CN101077352A - Eye preparation containing lactose-azithromycin - Google Patents
Eye preparation containing lactose-azithromycin Download PDFInfo
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- CN101077352A CN101077352A CNA2006100466168A CN200610046616A CN101077352A CN 101077352 A CN101077352 A CN 101077352A CN A2006100466168 A CNA2006100466168 A CN A2006100466168A CN 200610046616 A CN200610046616 A CN 200610046616A CN 101077352 A CN101077352 A CN 101077352A
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Abstract
The present invention is one kind of composition for eye medicine preparation. The composition contains antibiotic azithromycin lactobionate as active component; at least one kind of surfactant and/or co-surfactant, such as hydrogenated castor oil and Transcutol-p, in such amount as to form micro emulsion; and medicinal supplementary material, such as boric acid, borax and sodium bisulfite. The composition is prepared into eye drop or eye gel, and when it is prepared into gel, carbomer is used as the gel matrix. Compared with similar products, the composition of the present invention has high stability, less irritation to eye, capacity of be used to child and other advantages.
Description
Technical field
The invention belongs to field of pharmaceutical technology.
---lactobionic acid azithromycin---adds the preparation composition for eyes that medicinal adjuvant is processed into according to a conventional method to the present invention relates to a kind of antibiotic medicine, as dosage forms such as eye drop, gel for eye use.The present composition relates to lactobionic acid azithromycin eye drop and lactobionic acid azithromycin gel for eye use.
Background technology
Lactobionic acid azithromycin (Azithromycin Lactobionate) is a kind of macrolide antibiotics of semisynthetic assorted nitrogen fifteen-membered ring, and its chemical name is (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-and 13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-(L-nuclear-own pyrans glycosyl) oxygen)-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-seven methyl isophthalic acid 1-[(3,4,6-three deoxidations-3-(dimethylamino)-β-D-wood-own pyrans glycosyl) oxygen]-2 Lactobionates of 1-oxa--6-azacyclo-pentadecane-15 ketone, molecular formula C
38H
72N
2O
122C
12H
22O
12, molecular weight 1465.59, structural formula is as follows:
Azithromycin is to introduce NCH on the 9a position of erythromycin lactone ring
315 yuan of lopps antibiotic that substituent methyl makes are because the change of chemical constitution makes medicine that antibacterial characteristics, pharmaco-kinetic properties and therapeutic effect preferably be arranged: stable to acid, antimicrobial spectrum and erythromycin are close, act on byer force, high bioavailability is arranged, untoward reaction is lacked than erythromycin and light, absorb rapidly, surpass 10～100 times of serum-concentration at infection site tissue and IC, the length of holding time was eliminated the half-life above 40 hours.
The organic acid of disclosed azithromycin of CN1344541A and equivalent or inorganic acid reaction generate water soluble salt, then with this salt processing eye drop, be that " eye of being made up of water soluble Azithromycin salt and medical accessory is with sheet and by water and medical accessory, the special-purpose liquid that antibacterial is formed.During use with eye with the collyrium that obtains clear in the special-purpose liquid of sheet input through jolting, can splash into ophthalmic." preparation way, promptly 2 of " sheet+water " close 1 preparation.Illustrating that this patent fails to solve makes the existing stability problem of solution, can't make a kind of collyrium of long-term stability.In addition, said preparation has tangible eye irritation, and Most patients is difficult to stand, and it is restricted in ophthalmic applications.The combined preparation of " sheet+water " more has the inconvenience in many uses: can cause pollution once more as opening bottle, tablet weight variation and liquid medicine amount size can cause the dose inequality, and user is prepared also voluntarily might bring into eye drop etc. such as foreign body such as dust, fine, soft fur etc.
There are some researches show, all there are unstable factor in azithromycin and acid salt thereof, can cause it to tire as oxidation, hydrolysis etc. reduces and loses antibacterial activity, local toxicity obviously increases as the murder by poisoning to liver, tinnitus, dysacousis are taken place, local irritation increase and anaphylaxis etc. in the increase of vestibular system toxicity.
