmaceutical composition for accelerating wound healing
The implementation steps of this example are as follows:
A. liposome preparation
Dissolving 1.0 part by weight of campesterol phytosterol, 2.0 parts by weight of soybean lecithin and 0.5 part by weight of cholesterol in a mixture of chloroform and methanol according to a volume ratio of 1.5: 1, then carrying out rotary evaporation for 1.0 hour under the conditions of the temperature of 44 ℃ and the rotating speed of 36rpm in an RE-2000 rotary evaporator sold by Shanghai Yangrong biochemical instrument factory, then adding a phosphate buffer solution with the pH value of 7.4 and the concentration of 12mmol/L, stirring for 30 minutes by using a magnetic stirrer, then carrying out suction filtration for 3 times under the conditions of the temperature of 8 ℃ and the pressure of 0.3MPa by using a Nylon66 microporous filter membrane with the pore diameter of 0.22 mu m sold by Tianjin Shing experimental equipment limited, and carrying out ultrasonic oscillation treatment for 16 minutes on the obtained plasmid by using an SONGT-D ultrasonic oscillator sold by Guangdong Gute ultrasonic GmbH under the conditions of the temperature of 5 ℃ and the frequency of 14KHz to obtain the phytosterol liposome;
B. gel preparation
Dissolving 3.0 parts by weight of carbomer in 96.0 parts by weight of sterile water, swelling for 3.0 hours, and adjusting the pH value to 6.8 by using a sodium hydroxide solution with the concentration of 2.2mol/L to obtain gel;
C. mixing
And D, uniformly mixing the phytosterol liposome obtained in the step A with the gel obtained in the step B to obtain the pharmaceutical composition for accelerating wound healing, wherein the content of the phytosterol liposome gel in the pharmaceutical composition is 6.5% by weight.
Example 4: preparation of pharmaceutical composition for accelerating wound healing
The implementation steps of this example are as follows:
A. liposome preparation
Dissolving 0.5 part by weight of brassicasterol phytosterol, 1.7 parts by weight of soybean lecithin and 0.3 part by weight of cholesterol in a mixture of chloroform and methanol according to a volume ratio of 1.8: 1, then carrying out rotary evaporation for 1.3 hours in an RE-2000 rotary evaporator sold by Shanghai Yangrong biochemical instrument factory under the conditions of the temperature of 47 ℃ and the rotating speed of 50rpm, then adding a pH 7.4 phosphate buffer solution with the concentration of 10mmol/L, stirring for 10 minutes by using a magnetic stirrer, then carrying out suction filtration for 2 times by using a Nylon66 microporous filter membrane with the pore diameter of 0.22 mu m sold by Tianjin Shing experimental equipment limited company under the conditions of the temperature of 10 ℃ and the pressure of 0.4MPa, and carrying out ultrasonic oscillation treatment on the obtained plasmid for 12 minutes by using an SONGT-D ultrasonic oscillator sold by Guangdong Gute ultrasonic GmbH under the conditions of the temperature of 3 ℃ and the frequency of 10KHz to obtain the phytosterol liposome;
B. gel preparation
Dissolving 2.2 parts by weight of carbomer in 99.0 parts by weight of sterile water, swelling for 1.6 hours, and adjusting the pH value to 7.0 by using a sodium hydroxide solution with the concentration of 2.4mol/L to obtain a gel;
C. mixing
And D, uniformly mixing the phytosterol liposome obtained in the step A with the gel obtained in the step B to obtain the pharmaceutical composition for accelerating wound healing, wherein the content of the phytosterol liposome gel in the pharmaceutical composition is 4.7% by weight.
Test example 1: anti-inflammatory assay for pharmaceutical compositions of the invention
The method of implementation of this test example is as follows:
the test basis is as follows: authors Weiwei, methodology of pharmacological experiments (fourth edition), national public health Press (2008)
Test animals:
ICR mouse (male) body weight: 22 g-25 g, 40 groups of 4; the test animal uses the license number: SYXK 2014-2018
Test samples:
sample group: example 1 phytosterol liposomes obtained in step a;
positive group: clobetasol propionate cream (10 g: 2 mg); products of Jiangsu Yunhou pharmaceutical companies;
model group: xylene, a drug sold by national drug Agents;
blank group: no medicament is used;
the test method comprises the following steps:
xylene was used to dissolve the sample to be tested. The test mice were coated with an inflammatory agent or other test sample as described above on both the front and back of the right ear. The volume of the inflammatory agent was 0.02 ml/tube. After 1h, the test mice are anesthetized and killed, double ears are cut off, round ear pieces are respectively punched at the same part by a puncher with the diameter of 9mm, the round ear pieces are weighed, the swelling degree is obtained by subtracting the weight of the left ear from the weight of the right ear of each mouse, the swelling degrees of the sample group and the blank group are subjected to statistical treatment, and the swelling inhibition ratio (%) is calculated.
