CN1883488A - Preparation method of minocycline hydrochloride chitosan microsphere and application thereof - Google Patents
Preparation method of minocycline hydrochloride chitosan microsphere and application thereof Download PDFInfo
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- CN1883488A CN1883488A CN 200510077602 CN200510077602A CN1883488A CN 1883488 A CN1883488 A CN 1883488A CN 200510077602 CN200510077602 CN 200510077602 CN 200510077602 A CN200510077602 A CN 200510077602A CN 1883488 A CN1883488 A CN 1883488A
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Abstract
The invention discloses a Minocycline hydrochloride chitosan microsphere and the process for preparing the microsphere. The prepared microsphere can be used for the treatment of oral diseases such as periodontitis.
Description
Technical field
The present invention relates to a kind of biodegradable minocycline hydrochloride chitosan microsphere, the preparation method of this microsphere, this microball preparation is used for the treatment of the oral cavity periodontal disease.
Background technology
Minocycline is a tetracycline derivant, except having advantages such as tetracycline has a broad antifungal spectrum, inhibition collagenase, antibacterial action to the periodontal pathogenic microorganism is the strongest in telracycline family, 98% periodontal pathogen can both be suppressed by the minocycline of 5 μ g/mL, paradenlal tissue regeneration there is facilitation, periodontal tissue's male hormone metabolism is worked.But during systemic administration, GCF (Gingival Crevicular Fluid) Chinese medicine concentration is low, easily inducible resistance bacterial strain and superinfection.Local application is substituting systemic administration gradually in the periodontal treatment, because the toxic and side effects of topical can reduce the whole body administration on the one hand the time; On the other hand, can make lesions position keep higher drug level, help kill pathogens, improve the curative effect of medicine.
According to the characteristics of periodontal, the local delivery system clinical practice form of minocycline for the treatment of periodontal disease at present mainly is divided into film type, ointment type and microspheric.Film type is the minocycline that contains in ethyl cellulose about 30%, for example the home-made Ai Yalin of Korea Spro (Dung Kook minocycline strip).Ointment type is that 2% minocycline hydrochloride is placed in the ointment, and every ointment capacity 0.5g contains minocycline 10mg, and for example the Pai Liao (Periocline) of Japan's production has been used for the clinical several years.Microspheric is that the minocycline microgranule is combined in the polymer microsphere, inserts in the periodontal pocket with plastic injector, and drug slow discharges the purpose that reaches treatment.The therapeutant of common treatment periodontal disease needs to take out once more usually behind the administration certain hour, and this has brought very big inconvenience to the patient; Pharmaceutical preparation is difficult to reach the bottom of periodontal pocket in addition, is unfavorable for eradicating the pathogenic bacteria of depths.Therefore the pharmaceutical dosage form of development of new can make things convenient for administration, need not after the medication to take out, and pharmaceutical dosage form can reach bottom the periodontal pocket, with significant.Reach this purpose and can adopt the minocycline hydrochloride microballoons preparation, micro-sphere material adopts degradable to absorb, and has the material of biocompatibility, and microsphere can be degraded and absorbed and need not to take out like this, has made things convenient for the patient; And, can discharge medicine in the bottom because small-sized (tens micron orders) of microsphere can reach the periodontal pocket depths, be beneficial to and eradicate pathogenic bacteria.And the key of this microball preparation is the preparation of microsphere and the selection of micro-sphere material.
