CN100408046C - Macrolide antibiotics sodium hyaluronate eye transfer system - Google Patents
Macrolide antibiotics sodium hyaluronate eye transfer system Download PDFInfo
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- CN100408046C CN100408046C CNB2005101319829A CN200510131982A CN100408046C CN 100408046 C CN100408046 C CN 100408046C CN B2005101319829 A CNB2005101319829 A CN B2005101319829A CN 200510131982 A CN200510131982 A CN 200510131982A CN 100408046 C CN100408046 C CN 100408046C
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- Prior art keywords
- eye
- azithromycin
- amount
- sodium
- antibiotics
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- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 title claims abstract description 18
- 239000003120 macrolide antibiotic agent Substances 0.000 title abstract description 9
- 229920002385 Sodium hyaluronate Polymers 0.000 title abstract description 3
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- 238000012546 transfer Methods 0.000 title description 3
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- 230000000284 resting effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 231100000886 tinnitus Toxicity 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 210000004127 vitreous body Anatomy 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to an ocular transmission system for macrolide antibiotic sodium hyaluronate. The present invention aims to provide macrolide antibiotic ocular medicinal preparation which takes hyaluronic acid or salt thereof as carriers and is used for curing bacillary ocular infection. Macrolide antibiotics in the present invention comprise all antibiotics which have 14 element, 15 element or 16 element macrocyclic structural characteristics, such as natural antibiotics generated by streptomycete, erythromycin, josamycin, spiramycin, medicamycin, etc., and comprise semi-synthetic derivatives which structurally modify natural antibiotics, such as roxithromycin, azithromycin, clarithromycin, rokitamycin, telithromycin, etc.
Description
Technical field
The present invention is for being the macrolide antibiotics eye transfer system of carrier with glass acid and salt thereof.
Technical background
(Macrolide Antibiotics, the English abbreviation: MA) be a class alkalescence antibiotic that is produced by streptomycete, its architectural feature is 14, the 15 or ten hexa-atomic macro ring that contain a lactone structure in the molecule to macrolide antibiotics.
MA is widely used clinically, mainly acts on sensitive organism ribosome 50S subunit, and it is synthetic to suppress RNA, and hinder antibacterial and change the peptide process, thereby suppress the synthetic of bacterioprotein, be antibacterial resting stage.Because it has better anti-bacterial effect, and is widely used in the treatment of clinical each section's infectious disease, is clinical practice one of antibacterials the most widely.It is first on behalf of natural kind, as erythromycin, josamycin, midecamycin, spiramycin etc.; Second on behalf of semi-synthetic, as Roxithromycin, azithromycin, clarithromycin etc.; The third generation is a MA subclass of new generation, as Ketek etc.This class medicine main adverse reaction is the reaction of digestive system, abdominal discomfort, feel sick, vomiting etc., the visible abnormal liver function of idol, drug eruption, tinnitus, dysacousis allergy etc.
Eyes are the windows in the human perception world, are again simultaneously extremely responsive organs.The normal conjunctiva capsule has multiple microorganism to live away from home, but not pathogenic, and when part or whole body defense function are low under specific circumstances, the dysbacteriosis, the surperficial defensive barrier of eye that cause conjunctival sac are impaired, and ocular injury or operation wound then constitute pathogenic condition.Microorganisms such as antibacterial, fungus, virus can directly attack eye or by blood, close on organ and spread and enter ocular infection.Generally speaking, MA is a broad-spectrum antibiotic, and is all effective to multiple gram positive bacteria and negative bacterium, mycoplasma, chlamydia, fine and close spirillum and rickettsia.Therefore, MA can be used for treating bacillary ocular infection.Although after the administration of MA whole body, can be distributed in widely in the tissue and (comprise part tissue of eye),, want to reach minimum inhibitory concentration (MIC) in ocular tissue, must increase MA dosage.So will certainly cause very big waste, but also can cause in each tissue of whole body higher blood drug level being arranged all, thereby cause side effect, burden of liver heavily to wait adverse consequences.Simultaneously, n of high dose oral MA may disturb normal flora in the intestinal.Therefore, MA is directly applied to eye, can avoid the side effect that brings by the whole body administration, can also avoid producing the drug resistance flora.
