CN104116705A - Medicine composition for preventing millimeter wave damages, use method and application of medicine composition - Google Patents
Medicine composition for preventing millimeter wave damages, use method and application of medicine composition Download PDFInfo
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Abstract
The invention discloses application of hydrogel in preparation of a medicine for preventing millimeter wave damages, a medicine composition prepared from the hydrogel and used for preventing the millimeter wave damages and an application method of the medicine composition. The medicine composition is characterized in that the surface of animal skin is externally coated by the hydrogel to form a gel protective layer in certain thickness, namely an''artificial fake skin''protective layer is formed and used for fully absorbing millimeter waves acting on the surface of the skin, so that the damages of the millimeter waves on tissues such as the skin are remarkably reduced or eliminated, and no toxic or side effects are caused. In addition, the hydrogel is wide in source, simple in preparation process, few in side effects, stable and controllable in quality, capable of being used as an active ingredient for preparing the medicine for preventing the millimeter wave damages, especially applicable to prevention and treatment on biological damages caused by long-term exposure in a millimeter wave environment, and wide in application prospects.
Description
Technical field
The present invention relates to field of medicaments, particularly relate to a kind of application for protecting the pharmaceutical composition of millimeter wave damage and the using method of this compositions and protecting the medicine of millimeter wave damage in preparation.
Background technology
Millimeter wave (Millimeter wave, MMW) is the electromagnetic wave between microwave and light wave, and frequency is 30-300GHz, wavelength 1-10mm.The wavelength of millimeter wave is short, and frequency is high, and penetration depth is little, and easily by water and moisture many biological tissues, is absorbed.Tissue is rich in moisture, thereby millimeter wave is poor to the penetration capacity of human body skin, can only see through shallow-layer skin, in the tissue that is 0.4mm, with regard to 70% the energy of having an appointment, is absorbed in the degree of depth; And along with the increase of millimeter-wave frequency, penetration depth reduces, and if 30GHz millimeter wave is 0.78mm to the penetration depth of skin, the penetration depth of 100GHz millimeter wave is 0.318mm.
Along with the extensive use of the new concept weapon such as high power microwave weapon, laser weapon in modern war, high power millimeter wave weapon---non-fatal " Active denial system " (active denial system, ADS) application militarily comes into one's own gradually.The millimeter wave electromagnetic pulse that millimeter wave weapon is launched directly acts on skin with the light velocity, also can penetrate medicated clothing and act on shallow-layer skin, and human body skin is caused to the twinge as baked wheaten cake, and millimeter wave electromagnetic pulse disappears once leaving this pain of skin.Millimeter wave continues the damage that direct irradiation can cause the tissues such as cornea, skin, but internally not significantly damage of internal organs official rank can not produce lethal effect conventionally yet.Because this weapon can not bring lethal injury to human body as other weapons, such as, various firearms, bomb, cannon, chemical and biological weapons etc., therefore this millimeter wave weapon is except can be for fighting, be more suitable for peace-keeping operations, carry out humanistic task and other and do not need to put people in disability, dead occasion, as in order not creating civilian casualties, with millimeter wave weapon, to disperse crowded crowd, thereby avoid armed member to start to attack by crowded crowd's shielding.
Although at present multinational all at the high-power millimeter wave weapon of research and development, for protecting the medicine of millimeter wave damage, but there is not yet report.Along with millimeter wave weapon is promoted more and more on a large scale, to the demand of millimeter wave injury protection medicine, also can get more and more, the medicine of developing as early as possible the damage of protection millimeter wave becomes current those skilled in the art and is badly in need of the important topic of capturing.
Summary of the invention
Main purpose of the present invention is to provide a kind of new purposes of hydrogel, is about to hydrogel for the preparation of protection millimeter wave damage medicine.
Described hydrogel is selected from a kind of in thermosensitive in situ gel, carbomer hydrogel, polyvinyl alcohol-gelatine hydrogel, hyaluronic acid and carboxymethyl cellulose sodium hydrogel, polyvinyl alcohol-aquagel and sodium alginate-chitosan derivant hydrogel.
Described hydrogel is one of following:
Thermosensitive in situ gel: comprising the poloxamer188 of 10-30% (mass/volume percent, the g/100mL of unit) and the PLURONICS F87 of 10-30% (mass/volume percent, the g/100mL of unit);
Carbomer hydrogel: wherein carbomer content is 0.5-3% (mass/volume percent, the g/100mL of unit);
Polyvinyl alcohol-gelatine hydrogel: wherein polyvinyl alcohol content is 5-20% (mass/volume percent, the g/100mL of unit), gelatine content is 5-15% (mass/volume percent, the g/100mL of unit);
Hyaluronic acid and carboxymethyl cellulose sodium hydrogel: comprising the hyaluronic acid of 0.5-4% (mass/volume percent, the g/100mL of unit) and the sodium carboxymethyl cellulose of 0.1-2% (mass/volume percent, the g/100mL of unit);
Polyvinyl alcohol-aquagel: comprising the polyvinyl alcohol of 1-6% (mass/volume percent, the g/100mL of unit) and the chitosan of 0.5-3% (mass/volume percent, the g/100mL of unit);
Sodium alginate-chitosan derivant hydrogel: comprising the sodium alginate of 0.5-5% (mass/volume percent, the g/100mL of unit) and the chitosan derivatives of 0.5-3% (mass/volume percent, the g/100mL of unit).