Be confined to the unstability of azithromycin and the zest of ophthalmic preparation, the domestic market does not have list marketings such as Azithromycin eye-drops, gel for eye use at present, also there are some technical deficiencies just because of the preparation ophthalmic preparation, mainly show on the stability of ophthalmic preparation of azithromycin and acid salt thereof, technical Azithromycin eye-drops and the gel for eye use of can not guaranteeing is stable in the effect duration in 2 years, and that just only does " sheet+water " 2 closes 1 preparation.
Researcheres of the present invention are selected lactobionic acid azithromycin from numerous acid salt of azithromycin, carried out the research of a series of stability and eye irritation, successfully develop lactobionic acid azithromycin eye drop and gel for eye use.
The acid salt of azithromycin comprises phosphate, hydrochlorate, sulfate, citrate, citrate, aspartate, lactate etc., researcheres of the present invention are selected lactobionic acid azithromycin through the experiment contrast, be processed into eye drop and gel for eye use, local application's amount is few, therapeutic effect is good, be to overcome the big optimum selection of oral medication dosage, so initial antibiotic medicine involved in the present invention, only refer to lactobionic acid azithromycin, technological core of the present invention is the stability problem that has solved ophthalmic preparation.
Summary of the invention
The present composition comprises 2 dosage forms, i.e. lactobionic acid azithromycin eye drop and gel for eye use.Its technological core is to have solved stability of formulation, eye irritation and ease of use problem.
The technical scheme that solves lactobionic acid azithromycin eye drop and gel for eye use stability can be divided three aspects; the one, in preparation, add suitable antioxidative stabilizer; as vitamin C, sodium pyrosulfite, sodium sulfite, mannitol, sorbic acid, taurine, propylene glycol, glycerol, boric acid etc.; can be wherein any or appoint several mixture; with sodium sulfite and ascorbic result of use the best, and suitable eye is used.
In addition, when having macromolecular substances to exist in the solution, often can increase stability of formulation, especially all the more so when this macromolecular substances is amphiprotic substance, so can add stabilizing agent such as hydroxypropyl methylcellulose, castor oil hydrogenated, 30 POVIDONE K 30 BP/USP in the present composition
30, β～cyclodextrin, Polyethylene Glycol, hyaluronic acid sodium, chitosan, lactose, lecithin etc., can be wherein any or appoint several mixture, with 30 POVIDONE K 30 BP/USP
30Result of use the best with castor oil hydrogenated.
Prior, be the present invention adopts micro-emulsion technology, killing three birds with one stone solved exist such as poor stability, zest is big and use problem such as inconvenience.
Microemulsion is by spontaneous a kind of transparent or semitransparent low viscous each homogeny and the thermodynamically stable solution system that forms of proper proportion by water, oil phase, surfactant and cosurfactant.The amount of the surfactant that microemulsion is contained is significantly higher than common emulsion; usually also need add cosurfactant; mostly the particle of microemulsion is effective ingredient; particle diameter is even; generally between 10～100nm; usually as if the subparticle that emulsion particle can be made below the 1um; its functional being increased sharply then; even acquisition specific performance; compare with the common emulsion of thermodynamic instability; microemulsion is thermodynamically stable dispersion, and stability is very high, as long as each component ratio is suitable; do not need the external force acting to form; and irrelevant with profit addition sequence mutually, within the specific limits can with the oil phase mixing again can with the water mixing, place for a long time or centrifugal all not stratified.
The oil phase of lactobionic acid azithromycin eye drop is by castor oil hydrogenated, medium chain triglycerides, Transcutol-p (transliteration: full department oil) form by the microemulsion conventional amount used.
Microemulsion technology between the present composition can successful Application, make lactobionic acid azithromycin be prepared into the solution of eyedrop agent or gel becomes possibility, and needn't adopt " sheet+water " again 2 close 1 preparation.
In addition, be in stable and suitable pH scope, can use following three kinds of buffer solution by low consumption: ancient Fei Shi buffer, Shuan Shi buffer and Pasteur's buffer for guaranteeing the present composition.
Regulating its osmotic pressure and tear etc. with sodium chloride or lactose in the lactobionic acid azithromycin eye drop oozes, the other benefit that adopts lactose is to suppress the chemolysis reaction of lactobionic acid azithromycin, and it is moved towards the direction that helps generating lactobionic acid azithromycin.
