CN103830767A - Sucrose acetate isobutyrate gel and application thereof - Google Patents

Abstract

The invention relates to a gel material which comprises 3-80 wt% of sucrose acetate isobutyrate colloidal particle, 0.1-30 wt% of pharmaceutical active component, 0-60 wt% of assistant and the balance of water. The gel material is applicable to promoting bone healing and new bone formation in tooth cavities after implementation of tooth extraction. The bone healing is wound healing after implementation of tooth extraction; and the new bone formation is new bone formation in a tooth implantation process. The gel material can also be used for temporary sealing after cavity preparation and during dental pulp disease treatment in the tooth disease treatment process.

Description

Sucrose acetoisobutyrate gel and uses thereof

Technical field

The present invention relates to a kind of gel rubber material and uses thereof, especially relate to gel comprising Sucrose acetoisobutyrate and uses thereof.

Background technology

Dental extraction is alveolus surgery modal operation clinically, dental extraction is as a kind of surgical operation, inevitably cause the damage in various degree of art district soft tissue and sclerous tissues, produce the reactions such as hemorrhage, pain, swelling, also can cause general reaction in various degree simultaneously, can cause intensifying or increasing the weight of of other system disease, also very easily occur the complication such as alveolus infection, pain.The wound producing after operation is called tooth extraction wound.The agglutination of tooth extraction wound needs for a long time, and is not often very smooth.At present clinically, pulling out after tooth, adopting cotton balls to cram exodontia nest hemostasis prevention infection, on tooth extraction wound surface, in both sides alveolar ridge, advising patient to sting reject after tight a period of time with the gauze lap crossbearer of sterilization.But, due to individual physique difference, the molding speed difference of blood clot, the patient after a lot of exodontias is spuing after Cotton Gossypii, can cause wound to expose, and then cause and infect.But except cramming with cotton balls, clinically tooth extraction wound is not had to other better processing method at present.Therefore, the malaise symptoms such as after exodontia, people usually can produce that gingiva is rubescent, swelling, tenderness and spontaneous pain, conventionally through 3 to 10, its symptom just can alleviate gradually, and finally in exodontia nest, clot machine changes into the new bone of bone formation healing.But if implement after extraction, wound has residue to fall into when exposing or eating meal, can produce a lot of serious infection.Stay next empty tooth nest because do not have blood clot or blood clot to decompose in exodontia nest, can cause take anaerobe as main mixed cell and infect, such as dry socket etc.In addition, the maintenance of the absorption of alveolar bone to disappearance district's artificial tooth reparation and implantation body after exodontia, attractive in appearance and function all can exert an influence.Therefore, for avoiding producing above-mentioned symptom, people wish tooth extraction wound quickly-healing, and the new bone in exodontia nest generates rapidly.After exodontia, the absorption of alveolar ridge causes the variation of jaw structure and shape directly to affect the quality that artificial tooth is repaired.Experts and scholars both domestic and external are finding always and are effectively reducing the method that the rear alveolar ridge of exodontia absorbs.

In the treatment of dental pulp disease and periapical disease, tooth body is permanent to be repaired owing to can not once complete time, need to use temporary stopping sealing pulp cavity entrance, stops as far as possible saliva of buccal cavity and microorganism during making an appointment, to invade root pipe.It is the principal element that causes dental pulp disease and periapical disease that antibacterial infects, and when temporary stopping quality is not good, micro-seepage will occur, make pulp cavity and mouthful in an environmental communication, cause disinfecting drug seepage, and make antibacterial in saliva enter pulp cavity to affect therapeutic effect.Therefore, temporary stopping is the key factor that affects therapeutic effect.The object of envelope is in order to prevent that antibacterial from entering root pipe inside and causing secondary infection temporarily, strengthens drug effect and stops medicine to ooze out.At present, use gutta-percha, zinc oxide preparation, zinc phosphate preparation or paste as temporary stopping more, but use above-mentioned material while sealing temporarily, inevitably can cause the edge micro chink between tissue of tooth, thereby because the antibacterial in saliva is infiltrated to cause and infects; And the common time that needs 1 month of the process of sealing temporarily, patient's constantly further consultation during this period, the situation of the antiinflammatory of inspection, not only bothers but also time-consuming.For example gutta-percha needs heating in operating process, and operating time and heating are wayward, the contiguous oral mucosa if roasting hot gutta-percha careless manipulation is easily burnt, and the wearing no resistance of gutta-percha, hardness are low, can not bear masticatory pressure, lack caking property, easily come off; Zinc phosphate cement is powder liquid two-component type, and intensity is higher, is inconvenient to need be in harmonious proportion, and is difficult for removing when use, often needs wornly, has extended the operating time, and worn process has increased opportunities for contamination, also easily causes the secondary damage to tooth.

Visible, said process is not only painful, and the time is long, also easily causes antibacterial to infect.Therefore, wish to obtain a kind ofly can substitute that cotton balls stops blooding, antiinflammatory and efficient dental composition easy to use in the process of exodontia and treatment dental pulp dental disease.

