CN104586888A - Pharmaceutical composition for treating periodontitis and method for preparing pharmaceutical composition for treating periodontitis - Google Patents
Pharmaceutical composition for treating periodontitis and method for preparing pharmaceutical composition for treating periodontitis Download PDFInfo
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Abstract
The invention discloses a pharmaceutical composition for treating periodontitis. The pharmaceutical composition comprises a main medicine, matrix auxiliary materials and a solvent, wherein the main medicine is any one of iodine, iodoform, chlorhexidine, chlorhexidine iodine, benzalkonium bromide, benzalkonium chloride, povidone iodine, triclosan, rivanol, furacilin, domiphen, myristylpicolinum bromide, silver nitrate and nanometer silver, or is a mixture of two or more of synergetic main medicines. The pharmaceutical composition disclosed by the invention automatically turns into a semisolid or solid substance with sustained-release effect and slowly releases with the effective treatment medicine amount for 3-6 days when injected into the periodontal pocket of a patient in the liquid form, thereby greatly bringing convenience for the patient to use the pharmaceutical composition and reducing the treatment expense.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition for the treatment of periodontitis and preparation method thereof, belong to field of medicaments, concrete belongs to department of stomatology periodontitis Drug therapy field.
Background technology
One, the harm of periodontitis
periodontitisbe involve four kinds of Periodontal Supporting Tissue (
gingiva,
periodontal membrane, alveolar bone and cementum) chronic infectious disease, often cause the inflammatory destruction of Periodontal Supporting Tissue.Its harm is large, and sickness rate is high, is come to a conclusion as after cancer and cardiovascular and cerebrovascular disease at present in medical circle, and human body health is produced to the third-largest killer of harm, be also oral health " number one killer " simultaneously.
Periodontal disease can cause the infringement of teeth, periodontal, if can not get timely medical treatment, its pathogenic bacterium can arrive each position of health by blood circulation, cause the disease of other Organ and tissues of health.Such as antibacterial coagulation platelet can form thrombosis, and clinical research finds that infective endocarditis and odontogenic infection have substantial connection.The antibacterial causing periodontal local chronic to infect and toxic product thereof can enter in the blood of patient, and these antibacterials and toxic product can increase and increase the weight of arteriosclerosis and thrombosis, make periodontitis become the risk factor of apoplexy generation.Research finds can helicobacter pylori be detected in the saliva of patients with periodontal disease, in subgingival plaque in patient's periodontal pocket, the recall rate of this bacterium is higher, periodontal disease likely increases helicobacter pylori infections as can be seen here, and the increase of the latter can cause the generation of chronic gastritis, gastric ulcer and gastric cancer.Diabetics is high with the Hazard ratio ND of periodontitis, and periodontitis can promote that patient blood glucose raises, therebetween have common genetic base, diabetes also promote the generation of periodontitis by the impact of the function on periodontal flora, neutrophilic granulocyte, inflammatory reaction, organization healing ability.Periodontitis pathogen cell toxin can damage nephron and blood vessel bunch cell, thus kidney is worked the mischief, and the periodontitis prevalence of Patients with Chronic Kidney Disease also can increase, according to Third National oral health epidemiological investigation display, China adult periodontal disease prevalence can reach more than 80%.
Under army corps and special operation environment, periodontitis sickness rate is higher.Officers and men under the special operation environment such as submarine, remote island, due to reasons such as work strain undernutritions, periodontal disease is particularly outstanding.And the crewman of long-time oceangoing voyage due to narrow space on ship, hygienic habit poor, restricted with water, and the reason such as nutritional imbalance, its onset of periodontitis rate is up to 91%.Research finds that ship rocking periodontal disease condition is apparently higher than the diligent personnel of bank, and its reason is on ship rocking long-term work life naval vessels, and because fresh water is limited during oceangoing voyage, shipwreck for toothbrushing is to be protected.All ages and classes, post, schooling ship rocking suffers from periodontal situation also difference, officer is apparently higher than soldier, sergeant, this is obviously longer than young soldier and sergeant due to officer's life-time on naval vessels, makes its periodontitis and gingivitis prevalence showed increased.Also there is certain relation generation and the region of army's periodontal inflammation, the prevalence of rural area officers and men is a little more than city, cities and towns officers and men, not only relevant with personal oral hygiene, depend primarily on guard station ambient water quality comparatively hard, add the ratio that this officers and men suffer from dental calculus, periodontitis.Therefore the healthy of people in periodontal disease serious harm, threatens officers and men and particularly performs the healthy of the officers and men of special duty, cause harmful effect to combat effectiveness of the troops.