Described hydrogel is any at least two kinds of composite aquogels that combine of the functional component in above mentioned hydrogel; Functional component in described hydrogel is respectively poloxamer188, carbomer, polyvinyl alcohol, hyaluronic acid, polyvinyl alcohol and sodium alginate.
Described composite aquogel is one of following:
Poloxamer-carbomer composite aquogel: comprising the poloxamer188 of 5-25% (mass/volume percent, the g/100mL of unit) and the carbomer of 0.2-4% (mass/volume percent, the g/100mL of unit);
Hyaluronic acid-sodium alginate-polyvinyl alcohol composite hydrogel: comprising 0.5-4% (mass/volume percent, the g/100mL of unit) hyaluronic acid, 0.5-5% (mass/volume percent, the g/100mL of unit) polyvinyl alcohol of sodium alginate and 1-3% (mass/volume percent, the g/100mL of unit).
In described hydrogel, also comprise refrigerant preparation and/or wound healing promoting preparation.
Described refrigerant preparation includes but not limited to one or more in menthol, Borneolum Syntheticum and Aloe extract; Described wound healing promoting preparation includes but not limited to VEGF and/or basic fibroblast growth factor.
In described hydrogel, the concentration of menthol is 20mg/mL; The concentration of described hydrogel VEGF is 50 μ g/mL; The concentration of described hydrogel bFGF is 300-600IU/mL.
Another object of the present invention is to provide a kind of for protecting the pharmaceutical composition of millimeter wave damage, this pharmaceutical composition is to be prepared from by above-mentioned composite aquogel.
A further object of the invention is to provide the using method by this pharmaceutical composition, and described hydrogel is spread upon to skin surface, and consumption is 0.5-1mL hydrogel/25mm
2skin/time, within one day, be coated with 2-3 time, continue 4-6 days.
More than the invention discloses the application of hydrogel in preparation protection millimeter wave damage medicine.Its core is above-mentioned hydrogel external application on animal skin surfaces, form certain thickness gel overcoat, form one deck " artificial imitation leather " overcoat, fully Absorption is in the millimeter wave of skin surface, thereby significantly reduce or eliminate the damage that millimeter wave causes tissues such as skins, and have no side effect.Also can in hydrogel, load medicine according to actual needs, in protection millimeter wave, treat other disease.In addition, hydrogel wide material sources, processing technology is simple, few side effects, stable and controllable for quality, can it for onset composition, prepare and protect medicine that millimeter wave damages, especially can be used for prevention and treatment long term exposure in the biological damage of millimeter wave environment, have a extensive future.
Below in conjunction with specific embodiment, the present invention is described in further details.
Accompanying drawing explanation
Fig. 1 a is that thermosensitive in situ gel occurs to respectively organizing mice in the protection of mice millimeter-wave radiation damage the time and the body surface maximum temperature post figure that escape;
Fig. 1 b is that thermosensitive in situ gel is to respectively organizing mice body surface maximum temperature post figure before and after the protection of mice millimeter-wave radiation damage;
Fig. 2 a is that carbomer hydrogel occurs to respectively organizing mice in the protection of mice millimeter-wave radiation damage the time and the body surface maximum temperature post figure that escape;
Fig. 2 b is that carbomer hydrogel is to respectively organizing mice body surface maximum temperature post figure before and after the protection of mice millimeter-wave radiation damage;
Fig. 3 a is that polyvinyl alcohol-gelatine hydrogel occurs to respectively organizing mice in the protection of mice millimeter-wave radiation damage the time and the body surface maximum temperature post figure that escape;
Fig. 3 b is that polyvinyl alcohol-gelatine hydrogel is to respectively organizing mice body surface maximum temperature post figure before and after the protection of mice millimeter-wave radiation damage;
Fig. 4 a is loaded with BFGF hydrogel to respectively organizing mice body surface maximum temperature post figure before and after the protection of mice millimeter-wave radiation damage;
Fig. 4 b is loaded with the string diagram of BFGF hydrogel to wound healing effect.
The specific embodiment
Hydrogel (Hydrogel) is a kind of gel that water is disperse medium of take, in thering is the water soluble polymer of cross-linked network, to introduce a part of hydrophobic group and hydrophilic residue, wherein, hydrophilic residue and water molecules, hydrone is connected to netted inside, and the cross linked polymer that hydrophobic residue water-swellable forms is just called hydrogel.Hydrogel has three-dimensional network, character is soft, can keep certain shape, can absorb a large amount of moisture content simultaneously, be used as embolism materials, medicine controlled release carrier and tissue engineering bracket etc., but the medicine for the preparation of the damage of protection millimeter wave have not been reported by hydrogel.If the specific medicament that therefore various hydrogels can be damaged for the preparation of protection millimeter wave, will open a new research direction for this area, the specific medicament of preparing based on hydrogel also can have potential application prospect.
Screening through some experiments, following hydrogel can be used for the medicine of preparation protection millimeter wave damage: thermosensitive in situ gel, carbomer hydrogel, polyvinyl alcohol-gelatine hydrogel, hyaluronic acid and carboxymethyl cellulose sodium hydrogel, polyvinyl alcohol-aquagel, sodium alginate-chitosan derivant hydrogel, these hydrogels all only contain a kind of functional component, are therefore also called the hydrogel of simple function composition; Except filtering out these hydrogels, also find to get at least two kinds of composite aquogels that combine of functional component in above-mentioned hydrogel and also can be used in the medicine that preparation protection millimeter wave damages, composite aquogel can be poloxamer-carbomer composite aquogel, hyaluronic acid-sodium alginate-polyvinyl alcohol composite hydrogel.