Usually need in the eye drop to use antibacterial, spendable antibacterial has ethyl hydroxybenzoate, benzalkonium chloride, benzalkonium bromide, chlorobutanol, phenoxyethanol etc. in the present composition, with result of use the best of ethyl hydroxybenzoate.
During the preparation gel for eye use, can adopt card pool nurse, hydroxypropyl methylcellulose etc. to do gel-type vehicle, with result of use the best of card pool nurse 940.
And the size of eye irritation is relevant, especially relevant with oil phase component and consumption with component and consumption collocation in the compositions.Select suitable amounts of components, can reduce stimulation to greatest extent.
So far, the present composition can comprise following component:
1. eye drop contains following component: lactobionic acid azithromycin, sodium sulfite or vitamin C, 30 POVIDONE K 30 BP/USP
30, castor oil hydrogenated, medium chain triglycerides, Transcutol-p, boric acid～Borax, lactose, ethyl hydroxybenzoate.
2. gel for eye use contains following component: lactobionic acid azithromycin, card pool nurse 940, Borax, sodium sulfite, castor oil hydrogenated, medium chain triglycerides, Transcutol-p, boric acid, lactose, ethyl hydroxybenzoate.Conventional use amount of each component such as following table 1
Table 1: each amounts of components table in the compositions
| Component | The lactobionic acid azithromycin eye drop | The lactobionic acid azithromycin gel for eye use |
| Lactobionic acid azithromycin * | 0.59％ | 0.59％ |
| Card pool nurse 940 | - | 0.35％ |
| Sodium sulfite | Or sodium sulfite 1.0% or vitamin C 0.6% | 1.0％ |
| Vitamin C | - | |
| 30 POVIDONE K 30 BP/USP 30 | 0.5％ | - |
| Castor oil hydrogenated | 0.8％ | 1.5％ |
| Medium chain triglycerides | 0.1％ | 0.3％ |
| Transcutol-p | 0.4％ | 0.6％ |
| Boric acid | 1.0％ | 0.1％ |
| Borax | 0.2％ | 1.1％ |
| Lactose | 0.75％ | 0.5％ |
| Ethyl hydroxybenzoate | 0.03％ | 0.03％ |
| Water for injection | Add to 100% | Add to 100% |
*The use amount of lactobionic acid azithromycin counts 0.3% with azithromycin.
The preparation process division of the present composition is as follows:
The preparation process of preparation 1. lactobionic acid azithromycin eye drops
Oil phase: get castor oil hydrogenated, medium chain triglycerides, Transcutol-p three components and mix, it is even to grind melting under the 50-55 ℃ of preference temperature, cools to about 35 ℃, adds lactobionic acid azithromycin, and careful the grinding evenly is standby.
Water: 85-90 ℃ an amount of water for injection dissolving ethyl hydroxybenzoate is cooled to 40-45 ℃, dissolves sodium sulfite or vitamin C, boric acid, Borax, lactose more successively, and complete molten back adds prior dissolved 30 POVIDONE K 30 BP/USP
30Solution, mix homogeneously, it is standby to lower the temperature.
Allotment: stir down oil phase is joined aqueous phase, moisturizing carefully stirs to full dose, and packing promptly.
The preparation process of preparation 2. lactobionic acid azithromycin gel for eye use
Oil phase: get castor oil hydrogenated, medium chain triglycerides, Transcutol-p three components and mix, it is even to grind melting under the 50-55 ℃ of preference temperature, cools to about 35 ℃, adds lactobionic acid azithromycin, and careful the grinding evenly is standby.
Water: 85-90 ℃ an amount of water for injection dissolving ethyl hydroxybenzoate is cooled to 40-45 ℃, dissolves boric acid, lactose and sodium sulfite more successively, and mix homogeneously is standby.
The glue phase: card pool nurse is mixed with 2% solution, and Borax adds wherein after with an amount of water dissolution, stirs into the thickness paste, and is standby.
Allotment: stir down oil phase is joined aqueous phase, the careful stirring forms stable microemulsion liquid, slowly joins Jiao Xiangzhong again, is stirred to the homogeneous glue, and moisturizing continues to stir to full dose, and packing promptly.