Two, periodontitis Current medicine treatment
Periodontal disease is mainly due to the microbial infectious disease that causes a disease, and the major virulent factor of periodontitis is bacterial plaque microorganism.Adopt separately the method removing diseased Root Surfaces tooth maculose clinically, usually can not remove the pathogenic microorganism in periodontal pocket, need to coordinate antibacterial drug therapy could eradicate the cause of disease of periodontal disease.
(1) systemic treatment.Kind difference according to pathogenic bacterium can orally use agents: the 1) compound formulation of the amoxicillin of penicillins, ampicillin or amoxicillin and clavulanic acid; 2) tetracycline, Doxycycline or minocycline; 3) Macrocyclolactone lactone kind medicine azithromycin; 4) nitroimidazoles medicine metronidazole, tinidazole or ornidazole; 5) quinolones; 6) metronidazole and other antibiotic therapeutic alliances.
(2) topical therapeutic.1) tetracycline vinyl acetate fiber controlled release preparation, containing tetracycline 2.5%, can maintain active drug concentration about 10 days in periodontal pocket, because vinyl acetate fiber belongs to non-biodegradation type, needs to take out after 10 days.2) minocycline gel and minocycline microcapsule the former be slow release lipid gel containing 2% minocycline, the latter is the Absorbable rod Microencapsulated Slow system containing 2% minocycline.3) doxycycline hydrochloride gel is containing the gel controlled release agent of 10% doxycycline hydrochloride, can maintain valid density 7 days.4) Metrogel degradable gel shape controlled release agent, drug content 25%, can maintain active drug concentration 1 week after being injected into periodontal pocket.5) the hydrochloric doxycycline 10% of doxycycline hydrochloride situ-gel, is injected in periodontal pocket and can forms semisolid drug-reservoir, and slow releasing medicine about 10 days, is still in conceptual phase.6) iodine glycerol treatment periodontitis.
Three, the deficiency of periodontitis Drug therapy
Compared with topical therapeutic, whole body therapeutic dosage is relatively large, and the dose arriving affected part, local is relatively less, and bioavailability is relatively low, and from the viewpoint of safety and effectiveness, periodontitis local application is more excellent.But no matter be whole body application antibiotic or periodontal pocket topical application antibiotic, all there is following deficiency: 1) antimicrobial spectrum problem: antibiotic has good therapeutical effect to the microbial periodontitis of sensitivity, poor to the curative effect of non-sensitive microbial periodontitis, and the pathogenic bacterium of periodontitis are diversified, there are gram positive bacteria, gram negative bacteria, anaerobe etc.The difference of antibiotic antimicrobial spectrum and periodontitis Pathogen category, makes antibiotic be difficult to meet the Treatment need of periodontitis.2) drug resistance problems: antibiotics resistance sex chromosome mosaicism makes the antibiotic of a lot of anti-microbial property excellence in the past lose antibacterial action gradually, how long can the antibiotic therapeutic effect for the treatment of periodontitis maintain at present?
Iodine glycerol can be used for the treatment of periodontitis, and its shortcoming is: because dosage form is simple, medicine is difficult to be directly used in affected part: in periodontal pocket, and medicine is applied to the curative effect that have impact on medicine outside periodontal band; Iodine glycerol is very fast after smearing to dissipate from affected part, and within one day, need smear for several times, its dosage is inaccurate, easily causes the excessive and corresponding side effect of iodine systemic Absorption.
Summary of the invention
In view of the deficiency of current periodontitis Drug therapy, technical problem to be solved by this invention is, prepares the pharmaceutical preparation of a kind of safe and effective, has a broad antifungal spectrum, the problem that has no drug resistance, treatment periodontitis easy to use, to solve the deficiency of this medicine treatment at present.