Embodiment implements take technical solution of the present invention under prerequisite, has provided detailed embodiment and concrete operating process, should be appreciated that specific embodiment described herein, only in order to explain the present invention, is not intended to limit the present invention.
In embodiment, the source of biomaterial used is widely, any keep on the right side of the law and the moral ethics biomaterial that can obtain can be replaced and use according to the prompting in embodiment.Method therefor is conventional method if no special instructions.If no special instructions, in each embodiment, the material of same names or reagent content are identical.
The preparation of embodiment 1, hydrogel
One, the preparation of thermosensitive in situ gel
Situ-gel (in situ gel) be a class with solution state administration after, can occur immediately to change mutually at agents area, by liquid state, transformed into non-chemically the hydrogel of crosslinked semi-solid gel.Situ-gel has the hydrophilic three-dimensional net structure of gel and good histocompatibility, and meanwhile, unique solution-gel conversion character makes it have the advantages such as preparation is simple, easy to use, strong with mucous membrane tissue affinity, the holdup time is long concurrently.The formation mechanism of situ-gel is the response that utilizes macromolecular material to stimulate to external world, makes polymer issue the reversible change of raw dispersity or conformation at physiological condition, completes the conversion process to gel by solution.Correspondingly, this special gel can be divided into the types such as temperature, ionic strength or pH sensitivity.Wherein, thermosensitive in situ gel is the most a kind of situ-gel of research at present.Its response to variations in temperature has two types, and a kind of is high-temperature shrinkage type: with temperature, raise and water solublity reduction, another kind is low-temperature shrink type: when temperature reduces, water solublity reduces.That in the present embodiment, use is the former.
During preparation, get 12g poloxamer188,12g PLURONICS F87 in 20mL water, stirring makes its dispersion, then be placed under 4 ℃ of conditions and place more than 6 hours, add water to again 50mL, obtain poloxamer188 concentration and be the thermosensitive in situ gel of 24% (mass/volume percent, the g/100mL of unit) (because poloxamer188 is the functional component in this gel, therefore by the concentration of this material, represent the concentration of this gel), be numbered 1
#hydrogel.
Two, the preparation of carbomer hydrogel
Carbomer (carbomer) is the high molecular polymer of acrylic acid bonding allyl sucrose or tetramethylolmethane allyl ether, it is the very important rheology control agent of a class, carbomer after neutralization is outstanding gel-type vehicle, there are the important use such as thickening, suspension, technique is simple, good stability, is widely used in emulsion, cream frost, gel.Carbomer solution can gelling become stable hydrogel when pH is 6-12, is the functional component in hydrogel, and its release soon, is easily coated with exhibition, to skin and mucosa nonirritant, has good bioadhesive.
During preparation, get 1.2g carbomer and add in 75mL water, limit edged stirs, and adds to continue to stir after carbomer it is dissolved completely, places more than 6 hours, obtains carbomer solution; Get 2g triethanolamine again and mix homogeneously with 3mL ethanol, then add in the carbomer solution obtaining, limit edged stirs, and adds rear continuation and stirs 10min, obtains carbomer gel, is numbered 2
#hydrogel.
Three, the preparation of polyvinyl alcohol-gelatine hydrogel
Polyvinyl alcohol (PVA) is one of a kind of common water soluble polymer, its molecular backbone is carbochain, on each repetitive, contain a hydroxyl, because hydroxyl size is little, polarity is strong, easily form hydrogen bond, therefore PVA has good water solublity, film property, cohesion and emulsibility, good grease resistance and solvent resistance; PVA at room temperature forms hydrogel by hydrogen bond, this hydrogel because its water content is high, toxicity is low, good biocompatibility, be easy to the features such as processing and be widely used gradually, relate generally to the fields such as agricultural, industry, health care, but its poor mechanical properties, biological degradability can not be controlled, therefore can not use separately.Gelatin is to be obtained by collagen hydrolysate, and source is abundant, owing to having good bioaffinity and degradability, is widely used in medical domain; But the shortcomings such as the existence of uncrosslinked gelatin is firmly crisp, poor mechanical property.The PVA-gelatin hydrogel forming after polyvinyl alcohol and gelatin are crosslinked is a kind of novel hydrogel wound dressing, wherein polyvinyl alcohol is functional component, studies confirm that this aquagel membrane has good physicochemical property, as suitable swellbility and the anti-intensity that rises, there is good hydrophilic and permeability, can allow oxygen and hydrone by and do not allow antibacterial pass through.
During preparation, get 2g polyvinyl alcohol and be placed in 20mL water, be heated to 90 ℃ polyvinyl alcohol is dissolved; Add 1g gelatin to stir, then add the hydrochloric acid of 0.01mL10% (v/v) to stir 4h to mix homogeneously in 20 ℃ of room temperatures; After sufficient reacting, be poured into freezing 12h in mould, then heating and melting, freezing and heating and melting process repeats, after 2-3 time, to wash residual hydrochloric acid, dry, obtains membranaceous PVA-gelatin hydrogel, is numbered 3
#hydrogel.