Chitosan is the de-acetyl chitin thing, has film property, spinnability, and functions such as the wound healing of promotion, bone formation are arranged, and the utilization that can be absorbed by the body has excellent biological compatibility.Chitosan has caused people's attention in recent years gradually in the research and the application in stomatology field, the application report of existing chitosan numerous areas such as dry socket prevention and filling material of bone after periodontal disease, the sick control of tooth body, extraction.The effect of chitosan in oral disease comprises: 1. bacteriostasis: except that bidentate bifid ATCC27534 is not had the agglutination, chitosan all has in various degree agglutination to other common bacteria of oral cavity.Simultaneously, chitosan has certain desorption to the Streptococcus mutans that adheres to.Chitosan also tool suppresses the effect of bacterial activity, and (suppressing effect increases with the increase of molecular weight for Porphyromonas gingivalis, activity Pg) can to suppress the main pathogenic bacterium porphyromonas gingivalis of periodontal disease.Deacetylation is main pathogenic bacterium actinobacillus actinomycetem comitans (Actinobacillusactinimycetemcomitans, activity Aa) that 91.5% chitosan oligosaccharide (chitooligosaccharide) can reduce juvenile periodontitis; 2. make the periodontal lines as adjuvant: periodontal lines Chang Zuowei periodontal pocket local application, carrier mostly is non-degradable material.Riceardo etc. (Carbohydrate Polymers1993 (20) 7-14) place patient's periodontal pocket with chitosan as ointment or the periodontal lines that adjuvant makes, and the lines degradable absorbs, and need not take out.Needleman etc. (Journal of ClinicalPeriodontology 1,998 25 (1) 74-82) discover that the slow release effect of chitin is better than other slow-release materials, can improve curative effect of medication.3. being used for periodontal postoperative plug controls: Muzzarelli etc. (Biomaterials 198910 (9) 598-606) add people's chitosan at Ascorbate and make the ascorbic acid gel, and the wound surface that is used for periodontal surgical intervention postoperative covers.Scanning electron microscope shows that it is cellular, helps the exchange of oxygen, can promote cell proliferation and tissue reconstruction.Make periodontal pack with it, easily degraded can be absorbed by the host, helps the reconstruction of periodontal tissue, in the clinical satisfactory therapeutic effects that obtains, depth of pocket reduction, tooth mobility is reduced.4. guide periodontal tissue to rebuild: periodontal guided tissue regeneration (guidedt issuer egeneration, GT R) is comparatively advanced at present periodontal treatment means.Laboratory detects and zoopery shows that all chitosan has excellent biological compatibility, no cytotoxicity, and sensitization not, and have the effect that promotes cell proliferation.The vesicular texture on chitosan film surface allows long people of host blood vessel and tissue to form, and is beneficial to defect repair.And the degradable absorption, needn't take out by second operation.Therefore have broad application prospects.
Periodontitis is the dental bed inflammation, and chronic periodontitis can cause odontoseisis and loss.It also with for example cardiovascular disease of other serious disease, osteoporosis, diabetes have relation.Periodontitis is badly in need of curative of new generation.From patient's feedback, it is good that the minocycline conventional capsule is used for the treatment of the periodontal therapeutic equivalence, but have certain side effect, and the clinician reflects that also being badly in need of the minocycline oral cavity partial solves this problem with preparation.Therefore research and development will have great clinical meaning and vast market prospect.
Goal of the invention
The novel therapeutic medicine that the purpose of this invention is to provide the effect aspect the periodontal disease treatment of requirement of a kind of comprehensive periodontitis topical and chitosan, i.e. minocycline hydrochloride chitosan microsphere preparation.Said preparation has slow releasing function, and pharmaceutical carrier need not to take out once more after administration, can be degraded and absorbed, and simultaneously said preparation has the advantage of chitosan, as bacteriostasis be beneficial to paradenlal tissue regeneration etc.
Another object of the present invention provides a kind of method for preparing this microsphere.
A further object of the present invention provides the application of this microsphere in periodontitis treatment.
Summary of the invention
The invention provides a kind of minocycline class medicine chitosan microball preparation that contains, it comprises minocycline hydrochloride medicine, chitosan, cross-linking agent, antiseptic and microsphere dispersant.
The invention provides a kind of minocycline class medicine chitosan microball preparation that contains, it comprises minocycline hydrochloride medicine, chitosan, is selected from sulphuric acid, sodium sulfate, citric acid, sodium citrate, Quadrafos, the cross-linking agent of formaldehyde, vanillin and glutaraldehyde, be selected from P-hydroxybenzoic acid first, second and propyl ester, benzalkonium bromide, Benzalkonii Chloridum, chlorobutanol, benzoic acid, the antiseptic of sorbic acid or phenol is selected from the dispersant of sodium stearate, magnesium and polymethyl methacrylate (PMMA).
The present invention also provides the method for the chitosan microball preparation that a kind of preparation contains the minocycline medicine, it comprises that minocycline hydrochloride medicine, chitosan solution and antiseptic are as interior water, vegetable oil is as outer oil phase, the microsphere dispersant joins in the outer oil phase, contains the chitosan microball preparation of minocycline medicine with the preparation of profit phase separation method.
According to the present invention, in microball preparation weight, microball preparation Chinese medicine content of the present invention is 0.5-20%; Chitosan, cross-linking agent, antiseptic and microsphere dispersant are 78-99%, and surplus is a moisture content.According to the present invention, microspherulite diameter of the present invention is 0.01-1mm.