After deliberation, iodine has following antibacterial characteristics: fungicidal spectrum is wide, sterilizing ability is strong, and not only to antibacterial, all having very strong inhibitory or killing effect to pathogenic microorganisms such as fungus, spore, viruses, is wide-spectrum bactericide; Not easily producing drug resistance, is a kind of desirable oral care medication.When current antibiotic bacterial resistance sex chromosome mosaicism is day by day serious, iodine is made the treatment that suitable preparation is used for periodontitis, be expected to play good therapeutical effect.The selection of dosage form: according to the Pathophysiology feature of periodontitis and the anatomical structure of periodontal tissue, prepare iodine polymer precipitation situ-gel, liquid preparation quantitatively injects after in periodontal pocket and automatically becomes solid-state or semisolid, this material can adhere to periodontal affected part and discharge medicine slowly, by the rate of release of the proportioning and concentration adjustment medicine that control wherein macromolecular material, make it reach the effect of single administration slow releasing therapeutic dose medicine for 3 ~ 6 days, be all better than conventional formulation iodine glycerol from curative effect, safety, compliance aspect.This dosage form substantially increases the medication compliance of patient, is particularly useful for officers and men, particularly performs the officers and men of special duty, as large-scale water surface naval vessels operating personnel, submarine personnel, diving operation personnel etc.
Therefore, for solving the problem, the technical solution used in the present invention is as follows:
A kind of pharmaceutical composition for the treatment of periodontitis, by principal agent, substrate adjuvant, solvent composition, described principal agent is iodine, in iodoform, hibitane, hibitane iodine, benzalkonium bromide, benzalkonium chloride, povidone iodine, triclosan, ethacridine, nitrofural, oradol, myristylpicolinum bromide, silver nitrate, nanometer silver any one or there is two or more combination synergistic.
A kind of preparation method for the treatment of the pharmaceutical composition of periodontitis, comprise the following steps: principal agent, substrate adjuvant are dissolved in solvent respectively, mix homogeneously, obtain, wherein said principal agent be iodine, in iodoform, hibitane, hibitane iodine, benzalkonium bromide, benzalkonium chloride, povidone iodine, triclosan, ethacridine, nitrofural, oradol, myristylpicolinum bromide, silver nitrate, nanometer silver any one or there is two or more combination synergistic.
Wherein, substrate adjuvant is two or more the mixture in following adjuvant: poly-levorotatory lactide, poly-meso-lactide, PLGA 90/10, PLGA 75/25, PLGA 60/40, PLGA 50/50, end carboxyl polylactic acid, end carboxyl PLGA, D-lactic acid/co-glycolic acid, D-lactic acid/racemic lactic acid copolymer, polyethylene glycol modified polylactide, polyethylene glycol modified polylactide-co-glycolic acid, poly glycol monomethyl ether polydactyl acid, poly glycol monomethyl ether modification PLGA, lactide coglycolide--caprolactone copolymer, lactide--caprolactone copolymer, lactide coglycolide-trimethylene carbonate PLGTmc, polyvinylpyrrolidone, Polyethylene Glycol, the husky nurse of POLO, aminoacid, potassium iodide.
Wherein, substrate adjuvant is: PLGA 50/50, PLGA 75/25 and polyvinylpyrrolidone, and three's mixed weight is than being 20-80:6-35:0.6-13.
Wherein, solvent is METHYLPYRROLIDONE, ethyl acetate, triacetyl glycerine, 2-Pyrrolidone, ethyl lactate, dimethyl sulfoxide, glycerol formal.
Wherein, in compositions, drug content is 0.5%-20% (percentage by weight).
Wherein, the content of compositions mesostroma adjuvant is 10%-92% (percentage by weight).
The purposes of aforementioned pharmaceutical compositions in periodontitis treatment.
Detailed description of the invention
For the ease of understanding, below will be described in detail the present invention by specific embodiment.It is important to note that these descriptions are only exemplary descriptions, do not form limitation of the scope of the invention.
Embodiment 1
By the iodine 1.3g of recipe quantity, polyvinylpyrrolidone 12.1g, PLGA 50/5021.6g, PLGA 60/4011.3g, be dissolved in qs glycerin formal respectively, mix homogeneously, obtains pharmaceutical composition.
Embodiment 2
By the iodine 2.1g of recipe quantity, polyvinylpyrrolidone 5.1g, PLGA 60/4023.8g PLGA 75/259.8g, be dissolved in appropriate ethyl lactate respectively, mix homogeneously, obtains pharmaceutical composition.
Embodiment 3
By the iodine 11.6g of recipe quantity, poly-meso-lactide 43.1g, polyvinylpyrrolidone 6.4g, be dissolved in appropriate METHYLPYRROLIDONE respectively, mix homogeneously, obtains pharmaceutical composition.