Four, the preparation of hyaluronic acid and carboxymethyl cellulose sodium hydrogel
Hyaluronic acid is a kind of acid mucopolysaccharide, with its unique molecular structure and physicochemical property, in body, demonstrate multiple important physiological function, as lubricated joint, regulate the permeability of blood vessel wall, regulate protein, Water-Electrolyte diffusion and running, promote wound healing etc.Particularly importantly, hyaluronic acid has special water retention (2% hyaluronic acid aqueous solution can keep 98% moisture securely).Hyaluronic acid is a kind of multi-functional substrate, is distributed widely in partes corporis humani position, especially in skin, contains a large amount of hyaluronic acids.It can improve skin-nourishing metabolism, make skin tender, smooth, increase elasticity, in moisturizing, be again good Percutaneous absorption enhancer.
Sodium carboxymethyl cellulose (Carboxymethylcellulose sodium; CMCNa) be the sodium salt of carboxymethyl cellulose ether; be easy to be dispersed in water into transparent colloidal solution; through WHO approval, can be used in food; in food industry, be used as thickening agent, in medical industry, be used as pharmaceutical carrier, in daily chemical industry, be used as adhesive, resist dignified dose again; in printing and dyeing industry, be used as the protecting colloid of sizing agent and printing gum etc., in petrochemical industry, can be used as oil recovery fracturing fluid composition.
During preparation, about 50mL distilled water is boiled, add propylene glycol to mix, be cooled to 50-60 ℃, under stirring, add 2.5g hyaluronic acid and 0.5g sodium carboxymethyl cellulose, standing 24h after mix homogeneously, make its abundant swelling, add water to again 100mL mix homogeneously, obtain hyaluronic acid and carboxymethyl cellulose sodium hydrogel, be numbered 4
#hydrogel, wherein hyaluronic acid is functional component.
Five, the preparation of polyvinyl alcohol-aquagel
Chitosan is the unique cationic polymer of occurring in nature, its stock number is only second to the abundantest cellulose of occurring in nature content, because chitosan has good biocompatibility and biological degradability, be widely used in the fields such as medical science, food, biological engineering and weaving.In chitosan molecule, contain a large amount of amino, make chitosan gel rubber there is pH/ ion-sensitive, but the chitosan gel rubber intensity of one-component is poor, thereby limited its application.
Owing to not containing ionic group on high-molecular polyvinyl alcohol chain, therefore polyvinyl alcohol gel does not have pH/ ion-sensitive.Polyvinyl alcohol and chitosan blend can be obtained to not only have better mechanical strength, but also have stimulating responsive composite aquogel, and polyvinyl alcohol is the functional component in such hydrogel.
During preparation, get 3g polyvinyl alcohol in 20mL water, heating is dissolved polyvinyl alcohol; After cooling, add 2mL glacial acetic acid to mix, add 1g chitosan under stirring, standing 12h, makes its abundant swelling; Add water to again 100mL mix homogeneously, obtain PVA-aquagel, be numbered 5
#hydrogel.
Six, the preparation of sodium alginate-chitosan derivant hydrogel
Sodium alginate is a kind of natural polymer being extensively present in all kinds of brown Sargassums, can form simple gel with polyvalent cation, be the functional component in the hydrogel forming, plastic mild condition, and this gel, to body avirulence, is used as medicine embedded material.
Chitosan, as introduced in the present embodiment, contains firsts and seconds hydroxyl and one-level amino group, so it can carry out many derivative reactions, obtains diversified derivant.Different groups is different on the impact of chitosan character, can to chitosan, position chemical modification selectively, prepares many chitosan derivatives with specific function.
During preparation, get 100mL water and under stirring, add 4g CMC, standing 12h after mix homogeneously, makes its abundant swelling; Get 4.8g sodium alginate and add in 80mL water, standing 24h after mix homogeneously, makes its abundant swelling; The sodium alginate soln preparing is added in CMC aqueous solution and mixed, hatch 15min in 37 ℃, add water to 200mL, obtain sodium alginate-chitosan derivant hydrogel, be numbered 6
#hydrogel.
Below only prepare the hydrogel with simple function composition, in order more fully to confirm the application of hydrogel in the damage of protection millimeter wave, below prepared several hydrogels with several functions composition.
Seven, the preparation of poloxamer-carbomer composite aquogel
Get 12g poloxamer188 and 1g carbomer in 50mL water, stir it is disperseed, more than being then placed in and placing 6h under 4 ℃ of conditions, obtain poloxamer-carbomer solution; Get 2g triethanolamine again and mix homogeneously with 3mL ethanol, then add in the poloxamer-carbomer solution obtaining, limit edged stirs, and adds rear continuation and stirs 10min, then add water to 100mL, obtains poloxamer-carbomer composite aquogel, is numbered 7
#hydrogel.
Eight, the preparation of hyaluronic acid-sodium alginate-polyvinyl alcohol composite hydrogel
Get 2g polyvinyl alcohol, 2g hyaluronic acid in 20mL water, be heated to 90 ℃ it is fully dissolved, obtain hyaluronic acid-poly vinyl alcohol solution; Get 3g sodium alginate in 50mL water, standing 24h, makes its abundant swelling, obtains sodium alginate soln; By hyaluronic acid-poly vinyl alcohol solution and sodium alginate soln mix homogeneously, add water to 100mL, obtain hyaluronic acid-sodium alginate-PVA composite aquogel, be numbered 8
#hydrogel.