The good effect of invention
Compare advantage of the present invention with the lactobionic acid azithromycin dosage form of prior art: 1. medicine stability is good, no matter is eye drop or gel for eye use, and all stable in the effect duration in 2 years, appearance character does not have significant change, stable content.2. eye irritation is little, and imperceptible stimulation when most patients use is used so also be fit to youngster's chapter.3. easy to use, the chance of recontaminate in the minimizing use.The present invention plays the effect of highly significant aspect above three.
The specific embodiment
Embodiment 1: be made up of following component and mass percent, wherein contain: lactobionic acid azithromycin 0.59% (counting 0.3% with azithromycin), sodium sulfite 1.0%, 30 POVIDONE K 30 BP/USP
30Be 0.5%, castor oil hydrogenated 0.8%, medium chain triglycerides 0.1%, Transcutol-p are 0.4%, boric acid 1.0%, Borax 0.2%, lactose 0.75%, ethyl hydroxybenzoate 0.03%, all the other compositions are water.Preparation process is the same.
Embodiment 2: be made up of following component and mass percent, wherein contain: lactobionic acid azithromycin 0.59% (counting 0.3% with azithromycin), vitamin C are 0.6%, 30 POVIDONE K 30 BP/USP
30Be 0.5%, castor oil hydrogenated 0.8%, medium chain triglycerides 0.1%, Transcutol-p are 0.4%, boric acid 1.0%, Borax 0.2%, lactose 0.75%, ethyl hydroxybenzoate 0.03%, all the other compositions are water.Preparation process is the same.
Embodiment 3: be made up of following component and mass percent, wherein contain: lactobionic acid azithromycin 0.59% (counting 0.3%), card pool nurse 0.5%, Borax 1.4% with azithromycin, sodium sulfite 1.0%, castor oil hydrogenated 1.5%, medium chain triglycerides 0.3%, Transcutol-p are 0.6%, boric acid 0.1%, lactose 0.5%, ethyl hydroxybenzoate 0.03%, all the other compositions are water.Preparation process is the same.
Claims (10)
1 one kinds of ophthalmic remedy compositions is characterized in that said composition contains lactobionic acid azithromycin, castor oil hydrogenated, medium chain triglycerides, Transcutol-p.
The ophthalmic remedy compositions of 2 claim 1 is characterized in that said composition also contains at least a following component that is selected from: sodium sulfite or vitamin C, card pool nurse, Borax, boric acid, 30 POVIDONE K 30 BP/USP
30, lactose, ethyl hydroxybenzoate.
The ophthalmic remedy compositions of one of 3 claim 1 to 2 is characterized in that containing lactobionic acid azithromycin in weight/volume percent in the said composition is 0.3～1.0%.
The ophthalmic remedy compositions of one of 4 claim 1 to 2 is characterized in that containing castor oil hydrogenated in weight/volume percent in the said composition is 0.5～2.5%, and medium chain triglycerides is 0.05～0.4%, and Transcutol-p is 0.2～1.0%.
The ophthalmic remedy compositions of one of 5 claim 1 to 2, it is characterized in that in the said composition in weight/volume percent contain sodium sulfite be 0.5～2.5% or vitamin C be 0.3～1.5%.
The ophthalmic remedy compositions of one of 6 claim 1 to 2 is characterized in that containing card pool nurse in weight/volume percent in the said composition is 0.2～1.0%, and Borax is 0.2～1.2%, and boric acid is 0.1～1.0%, 30 POVIDONE K 30 BP/USP
30Be 0.3～1.5%, lactose is 0.4～2.0%, ethyl hydroxybenzoate is 0.02～0.08%.
The ophthalmic remedy compositions of one of 7 claim 1 to 2 is characterized in that containing lactobionic acid azithromycin 0.59% in weight/volume percent in the said composition, sodium sulfite 1.0% or vitamin C 0.6%, 30 POVIDONE K 30 BP/USP
300.5%, castor oil hydrogenated 0.8%, medium chain triglycerides 0.1%, Transcutol-p 0.4%, boric acid 1.0%, Borax 0.2%, lactose 0.75%, ethyl hydroxybenzoate 0.03%, all the other compositions are water.