Eye topical treatment ocular disease, though the advantage strong targetedly, that the whole body toxic and side effects is little, the dilution and the souring of and tear little because of the volume in the conjunctival sac make the medicine amount retained little, lack action time, thereby limited the performance of drug effect.At this shortcoming, once the synthetic high polymer stickum was added into the viscosity that improves medicinal liquid in the eye drop as thickening agent, to reach was prolonged medicinal liquid time of staying in conjunctival sac, improved the purpose of drug effect.Is the viscosity that thickening agent increases the dipivefrine hydrochloride eye drop with HPMC, combines with the sticking glycoprotein that covers before the cornea behind the eye drip, prolong drug and eye time of contact delay the release of medicine, reach the effect of slow release.The document Wang Li that sees reference eats, opens strong. the research of dipivefrine hydrochloride gel for eye. and Chinese Journal of New Drugs .2002,11 (4): 300-303. also has the report of high molecular polymers such as many employing carbomer classes and poloxamer class as the ophthalmic administration carrier abroad, the characteristics of utilizing their solution to take place to change mutually, form gel at body, thereby improve bioavailability of medicament.Document Hong-Ru Lin sees reference, K.C.Sung.Carbopol/Pluronic phase change solutions for ophthalmic drugdelivery.Journal of Controlled Release.2000,69:379-388. research structure in recent years shows: adopting natural mucopolysaccharide hyaluronic acid sodium is carrier, and the effect that is played makes the synthetic high polymer cohesive material incomparable.
Glass acid (hyaluronic acid, hyaluronan, the English HA that is called for short, its sodium salt is called for short SH), have another name called hyaluronic acid, its structure system is with β-1, the mucopolysaccharide that the bonded disaccharidase repetitive of 4 glucuronic acids and β-1,3 acetylglucosamine is constituted, mean molecule quantity is about 5.0 * 10
4～8.0 * 10
6, its structural formula is as follows:
Glass acid extensively is present in the connective tissue of people and animal, is found in vitreum and name therefrom in 1934 by Meyer and Palmer the earliest.Document Meyer K.Palmer JW.Thepolysaccharide of the vitreous humor.J Biol Chem.1934 sees reference, 107:629-634. glass acid has water conservation, physiological action such as lubricated, because of viscoelasticity, false plasticity, permeability and the excellent biological compatibility of its height, therefore in ophthalmology, have a wide range of applications again.
SH is applied to clinically first as ophthalmology viscoelasticity protective agent in the seventies in 20th century, becomes one of ophthalmologic major progress.Along with deepening continuously of research, its application has clinically expanded to capsule and has reached kind operation surplus extraction of cataract, keratoplasty, trabeculectomy for glaucoma art, cornea reatlachment and the traumatic ocular operation etc. 20 in the capsule outward.HA solution can be used for treating xerophthalmia, and 0.1%HA solution can obviously prolong the time of tear film rupture.Because HA has significant hydrophilic ability and lubrication, therefore, can obviously alleviate xerophthalmia pain, itch, clinical symptoms such as burn feeling, foreign body sensation.Remove this, HA also is considered to the best carrier of present ophthalmic preparation (media), both can increase bioavailability of medicament, also can alleviate the stimulation of medicine to eye, promotes the healing of eye wound, alleviates the ophthalmic uncomfortable symptom rapidly.HA solution has the characteristic and the excellent biological compatibility of non-Newtonian fluid, and viscosity reduces with the increase of shearforce, has overcome the shortcoming that eyelid is difficult for blinking.See reference that the document beam is red, Ling Peixue, He Yanli, Zhang Tianmin, the applied research progress that contains the hyaluronic acid sodium preparation. Chinese clinical medicine, 2003:4 (6) 46-48. is along with research gos deep into, finder and animal corneal epithelial cell show that face exists glass acid binding site, with glass acid is after the eye drop of carrier enters ophthalmic, combination by glass acid and binding site makes medicinal liquid be stranded in the corneal epithelium surface for a long time.Document Annick Ludwig The use of mucoadhesive polymers in ocular drug delicery.Advanced Drug Delivery Reviews.2005 sees reference, 57:1595-1639. the Runshu eye drops that has gone on the market (Chloramphenicol Eye Drop that contains HA) through clinical observation on the therapeutic effect, finds that it has better therapeutic effect to multiple eye surface diseases.Reference literature Sun Hong minister, Huang Jiangang, yellow red dark etc., the clinical efficacy of Runshu eye drops treatment eye surface diseases. the journal .1994 of Dalian Medical College, 16 (4): 260-262.