Embodiment 2, be loaded with the preparation of medicine hydrogel
One, be loaded with the preparation of VEGF hydrogel
Vascular endothelial cell growth factor (vascular endothelial growth factor, VEGF) be a kind of specificity growth factor relevant with angiogenic growth, the specific receptor of energy specific effect on vascular endothelial cell, make endotheliocyte move, breed, thereby there is the effect that promotes endotheliosis, acceleration new vessels to form, reduce cicatrix.
During preparation, use water dissolution VEGF, obtain the aqueous solution of VEGF, then the aqueous solution of its VEGF is added in the hydrogel of embodiment 1 preparation, mix homogeneously.
For example, get 12g poloxamer188,12g PLURONICS F87 in 20mL water, stir it is disperseed, be then placed under 4 ℃ of conditions and place more than 6 hours, obtaining poloxamer188 concentration is the thermosensitive in situ gel of 60% (mass/volume percent, the g/100mL of unit); With 10mL water dissolution 2.5mgVEGF, obtain the aqueous solution of VEGF; Both mixing are added water to 50mL again, and what obtain 50 μ g/mL is loaded with VEGF poloxamer hydrogel, is numbered 9
#hydrogel.
Two, be loaded with the preparation of BFGF hydrogel
Basic fibroblast growth factor (basic fibrablast growth facetor, BFGF) is a kind of multi-functional cell growth factor, evident in efficacy to various wound repair, can improve wound healing quality.Added in hydrogel matrix, except performance protection millimeter wave damaging action, can also be extended BFGF from the local holdup time of wound surface, brought into play promoting healing effect.
During preparation, in the hydrogel preparing at embodiment 1, add BFGF, after stirring, place more than 6 hours.
For example, get 12g poloxamer188,12g PLURONICS F87 in 20mL water, stir and make its dispersion, the BFGF that adds 30,000IU, stirs to be then placed under 4 ℃ of conditions and places more than 6 hours, add water to again 50mL, obtain being loaded with VEGF poloxamer hydrogel, be numbered 10
#hydrogel.Or get 1.2g carbomer and add in 75mL water, limit edged stirs, add to continue to stir after carbomer it is dissolved completely, then add the BFGF of 30,000IU, place more than 6 hours, obtain BFGF carbomer solution; Get 2g triethanolamine again and mix homogeneously with 3mL ethanol, then add in the BFGF carbomer solution obtaining, limit edged stirs, and after adding, adds water to 100mL, continues to stir 10min, obtains being loaded with BFGF carbomer hydrogel.
Three, be loaded with the preparation of refrigerant formulation hydrogel
Refrigerant preparation is as the term suggests be to make local skin produce the preparation of refrigerant sense, and conventional have menthol, Borneolum Syntheticum, an Aloe extract etc.Menthol energy chafe teleneuron sensor, produces cool sensation, and can infiltrate through lentamente Intradermal, reaches the effect for the treatment of epidermis hyperemia, local antipruritic, the pain relieving of performance, refrigerant effect; Borneolum Syntheticum also has the effect of reducing swelling and alleviating pain; Aloe extract has the effect of protection skin mucosa, pathogenic fire purging, removing heat from blood, pain relieving, is particularly useful for burn and scald.In hydrogel, add so refrigerant preparation can not only play the effect of protection millimeter wave damage, can also increase skin comfort level and play the effect that treatment millimeter wave damages.
For example, get 12g poloxamer188,12g PLURONICS F87 in 20mL water, stir it is disperseed, be then placed under 4 ℃ of conditions and place more than 6 hours, obtaining poloxamer188 concentration is the thermosensitive in situ gel of 60% (mass/volume percent, the g/100mL of unit); With 2mL dissolve with ethanol 1g menthol, obtain the alcoholic solution of menthol; Both mixing are added water to 50mL again, and what obtain 20mg/mL is loaded with menthol poloxamer hydrogel, is numbered 11
#hydrogel.
Embodiment 3, the protection effect of detection hydrogel to the radiation damage of mice high power millimeter wave
One, material, method
Radiation source: operating frequency is 35GHz, peak power output 13.2W; 8mm high power millimeter wave source is purchased from the dynamo-electric company limited in the Yellow River, Xi'an.
Laboratory animal: 20 of male Balb/c mices, purchased from Beijing dimension tonneau China laboratory animal company limited.Mice feeding environment temperature is 22 ± 2 ℃, and humidity is 50 ± 5%, and animal can freely take food, and when experiment starts, the weight of animals is 20-24g.
Experiment grouping: matched group: back epidermis is coated with 1mL distilled water, radiation group: accept millimeter-wave radiation, administration group in screened room: back epidermis is coated with 1mL hydrogel.
Evaluate medicine: the product that uses embodiment 1 and 2 preparations.
Experimental technique: remove mouse back hair, after weighing in, with adhesive plaster, mice is fixed on special plank to high power millimeter wave Radiata back; Radiation parameters is: pulsewidth 0.5 μ s, repetition rate 1000Hz, voltage 13KV, radiation 2min.In experiment back part of animal be placed in high power millimeter wave source focusing anteena under accept radiation.In radiative process, with infrared radiation thermometer, measure in real time the temperature of back part of animal, and change with flight behavior time of origin and the behavioristics of video monitoring system real time record mice.
Two, result
The testing result of the protection effect that 1, thermosensitive in situ gel damages mice millimeter-wave radiation is as Fig. 1 a and 1b.