According to the present invention, minocycline hydrochloride chitosan microsphere preparation of the present invention can be injected in the periodontal pocket by plastic injection device, realizes the purpose of topical.
Detailed Description Of The Invention
The method for preparing microsphere of the present invention comprises the steps:
(1) preparation dilute acid soln, molar concentration is 0.01M-1M;
(2) take by weighing the chitosan of certain mass, join in the dilute acid soln, fully dissolving is with the solution of the chitosan of preparation 0.5-6% (W/V);
(3) take by weighing a certain amount of minocycline hydrochloride and join in the chitosan solution, fully dissolving;
(4) react in oil phase, the chitosan solution that preparation microsphere: a. gets hydrochloric minocycline joins in the oil phase as interior water, and interior water is 1 with the volume ratio of outer oil phase: 4-15, dispersed with stirring under 500-3500 rev/min of condition; B. add antiseptic again, antiseptic can be P-hydroxybenzoic acid first, second and propyl ester, benzalkonium bromide, Benzalkonii Chloridum, chlorobutanol, benzoic acid, one or more in sorbic acid or the phenol; C. add the nonionic emulsifier that accounts for the about 0.1-5% of outer oil phase volume (V/V) again; D. add dispersant, the ratio of dispersant quality and interior water volume is 5-50: 1 (mg: ml), fully stirring, dispersant can be one or more in stearic acid or the stearate; E. add 0.1-3 doubly to the 5-60% of interior water volume (W/W) sulphuric acid sodium citrate or polyphosphate sodium solution as cross-linking agent, stirred 10-180 minute;
(5) promptly get the ionomer chitosan microball behind centrifugalize, washing, the vacuum drying.
Preferably in step (1), adopt acid solution dissolving chitosans such as acetic acid, citric acid, tartaric acid, formic acid, aminoacid or ethanedioic acid.
Be that preferably antiseptic is P-hydroxybenzoic acid first, second and propyl ester in the step (4), sorbic acid or phenol; Further preferred methyl parahydroxybenzoate, second and the propyl ester etc. of adopting.
Be that preferably oil phase is mineral oil or vegetable oil in the step (4); Further preferred Oleum Helianthi, Oleum Brassicae campestris, soybean oil, the Semen arachidis hypogaeae wet goods of adopting.
Stearate dispersant in the preferred steps (4) is selected from magnesium stearate, calcium stearate, potassium stearate, sodium stearate etc.
Adopt ether, ethanol or acetone solution dispersant stearic acid and stearate in the preferred steps (4).
Preferably nonionic emulsifier is the compound emulsifying agent of Span type emulsifying agent or Span type and Tween type emulsifying agent composition in step (4); The Span type emulsifying agent of further preferred this preparation method can be Span80, Span85, Span83; Preferred Tween type emulsifying agent is Tween20, Tween60 or Tween80; Preferred compound emulsifying agent is that the HLB value that Span80 and Tween60 form is the compound emulsifying agent of 6-9.
Preferably the cross-linking agent among the e in step (4) is sulphuric acid, sodium sulfate, citric acid, sodium citrate, polyphosphate sodium, formaldehyde, vanillin; Further preferred sulphuric acid, the sodium citrate vanillin solution etc. of adopting.
Preferably among the e in step (4) add 5-60% (W/W) after, it is doubly further crosslinked to the 5-60% of interior water volume (W/W) sulphuric acid, sodium citrate or vanillin solution to spend 10-150 minute and add 0.1-3.
The minocycline hydrochloride chitosan microsphere of ionomer provided by the invention can be used for the pharmaceutical preparation as the treatment periodontitis.
The present invention selects for use sulphuric acid, polyphosphate sodium or sodium citrate solution as ion crosslinking agent, toxicity or other side effect that can avoid chemical crosslinking to cause; In the process of preparation, add stearic acid simultaneously, make microsphere have good dispersibility as dispersant; But also can be by regulating process conditions such as rotating speed, chitosan solution concentration, than the pattern and the particle size distribution that are easier to control microsphere.
Description of drawings
Fig. 1 is under embodiment 1 preparation condition, minocycline hydrochloride chitosan microsphere Electronic Speculum picture.
Fig. 2 is under embodiment 2 preparation conditions, the particle size distribution figure of minocycline hydrochloride chitosan microsphere.
The specific embodiment
Following embodiment further specifies of the present invention, and it is not intended that the invention be limited to this.