Embodiment 4
By the iodine 4.9g of recipe quantity, polyvinylpyrrolidone 12.6g, PLGA 50/5065.3g, PLGA 75/2510.9g, be dissolved in respectively in dimethyl sulfoxide, mix homogeneously, obtains pharmaceutical composition.
Embodiment 5
By the iodine 8.9g of recipe quantity, polyvinylpyrrolidone 5.9g, PLGA 60/4053.6g, be dissolved in respectively in appropriate 2-Pyrrolidone, mix homogeneously, obtains pharmaceutical composition.
Embodiment 6
By chlorhexidine acetate 0.05g, benzalkonium bromide 0.01g, polyvinylpyrrolidone 6.1g, PLGA 60/4035.8g, PLGA 75/258.8g, be dissolved in appropriate METHYLPYRROLIDONE respectively, mix homogeneously, obtains pharmaceutical composition.
This medicine injects periodontal pocket in liquid form, automatically becomes the semisolid or solid matter with slow releasing function, and slow releasing effective dose medicine reaches about 5 days, greatly facilitates patient medication, reduces medical expense.Technique effect of the present invention is verified below by animal pharmacodynamic experiment and human body pharmacodynamic experiment.
(1) animal pharmacodynamic experiment
1. the foundation of Periodontitis Model and grouping: select 38 tooth body dentures complete, the SD rat of and periodontal disease bad without dental caries, random selecting 5 is matched group (N group), and all the other are periodontitis group (P group).After N group 20% urethane anesthetized animal, fixing animal, be slightly separated the labial surface gingiva of Rat Mandibular incisor, artificial formation does not amputate alveolar bone, only peels off the periodontal pocket of dark about 5mm completely from alveolar bone surface, does not do other process, to compare.Routine Test Lab feedstuff and clear water are fed.After P group 20% urethane anesthetized animal, fixing animal, slightly be separated the labial surface gingiva of Rat Mandibular incisor, artificial formation does not amputate alveolar bone, the periodontal pocket of dark about 5mm is only peeled off completely from alveolar bone surface, use sterile suture ligation in neck portion (taking to stitch the way of 2 pins on neck) again, to cause persistence, the mechanical irritation to periodontal tissue.In rat hindlimb quadriceps femoris, inject prednisolone acetate, every 125mgkg-1d-1, injects 7d continuously simultaneously, replaces clear water to feed simultaneously, and loosen tooth every day with conventional feed+10% sucrose solution.
Through the rat of above-mentioned process after experiment starts, the Clinical changes at routine observation rat experiment position is also noted down.After experiment, within the 4th week, often organize each execution 1 rat, draw materials from Test sites, basis of microscopic observation gingiva tissue pathologic condition.
2. divide into groups: at random rat model is divided into 3 groups, often organize 8, every only 16 teeth.Administration group: injection the present embodiment 1 medicine in periodontal pocket; Positive drug control group: injection minocycline hydrochloride situ-gel in periodontal pocket; Negative control group: in periodontal pocket, injection is not containing the bare substrate of iodine.Each group is all carried out normal diet above, does not inject prednisolone acetate.
3. administration: time baseline (0d), checks animal oral cavity, is loaded in special syringe by the present embodiment 1 medicine in advance.After ether light anesthesia animal, fixing animal, exposes incisor and gingiva position thereof, and use periodontal probe to be removed by gum edge pyorrhea, be then inserted at the bottom of periodontal pocket by the syringe needle of the syringe that normal saline is housed, slow saline injection, flushes out periodontal pocket by pyorrhea.Suck the normal saline in periodontal pocket with filter paper or cotton balls after, inject the present embodiment 1 medicine, until the present embodiment 1 medicine slightly overflows from periodontal pocket.Per-Hop behavior 1 time, continuous 4 weeks.
4. inspection target: respectively at before administration and after administration 1 day, 4 days, 7 days, 2 weeks, 3 weeks, 4 weeks, detect the gingival index of each group of rat, depth of pocket and spy and examine bleeding.
5. statistical procedures
Compare employing variance analysis between group, compare between two and adopt SNK-q inspection.With P < 0.05 for difference has statistical significance.
