CN104367547A - Controlled release tinidazole ointment suitable for being orally administered - Google Patents
Controlled release tinidazole ointment suitable for being orally administered Download PDFInfo
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- CN104367547A CN104367547A CN201410591935.1A CN201410591935A CN104367547A CN 104367547 A CN104367547 A CN 104367547A CN 201410591935 A CN201410591935 A CN 201410591935A CN 104367547 A CN104367547 A CN 104367547A
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- tinidazole
- ointment
- release
- vaseline
- controlled release
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- 239000002674 ointment Substances 0.000 title claims abstract description 70
- HJLSLZFTEKNLFI-UHFFFAOYSA-N Tinidazole Chemical compound CCS(=O)(=O)CCN1C(C)=NC=C1[N+]([O-])=O HJLSLZFTEKNLFI-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 229960005053 tinidazole Drugs 0.000 title claims abstract description 46
- 238000013270 controlled release Methods 0.000 title claims abstract description 14
- -1 sucrose fatty acid ester Chemical class 0.000 claims abstract description 44
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- 239000000194 fatty acid Substances 0.000 claims abstract description 24
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- 208000005888 Periodontal Pocket Diseases 0.000 claims abstract description 5
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- 229940049654 glyceryl behenate Drugs 0.000 claims description 16
- 239000003883 ointment base Substances 0.000 claims description 12
- 239000002245 particle Substances 0.000 claims description 3
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a controlled release tinidazole ointment suitable for being orally administered, belonging to the technical field of pharmaceutical preparations. According to the controlled release tinidazole ointment, sucrose fatty acid ester, hydroxypropyl methyl cellulose, behenic acid glyceride and vaseline are taken as ointment matrixes and are mixed and ground together with tinidazole to form the non-corrosion controlled release tinidazole ointment with good heat stability; the ointment swells under in vitro release conditions that the temperature is 37 DEG C and the rotation speed is 100rpm and releases medicine at a zero level or an approximate zero level for a long time; vaseline has good adaptability to human tissues, is clinically used for treating tissue injury and has the effect of promoting wound healing; sucrose fatty acid ester can absorb body fluid so that the combined matrixes swells to form medicine release channels; behenic acid glyceride has good biocompatibility, and after behenic acid glyceride is mixed with vaseline, the heat stability of the ointment is increased; by virtue of adhesive effect of hydroxypropyl methyl cellulose, the corrosion of the matrixes is avoided and the release of the medicines is promoted. The controlled release tinidazole ointment can be injected to a periodontal pocket of an oral cavity.
Description
Technical field
The present invention relates to a kind of slow controlled release Tinidazole unguentum being applicable to oral administration, it belongs to technical field of medicine.
Background technology
Sustained-release preparation be by the curative effect of medicine only with vivo medicine concentration about and to have nothing to do the third generation dosage form developed based on this concept with administration time.Sustained-release preparation can reduce blood concentration fluctuation, reduces administration number of times, improves curative effect, reduces untoward reaction, and easy to use, therefore more and more gets more and more people's extensive concerning.Traditional pharmaceutical research shows: cardiovascular disease, asthma, gastric acid secretion, arthritis, migraine etc. have daily rhythmicity, such as asthma, myocardial infarction etc. are many to show effect in morning, traditional preparation can not effectively prevent and treat the generation of these diseases in the most dangerous moment, and sustained-release preparation then can overcome some shortcoming of conventional formulation.Along with continuing to bring out of some new adjuvant, new material, new equipment and new technologies, for the development of sustained-release preparation provides broad space.Its Theory and technology development at present reaches its maturity, and the types of drugs studied and preparation type all constantly increase and expand.Present existing sustained-release preparation has tablet, injection, capsule, implant, transdermal patch, ointment etc.Wherein slow controlled ointment is mainly used in skin, oral cavity, the local of rectum or vagina and Formulations for systemic administration.
