CN104840428A - Hyaluronic acid-chitosan microsphere carrying epidermal growth factor and preparation method and application of hyaluronic acid-chitosan microsphere - Google Patents
Hyaluronic acid-chitosan microsphere carrying epidermal growth factor and preparation method and application of hyaluronic acid-chitosan microsphere Download PDFInfo
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- hyaluronic acid
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Abstract
The invention provides an environment-friendly and simple preparation method for a hyaluronic acid-chitosan microsphere carrying an epidermal growth factor. The hyaluronic acid-chitosan microsphere is prepared via ionic polymerization, centrifugation, purification, and freeze-drying under the protection of a protective agent. The hyaluronic acid-chitosan microsphere carrying the epidermal growth factor can be used for preparing pharmaceutical preparations (including a gel, a film agent, a powder agent, an ointment, and the like) for treating burn and scald wounds. According to the hyaluronic acid-chitosan microsphere carrying the epidermal growth factor and the pharmaceutical preparations of the hyaluronic acid-chitosan microsphere, sustained release of the epidermal growth factor on the burn and scald wounds is realized; wound cell proliferation is promoted; and functions, of protecting burn and scald tissues and promoting wound healing, of sodium hyaluronate and chitosan are developed. The hyaluronic acid-chitosan microsphere can provide a support for wound cell proliferation, and an excellent medicine for treating burn and scald wounds is obtained.
Description
Technical field:
The present invention designs a kind of hyaluronic acid-chitosan microsphere being loaded with epidermal growth factor and preparation method thereof and applies with its pharmaceutical composition being active component.
Background technology:
Burn is one of disease that in current all diseases, misery is maximum, treatment difficulty is the highest.The therapy system occupying dominant position at present in burn treating field promotes wound surface drying incrustation, then carry out the topical therapeutic of cutting scab, in conjunction with whole body therapeutics such as shock, infection, nutritional supports.This Therapeutic Method greatly reduces the mortality rate of large-area burns, but also exists that patient suffering is large, cicatrix incidence rate is high, the high serious drawback of medical expense.Therefore, new Therapeutic Method is found and medicine has positive effect.In the healing that burn waits the skin serious defect that causes and wound surface, it is very important for carrying out covering rapidly to wound surface with suitable dressing (pastille or not pastille), the body fluid and protein-loss that reduce wound surface can be played, prevent the effect of the tissue injury of bacteriological infection and secondary, in some cases, also can be proliferative cell and provide support, wound healing.Over the past two decades, this has become the study hotspot direction in the repair in trauma fields such as serious burn.
Epidermal growth factor (epidermal growth factor, EGF) is one of multiple somatomedin related in repair in trauma.Existing research shows, EGF is that the stimulation of various kinds of cell division growth is former, can promote wound surface cell migration, and granulation tissue is grown and accelerates, in granulation, the composition such as DNA, RNA, collagen fiber, hyaluronic acid increases.The propagation of the angle albuminous cell that EGF can stimulate wound healing to rely on and migration.Animal and clinical research all show, EGF can obvious wound healing, especially better to some difficult healing wound surface effects.Domestic and international existing EGF drug-supplying system comprises ointment, spray, injection and controlled release system etc.Because the half-life of epidermal growth factor is short, shorter in the time of contact of wound face itself and cell, and add the Degradation of the protease that itself unstability and wound surface exist, often make epidermal growth factor inactivation very fast, practical function limited time.Therefore, adopt the mode of multiple dosing clinically, but be unfavorable for that the compliance of patient turn increases financial burden like this.And the microsphere formed by porous, degradable matrix encapsulation epidermal growth factor, both can reach the sustained release of epidermal growth factor, stimulate wound surface cell proliferation, can be again proliferative cell and provide adsorbing medium, is the first-selection of epidermal growth factor drug-supplying system.