6. result
As shown in Table 1, drug containing component and positive controls indices (hemorrhage, gingival index, depth of pocket are examined in spy) all have statistical significance with difference during baseline in 1 day upon administration, the present embodiment 1 medicine prepared by explanation and positive drug just make every clinical indices of periodontitis there occurs obvious change for 1 day in administration afterwards, along with the increase of giving number of times, the indices of two groups all constantly declines, and the present embodiment 1 medicine prepared by explanation has therapeutical effect to periodontitis.All there is not obvious change in every periodontal disease index of negative control group, indices and baseline phase, than no significant difference, illustrate that the treatment of bare substrate to periodontitis does not act in experimental period.
Compare between two between many groups that at the end of experiment, (4th week) has carried out the sick index of rat periodontal ligament, result shows, positive controls and the present embodiment 1 medicine all have good therapeutical effect to periodontitis, the two no difference of science of statistics; Negative control group is without therapeutical effect.
Table 1 is respectively organized before treatment and the rear different time periodontal disease Indexes Comparison for the treatment of
(2) human body pharmacodynamics test
1 data and method
Severe chronic periodontitis patient 150 example in 1.1 physical data, wherein male 96 example, women 54 example, 31 ~ 66 years old age, 43.2 years old mean age; Include condition in: 1. healthy, unsystematic disease.2. without pregnant or non-nursing women.3. without tetracycline allergies.4. antibiotic and NSAID (non-steroidal anti-inflammatory drug) is not taken in 2 months.5. do not carry out periodontal disease therapeutic at least 1 week, in oral cavity, retain tooth > 20.6. the Periodontal Probing Depth (PD) of every patient at least 4 teeth reaches 5mm, and there have spy to examine to be hemorrhage.All patients are divided into 3 groups at random, administration group (injecting the present embodiment 2 medicine in periodontal pocket), positive controls (injecting pike change in periodontal pocket), negative control group (giving iodine glycerol to smear), each 50 routine patients, three groups of patients equal no significant difference in sex, age, the course of disease and Clinical typing etc., and no significant difference (P > 0.05), three groups have comparability.
1.2 method three groups patients all give that gingiva is clean, lower gum is scraped treatments such as controlling, and kept root planing, apply 3% hydrogen peroxide and 0.9% normal saline fully rinses periodontal pocket.The present embodiment 2 medicine is filled in the syringe of oral cavity by administration group on this basis, and is put into bottom periodontal pocket by syringe tip and inject gently, until medicine overflows in bag mouth; Pike change ointment (Minocycline ointment) injects in periodontal pocket with method by positive controls, and iodine glycerol injects in periodontal pocket with method by negative control group.Three groups of patients inject all weekly once, judge after treating 4 weeks to curative effect, and advise patient must not drink water, take food and gargle in 2h after medication.
Before 1.3 observation index treatments and treatment respectively the gingival index (GI) of patient, depth of pocket (PD) are carried out mensuration and are compared after 4 weeks.
1.4 curative effect determinate standards are effective: clinical symptoms disappears completely or substantially, and more than GI drop by half, PD minimizing >=2mm; Effective: clinical symptoms is obviously improved, PD reduces by 1 ~ 2mm; Invalid: clinical symptoms is without improvement or even increase the weight of.
1.5 this data of statistical method the data obtaineds all adopt SPSS16.0 to carry out statistical analysis, and measurement data adopts t inspection to analyze, enumeration data application chi-square criterion; P < 0.05 has statistical significance for difference.
2 results
2.1 clinical indices relatively compare GI and the PD index before three groups of patient treatments and after treatment, treatment first three groups index no significant difference, GI and the PD index of the rear administration group for the treatment of and positive controls is significantly less than negative control group and difference has significant statistical significance (P < 0.05), after treatment, GI and the PD index of administration group and positive controls is in the same size, no difference of science of statistics.Refer to table 2.
Before and after table 2 three groups of patient treatments, clinical indices change is compared
The total effective rate of 2.2 comparitive study administration groups and positive controls is 95%, is obviously greater than the total effective rate 70% of negative control group, and difference has significant statistical significance (P < 0.05).The results are shown in Table 3.