Periodontitis (periodontitis) is oral health " number one killer ", and the advanced symptoms of appearance is also the principal character that oral cavity " subhealth state " is worsened.Periodontitis is the inflammation invading gingiva and periodontal tissue, and being a kind of chronic, Progressive symmetric erythrokeratodermia, destructive disease, is the main cause of adult's loss of tooth.Primary disease is many because bacterial plaque, tartar, food impaction, and ill fitting prosthesis, stings wound etc. and cause, various focusing depths represented swelling, makes bacterial plaque pile up simultaneously and increases the weight of, and prolongs by expanding under gingivally on gum.Due to subgingival microbe environment, in subgingival plaque, grow a large amount of periodontitis pathogenic bacterium, mainly anaerobe, as gingiva bacteroid, intermediate bacillus, spirillum etc., make the increased inflammation of gingiva and expand to prolong, cause periodontal pocket to be formed and frontal resorption, cause periodontitis.The Therapeutic Method of periodontitis routine removes or controls clinical inflammatory and paathogenic factor, comprises oral cavity self-cleaning, pull out the tooth of problem and unfavorable reparation, scaling on gum, and subgingival debridement, to remove bacterial plaque, tartar etc., must use antimicrobial drug to control inflammation simultaneously.At present, treatment periodontitis mainly contains oral administration and periodontal topical two kinds of approach, and qf oral administration dosage is large, and easily causes the side effect of whole body system.Therefore the Therapeutic Method of oral administration is replaced by local application gradually.Periodontal local application mainly applies the antibiotic medicine such as nitroimidazoles medicine, minocycline, dosage form has periodontal mouth paster, periodontal bar and collutory body preparation etc., mainly there is following problem in these dosage forms: 1) periodontal bar has foreign body sensation when medication, hard, uncomfortable.2) periodontal mouth paster one dental bed a slice, 1 day 2 times, under oral environment, applicating property is poor.3) other liquid mouthwash formulation Local Residence Time are short, and need frequent drug administration, patient compliance is poor., also there is the easy corrosion of oral environment, the problems such as the drug action time is short in the ointment medication of common oral cavity, and it is long to retain a percentage of the total profits for the enterprise's own use the time after slow release ointment for topical application, clinical experience is comfortable, can continual and steady release, side effect is little, reduces medicine frequency, significantly improves patient compliance.
Minocycline hydrochloride controlled-release nano-liposome prepared by patent CN102166191A is the lyophilized preparation be prepared into by minocycline hydrochloride, fat phase, organic solvent, caffolding agent and buffer solution prescription, then is prepared into external use liquid, ointment, gel, patch or liniment.Route of administration of the present invention is various, realizing controlled-release Nano medication, can reach the object of targeted, improves the treatment concentration of medicine at target site, to normal cell then harmless or inhibitory action, alleviates or avoids toxicity; Preparation film material is similar to mammalian cell, can not cause local tissue damage and immunosuppressive action, does not bring out anaphylaxis and can repeatedly life-time service, to human non-toxic's evil.Biodegradable extended release preparation core prepared by patent CN1098105C is made up of medicine and polysaccharide (i.e. sodium alginate), and coated by the chitosan of positively charged.By means of the preparation clad of chitosan composition, sustained release, and this carrier is decomposed completely by lysozyme in vivo after drug release.It is microball preparation.But nanometer liposome preparation section prepared by patent CN102166191A is loaded down with trivial details, and centre is with an organic solvent, not too easily eliminates, and can not direct oral cavity local medication, can not at once use.Be prepared as with regard to unguentum again with regard to lyophilized preparation, emulsifiable paste does not have ointment to drug substance stable.Biodegradable extended release preparation prepared by patent CN1098105C is microball preparation, is expelled to the administration of periodontal cyst place, and its adhesiveness is not high, easily runs off; Its drug release behavior is relevant with lysozyme activity, and the included figure of its patent shows that medicine non-controlling discharges.Pike change ointment prepared by patent US6566350B2 is the ointment be prepared into by minocycline hydrochloride, oleaginous base, cellulose derivative and fatty acid ester, from Patent right requirement and description, its invention essence is the stability action of ointment base to minocycline hydrochloride.Found by comparative study, the present invention and patent US6566350B2 substrate form and medicine all inconsistent, and also there is notable difference in the usage ratio of identical component.
Summary of the invention
For solving problems of the prior art, the present invention is directed to the technical need that controlled release drug administration is delayed in oral cavity, a kind of Tinidazole unguentum being suitable for oral administration is provided.
Technical scheme of the present invention is: a kind of slow controlled release Tinidazole unguentum being applicable to oral administration, the ointment base that this Tinidazole unguentum adopts contains sucrose fatty acid ester, hydroxypropyl emthylcellulose, Glyceryl Behenate, vaseline, is that the ointment base of benchmark contains with 100g:
Sucrose fatty acid ester 4-10g,
Hydroxypropyl emthylcellulose 5-20g,
Glyceryl Behenate 3-7g,
Vaseline 70-85g,
The hydrophile-lipophile balance value HLB of described sucrose fatty acid ester is 15, above-mentioned 100g ointment base and 0.1-10g tinidazole is ground to mix and prepares Tinidazole unguentum; Described tinidazole is dispersed in ointment, and tinidazole particle diameter is no more than 50 μm.