CN1582139A discloses a kind of hydrogel composition of sending as mist, and it comprises thermal response viscosity modifier, is used for the treatment of dentistry disease.For example: dental caries, dental calculus, xerostomia, gingivitis, antibacterial infection etc.The thermal response viscosity modifier of its use is polyoxyalkylene polymers, but it does not relate in the processing procedure that is applied to tooth extraction wound.

CN101647756A has recorded one and has comprised ZnO and ZrO₂mix nanoparticles take amide or ester as the polyalcohol hydrogel of monomer, especially there is swellability, therefore can avoid occurring gap or occurring coronal leakage phenomenon between traditional temporary stopping and root canal wall.But this polymer gel preparation is complicated, and cost is higher, is not suitable for extensive use.

Therefore, all do not relate to simple and easy to getly in prior art, and cost is lower, substitutes the stop blooding succedaneum of disinfective action of cotton balls in the process of exodontia and treatment dental pulp and dental disease.

Summary of the invention

The technical problem to be solved in the present invention has two, the one, find a kind of suitable Cotton Gossypii that can substitute and cram the materials and methods that exodontia nest stops blooding after dental extraction, better to process tooth extraction wound, avoid antibacterial to infect, promote knitting, wound healing simultaneously and induce the formation of new bone, shorten the cycle of tooth extraction wound knitting.

The 2nd, in tooth body disease of pulp of tooth therapeutic process, find one and can substitute the temporary stopping such as traditional gutta-percha, zinc phosphate ethanol Men Ting, and can cram plug nest hole completely and avoid micro-gel rubber material oozing.Use this material to seal temporarily, not only can avoid antibacterial to infect, the disposable function that completes sterilization, detumescence, antiinflammatory, shortens the dental filling cycle, reduces further consultation number of times, and this material is cheaply easy to get simultaneously, is applicable to being widely used on a large scale.

Technical scheme of the present invention is as follows:

A kind of gel rubber material, it comprises the Sucrose acetoisobutyrate colloidal particle of 3-80wt%, the active constituents of medicine of 0.1-30wt%, the auxiliary agent of 0-60wt% and the nonaqueous solvent of surplus.Wherein, the preferred 5-70wt% of Sucrose acetoisobutyrate colloidal particle, more preferably 10-60wt%, more preferably 15-50wt%; The preferred 0.5-20wt% of active component, more preferably 1-10wt%; The preferred 0-50wt% of other composition, more preferably 0-30wt%, more preferably 0-10wt%.

Wherein active component is selected from: one or more in clot-promoting factor, biotic factor, somatomedin, infection Western medicine, analgesic, hormone, Chinese medicine, statins, nitrogen bisphosphonates or anesthetis; Nonaqueous solvent is selected from one or more in methanol, ethanol, dimethyl sulfoxide, ethyl lactate or N-Methyl pyrrolidone solvent, one or more in preferred alcohol or ethyl lactate, more preferably ethanol.

Wherein promote blood-clotting agent to select one or more in thrombin, glycoleucine, adhesive fibrin, reptilase (a kind of batroxobin that Agkistrodon halys saliva is extracted), tranexamic acid, etamsylate or 5-sodium morrhuate; Biotic factor is selected from: in recombinant human bone morphorgenetic protein-2, bone morphogenetic protein(BMP) and analog thereof, marrow stromal cell, osteoblast or bioss collagen one or more, homocarnosine, fibrin sealant; Somatomedin is selected from: one or more in basic fibroblast growth factor, integrin alpha-1, people's transforming growth factor, recombinant human epidermal growth factor or insulin like growth factor; Infection Western medicine is selected from: sulfonamides antibiotic, quinolone antibiotic, lincosamides, beta-lactam antibiotic, macrolide antibiotics, aminoglycoside antibiotics, metronidazole, tinidazole, ornidazole, for one or more in true azoles, metronidazole, formaldehyde cresol formocresol, diclofenac potassium, sodium humate, povidone iodine, iodine phenol, colloid silver, low concentration hydrogen peroxide, ethylenediaminetetraacetic acid; Chinese medicine is selected from: emodin, propolis, garlicin, phenol camphor, aloe ointment, Radix Cirsii Japonici carbon powder, berberine, ferric subsulfate (Basic Ferric Sulfate Solution), Folium et Cacumen Artemisiae Halodendri are loose, Radix Rubiae powder, Radix Notoginseng powder, red white lead, match one or more in mould peace powder, Radix Cirsii Japonici styptic powder, berberine or ephedrine; Anti-inflammatory analgesic is selected from: aspirin, ibuprofen; Hormone is selected from: dexamethasone, beta-aescin sodium, prednisone, hyaluronidase; Statins is selected from simvastatin, pravastatin; Nitrogen bisphosphonates is selected from zoledronic acid; Anesthetis is selected from: lignocaine, green blue fiber crops.

Wherein other composition is selected from: one or more in mannitol, lactose, polylactic acid, polyglycolic acid, Polyethylene Glycol, glycerol, glycerophosphate, acetin, alginate, hydroxyapatite, calcium sulfate, foam silicon carbon, Coral Composited Artificial, bioactivity glass, demineralized bone matrix, calcium phosphate ceramic, calcium phosphate bone ethanol mud, zirconium oxide or calcium hydroxide.