The method preparing the sustained-release micro-spheres of albumen or polypeptide drug at present has emulsion-solvent evaporation method, cross-linked polymeric method, spray drying method etc.For emulsion-solvent evaporation method, cross-linked polymeric method, need in the preparation to use organic solvent or cross-linking agent, on the one hand can cause environmental pollution, there is organic solvent in finished product on the other hand or cross-linking agent remains.Although spray drying method can not with an organic solvent, baking temperature is general higher, easily causes albumen or polypeptide drugs degeneration.
Chitosan and hyaluronic acid are all natural degradable macromolecular material, all have good biocompatibility, are therefore often used to the carrier preparing various drug-supplying system.In the early stage external application Chitosan powder of burn, the early stage damage of burn can be stoped to increase the weight of, have significant protective effect to burn wound tissue, obviously can alleviate and even reverse degree of injury.Be equipped with hyaluronic acid the powder that appropriate amount of auxiliary materials makes and can absorb burn wound's transudate, effectively protect, wound closure, alleviate edema wound, have and suppress scar tissue to be formed and promote the function of burn wound healing.
Summary of the invention:
The invention provides a kind of environmental protection, easy sustained release microsphere of epidermal growth factor preparation method; the hyaluronic acid-chitosan microsphere being loaded with epidermal growth factor of preparation; the sustained release of epidermal growth factor at empyrosis wound surface can be realized; promote wound surface cell proliferation; also play hyaluronic acid sodium and chitosan to the protective effect of burned tissue and supporting wound healing effect simultaneously; and provide support for wound surface proliferative cell, thus obtain a kind of good curing burn and scald thing.
The hyaluronic acid-chitosan microsphere being loaded with epidermal growth factor provided by the present invention, by ionic polymerization under protective agent effect, centrifugation, purification, lyophilizing and obtaining, concrete preparation method is as follows:
(1) hyaluronic acid, sodium tripolyphosphate, epidermal growth factor are dissolved in the water.
(2) chitosan is dissolved in the water.
(3) solution obtained in step (1) and step (2) is uniformly mixed, obtains the suspension containing hyaluronic acid-chitosan microsphere.
(4) by centrifugal for the suspension obtained in above-mentioned steps (3), abandoning supernatant, collecting precipitation.
(5) precipitation that above-mentioned steps (4) obtains is added purified water, jolting disperses.
(6) suspension above-mentioned steps (5) obtained is centrifugal, abandoning supernatant, collecting precipitation.
(7) lyophilizing removing moisture will be precipitated, obtain finished product.
The described hyaluronic acid-chitosan microsphere being loaded with epidermal growth factor, the mass percent of epidermal growth factor in microsphere is 0.01% ~ 10%.
The described hyaluronic acid-chitosan microsphere being loaded with epidermal growth factor, the mass ratio of hyaluronic acid and chitosan is hyaluronic acid: chitosan=1:3 ~ 1:9.
The described hyaluronic acid-chitosan microsphere being loaded with epidermal growth factor, chitosan has the advantages that molecular weight is low, deacetylation is high.
The described hyaluronic acid-chitosan microsphere being loaded with epidermal growth factor, the deacetylation of chitosan is greater than 70%, and preferably 80% ~ 95%.
The described hyaluronic acid-chitosan microsphere being loaded with epidermal growth factor, the average molecular mass of chitosan is less than 0.2 × 10
6, be preferably less than 0.1 × 10
6.
The described preparation method being loaded with the hyaluronic acid-chitosan microsphere of epidermal growth factor, the hyaluronic acid concentration in step (1) is 0.1mg/ml ~ 0.5mg/ml.
The described preparation method being loaded with the hyaluronic acid-chitosan microsphere of epidermal growth factor, the tripolyphosphate na concn in step (1) is 0.01mg/ml ~ 0.1mg/ml.
The described preparation method being loaded with the hyaluronic acid-chitosan microsphere of epidermal growth factor, the chitosan concentration in step (2) is 0.5mg/ml ~ 3.0mg/ml.