The results of the experiments of this test example are shown in table 1.
Table 1: test result of influence of phytosterol liposome on mouse auricle swelling
| Group of | Number of animals | Ear piece weight | Inhibition ratio (%) | P |
| Blank space | 10 | 0.83±0.37 | ||
| Model (model) | 10 | 3.41±1.95 | ||
| Sample (I) | 10 | 0.90±0.51 | 73.6 | ＜0.01 |
| Positive for | 10 | 1.34±0.75 | 54.2 | ＜0.01 |
The results shown in table 1 clearly show that the addition of the phytosterol liposome sample group can significantly inhibit skin inflammation compared with the model group and the blank group; compared with the positive group, the sample group has higher inhibition rate and good effect.
Test example 2: pharmaceutical composition repair test of the invention
The method of implementation of this test example is as follows:
the test basis is as follows: authors Weiwei, methodology of pharmacological experiments (fourth edition), national public health Press (2008)
Test animals:
ICR mouse (male) body weight: 22 g-25 g, 40 animals are divided into 4 groups, and the test animals use license number SYXK (Shanghai) 2014-2018;
test samples:
blank group: no operation is carried out;
sample group: the resulting pharmaceutical composition prepared in example 1;
model group: no operation is carried out after the molding;
control group: example 1 gel from step B;
the test method comprises the following steps:
12 (8-10 weeks) male mice were selected and randomly divided into four groups, blank, sample, model and control. Continuously sticking and rapidly tearing 3cm x 3cm test parts of the skin on the left side and the right side of a mouse by using an adhesive tape for a plurality of times until the skin has a small blood spot, then smearing the pharmaceutical composition on a sample group, smearing blank gel without liposome on a control group, and carrying out no operation after model building and no operation on the blank group; once daily for 5 consecutive days, mice were sacrificed to obtain skin tissue from the test sites and pathological section photographs were taken, which are shown in fig. 2-5.
The results of the experiments of this test example are shown in table 2.
Table 2: test results of influence of pharmaceutical composition on mouse auricle swelling
| Group of | Microscopic observation |
| Blank group | The stratum corneum of the epidermis of the skin is normal, see FIG. 2 |
| Sample set | Restoration of the stratum corneum layer of the epidermis of the skin, see fig. 3 |
| Control group | The stratum corneum of the epidermis of the skin does not recover significantly, see figure 4 |
| Model set | Epidermal cuticle exfoliation injury of skin, see FIG. 5 |
As can be seen from the accompanying figures 2-5, compared with the test results of the control group and the model group, the damaged skin can be effectively repaired after the skin at the damaged part is treated by the pharmaceutical composition of the invention.
Test example 3: wound healing test of the pharmaceutical composition of the invention
The method of implementation of this test example is as follows:
the test basis is as follows: authors Weiwei, methodology of pharmacological experiments (fourth edition), national public health Press (2008)
Test animals:
KM mouse (male) body weight: 22 g-25 g, 40 animals are divided into 4 groups, and the test animals use license number SYXK (shan) 2020-005;
test samples:
control group: the resulting pharmaceutical composition prepared in example 1;
model group: no operation is carried out after the molding;
sample group: example 1 gel from step B;
the test method comprises the following steps:
selecting 15 healthy male KM mice, randomly dividing into a model group, a sample group and a control group, removing the back hairs of the mice for skin preparation one day before the model is established, using 2% pentobarbital with the dosage of 45mg/kg 1h before the model is established, carrying out intraperitoneal injection to anaesthetize the mice, then using a puncher to take down the whole skin tissue on the back of the mice to cause a mechanical wound with the diameter of 7mm, and using hemostatic cotton to stop bleeding. The control group was wound-lined with the composition prepared in example 1, the model group was not subjected to any subsequent treatment, and the sample group was lined with the gel obtained in step B of example 1. The wounds of the sample group and the control group were kept moist by twice daily medication, and the mice were observed for healing on days 0, 4, 8 and 12, respectively.