Described gel rubber material is applied to and in the tooth nest of implementing after extraction, promotes knitting and new bone formation.Described knitting is the healing of tooth extraction wound; Described new bone formation is the new bone formation in Dental Implant process.Described gel rubber material also can be applied to the various tooth bodies for the treatment of and disease of pulp of tooth, in the tooth nest hole of opening after pulp cavity, seals temporarily.

Technical scheme of the present invention can reach following technique effect:

1. gel rubber material of the present invention is applied in the tooth socket after dental extraction, not only can accelerate hemostasis, promote blood coagulation, induce new bone formation, can also be anticorrosion, granulation promoting broad-spectrum sterilization, medicine is evenly distributed in tooth nest, the generation of prevention infection and complication.

2. use gel rubber material of the present invention can well fill the tooth socket after exodontia, make wound lower and can suppress the too much absorption of alveolar bone, make the damaged recovery of bone fast, enforcement tooth-planting art that can be early, shorten the whole cycle of Dental Implant, as implement Implant at once, described material also can promote the bone of implantation body to integrate.

3. gel rubber material of the present invention is applied in the tooth nest hole in dental filling process, not only can stops blooding; And due to its can with pipe seamless combination at all, therefore can disposablely complete sterilization and antiinflammatory, reduce the time of envelope and the number of times of further consultation temporarily.

4. gel rubber material of the present invention can be degraded in time, after injection without subsequent treatment; Due to its special character, also can all in tooth nest, remove at any time as the case may be.

In dental extraction and tooth body disease of pulp of tooth therapeutic process, be mainly based on following reason by Sucrose acetoisobutyrate gel application:

Sucrose acetoisobutyrate gel is a kind of solvent responsive type gel.The feature of solvent responsive type gel rubber material is, itself is water insoluble, but is soluble in solvent, and after it is by dissolution with solvents, viscosity reduces, and forms the liquid form with mobility, is easy to injection; After this solution is injected in vivo, solvent reduces so that lose rapidly under the dilution of body fluid or in being exposed to air, and due to minimizing or the disappearance of solvent, in the aqueous environments of oral cavity, solvent responsive type gel rubber material is separated out with solid-state form, thereby crams exodontia nest.If do not feel like oneself, or other reason, can gargle with solvent, by solvent responsive type gel rubber material band outlet plenum.

Because this gel has special mushy stage property of transition, it can be injected when the liquid state in exodontia nest, it changes rapidly the solid-state tooth extraction wound of cramming in oral environment, can not only make wound lower, promote the healing of tooth extraction wound and the production of new bone, and the antibacterial infection of having avoided wound to expose causing.In addition, the too much absorption that it can also stop alveolar bone, forms the second best in quality implant bed bone form, and enforcement tooth-planting art that can be early shortens cycle of Dental Implant.Also it can be injected to the standby hole of exodontia when the liquid state, tooth cavity is full of, it changes rapidly the solid-state tooth cavity of cramming in oral environment, therefore causes temporary stopping and the seamless combination of pipe at all, has avoided the antibacterial that the antibacterial seepage in saliva causes to infect.Due to, it can disposablely complete hemostasis, sterilization and antiinflammation, and therefore patient needn't further consultation, only need after once having sealed temporarily, carry out next step filling, therefore shorten the cycle of dental filling, has saved patient's time and expense.

Clinically, it uses easily, injects tooth nest after patient's exodontia or dental filling for hole in the time of liquid state, as patient does not feel well or when other reason need to remove, can gargle its removing with epoxy resin solvent.

The specific embodiment

Sucrose acetoisobutyrate gel rubber material of the present invention can adopt diverse ways preparation, also can adopt different inspection methods to detect its effect, and above-mentioned diverse ways all can not affect its purposes.

Test method: select 6-8 body weight 180-220g in age in week, 30 rats (Periodontal Status is good) that male and female are not limit, are divided into experimental group and matched group at random, with 3% pentobarbital sodium (40mg/kg), intraperitoneal injection of anesthesia.After animal LOM, 1% iodine disinfection in oral cavity.Respectively get 15 rats for two groups and pull out upper left labial teeth, pull out lower-left labial teeth for another 15.After experimental group exodontia, immediately gel rubber material of the present invention is injected to tooth nest, until be full of hemostasis sealing wound.After control animals exodontia, conventional gauze pressing hemostasis 20～30 minutes, tooth extraction wound to be determined has blood clot and finishes without operation after bleeding.In every group of different time sections after exodontia, in the oral cavity exodontia nest respectively at animal, take a sample to check (following examples are without all adopting this test method in the situation of specified otherwise).