The described preparation method being loaded with the hyaluronic acid-chitosan microsphere of epidermal growth factor, the mixed volume ratio of two kinds of solution in step (3) is the solution that step (1) obtains: the solution=1:0.5 ~ 1:2 obtained in step (2).
The described preparation method being loaded with the hyaluronic acid-chitosan microsphere of epidermal growth factor, the addition sequence of two kinds of solution in step (3) is that the solution that step (1) obtains is joined the solution obtained in step (2), and the joining day is 10min ~ 30min.
The described preparation method being loaded with the hyaluronic acid-chitosan microsphere of epidermal growth factor, the time that is uniformly mixed of two kinds of solution in step (3) is 10min ~ 60min, and mixing rotating speed is 60 revs/min ~ 1000 revs/min, and mixing temperature is room temperature.
The described preparation method being loaded with the hyaluronic acid-chitosan microsphere of epidermal growth factor, in the centrifugal process in step (4) and step (6), centrifugal force is 5000g ~ 20000g.
The described preparation method being loaded with the hyaluronic acid-chitosan microsphere of epidermal growth factor, the centrifugation time in step (4) and step (6) is 15min ~ 60min.
The described preparation method being loaded with the hyaluronic acid-chitosan microsphere of epidermal growth factor, the quantity adding purified water in step (5) is 10 times ~ 50 times of collecting precipitation quality in step (4).
The described preparation method being loaded with the hyaluronic acid-chitosan microsphere of epidermal growth factor, the object in step (5) and step (6) is purification gained hyaluronic acid-chitosan microsphere, removes unreacted substrate.
The described preparation method being loaded with the hyaluronic acid-chitosan microsphere of epidermal growth factor, can repetitive operation 2 times ~ 4 times in step (5) and step (6).
Pharmaceutical composition with the hyaluronic acid-chitosan microsphere being loaded with epidermal growth factor of the present invention is external preparation, is generally gel, membrane, powder agent and ointment etc., is and adopts customary adjuvant and conventional method prepare and obtain.Of the present invention with the pharmaceutical composition of the hyaluronic acid-chitosan microsphere being loaded with epidermal growth factor, also can be combined to form compound preparation with other drug.
Of the present invention with the pharmaceutical composition of the hyaluronic acid-chitosan microsphere being loaded with epidermal growth factor; make burn and scald medicine preparation and be applied to empyrosis wound surface; the release that epidermal growth factor can slowly continue; reach protection wound surface, accelerate healing rate, improve the objects such as healing quality, thus obtain a kind of good curing burn and scald thing.
Detailed description of the invention:
Below by way of specific embodiment, the present invention is described in detail:
Embodiment 1:
Be loaded with the preparation of the hyaluronic acid-chitosan microsphere of epidermal growth factor
(1) by respectively by hyaluronic acid (average molecular mass 0.12 × 10
6) 0.2g, sodium tripolyphosphate 0.05g, epidermal growth factor 0.1g be dissolved in 1000ml purification.
(2) by chitosan (average molecular mass 0.08 × 10
6, deacetylation 88%) and 1.2g is dissolved in 1000ml purified water.
(3) solution that step (1) obtains to be joined in the solution that step (2) obtains and to be constantly uniformly mixed with magnetic stirrer, add speed 50ml/min, joining day 20min, speed of agitator: 300 turns/min, mixing time 30min, obtains the suspension containing hyaluronic acid-chitosan microsphere.
(4) by centrifugal for the suspension obtained in above-mentioned steps (3), centrifugal force 10000g, centrifugation time 30min; Abandoning supernatant, collecting precipitation.
(5) join in purified water by the precipitation that above-mentioned steps (4) obtains, the quality of purified water is 30 times of precipitation, and its jolting is disperseed with agitator.