Result demonstration, in irradiating 14.29 ± 0.92s, there is escape reaction in radiation group mice; Administration group mice 65.39 ± 9.41s after radiation escapes, significantly lag behind radiation group (p<0.05, Fig. 1 a); Control group mice 17.62 ± 6.72s after radiation escapes, and escape time of origin and radiation group are without significant difference, (p<0.05, Fig. 1 a) with administration group significant difference.Mice body surface is smeared (being administration group and matched group) after hydrogel or distilled water, and shell temperature is slightly lower than radiation group (Fig. 1 b), but without significant difference, the highest shell temperature when radiation finishes also has no significant difference (Fig. 1 b) between three groups.
The above results shows, thermosensitive in situ gel can significantly be postponed mice and be occurred the time of escaping, and the skin of back tissue of administration group mice has no obvious damage, and the skin of back of radiation group mice occurs that redness and skin temperature rise to rapidly pain threshold (42 ℃) in the short time, cause mice to occur escape reaction.This is because hydrogel can form overcoat at animal body surface, fully absorbs the energy of millimeter wave, significantly postpones the time that animal experiences millimeter wave twinge, thereby significantly postponed animal, occurs the time of escaping.Visible, thermosensitive in situ gel has good high power millimeter wave injury protection effect, and has biological safety.Thereby, can be using thermosensitive in situ gel as the medicine of preparing high power millimeter wave radiation damage protection.
The testing result of the protection effect that 2, carbomer hydrogel damages mice millimeter-wave radiation is as Fig. 2 a and 2b.
Result demonstration, radiation group mice occurs escape reaction in irradiation 14.29 ± 0.92s, and (Fig. 2 is a); Administration group mice 61.35 ± 6.78s after radiation escapes, significantly lag behind radiation group (p<0.01, Fig. 2 a); Control group mice 17.62 ± 6.72s after radiation escapes, and (Fig. 2 a), escape time of origin and radiation group are without significant difference, (p<0.01, Fig. 2 a) with administration group significant difference.Mice body surface is smeared (being administration group and matched group) after hydrogel or distilled water, and shell temperature is slightly lower than radiation group (Fig. 2 b), but without significant difference, the highest shell temperature when radiation finishes also has no significant difference (Fig. 2 b) between three groups.
The above results shows, the skin of back of radiation group mice occurs red and swollen, temperature rises to rapidly pain threshold (42 ℃) in the short time, cause mice to occur escape reaction, and carbomer hydrogel not only can significantly be postponed the time that escape appears in mice, and the skin of back tissue of mice has no obvious damage.This is because carbomer hydrogel can form overcoat at animal body surface, fully absorbs the energy of millimeter wave, significantly postpones the time that animal experiences millimeter wave twinge, thereby significantly postponed animal, occurs the time of escaping.Visible, carbomer hydrogel has good high power millimeter wave injury protection effect, and has biological safety.Thereby, can be using carbomer hydrogel as the medicine of preparing high power millimeter wave radiation damage protection.
The testing result of the protection effect that 3, polyvinyl alcohol-gelatine hydrogel damages mice millimeter-wave radiation is as Fig. 3 a and 3b.
Result demonstration, radiation group mice occurs escape reaction in irradiation 14.29 ± 0.92s, and (Fig. 3 is a); Administration group mice 110.19 ± 5.78s after radiation escapes, significantly lag behind radiation group (p<0.01, Fig. 3 a); Control group mice 17.62 ± 6.72s after radiation escapes, and (Fig. 3 a), escape time of origin and radiation group are without significant difference, (p<0.01, Fig. 3 a) with administration group significant difference.Mice body surface is smeared (being administration group and matched group) after hydrogel or distilled water, and shell temperature is slightly lower than radiation group (Fig. 3 b), but without significant difference, the highest shell temperature when radiation finishes also has no significant difference (Fig. 3 b) between three groups.
The above results shows, there is blister in the skin of back of radiation group mice, temperature rises to rapidly pain threshold (42 ℃) in the short time, cause mice to occur escape reaction, and polyvinyl alcohol-gelatine hydrogel not only can significantly be postponed the time that escape appears in mice, and the skin of back tissue of mice has no obvious damage.This is because polyvinyl alcohol-gelatine hydrogel can form overcoat at animal body surface, fully absorbs the energy of millimeter wave, significantly postpones the time that animal experiences millimeter wave twinge, thereby significantly postponed animal, occurs the time of escaping.Visible, polyvinyl alcohol-gelatine hydrogel has good high power millimeter wave injury protection effect, and has biological safety.Thereby, can be using polyvinyl alcohol-gelatine hydrogel as the medicine of preparing high power millimeter wave radiation damage protection.
4, the protection effect of other hydrogels to the damage of mice millimeter-wave radiation
4
#-11
#hydrogel all can significantly be postponed mice and be occurred the time (the results are shown in Table 1) of escaping, and the skin of back tissue of administration group mice has no obvious damage, and the skin of back of radiation group mice burn in various degree, as red and swollen, have ooze out, edema, blister even, skin temperature rises to rapidly pain threshold (42 ℃) in the short time, cause mice to occur escape reaction.This is to be all because hydrogel can form overcoat at animal body surface, fully absorbs the energy of millimeter wave, significantly postpones the time that animal experiences millimeter wave twinge, thereby significantly postponed animal, occurs the time of escaping.