Table 3 three groups of patients's comparitive study (n)
| Group | n | Effective | Effectively | Invalid | Total effective rate (%) |
| Administration group | 50 | 36 | 11 | 3 | 94.0 |
| Positive controls | 50 | 37 | 10 | 3 | 94.0 |
| Negative control group | 50 | 24 | 11 | 15 | 70 |
To those skilled in the art, obviously the invention is not restricted to the details of above-mentioned one exemplary embodiment, and when not deviating from spirit of the present invention or basic feature, the present invention can be realized in other specific forms.Therefore, no matter from which point, all should embodiment be regarded as exemplary, and be nonrestrictive, scope of the present invention is limited by claims instead of above-mentioned explanation, and all changes be therefore intended in the implication of the equivalency by dropping on claim and scope are included in the present invention.
Claims (8)
1. treat the pharmaceutical composition of periodontitis for one kind, by principal agent, substrate adjuvant, solvent composition, it is characterized in that: described principal agent is iodine, in iodoform, hibitane, hibitane iodine, benzalkonium bromide, benzalkonium chloride, povidone iodine, triclosan, ethacridine, nitrofural, oradol, myristylpicolinum bromide, silver nitrate, nanometer silver any one or there is two or more combination synergistic.
2. treat the preparation method of the pharmaceutical composition of periodontitis for one kind, comprise the following steps: principal agent, substrate adjuvant are dissolved in solvent respectively, mix homogeneously, obtain, it is characterized in that: described principal agent is iodine, in iodoform, hibitane, hibitane iodine, benzalkonium bromide, benzalkonium chloride, povidone iodine, triclosan, ethacridine, nitrofural, oradol, myristylpicolinum bromide, silver nitrate, nanometer silver any one or there is two or more combination synergistic.
3. compositions according to claim 1 and 2, is characterized in that: described substrate adjuvant is two or more the combination in following adjuvant: poly-levorotatory lactide, poly-meso-lactide, PLGA 90/10, PLGA 75/25, PLGA 60/40, PLGA 50/50, end carboxyl polylactic acid, end carboxyl PLGA, D-lactic acid/co-glycolic acid, D-lactic acid/racemic lactic acid copolymer, polyethylene glycol modified polylactide, polyethylene glycol modified polylactide-co-glycolic acid, poly glycol monomethyl ether polydactyl acid, poly glycol monomethyl ether modification PLGA, lactide coglycolide--caprolactone copolymer, lactide--caprolactone copolymer, lactide coglycolide-trimethylene carbonate PLGTmc, polyvinylpyrrolidone, Polyethylene Glycol, the husky nurse of POLO, aminoacid, potassium iodide.
4. compositions according to claim 3, it is characterized in that: described substrate adjuvant is: PLGA 50/50, PLGA 75/25 and polyvinylpyrrolidone, three's mixed weight is than being 20-80:6-35:0.6-13.
5. compositions according to claim 1 and 2, is characterized in that: described solvent is METHYLPYRROLIDONE, ethyl acetate, triacetyl glycerine, 2-Pyrrolidone, ethyl lactate, dimethyl sulfoxide, glycerol formal.
6. compositions according to claim 1 and 2, is characterized in that: described drug content is 0.5%-20% (percentage by weight).
7. compositions according to claim 1 and 2, is characterized in that: the content of described substrate adjuvant is 10-92% (percentage by weight).
8. the arbitrary described purposes of pharmaceutical composition in periodontitis treatment of claim 1-2.
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| RU2600036C1 (en) * | 2015-07-21 | 2016-10-20 | Автономная некоммерческая организация высшего профессионального образования "Белгородский университет кооперации, экономики и права" | Method of producing biocide agent in the form of furacilin solution |
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| WO2018202687A1 (en) * | 2017-05-02 | 2018-11-08 | Pierre Fabre Medicament | Antiseptic composition combining chlorhexidine and iodine |
| FR3065879A1 (en) * | 2017-05-02 | 2018-11-09 | Pierre Fabre Medicament | ANTISEPTIC COMPOSITION OF A CHLORHEXIDINE AND IODINE ASSOCIATION |
| CN108030788A (en) * | 2017-12-15 | 2018-05-15 | 保髓特（天津）生物科技有限公司 | A kind of pulpitis treatment paste and its application |
| CN107898521A (en) * | 2017-12-22 | 2018-04-13 | 大连三生科技发展有限公司 | A kind of cleaning method of planting body |
| CN110151945A (en) * | 2019-04-26 | 2019-08-23 | 西安交通大学 | The composition of periodontitis and its application in the drug of preparation treatment periodontitis |
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