Described Tinidazole unguentum is placed in syringe, is injected in periodontal pocket by Tinidazole unguentum clinically and uses.
Sucrose fatty acid ester in the present invention and hydroxypropyl emthylcellulose all have certain hydratability, and adhesive effect after hydroxypropyl emthylcellulose hydration, can also be produced, therefore porogen and adhesive effect is played, in ointment, ointment base both can be allowed swelling and not corrosion, ensure good formability, can medicine-releasing performance be improved again; Vaseline is conventional oleaginous base, physiological inertia, medicine stability can be kept, and there is the effect delaying drug release, the fine and smooth softening nonvoluntary flowing again under human body temperature condition of Vaseline basis simultaneously, be combined closely with medicine-feeding part, research also shows that vaseline has certain healing ability to wound, it is often used in medicament for treating scald as substrate, vaseline and hydroxypropyl emthylcellulose grind mixed under sucrose fatty acid ester effect in addition, and vaseline can be made under aqueous environment condition to keep good form for a long time.
As the main component vaseline of substrate and tissue adaptability good, adhesion is good, but places easily softening in hot environment, easily causes ointment Chinese medicine release behavior to change, and producing dashes forward releases phenomenon, and ointment heat stability is poor.Vaseline and Glyceryl Behenate or acrylic resin grind mixed after oleaginous base good thermal stability, ointment good thermal stabilities after placing at-20 ~ 40 DEG C, extracorporeal releasing test shows, significant change does not occur drug release.Find that the compatibility of Glyceryl Behenate and vaseline is better through experiment.It is mixed that the present invention adopts Glyceryl Behenate and vaseline to grind, and increases the heat stability of ointment.
The preparation method of this ointment, step is as follows:
(1) stir vaseline under certain rotating speed, successively add Glyceryl Behenate, sucrose fatty acid ester (HLB=15) and hydroxypropyl emthylcellulose room temperature airtight stirring 1-2h, add tinidazole, more airtight stirring 1-2 hour; Tinidazole should grind in advance, makes diameter of aspirin particle <50 μm, then mixes with ointment base and is uniformly dispersed;
(2) said mixture is heated to glutinous stream mode, then ground and mixed, after condensation.
The present invention is using vitro release as the evaluation criterion of ointment, and vitro release assay method is: the ointment of preparation, with reference to the vitro release method of testing of solid preparation, carries out vitro release mensuration to it.Chinese Pharmacopoeia 2010 editions annex second methods (paddle method) are adopted to measure the release in vitro of this ointment.Release conditions with normal saline or distilled water 500ml for release medium, rotating speed 100rpm, temperature (37 ± 0.5) DEG C.Get product to be tested, evenly stand cloth is in the specimen disk of having weighed, and this disk is made by stainless steel, and the depth of groove of disk is 0.5mm, diameter 30mm, and the external diameter of disk is 40mm, and the thickness of disk is 5mm.Its weight of accurate title, this platter faced up, level sinks in acceptable solution.Each sample point sampling 5ml, after add the blank solution of identical temperature immediately.
Wherein: Q: drug release rate, W: contained drug total amount (ug) in platter, Mi(Mj): the drug level (ug/ml) that i-th time (jth time) records sample time.I=1,2,3, j=1,2,3(corresponding sample time 1h, 3h, 7h).
This ointment limited swelling slow releasing tinidazole in normal saline or distilled water.In this ointment, the release rate of tinidazole is: 1h:5-30%, 3h:15-45%, 7h:40-90%.
The invention has the beneficial effects as follows: adopt vaseline, Glyceryl Behenate, hydroxypropyl emthylcellulose and sucrose fatty acid ester to prepare a kind of non-erodible and have the slow controlled ointment compound stroma of good heat stability.It can carry out administration in the periodontal pocket of oral cavity with smear or injection system etc., easy to use, and the selection of consumption can be dependent on the size in affected part and disease degree and determines.This Tinidazole unguentum farthest can contact affected area, and histocompatibility is good, and mucous membrane irritation is little, can maintain long-time topical, effective mitigate the disease; If there is discomfort, can remove at once.This Tinidazole unguentum has good stability, and after placing in the temperature range of-20 ~ 40 DEG C, release performance is good, does not occur dashing forward releasing phenomenon.In this ointment, tinidazole can closely zero level feature lasts release.