Embodiment 1
Get the chitosan solution 10ml of 5% (w/v), add the 400mg minocycline hydrochloride, add an amount of methyl parahydroxybenzoate, abundant stirring and dissolving, the chitosan solution that will contain minocycline hydrochloride then joins the 80ml liquid paraffin is housed, in the there-necked flask of an amount of Span80 and Tween60, add again and be dissolved in the magnesium stearate of ether as dispersant, the quality of magnesium stearate is 50mg, 25 ℃, stir the sulfuric acid solution 5ml that adds 30% (W/W) after 10 minutes under 600 rev/mins of conditions, the sulfuric acid solution 5ml that added this concentration in 35 minutes again, stop after 70 minutes stirring, centrifugalize under 2500 rev/mins of conditions, use volatile organic solvent, deionized water replaces the thorough washing solid product, last 30 ℃ of following vacuum dryings.The particle diameter of microsphere is 80-300 μ m (＞80%).The microsphere electromicroscopic photograph is seen shown in Figure 1.
Embodiment 2
Get the chitosan solution 20ml of 4% (w/v), add the 200mg minocycline hydrochloride, add an amount of methyl parahydroxybenzoate, abundant stirring and dissolving, the chitosan solution that will contain minocycline hydrochloride then joins the 80ml Oleum Helianthi is housed, in the there-necked flask of an amount of Span80 and Tween60, add again and be dissolved in the magnesium stearate of ether as dispersant, the quality of magnesium stearate is 100mg, 25 ℃, stir the sodium citrate solution 5ml that adds 30% (W/W) after 10 minutes under 2000 rev/mins of conditions, the sodium citrate solution 5ml that added this concentration in 35 minutes again, stop after 60 minutes stirring, centrifugalize under 3000 rev/mins of conditions, use petroleum ether, acetone and deionized water replace the thorough washing solid product, last 50 ℃ of following vacuum dryings.The particle diameter of microsphere is 150-220 μ m (＞70%).The microspherulite diameter distribution is seen shown in Figure 2.
Claims (10)
1. minocycline hydrochloride chitosan microsphere preparation, it comprises minocycline hydrochloride medicine, chitosan, cross-linking agent, antiseptic and microsphere dispersant.
2. the minocycline hydrochloride microballoons preparation of claim 1, wherein chitosan is as the medicine microsphere carrier material.
3. the minocycline hydrochloride microballoons preparation of claim 1, wherein cross-linking agent is selected from sulphuric acid, sodium sulfate, citric acid, sodium citrate, polyphosphate sodium, formaldehyde, vanillin or glutaraldehyde.
4. the minocycline hydrochloride microballoons preparation of claim 1, wherein antiseptic is selected from P-hydroxybenzoic acid first, second and propyl ester, benzalkonium bromide, Benzalkonii Chloridum, chlorobutanol, benzoic acid, sorbic acid or phenol
5. the minocycline hydrochloride microballoons preparation of claim 1, wherein dispersant is selected from sodium stearate, magnesium and polymethyl methacrylate (PMMA).
6. the minocycline hydrochloride microballoons preparation of the arbitrary requirement of claim 1-5, wherein cross-linking agent is a sodium citrate.
7. the minocycline hydrochloride microballoons preparation of the arbitrary requirement of claim 1-5, wherein dispersant is a magnesium stearate.
8. the minocycline hydrochloride microballoons preparation of the arbitrary requirement of claim 1-5, wherein antiseptic is a methyl parahydroxybenzoate.
9. the minocycline hydrochloride microballoons preparation of the arbitrary requirement of claim 1-5, wherein said microball preparation contains 1mg minocycline hydrochloride/unit dose.
10. the application of the described minocycline hydrochloride chitosan microsphere preparation of claim 1 in the treatment periodontitis.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200510077602 CN1883488A (en) | 2005-06-21 | 2005-06-21 | Preparation method of minocycline hydrochloride chitosan microsphere and application thereof |
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| CN 200510077602 CN1883488A (en) | 2005-06-21 | 2005-06-21 | Preparation method of minocycline hydrochloride chitosan microsphere and application thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101928641A (en) * | 2010-09-29 | 2010-12-29 | 江南大学 | Essence microcapsule with long-term effectiveness and preparation method thereof |
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- 2005-06-21 CN CN 200510077602 patent/CN1883488A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101928641A (en) * | 2010-09-29 | 2010-12-29 | 江南大学 | Essence microcapsule with long-term effectiveness and preparation method thereof |
| CN101928641B (en) * | 2010-09-29 | 2012-08-08 | 江南大学 | Essence microcapsule with long-term effectiveness and preparation method thereof |
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