Embodiment 1. is containing Sucrose acetoisobutyrate-acetin gel (solvent: ethanol) of metronidazole

Contain the preparation of Sucrose acetoisobutyrate-acetin gel of metronidazole: a certain amount of Sucrose acetoisobutyrate and acetin add heating in water bath in round-bottomed flask, stir, until completely dissolved, de-bubble, pour in certain mould, freezing 9-13h at-25 ℃, then be placed on the 3～4h that thaws under room temperature.After aforesaid 2～3 circulations, take out and steep in ethanol, in acetin, soak to take out afterwards for 3 days and draw the floating ethanol in surface, electronic analytical balance precision weighing, adding quality is the metronidazole of the 0.5wt% of gel, in vacuum, adsorb, 4 ℃ for subsequent use, and wherein Sucrose acetoisobutyrate accounts for the 60wt% of gel gross weight, acetin 10wt%.

The mensuration of minimal inhibitory concentration (MIC):

Sucrose acetoisobutyrate is accounted for to 60wt%, the gel of acetin 10wt%; The metronidazole solution of 0.5wt%, and the Sucrose acetoisobutyrate gel containing metronidazole of embodiment 1 carries out respectively MIC mensuration.MIC value is the least concentrations of naked eyes there are no the antibacterial of bacterial growth.The results are shown in following table.

The measurement result of table 1. minimal inhibitory concentration

This result shows, take the PLA bacteriostasis certain as matrix gel has, after it is combined with metronidazole, is no matter that the MIC value of gel-type vehicle or antibacterial all can significantly reduce, and bacteriostatic activity obviously strengthens.

Embodiment 2. is containing Sucrose acetoisobutyrate-calcium sulfate gel (solvent: ethyl lactate) of clindamycin

Method preparation according to embodiment 1 contains Sucrose acetoisobutyrate 40wt%, calcium sulfate 5wt%, the gel of clindamycin 30wt%.

Animal experiment in vitro:

By the gel of 0.1～0.3g embodiment 2 and 20mL ethyl lactate solution, (blank only adds 20mL0.9%NaCl solution, do not add gel) add swelling 20～30h in people 100mL conical flask, add wherein the more initial bacterium liquid of people 0.1mL, put shaking table (37 ℃, 150r/min), shaken cultivation 20～50min, survey viable bacteria concentration with colony counting method, antibacterial tests repeats 5 times, each 10 culture dishs, be as the criterion with reproducible results, be calculated as follows resin antibiotic rate:

η＝(N₀-N₁)/N₀*100

Wherein N₀, N₁represent respectively to add and contain the average clump count of bacterium liquid on culture dish after blank and gel sample pretreating.The results are shown in following table.

Table 2. is containing the antibiotic rate testing result of the Sucrose acetoisobutyrate gel of clindamycin

Group	N0	N1	η
				Matched group	41	36	12.19
Gel group	37	3	91.90

Result shows: compared with matched group, the Sucrose acetoisobutyrate gel sterilizing rate that contains clindamycin is 91.90%, and antibiotic rate exceedes 90%, has good bactericidal action, as the effectively bacteria growing inhibiting of implant of tooth extraction wound.

Embodiment 3.BMP-2-Sucrose acetoisobutyrate gel rubber material (solvent: ethanol)

Preparation: recombinant human bone morphorgenetic protein-2 (BMP-2) and liquid acetic acid isopropylformic acid. sucrose ester gel (are contained to Sucrose acetoisobutyrate 70wt%, ethanol 30wt%) by the weight ratio of 1: 30, liquid acetic acid isopropylformic acid. sucrose ester gel is inserted in the guanidine hydrochloride solution of BMP-2 of 10wt%.Above-mentioned mixed solution is dialysed (50 times of volumes) to ethanol together, 28 ℃, 4h; Change liquid 4 times, after BMP-2 precipitation forms, dialysis is retained to liquid lyophilizing and obtain BMP-2-Sucrose acetoisobutyrate gel rubber material.

Experiment in body:

Select 16 of healthy adult mongrels, both sexes have concurrently, and body weight 15～20kg is divided into 2 groups at random.After 2% Nembutal vein anesthetic, pull out both sides lower jaw the 2nd, 4 premolarss, the gel of injection liquid embodiment 3 in the exodontia nest of experimental group, till alveolar ridge level, matched group stops blooding with conventional gauze, and cheek-tongue side mucoperiosteum is suitably peeled off after lax and drawn tight stitching window over to one's side.Surveying record phatnoma bone height.Put to death respectively animal in postoperative 2 weeks, 4 weeks, 8 weeks, 12 weeks and 24 weeks, take off jawbone and do respectively gross examination of skeletal muscle, Histological section's observation and x-ray microscopic analysis (XMA), observe calcium element content in the new bone of implantation material surface.

Check result is as follows:

The complete color and luster of the experimental group plantation equal primary healing mucosa of position wound is normal, and each observation period alveolar bone is all aobvious plentiful.Matched group plantation position wound healing is bad, and color and luster is darker, and newborn mucosa is irregular.

Two groups of frontal resorption situation measurement results when table 3. the 24th week

Group	n	x±s(mm)
			Experimental group	8	0.79±0.29
Matched group	8	1.43±0.20

t＝8.10，P＜0.01

Result demonstration, the average that experimental group phatnoma bone height reduces is 0.79mm, matched group phatnoma bone height has on average reduced 1.43mm, illustrates that the gel rubber material of embodiment 3 has significantly reduced the absorption of alveolar bone.