The results of this test example are shown in Table 3 and FIG. 6.
Table 3: test result of pharmaceutical composition on skin tissue on back of mouse
| Grouping | Wound healing status |
| Sample set | Good healing condition, less inflammation and shallow scar |
| Control group | Better healing, swelling and inflammation around the woundSymptoms, deep scar |
| Model set | Slow healing, swelling around the wound, inflammation and deep scar |
As can be seen from fig. 6, after 12 days of wound healing, the model group had slow wound healing, severe swelling around the wound, and severe inflammation, and the wound scar was deep due to the dry surface of the wound; the control group has better healing condition, the swelling around the wound is heavier, certain inflammatory reaction is caused, the scar is deeper, but the healing speed is faster compared with that of the model group; the sample group has the advantages of light overall inflammation degree, small swelling around the wound all the time, shallow scar of the wound in 12 days, high wound healing speed and good healing condition. It can be seen that the wound treated with the pharmaceutical composition of the present invention heals rapidly, thereby reducing the occurrence of inflammation.
Claims (10)
1. A pharmaceutical composition for accelerating wound healing, characterized in that it consists of: in parts by weight
2. Pharmaceutical composition according to claim 1, characterized in that it consists of: in parts by weight
3. The pharmaceutical composition according to claim 1 or 2, characterized in that the phytosterol is one or more phytosterols selected from the group consisting of β -sitosterol, stigmasterol, campesterol and brassicasterol.
4. A pharmaceutical composition according to claim 1 or 2, characterized in that the carbomer is carbopol 934 or polyacrylic acid 934.
5. The pharmaceutical composition according to claim 1 or 2, wherein the concentration of the aqueous sodium hydroxide solution is 1.6 to 2.4 mol/L.
6. The process for preparing a pharmaceutical composition for accelerating wound healing according to claim 1, wherein the preparation process comprises the following steps:
A. liposome preparation
Dissolving 0.3-1.0 part by weight of phytosterol, 1.0-2.0 parts by weight of soybean lecithin and 0.01-0.5 part by weight of cholesterol in a mixture of chloroform and methanol according to a volume ratio of 1.5-2.5: 1, uniformly mixing, carrying out rotary evaporation for 1-2 hours in a rotary evaporator under the conditions of temperature of 40-50 ℃ and rotation speed of 30-50 rpm, adding a phosphate buffer solution with pH 7.4 and concentration of 8-12 mmol/L, stirring for 10-30 minutes by using a magnetic stirrer, carrying out suction filtration for 1-3 times by using a 0.22 mu m microporous filter membrane under the conditions of temperature of 5-10 ℃ and pressure of 0.3-0.5 MPa, and carrying out ultrasonic oscillation treatment for 10-20 minutes on the obtained plasmid under the conditions of temperature of 2-5 ℃ and frequency of 10-20 KHz to obtain the phytosterol liposome;
B. gel preparation
Dissolving 0.3-3.0 parts by weight of carbomer in 94.0-99.0 parts by weight of sterile water, swelling for 1-3 hours, and adjusting the pH value to 6-7 by using a sodium hydroxide solution with the concentration of 1.6-2.4 mol/L to obtain gel;
C. mixing
And D, uniformly mixing the phytosterol liposome obtained in the step A and the gel obtained in the step B to obtain the pharmaceutical composition for accelerating wound healing.
7. The pharmaceutical composition prepared by the preparation method according to claim 6, wherein the phytosterol liposome gel content of the pharmaceutical composition is 1.5-6.5% by weight.
8. Use of the pharmaceutical composition according to claim 1 or 2 or the pharmaceutical composition prepared by the preparation method according to claim 6 in the preparation of a medicament for accelerating wound healing.
9. Use according to claim 8, characterized in that the amount of the pharmaceutical composition applied to the skin per day is unlimited.
10. Use according to claim 9, characterized in that the skin applied is normal skin or damaged skin.
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| CN114601920A (en) * | 2022-03-23 | 2022-06-10 | 宁波御坊堂生物科技有限公司 | Oral liposome composition for improving bone joint health and preparation method thereof |
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