Term explanation
Ointment (Ointments): refer to the semi-solid external preparation with certain denseness that medicine and appropriate substrate Homogeneous phase mixing are made.Conventional substrate is divided into oil, water solublity and emulsion-type substrate, wherein claims ointment with the ointment being easy to be coated with that emulsion bases is made.Because medicine dispersity in substrate is different, with solution ointment agent and suspension type ointment agent point.Solution ointment agent is the ointment that medicine dissolution or congruent melting are made in substrate or matrix components, suspension type ointment agent be fine drug powder dispersed with substrate in the ointment made.
Ointment base: greasing base and water-soluble base can be divided into.What greasing base was conventional has vaseline, paraffin, liquid paraffin, silicone oil, Cera Flava, stearic acid, lanoline etc., and water-soluble base mainly contains Polyethylene Glycol.Ointment base should be even, fine and smooth, is applied on skin or mucosa and answers nonirritant, and in suspension type ointment agent, insoluble solid medicine should wear into fine powder by suitable method in advance, guarantees that granularity conforms with the regulations.
Surfactant: simultaneously its molecular characterization has the hydrophilic group of polarity and nonpolar lipophilic group, has amphipathic.General hydrophile-lipophile balance value (HLB) carrys out the comprehensive affinity to oil and water of hydrophilic and lipophilic group in presentation surface active agent molecule, HLB value is greater than 10 and belongs to hydrophilic surfactant active, the stronger surfactant of hydrophilic has higher HLB value, and lipophilic surfactant has lower HLB value.Sucrose fatty acid ester drops to 1 along with the increase HLB value 16 of degree of esterification, and usual hydrophilic sucrose fatty acid ester refers to the sucrose fatty acid ester that monoesters ratio is higher, and HLB is between 11 ~ 16, and the HLB as sucrose fatty acid ester SL-15 is about 15.
Cellulose derivative: refer to a series of materials obtained by carrying out chemical modification to cellulose.Cellulose ether and cellulose esters and cellulose ether-esters three major types can be divided into according to the construction features of cellulose derivative.Wherein cellulose ethers has: methylcellulose, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose and hydroxypropyl emthylcellulose etc.Cellulose ether derivatives is the macromolecular material with biodegradable, the feature such as nontoxic, inexpensive, is widely used in pharmaceutical arts slow releasing preparation adjuvant.They add usually used as blocker, framework material and viscosifier, meet water and can play adhesive effect, be commonly used for and make sustained-release matrix tablets, gastric solubility coating material, slow-releasing microcapsule lapping, slow-release material etc., use in the preparation such as gel and ointment.Cellulose ether derivatives produces regular change along with the change of himself molecular weight, substituent group and substitution value, and as increased along with cellulose derivative molecular weight (degree of polymerization), its viscosity and adhesive effect increase, water solublity declines, and slow releasing function strengthens; And substituent group obviously can change cellulosic dissolubility and release, such as hydroxypropyl emthylcellulose and carboxymethyl cellulose water soluble, improve the release of hydrophobic base Chinese medicine, and methylcellulose decreased solubility, colloid solution is swelled in water, ethyl cellulose is then insoluble in water, significantly improves the retardation to drug release.Therefore can according to different medicine carrying substrate and medicine on galenic pharmacy, by the object selecting cellulose ether derivatives and combination, the proportion of composing adjusted between them reaches slow controlled release drug administration.Hydroxypropyl emthylcellulose cohesive is good, can form good drug release passage, normal and other ointment bases with the use of.
Accompanying drawing explanation
Fig. 1 is the release profiles of tinidazole in the Tinidazole unguentum of embodiment 1, embodiment 2 and embodiment 3.
Fig. 2 be in embodiment 4 Tinidazole unguentum preserve under being placed on room temperature, 40 DEG C and-20 DEG C of conditions after the release profiles of tinidazole.