Embodiment 4. is loaded with the fibrinous Sucrose acetoisobutyrate gel of basic fibroblast growth factor (bFGF) (solvent: ethanol)

Preparation: be the bFGF of 1000U/ml to adding concentration in liquid Sucrose acetoisobutyrate gel (content is 60wt%, ethanol 40wt%), with ethanol (20 times) dialysis 20～25h, every 12h changes dialysis solution once.Lyophilizing in freezer dryer for dialysis solution, obtains the Sucrose acetoisobutyrate gel containing the bFGF of 0.05U/mg.Epoxyethane fumigation sterilization, 4 ℃ save backup.

Matched group stops blooding with conventional gauze, the gel of injection liquid embodiment 4 in the exodontia nest of experimental group, and till alveolar ridge level, check result is as follows:

2 groups of exodontia poor comparisons of nest bone defective region cheek-tongue side height of alveolar ridge of table 4. different time points (unit: mm, X ± S)

Group	2 weeks	4 weeks	8 weeks	12 weeks
					Matched group	-1.22±0.214	-2.21±0.225	-2.29±0.248	-2.38±0.131
Experimental group	-0.97±0.312	-1.86±0.135	-1.98±0.337	-2.17±0.222

Experimental results show that: experimental group can be grown by induced tissue, can stimulating osteoblast and the propagation of preosteoblast, suppress formation and the bone resorption of osteoclast, increase collagen synthesis capability, promote endothelial cell proliferation, induction new vessels generates, and stimulates the histiocytic division of polytype and propagation in body, promote that substrate is synthetic and deposit, promoting fibrous tissue to generate.

Embodiment 5. is loaded with the Sucrose acetoisobutyrate-glycerogel (solvent: dimethyl sulfoxide) of simvastatin

Preparation: slow 2g Sucrose acetoisobutyrate stirring is fully dissolved in the 10ml dimethyl sulfoxide of 37 ℃, adds successively 2.0ml glycerol, 0.02g simvastatin, slowly stir and become corresponding gel.Keep 37 ℃ of constant temperature, warp⁶⁰co irradiates 1～3min, with sterilization.4 ℃ of Refrigerator stores, for subsequent use.

Matched group stops blooding with conventional gauze, and the gel of injection liquid embodiment 5 in the exodontia nest of experimental group, till alveolar ridge level, carries out respectively Bone mineral density, and result is as follows:

The Bone mineral density result (gray scale) of table 5. alveolar bone

Group	1 week	2 weeks	5 weeks	8 weeks	11 weeks	14 weeks
							Matched group	118	72	68	67	69	90
Experimental group	123	149	153	149	135	141

The bone density of experimental group, apparently higher than the bone density of matched group, illustrates that this gel is conducive to form new bone.

Embodiment 6. is containing the Sucrose acetoisobutyrate gel (solvent: methanol) of dexamethasone

Preparation: get dexamethasone injectable powder, join under gnotobasis in Sucrose acetoisobutyrate gel solution (containing the colloidal particle of 30wt%, and the methanol of 70wt%), make the Sucrose acetoisobutyrate gel containing 0.2g/ml medicated powder.For subsequent use in 4 ℃.

Matched group stops blooding with conventional gauze, the gel of injection liquid embodiment 6 in the exodontia nest of experimental group, and till alveolar ridge level, check result is as follows:

Wound Area comparison result after table 6. exodontia

Time (my god)	Experimental group	Matched group
			0	3.78±0.2	3.78±0.3
2	3.32±0.3	3.62±0.4
			4	2.96±0.3*	3.29±0.3
6	2.35±0.4*	2.95±0.4
			8	1.37±0.4*	2.38±0.4
11	0.65±0.4*	1.87±0.3
			15	-	1.15±0.4
30	-	0.4±0.1
			45	-	-

Check result shows: show that experimental group wound healing speed is obviously faster than matched group.

Embodiment 7. is containing the Sucrose acetoisobutyrate gel (solvent: N-Methyl pyrrolidone) of SHUANGHUANLIAN and metronidazole

Under gnotobasis, SHUANGHUANLIAN and two kinds of medicines of metronidazole are mixed to bottling in 1: 2 ratio stand-by, getting SHUANGHUANLIAN medicated powder, metronidazole medicated powder and above-mentioned mixed powder joins respectively in the solution of Sucrose acetoisobutyrate, prepare respectively SHUANGHUANLIAN (5wt%) Sucrose acetoisobutyrate (50wt%) gel, metronidazole (10wt%) Sucrose acetoisobutyrate (50wt%) gel, and SHUANGHUANLIAN-Metrogel (wherein SHUANGHUANLIAN accounts for 5wt%, metronidazole accounts for 10wt%, and Sucrose acetoisobutyrate accounts for 50wt%).

Matched group stops blooding with conventional gauze, and three kinds of gels in the exodontia nest of experimental group in difference injection liquid embodiment 7, till alveolar ridge level, detect the time effect of rat Dental Follicle Cells propagation impact according to test method of the present invention.