(6) suspension above-mentioned steps (5) obtained is centrifugal, centrifugal force 10000g, centrifugation time 30min; Abandoning supernatant, collecting precipitation.
(7) lyophilizing removing moisture will be precipitated, obtain finished product.
Embodiment 2:
Be loaded with the preparation of the hyaluronic acid-chitosan microsphere of epidermal growth factor
(1) by respectively by hyaluronic acid (average molecular mass 0.06 × 10
6) 0.4g, sodium tripolyphosphate 0.1g, epidermal growth factor 0.1g be dissolved in 1000ml purification.
(2) by chitosan (average molecular mass 0.08 × 10
6, deacetylation 88%) and 2g is dissolved in 1000ml purified water.
(3) solution that step (1) obtains to be joined in the solution that step (2) obtains and to be constantly uniformly mixed with magnetic stirrer, add speed 100ml/min, joining day 10min, speed of agitator: 600 turns/min, mixing time 30min, obtains the suspension containing hyaluronic acid-chitosan microsphere.
(4) by centrifugal for the suspension obtained in above-mentioned steps (3), centrifugal force 10000g, centrifugation time 30min; Abandoning supernatant, collecting precipitation.
(5) join in purified water by the precipitation that above-mentioned steps (4) obtains, the quality of purified water is 20 times of precipitation, and its jolting is disperseed with agitator.
(6) suspension above-mentioned steps (5) obtained is centrifugal, centrifugal force 10000g, centrifugation time 30min; Abandoning supernatant, collecting precipitation.
(7) lyophilizing removing moisture will be precipitated, obtain finished product.
Embodiment 3
Membranous preparation containing epidermal growth factor microsphere
A. get polyvinyl alcohol (model 2699) 120g to join in 1000ml purified water and dissolve, get soluble starch 10g and add wherein and stirring and dissolving.Above-mentioned solution is heated to 70 DEG C ~ 80 DEG C, adds glycerol 20g, tween 10g, dimethicone 8g stirring respectively, room temperature places cooling, filters, adds the hyaluronic acid-chitosan microsphere that 2g is loaded with epidermal growth factor, for subsequent use.
B. the aqueous solution of 10% polyvinyl alcohol is prepared, for subsequent use.
C. nitrocellulose alcohol, the ether mixed liquor (alcohol ether volume ratio 1:1) of 4% is prepared, for subsequent use.
D. the glacial acetic acid solution of 4% collagen protein is prepared, for subsequent use.
B liquid is spread evenly across on glass plate, vacuum drying under 40 DEG C of conditions, is then coated with C liquid, A liquid, D liquid successively, and under 40 DEG C of conditions vacuum drying, be then divided into small pieces, obtain final product.
Embodiment 4
Gel preparation containing epidermal growth factor microsphere
(1) Kappa nurse (model 940) 10g being spread on uniformly 900ml distills on the water surface, leaves standstill 24h and dissolves, fully swelling.
(2) hyaluronic acid-chitosan microsphere 2g being loaded with epidermal growth factor is dispersed in above-mentioned carbomer solution.
(3) in above-mentioned solution, drip triethanolamine, be adjusted to pH value about 6 ~ 7, add water to 1000ml, stir, subpackage.
Embodiment 5
Powder agent preparation containing epidermal growth factor microsphere
Prescription:
Preparation: by sodium carboxymethyl cellulose, chitosan and hyaluronic acid mix homogeneously, then add containing epidermal growth factor microsphere, mix homogeneously, sterilizing, subpackage, to obtain final product.
Embodiment 6
The preparation of the ointment containing epidermal growth factor microsphere
Prescription:
Preparation: get liquid paraffin and vaseline and join in mortar and stir into pasty state, be sprinkled into the hyaluronic acid-chitosan microsphere containing epidermal growth factor, stir evenly and get final product.