The ophthalmic remedy compositions of one of 8 claim 1 to 2, it is characterized in that containing lactobionic acid azithromycin 0.59%, card pool nurse 0.35%, Borax 1.1%, sodium sulfite 1.0%, castor oil hydrogenated 1.5%, medium chain triglycerides 0.1%, Transcutol-p 0.4%, boric acid 0.1%, lactose 0.5% in weight/volume percent in the said composition, ethyl hydroxybenzoate 0.03%, all the other compositions are water.
The ophthalmic remedy compositions of one of 9 claim 1 to 8 is characterized in that said composition is eye drop or gel for eye use.
The application of the compositions of 10 claim 1 in preparation treatment ophthalmology illness medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006100466168A CN101077352A (en) | 2006-05-22 | 2006-05-22 | Eye preparation containing lactose-azithromycin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006100466168A CN101077352A (en) | 2006-05-22 | 2006-05-22 | Eye preparation containing lactose-azithromycin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101077352A true CN101077352A (en) | 2007-11-28 |
Family
ID=38905123
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006100466168A Pending CN101077352A (en) | 2006-05-22 | 2006-05-22 | Eye preparation containing lactose-azithromycin |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009142950A1 (en) * | 2008-05-19 | 2009-11-26 | Alcon Research, Ltd. | Pharmaceutical compositions having carboxyvinyl polymer and povidone polymer |
| CN101433519B (en) * | 2008-12-19 | 2013-01-23 | 沈阳药科大学 | Azithromycin eye drops and preparation method thereof |
| CN104402947A (en) * | 2014-11-06 | 2015-03-11 | 哈药集团制药总厂 | Preparation method of aseptic azithromycin lactobionate |
| CN105363071A (en) * | 2015-11-23 | 2016-03-02 | 金仕生物科技（常熟）有限公司 | Anti-calcification treatment method for biological materials |
| CN107296791A (en) * | 2017-07-18 | 2017-10-27 | 沈小玲 | A kind of azithromycin micro emulsion eye drops |
| CN107412246A (en) * | 2017-07-18 | 2017-12-01 | 沈小玲 | A kind of preparation method of azithromycin micro emulsion eye drops |
| CN110354074A (en) * | 2019-08-16 | 2019-10-22 | 合肥华威药业有限公司 | A kind of slow-release moxifloxacin hydrochloride eye-drops preparations and preparation method thereof |
| CN111214437A (en) * | 2018-11-27 | 2020-06-02 | 武汉武药科技有限公司 | Azithromycin microemulsion gel and preparation method and application thereof |
-
2006
- 2006-05-22 CN CNA2006100466168A patent/CN101077352A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009142950A1 (en) * | 2008-05-19 | 2009-11-26 | Alcon Research, Ltd. | Pharmaceutical compositions having carboxyvinyl polymer and povidone polymer |
| CN101433519B (en) * | 2008-12-19 | 2013-01-23 | 沈阳药科大学 | Azithromycin eye drops and preparation method thereof |
| CN104402947A (en) * | 2014-11-06 | 2015-03-11 | 哈药集团制药总厂 | Preparation method of aseptic azithromycin lactobionate |
| CN105363071A (en) * | 2015-11-23 | 2016-03-02 | 金仕生物科技（常熟）有限公司 | Anti-calcification treatment method for biological materials |
| CN107296791A (en) * | 2017-07-18 | 2017-10-27 | 沈小玲 | A kind of azithromycin micro emulsion eye drops |
| CN107412246A (en) * | 2017-07-18 | 2017-12-01 | 沈小玲 | A kind of preparation method of azithromycin micro emulsion eye drops |
| CN111214437A (en) * | 2018-11-27 | 2020-06-02 | 武汉武药科技有限公司 | Azithromycin microemulsion gel and preparation method and application thereof |
| CN110354074A (en) * | 2019-08-16 | 2019-10-22 | 合肥华威药业有限公司 | A kind of slow-release moxifloxacin hydrochloride eye-drops preparations and preparation method thereof |
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Open date: 20071128 |