The testing result (A490 value) of the time effect of table 7. rat Dental Follicle Cells propagation

Group	1 day	3 days	5 days
				Matched group	0.136±0.0185	0.093±0.0079	0.063±0.0038
SHUANGHUANLIAN group	0.124±0.0189	0.157±0.0038	0.129±0.0178
				Metronidazole group	0.142±0.0115	0.148±0.0086	0.112±0.0185
SHUANGHUANLIAN+metronidazole group	0.131±0.0146	0.157±0.0174	0.153±0.0230

Result shows: the 1st day, and cell proliferation there are no significant difference between SHUANGHUANLIAN group, metronidazole group, SHUANGHUANLIAN+metronidazole group and matched group; The 3rd day, SHUANGHUANLIAN group, metronidazole group, SHUANGHUANLIAN+metronidazole group significantly promoted the propagation of Dental Follicle Cells compared with matched group.

Embodiment 8. is containing the Sucrose acetoisobutyrate gel (solvent: ethanol) of BMP-2 and dexamethasone

Preparation: the concentration of preparation BMP-2 is that the concentration of 100ng/ml, dexamethasone is 10^-8mol/ml, is added in Sucrose acetoisobutyrate gel solution and is made containing BMP-2 and dexamethasone (10^-8mol/ml) Sucrose acetoisobutyrate (50wt%) gel.

Matched group stops blooding with conventional gauze, and the gel in the exodontia nest of experimental group in difference injection liquid embodiment 8, till alveolar ridge level, detects the time effect of rat Dental Follicle Cells propagation impact according to test method of the present invention.

The testing result (A490 value) of the time effect of table 8. rat Dental Follicle Cells propagation

Group	1 day	3 days	5 days
				Matched group	0.138±0.0130	0.094±0.0099	0.067±0.0038

BMP-2 group (prepared by embodiment 3)	0.126±0.0190	0.153±0.0038	0.125±0.0168
				Dexamethasone group (prepared by embodiment 6)	0.148±0.0100	0.144±0.0066	0.113±0.0185
BMP-2+ Dexamethasone group	0.132±0.0130	0.151±0.0174	0.142±0.0230

Result shows: the 1st day, and cell proliferation there are no significant difference between BMP-2 gel group, dexamethasone gel group, BMP-2 and dexamethasone gel group and matched group.The 3rd day, BMP-2 gel group, dexamethasone gel group, BMP-2 and dexamethasone gel group significantly promoted the propagation of Dental Follicle Cells compared with matched group.

Sucrose acetoisobutyrate-sodium alginate gel (solvent: ethyl lactate) that embodiment 9. contains aspirin and lignocaine

Preparation: by the sodium alginate of 5～8g, the Sucrose acetoisobutyrate of 9～10g, joins in 10ml ethyl lactate, heating in water bath is to dissolving completely.Liquid acetic acid isopropylformic acid. sucrose ester-sodium alginate gel is inserted in the ethyl lactate solution containing the aspirin of 10wt% and the lignocaine of 5wt%.After aspirin and the formation of lignocaine precipitation, dialysis being retained to liquid lyophilizing obtains containing aspirin and lignocaine-Sucrose acetoisobutyrate-sodium alginate gel material.

Matched group stops blooding with conventional gauze, the gel (solvent is ethyl lactate) in the exodontia nest of experimental group in difference injection liquid embodiment 9, and till alveolar ridge level, gel is on the active impact of people's pulp cells alkali phosphatase (ALP).In pulp cells culture of continuous cultivation, with the prolongation of incubation time, ALP increased activity, compared with blank group, active significantly strengthen (the P < 0.05) of the ALP of experimental group pulp cells.The results are shown in Table

Table 9

Gel to embodiment 1-9 and gutta-percha carry out following test respectively:

1) temporary testing sealing

Experimental procedure: 15 of local dogs; after opening marrow envelope endotoxin, make periapicalitis model; tested tooth is carried out to root canal to be sealed temporarily with the material such as gel rubber material and gutta-percha, zinc oxide clove oil subsequently; respectively at the 7th day; the 14th day, within the 21st day and the 28th day, treat, if find, envelope is effective temporarily; can reach the nest hole of filling up tooth, or finish to treat and record when corona is installed with protection residue dentine by the end of time of whole therapeutic process at that time.

Table 10 is the timing result of envelope process temporarily

Group	The temporary envelope time (my god)
		Gutta-percha	28
Embodiment 1	14
		Embodiment 2	15
Embodiment 3	13
		Embodiment 4	13
Embodiment 5	14
		Embodiment 6	14
Embodiment 7	15
		Embodiment 8	14
Embodiment 9	14

Result shows that this tests gel rubber material used and greatly reduced the temporary envelope time.

2) in vivo test, skin anaphylactic test is evaluated its sensitization

Laboratory animal: 160 of healthy albino guinea-pigs, male and female all can, body weight 300-500 gram, is divided into 16 groups at random, wherein 14 groups is that temporary stopping group, other two groups are made as negative control group and positive controls, every group of 10 Mus.Sample preparation: gel rubber material is placed in to physiology salt ethanol in the ratio of 0.2～0.4g/ml, lixiviate 1 day at 37 ℃ of temperature.Positive controls is selected 5% formaldehyde, and negative control group is selected 0.9% physiology salt ethanol.