Embodiment 7
The zoopery that the hyaluronic acid-chitosan microsphere being loaded with epidermal growth factor is treated for burn and scald
Adopt the dark II degree of burn and scald model of rat, observe hyaluronic acid-chitosan microsphere (the embodiment 1 method obtains) therapeutical effect to burned tissue being loaded with epidermal growth factor.Particular content is as follows: get Wistar rat 90, be divided into three groups at random, often organizes 30, i.e. medicine carrying microballoons experimental group, blank microsphere experimental group, positive controls and negative control group.Coat sodium sulfide depilatory at rat back, scrape off gently after several minutes, clean with clear water, make back depilation area reach 8cm × 6cm.Lose hair or feathers latter 24 hours, press 36mg/kg anesthetized rat with 1.8% pentobarbital sodium.Rat is fixed on modeling plank by dorsal position, makes the skin of back of rat be exposed in pattern hole, template to be put in people's electric-heated thermostatic water bath 80 DEG C and scalds 12 seconds, cause dark II degree of scald.(get negative control group rat 1, within latter 48 hours, make pathological examination in scald, result shows that scalding local epidermis disappears, epidermis, corium and subcutaneous tissue vasodilation, subcutaneous tissue edema, visible acute and chronic cell infiltration in corium, subcutaneous tissue, meets the dark II degree of scald standard of rat).Scald after dry water stain gently with gauze, first with 0.1% bromo geramine liquid clean, then with 0.05% chlorhexidine acetate sterilize wound surface.For medicine carrying microballoons experimental group rat, remove with the microballoon lyophilized powder of the hyaluronic acid-chitosan being loaded with epidermal growth factor and be burned position at it, make uniformly one deck, every dosage is 150mg; For blank microsphere experimental group rat, use the not microballoon lyophilized powder of blank hyaluronic acid-chitosan of pastille to remove and be burned position at it, make uniformly one deck, every dosage is 150mg, and the preparation method of its empty microsphere is with embodiment 1; For positive controls rat, by Sulfadiazine Silver Cream swab stick uniform application in being burned position, every dosage is 250mg; Negative control group does not give any medicine.Single cage is raised.Observation index: the wound surface incrustation area of 1. the 7th day, the 14th day; 2. decrustation healing time.Experimental result carries out t inspection.
The hyaluronic acid-chitosan microsphere that table 1 is loaded with epidermal growth factor carries out zooperal empyrosis wound surface healing state
Note: compared with negative control group, " * " represents P<0.05, and " * * " represents P<0.01.
Claims (12)
1. be loaded with a hyaluronic acid-chitosan microsphere for epidermal growth factor, it is characterized in that being obtained by following methods:
(1) hyaluronic acid, sodium tripolyphosphate, epidermal growth factor are dissolved in the water,
(2) chitosan is dissolved in the water,
(3) solution obtained in step (1) and step (2) is uniformly mixed, obtains the suspension containing hyaluronic acid-chitosan microsphere,
(4) by centrifugal for the suspension obtained in above-mentioned steps (3), abandoning supernatant, collecting precipitation,
(5) precipitation that above-mentioned steps (4) obtains is added purified water, jolting disperses,
(6) suspension above-mentioned steps (5) obtained is centrifugal, abandoning supernatant, collecting precipitation,
(7) lyophilizing removing moisture will be precipitated, obtain finished product.
2. the hyaluronic acid-chitosan microsphere being loaded with epidermal growth factor according to claim 1, is characterized in that: the mass percent of described epidermal growth factor in microsphere is 0.01% ~ 10%.
3. the hyaluronic acid-chitosan microsphere being loaded with epidermal growth factor according to claim 1, is characterized in that: the mass ratio of described hyaluronic acid and chitosan is hyaluronic acid: chitosan=1:3 ~ 1:9.
4. the hyaluronic acid-chitosan microsphere being loaded with epidermal growth factor according to claim 1, is characterized in that: the deacetylation of described chitosan is greater than 70%.