Detailed description of the invention
In order to illustrate in greater detail the present invention, grinding to mix according to 100g substrate and tinidazole and prepare Tinidazole unguentum and provide following embodiment.But scope of the present invention is not limited thereto.
embodiment 1
70g vaseline and 7g Glyceryl Behenate are placed in beaker stir, above-mentioned substrate is heated to viscous state, add 5g sucrose fatty acid ester (HLB=15) wherein successively and 8g hydroxypropyl emthylcellulose stirs, the tinidazole adding 10g ground stirs, and grinds mixed obtained ointment after subsequently said mixture being heated to viscous state.
embodiment 2
75g vaseline and 5g Glyceryl Behenate are placed in beaker stir, above-mentioned substrate is heated to viscous state, add 6g sucrose fatty acid ester (HLB=15) wherein successively and 10g hydroxypropyl emthylcellulose stirs, the tinidazole adding 4g ground stirs, and grinds mixed obtained ointment after subsequently said mixture being heated to viscous state.
embodiment 3
85g vaseline and 3g Glyceryl Behenate are placed in beaker stir, above-mentioned substrate is heated to viscous state, add 4g sucrose fatty acid ester (HLB=15) wherein successively and 5g hydroxypropyl emthylcellulose stirs, the tinidazole adding 3g ground stirs, and grinds mixed obtained ointment after subsequently said mixture being heated to viscous state.
embodiment 4
77g vaseline and 5g Glyceryl Behenate are placed in beaker stir, above-mentioned substrate is heated to viscous state, add 6g sucrose fatty acid ester (HLB=15) wherein successively and 7g hydroxypropyl emthylcellulose stirs, the tinidazole adding 5g ground stirs, and grinds mixed obtained ointment after subsequently said mixture being heated to viscous state.
embodiment 5
79g vaseline and 4g Glyceryl Behenate are placed in beaker stir, above-mentioned substrate is heated to viscous state, add 10g sucrose fatty acid ester (HLB=15) wherein successively and 5g hydroxypropyl emthylcellulose stirs, the tinidazole adding 2g ground stirs, and grinds mixed obtained ointment after subsequently said mixture being heated to viscous state.
embodiment 6
70g vaseline and 4.9g Glyceryl Behenate are placed in beaker stir, above-mentioned substrate is heated to viscous state, add 5g sucrose fatty acid ester (HLB=15) wherein successively and 20g hydroxypropyl emthylcellulose stirs, the tinidazole adding 0.1g ground stirs, and grinds mixed obtained ointment after subsequently said mixture being heated to viscous state.
embodiment 7
75g vaseline and 4g Glyceryl Behenate are placed in beaker stir, above-mentioned substrate is heated to viscous state, add 6g sucrose fatty acid ester (HLB=15) wherein successively and 10g hydroxypropyl emthylcellulose stirs, the tinidazole adding 5g ground stirs, and grinds mixed obtained ointment after subsequently said mixture being heated to viscous state.
Claims (2)
1. one kind is applicable to the slow controlled release Tinidazole unguentum of oral administration, it is characterized in that: the ointment base that this Tinidazole unguentum adopts contains sucrose fatty acid ester, hydroxypropyl emthylcellulose, Glyceryl Behenate, vaseline, is that the ointment base of benchmark contains with 100g:
Sucrose fatty acid ester 4-10g,
Hydroxypropyl emthylcellulose 5-20g,
Glyceryl Behenate 3-7g,
Vaseline 70-85g,
The hydrophile-lipophile balance value HLB of described sucrose fatty acid ester is 15, above-mentioned 100g ointment base and 0.1-10g tinidazole is ground to mix and prepares Tinidazole unguentum; Described tinidazole is dispersed in ointment, and tinidazole particle diameter is no more than 50 μm.
2. a kind of slow controlled release Tinidazole unguentum being applicable to oral administration according to claim 1, is characterized in that: described Tinidazole unguentum is placed in syringe, is injected in periodontal pocket by Tinidazole unguentum clinically and uses.
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Cited By (2)
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| CN106727285A (en) * | 2017-01-13 | 2017-05-31 | 福元药业股份有限公司 | A kind of ointment oleaginous base and its application method |
| CN113230226A (en) * | 2021-05-28 | 2021-08-10 | 丽珠集团丽珠制药厂 | Tinidazole tablet and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106727285A (en) * | 2017-01-13 | 2017-05-31 | 福元药业股份有限公司 | A kind of ointment oleaginous base and its application method |
| CN113230226A (en) * | 2021-05-28 | 2021-08-10 | 丽珠集团丽珠制药厂 | Tinidazole tablet and preparation method thereof |
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