Get the complete Freund's adjuvant of equivalent and 0.9% physiology salt ethanol and 5% formaldehyde of temporary stopping lixiviating solution and equivalent are prepared into respectively mix emulsion fluid.

In guinea pig back cropping, size is 2cm*4cm, carry out routine disinfection, from the beginning be symmetry shape to tail in shoulder foot bone inside line and inject 6 points, symmetrical 2 are made as one group, are divided into altogether three groups, each some injection 0.1ml, one group of injection lixiviating solution, physiology salt ethanol or 5% formalin and complete Freund's adjuvant equal-volume emulsion, another group injection lixiviating solution, physiology salt ethanol or 5% formalin, inject the equal-volume emulsion of complete Freund's adjuvant and physiology salt ethanol for the 3rd group.

After one week in same area cropping, be coated with again 10% sodium lauryl sulphate at each injection point, after 24 hours, be 2cm*4cm filter paper by size and scribble given the test agent lixiviating solution and apply ointment or plaster and again pass through plucked injection site above-mentioned, then use gauze two-layer, cellophane one deck is covered, and its sealing is fixed 48 hours by non-stimulated adhesive plaster.

After two weeks after Rhizoma Atractylodis Macrocephalae time sensitization, in the back of Cavia porcellus cropping, the size of applying ointment or plaster in unhairing district is for 2cm*2cm and scribble given the test agent lixiviating solution filter paper, then uses gauze two-layer, and cellophane one deck is covered, and its sealing is fixed 24 hours by non-stimulated adhesive plaster.Same manipulation control animals.After exciting contact to finish, remove scribble given the test agent filter paper respectively at the 1st day, 2 days, the situation of observing its injection point for 3 days.And with skin reactive polypeptide degree standards of grading (in Table), the extent of reaction of each injection point is scored.In sensitization of skin test, represent the degree of sensitization with sensitization rate, reaction scoring be 1 or the above number of animals percentage ratio that accounts for this treated animal sum be sensitization rate, be sensitization rate=sensitized animal number/animal number * 100%, calculate sensitization rate, and by Mathussno sensitization rate grade scale (in Table) classification.

Table 11Mafhussno animal sensitization rate grade scale

Sensitization rate %	Classification	Intensity classification
			0-8	I	Weak sensitizer
9-28	II	Slight sensitizer
			29-64	III	Moderate sensitizer
65-80	IV	Intensity sensitizer
			81-100	V	Extremely strong sensitizer

Note: sensitization rate be reaction scoring be 1 or above number of animals account for the percentage ratio of this treated animal sum, I level sensitization degree is nonsensical, under reality is used without sensitization danger.

Sensitization rate is respectively organized in table 12. in vivo test

Group	Number of animals	Sensitization number	Sensitization rate	Calibration
					Positive group	10	10	100％	V
Negative group	10	0	0	I
					Embodiment 1	10	0	5％	I
Embodiment 2	10	1	0	II
					Embodiment 3	10	1	10％	II
Embodiment 4	10	0	0	I
					Embodiment 5	10	0	0	I
Embodiment 6	10	0	5％	I
					Embodiment 7	10	1	5％	II
Embodiment 8	10	0	0	I
					Embodiment 9	10	1	10％	II

Gutta-percha

10

4

40％

III

3) experiment in vitro

Select to be pulled out due to orthodontic treatment, have and completely occlusally grind one's teeth in sleep 56 in vitro, 4 every group.Be prepared into by same operator the I class hole type that size is 4mm × 3mm.Take out again 28 of deciduous molars (naturally coming off), 2 every group, to retain as much as possible normal teeth enamel as principle, be made into by same operator the block teeth that size is about 3mm × 3mm × 2mm.

Experimental procedure: 1. will clean, be dried, and behind acid etching nest hole, use gel rubber material to carry out filling, and add the block teeth that passed through acid etching in gel, and make gel rubber material by its complete embedding.Then making it routine solidifies and makes specimen tooth again.2. again specimen tooth is divided into 2 groups at random, gives respectively the hitting power with 0 time and 10000 times 300g.Then specimen tooth is separated from the sagittal direction of nest hole central authorities.The combination situation of section part block teeth, tooth body and gel rubber material is observed it by scanning electron microscope.And measure the length of impacting the block teeth of specimen tooth and the combination gap of tooth body and gel rubber material, parallel survey 3 times, asks its meansigma methods.

The combination gap result of impacting the block teeth of specimen tooth and the gel rubber material of tooth body and each embodiment for 0 time, 10000 times is as follows.

Table 13.0,10000 times impact in conjunction with gap length (x ± s)

Note: gel rubber material group compared with gutta-percha group,^*p < 0.05,^*p < 0.01

Comparative example

Get a healthy adult Canis familiaris L., carry out tooth seal temporarily comparison with the gel temporary stopping of embodiment 1 and zinc oxide eugenol cement and gutta-percha, respectively adaptation, comprcssive strength, dissolubility, pH value and destructive testing are tested, result is as follows.