5. the hyaluronic acid-chitosan microsphere being loaded with epidermal growth factor according to claim 1, is characterized in that: the average molecular mass of described chitosan is less than 0.2 × 10
6.
6. be loaded with the preparation method of the hyaluronic acid-chitosan microsphere of epidermal growth factor according to claim 1, it is characterized in that: the hyaluronic acid concentration in described step (1) is 0.1mg/ml ~ 0.5mg/ml.
7. be loaded with the preparation method of the hyaluronic acid-chitosan microsphere of epidermal growth factor according to claim 1, it is characterized in that: the tripolyphosphate na concn in described step (1) is 0.01mg/ml ~ 0.1mg/ml.
8. be loaded with the preparation method of the hyaluronic acid-chitosan microsphere of epidermal growth factor according to claim 1, it is characterized in that: in described step (2), the concentration of chitosan is 0.5mg/ml ~ 3.0mg/ml.
9. be loaded with the preparation method of the hyaluronic acid-chitosan microsphere of epidermal growth factor according to claim 1, it is characterized in that: the mixed volume ratio of two kinds of solution in described step (3) is the solution that step (1) obtains: the solution=1:0.5 ~ 1:2 obtained in step (2).
10. to be loaded with the pharmaceutical composition that the hyaluronic acid-chitosan microsphere of epidermal growth factor is active component.
11. pharmaceutical compositions according to claim 10, is characterized in that: the dosage form of described compositions is gel, membrane, powder agent and ointment.
12. pharmaceutical compositions according to claim 10 or 11 are preparing the application in burn and scald medicine.
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| CN105919944A (en) * | 2016-05-03 | 2016-09-07 | 苏州科技学院 | Degradable polymer microsphere containing gel core as well as preparation and application of polymer microsphere |
| CN106727246A (en) * | 2017-02-08 | 2017-05-31 | 上海元茵生物科技有限公司 | Calf serum cell nutrient solution |
| CN108913647A (en) * | 2018-08-08 | 2018-11-30 | 新乡医学院 | A kind of stem cell media and preparation method thereof |
| WO2019140715A1 (en) * | 2018-01-19 | 2019-07-25 | 近镒生技股份有限公司 | Carrier structure, drug carrier, preparation method therefor, and use thereof |
| CN112569345A (en) * | 2020-12-10 | 2021-03-30 | 广东省科学院化工研究所 | Dispersion containing growth factor and preparation method and application thereof |
| CN115779145A (en) * | 2022-12-20 | 2023-03-14 | 北京健康广济生物技术有限公司 | Preparation method of hyaluronic acid gel filled in face and containing chitosan microspheres |
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| CN115779145A (en) * | 2022-12-20 | 2023-03-14 | 北京健康广济生物技术有限公司 | Preparation method of hyaluronic acid gel filled in face and containing chitosan microspheres |
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| TA01 | Transfer of patent application right |
Effective date of registration: 20180105 Address after: Xinluo Avenue high tech Zone of Ji'nan City, Shandong Province, No. 989 250101 Applicant after: Pharmaceutical Sciences, Shandong Province Applicant after: Shandong Fu Ruida Pharmaceutical Group company Address before: Xinluo Avenue high tech Zone of Ji'nan City, Shandong Province, No. 989 250101 Applicant before: SHANDONG PROVINCE BIOMEDICAL ACADEMY OF SCIENCES Applicant before: Shandong Fu Ruida Pharmaceutical Group company |
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| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 250101 989 Xinjie street, Ji'nan high tech Zone, Shandong Co-patentee after: Shandong Freda Pharmaceutical Group Co., Ltd. Patentee after: Pharmaceutical Sciences, Shandong Province Address before: 250101 989 Xinjie street, Ji'nan high tech Zone, Shandong Co-patentee before: Shandong Fu Ruida Pharmaceutical Group company Patentee before: Pharmaceutical Sciences, Shandong Province |