5, conclusion
The escape time of above-mentioned multiple hydrogel group small mouse is difference (in Table 1) all, presents the phenomenon of the hydrogel group > matched group > radiation group of composite aquogel group > simple function composition; In composite aquogel, 8
#the mice escape time > 7 of hydrogel group
#hydrogel group; In medicine carrying hydrogel group, in the identical situation of medicine carrying substrate, being loaded with refrigerant preparation group > is loaded with BFGF group > and is loaded with VEGF group, but it is all longer than the escape time of simple function composition hydrogel to be only loaded with refrigerant preparation group, is loaded with BFGF and VEGF group and is all as good as with the hydrogel group of simple function composition; In the hydrogel group of simple function composition, 3
#hydrogel group > 5
#hydrogel group > 4
#hydrogel group > 6
#hydrogel group > 1
#hydrogel group > 2
#hydrogel group.This presentation of results composite aquogel than the better protecting effect to millimeter wave damage of simple function composition hydrogel and medicine carrying hydrogel; The simple function composition hydrogel that has added refrigerant preparation than other medicine carrying and not escape time of the simple function composition hydrogel of medicine carrying long, illustrate that refrigerant preparation can reduce the pain that millimeter wave damage brings to a certain extent; In addition, no matter be composite aquogel or simple function composition hydrogel, the hydrogel effect that contains polyvinyl alcohol be all significantly better than not containing its, show that polyvinyl alcohol having outstanding performance aspect the damage of protection millimeter wave.
Respectively organize as can be seen from Table 1 mice all different in the rising degree of experiment end back part skin temperature, totally present radiation group > matched group > administration group.Mouse back skin temperature raises to such an extent that higher explanation millimeter wave is larger to the damage of skin of back, this is consistent with the skin of back degree of impairment of observing, and radiation group is the most serious, and matched group takes second place, administration group, without obviously damage, illustrates that hydrogel can protect the damage of millimeter wave very effectively.But be not difficult to find, although smear after hydrogel, the skin of back of mice is all without obviously damage, but the skin of back temperature rising degree of each hydrogel group mice is different, the feature with the hydrogel group > medicine carrying hydrogel group > composite aquogel group of simple function composition, illustrate that composite aquogel is best to the damage effect of protection millimeter wave, medicine carrying hydrogel takes second place.Wherein, in composite aquogel group, 8
#the protection effect of hydrogel group is better than 7
#hydrogel group; In medicine carrying hydrogel group, in the situation that medicine carrying substrate is identical, the protection effect that is loaded with menthol hydrogel group is better than being loaded with VEGF group and is loaded with BFGF group, illustrates that refrigerant preparation can reduce the temperature of skin of back really; In the hydrogel group of simple function composition, protection effect is such: 3
#hydrogel group > 5
#hydrogel group > 4
#hydrogel group > 6
#hydrogel group > 1
#hydrogel group > 2
#hydrogel group, this shows, the hydrogel that functional component is polyvinyl alcohol is better than other and respectively organizes hydrogel, 4
#the protective capacities of hydrogel group is because its functional component hyaluronic acid has very strong water holding capacity and is only second to the group that functional component is polyvinyl alcohol.In general, the group that functional component contains polyvinyl alcohol is obviously better than other each groups of the same type to the protection effect of millimeter wave damage, the result of this result and mice escape time is perfectly in harmony, fully shown the remarkable result of polyvinyl alcohol in the damage of protection millimeter wave, in addition, be loaded with refrigerant preparation (as menthol), the hydrogel that is loaded with VEGF and BFGF also can reduce skin temperature to a certain extent, especially be loaded with the hydrogel of refrigerant preparation, can not only bring refrigerant sense, reduce the pain that skin of back raises and brings temperature, and can reduce the temperature of skin surface, protective action to millimeter wave is better, be only second to composite aquogel.The protection effect of other group hydrogels is all better than matched group, illustrates the protection of millimeter wave is also had to better effects.
The protection effect of table 1 hydrogel to the radiation damage of mice high power millimeter wave
Escape time and the skin of back temperature rising degree of comprehensive mice, can draw, the hydrogel that functional component contains polyvinyl alcohol is best to the protective action of millimeter wave damage in hydrogel of the same type; The protection effect of composite aquogel is best, and the hydrogel protection effect that is loaded with refrigerant preparation is also very outstanding, though not as good as composite aquogel, better than the hydrogel protection effect of simple function composition.
To sum up, hydrogel has good high power millimeter wave injury protection effect, and has biological safety.Thereby, can be using hydrogel as the medicine of preparing high power millimeter wave radiation damage protection.
Embodiment 4, the recovery dynatron effect of detection medicine carrying hydrogel to the radiation damage of mice high power millimeter wave
Except playing protective action millimeter wave damage, the hydrogel that is loaded with medicine can also be repaired the damage causing because of millimeter wave.
Test as follows:
Radiation source: with embodiment 3.
Laboratory animal: with embodiment 3.
Experiment grouping: matched group: back epidermis is coated with 1mL distilled water, radiation group: accept millimeter-wave radiation, administration group in screened room: back epidermis is coated with the hydrogel that 1mL is loaded with medicine.
Evaluate medicine: be loaded with BFGF hydrogel, i.e. 10 in embodiment 3
#hydrogel.
Experimental technique: remove mouse back hair, after weighing in, by the wound surface of mouse back incision of skin 0.5cm * 0.5cm, set up skin trauma mouse model, with adhesive plaster, mice is fixed on special plank to high power millimeter wave Radiata back; All the other are with embodiment 3.In radiative process, use flight behavior time of origin and the wound surface recovery situation of video monitoring system real time record mice.