The performance test of three kinds of temporary stoppings of table 14.

Test trifle:

Zinc oxide eugenol cement is two component powder liquid types, needs special messenger to allocate when use, and the difficult grasp of consumption, often causes waste of material; The gutta-percha used time needs naked light roasting soft, and roasting hot gutta-percha has stimulation to dental pulp, and its border seal performance is poor; The gel of embodiment 1 is temperature sensitive hydrogel, in the time that temperature is 37 ℃, the gel solution of embodiment 1 can solidify at once, therefore when clinical use, at room temperature configures gel solution, insert the impact of tooth nest hole inner recipient temperature and solidify at once, its expansion rate is large, closure is good, and before filling, rinsing the mouth temperature is opened ethanol higher than the temperature of 37 ℃, gel temporary stopping can be removed, thereby avoid the secondary damage of tooth.

Claims (9)

1. a gel rubber material, it comprises the Sucrose acetoisobutyrate colloidal particle of 3-80wt%, the active constituents of medicine of 0.1-30wt%, the auxiliary agent of 0-60wt% and the nonaqueous solvent of surplus.

2. the gel rubber material of claim 1, wherein active constituents of medicine is selected from: one or more in clot-promoting factor, biotic factor, somatomedin, infection Western medicine, analgesic, hormone, Chinese medicine, statins, nitrogen bisphosphonates or anesthetis; Nonaqueous solvent is selected from one or more in methanol, ethanol, dimethyl sulfoxide, ethyl lactate or N-Methyl pyrrolidone solvent.

3. the gel rubber material of claim 2, wherein promotes blood-clotting agent to select one or more in thrombin, glycoleucine, adhesive fibrin, reptilase (a kind of batroxobin that Agkistrodon halys saliva is extracted), tranexamic acid, etamsylate or 5-sodium morrhuate; Biotic factor is selected from: in recombinant human bone morphorgenetic protein-2, bone morphogenetic protein(BMP) and analog thereof, marrow stromal cell, osteoblast or bioss collagen one or more, homocarnosine, fibrin sealant; Somatomedin is selected from: one or more in basic fibroblast growth factor, integrin alpha-1, people's transforming growth factor, recombinant human epidermal growth factor or insulin like growth factor; Infection Western medicine is selected from: sulfonamides antibiotic, quinolone antibiotic, lincosamides, beta-lactam antibiotic, macrolide antibiotics, aminoglycoside antibiotics, metronidazole, tinidazole, ornidazole, for one or more in true azoles, metronidazole, formaldehyde cresol formocresol, diclofenac potassium, sodium humate, povidone iodine, iodine phenol, colloid silver, low concentration hydrogen peroxide, ethylenediaminetetraacetic acid; Chinese medicine is selected from: emodin, propolis, garlicin, phenol camphor, aloe ointment, Radix Cirsii Japonici carbon powder, berberine, ferric subsulfate (Basic Ferric Sulfate Solution), Folium et Cacumen Artemisiae Halodendri are loose, Radix Rubiae powder, Radix Notoginseng powder, red white lead, match one or more in mould peace powder, Radix Cirsii Japonici styptic powder, berberine or ephedrine; Anti-inflammatory analgesic is selected from: aspirin, ibuprofen; Hormone is selected from: dexamethasone, beta-aescin sodium, prednisone, hyaluronidase; Statins is selected from simvastatin, pravastatin; Nitrogen bisphosphonates is selected from zoledronic acid; Anesthetis is selected from: lignocaine, green blue fiber crops; Nonaqueous solvent is selected from one or more in ethanol or ethyl lactate, preferred alcohol.

4. the gel rubber material of claim 1, wherein auxiliary agent is selected from: one or more in mannitol, lactose, polylactic acid, polyglycolic acid, Polyethylene Glycol, glycerol, glycerophosphate, acetin, alginate, hydroxyapatite, calcium sulfate, foam silicon carbon, Coral Composited Artificial, bioactivity glass, demineralized bone matrix, calcium phosphate ceramic, calcium phosphate bone ethanol mud, zirconium oxide or calcium hydroxide.

5. the gel rubber material of claim 1, wherein Sucrose acetoisobutyrate colloidal particle is 5-70wt%, preferably 10-60wt%, more preferably 15-50wt%; Active component is 0.5-20wt%, more preferably 1-10wt%; Other composition is 0-50wt%, preferably 0-30wt%, more preferably 0-10wt%; And the nonaqueous solvent of surplus.

6. in claim 1-5, the gel rubber material of any one is applied in tooth and pulls out in process as exodontia nest and cram material, it is characterized in that described gel rubber material to be applied to and in the tooth nest of implementing after dental extraction, to promote knitting and new bone formation.

7. the application of claim 6, wherein said knitting is the healing of wound after dental extraction.

8. the application of claim 6, wherein said new bone formation is the new bone formation in Dental Implant process.

9. after in claim 1-5, the gel rubber material of any one is applied to the cavity preparation in dental disease therapeutic process or in disease of pulp of tooth therapeutic process as temporary stopping.