Result
Be loaded with BFGF hydrogel to the testing result of the protection effect of mice millimeter-wave radiation damage as Fig. 4 a and 4b.
Result shows that radiation group mice occurs escape reaction in irradiating 5.22 ± 0.6s, control group mice 11.56 ± 3.27s after radiation escapes and (sees Fig. 4 a), and administration group mice 29.41 ± 4.25s after radiation escapes, significantly lag behind radiation group and matched group (p<0.01, as shown in Fig. 4 a).Fig. 4 b demonstrates administration group wounds in mice healing rate significantly faster than radiation group and matched group.Be loaded with BFGF hydrogel in the damage of protection millimeter wave, wound healing has been played to facilitation.
The above results shows, be loaded with BFGF hydrogel and can significantly postpone the time that escape appears in mice, and radiation group mice is because rising to rapidly pain threshold (42 ℃) in the skin of back temperature short time, causes mice to occur escape reaction.This is because hydrogel can form overcoat at animal body surface, fully absorbs the energy of millimeter wave, significantly postpones the time that animal experiences millimeter wave twinge, thereby significantly postponed animal, occurs the time of escaping.By observation, respectively organize mouse back wound healing situation and find, the speed of the back wound healing of administration group mice is significantly accelerated, and within 4 days, has afterwards 60% wound healing, almost healing completely after 12 days, and radiation group only had the wound healing less than 70% after 12 days.Visible, be loaded with BFGF hydrogel and not only there is good high power millimeter wave injury protection effect, and can repair the damage causing because of millimeter wave, and there is biological safety.Thereby, can be using thermosensitive in situ gel as the medicine of preparing high power millimeter wave radiation damage protection.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. the application of hydrogel in preparation protection millimeter wave damage medicine.
2. application according to claim 1, it is characterized in that, described hydrogel is selected from a kind of in thermosensitive in situ gel, carbomer hydrogel, polyvinyl alcohol-gelatine hydrogel, hyaluronic acid and carboxymethyl cellulose sodium hydrogel, polyvinyl alcohol-aquagel and sodium alginate-chitosan derivant hydrogel.
3. application according to claim 2, is characterized in that, described hydrogel is one of following:
Thermosensitive in situ gel: comprising the poloxamer188 of 10-30% (mass/volume percent, the g/100mL of unit) and the PLURONICS F87 of 10-30% (mass/volume percent, the g/100mL of unit);
Carbomer hydrogel: wherein carbomer content is 0.5-3% (mass/volume percent, the g/100mL of unit);
Polyvinyl alcohol-gelatine hydrogel: wherein polyvinyl alcohol content is 5-20% (mass/volume percent, the g/100mL of unit), gelatine content is 5-15% (mass/volume percent, the g/100mL of unit);
Hyaluronic acid and carboxymethyl cellulose sodium hydrogel: comprising the hyaluronic acid of 0.5-4% (mass/volume percent, the g/100mL of unit) and the sodium carboxymethyl cellulose of 0.1-2% (mass/volume percent, the g/100mL of unit);
Polyvinyl alcohol-aquagel: comprising the polyvinyl alcohol of 1-6% (mass/volume percent, the g/100mL of unit) and the chitosan of 0.5-3% (mass/volume percent, the g/100mL of unit);
Sodium alginate-chitosan derivant hydrogel: comprising the sodium alginate of 0.5-5% (mass/volume percent, the g/100mL of unit) and the chitosan derivatives of 0.5-3% (mass/volume percent, the g/100mL of unit).
4. application according to claim 1, is characterized in that, described hydrogel is any at least two kinds of composite aquogels that combine of the functional component in the hydrogel of mentioning in claim 2 or 3; Functional component in described hydrogel is respectively poloxamer188, carbomer, polyvinyl alcohol, hyaluronic acid, polyvinyl alcohol and sodium alginate.
5. application according to claim 4, is characterized in that, described composite aquogel is one of following:
Poloxamer-carbomer composite aquogel: comprising the poloxamer188 of 5-25% (mass/volume percent, the g/100mL of unit) and the carbomer of 0.2-4% (mass/volume percent, the g/100mL of unit);
Hyaluronic acid-sodium alginate-polyvinyl alcohol composite hydrogel: comprising 0.5-4% (mass/volume percent, the g/100mL of unit) hyaluronic acid, 0.5-5% (mass/volume percent, the g/100mL of unit) polyvinyl alcohol of sodium alginate and 1-3% (mass/volume percent, the g/100mL of unit).
6. according to the arbitrary described application of claim 2-5, it is characterized in that, in described hydrogel, also comprise refrigerant preparation and/or wound healing promoting preparation.
7. application according to claim 6, is characterized in that, described refrigerant preparation includes but not limited to one or more in menthol, Borneolum Syntheticum and Aloe extract; Described wound healing promoting preparation includes but not limited to VEGF and/or basic fibroblast growth factor.
8. application according to claim 7, is characterized in that, in described hydrogel, the concentration of menthol is 20mg/mL; The concentration of described hydrogel VEGF is 50 μ g/mL; The concentration of described hydrogel bFGF is 300-600IU/mL.
9. the pharmaceutical composition of the protection millimeter wave damage of preparing based on the arbitrary described composite aquogel of claim 4-9.
10. the using method of arbitrary described hydrogel in claim 2-8, is characterized in that, described hydrogel is spread upon to skin surface, and consumption is 0.5-1mL hydrogel/25mm
2skin/time, within one day, be coated with 2-3 time, continue 4-6 days.
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