At present, the MA preparation that is used for eye has only erythromycin eye ointment.Though but the eye ointment long period rests in the conjunctival sac,, can make blurred vision, thereby be only limited to use in bed, bring inconvenience to the patient because of it is semi-solid.Insite Vision company has applied for relevant azacyclo-lactone antibiotic, is mainly azithromycin, the patent of eyes topical.See U.S. Pat 6269443, Dawson, Chandler has used two kinds of high molecular polymers to be carrier: HPMC and Noveon AA-1 (Ka Bofeier class) in this patent of R.Topicaltreatment or prevention of ocular infections..Domestic also relevant for the patent of azithromycin gel for eye use, the patent middle finger goes out to use at least a high molecular weight water soluble polymer, as carbopol, cellulose derivative, polyvinyl alcohol etc.See Chinese patent CN14100071A; yet Wu Wenyao, Wang Ling. the azithromycin gel for eye use.; synthesising macromolecule copolymer lacks biocompatibility and has the characteristic of Newtonian fluid; to be viscosity improve with the increase of concentration but be not subjected to the influence of shearforce; reach certain degree and work as viscosity; can make eyelid be difficult for blinking and high concentration regular meeting produces the ocular tissue of sensitivity and stimulates, eye can not be tolerated.In addition, the potentiation that produces with synthetic high polymer is limitation very also, and when medicinal liquid reaches certain viscosity, even increasing high molecular concentration, drug effect can not strengthen yet.Above effects limit the application of MA class medicine in ophthalmology.
The present invention finds that unexpectedly MA class medicine and HA or its pharmaceutical salts combined formulation can overcome above defective, have proposed the present invention for this reason.
Summary of the invention:
The objective of the invention is to, providing a kind of is the eye medicinal preparation of the macrolide antibiotics of carrier with glass acid or its salt, is used for the treatment of bacillary ocular infection.It is strong that said preparation has effect, and zest is little, simultaneously eye had extremely strong moistening and lubrication, and have the advantage of slow release.
Related MA comprises the antibiotic that all has 14 yuan, 15 yuan or 16 yuan macrocyclic structure features among the present invention, as: by the natural antibiotics of streptomycete generation, as erythromycin, josamycin, spiramycin, midecamycin etc., and natural antibiotics carried out structural modification and semisynthetic derivant, as Roxithromycin, azithromycin, clarithromycin, rokitamycin, Ketek etc.Preferably erythromycin, azithromycin, Roxithromycin, clarithromycin, Ketek etc., more preferably azithromycin, clarithromycin, Ketek etc.
Related glass acid and salt thereof comprise the various salt of glass acid and glass acid among the present invention, comprise sodium salt, potassium salt, calcium salt, zinc salt, magnesium salt and ammonium salt; Glass acid and salt thereof the concentration range in preparation of the present invention is 0.01～1000mg/100ml.Preferably 0.1～100mg/100ml, more preferably 0.5～50mg/100ml.
Related eye medicinal preparation among the present invention also can add other auxiliary elements as required, as osmotic pressure regulator, antibacterial, thickening agent, pH regulator agent etc.Osmotic pressure regulator is electrolyteses such as sodium chloride commonly used, sodium hydrogen phosphate, Borax, boric acid, and non-electrolyte classes such as glycerol, glucose.The antibacterial of antibacterial for using in the ophthalmic preparation commonly used comprises: (1) organic mercury class, as phenylmercuric nitrate, thimerosal etc.; (2) quaternary ammonium salt is as benzalkonium chloride, benzalkonium bromide, hibitane etc.; (3) alcohols is as chlorobutanol, phenethanol etc.; (4) esters is as Metagin, second, third, butyl ester etc.; (5) acids is as sorbic acid etc.Thickening agent is the macromolecule stickum, as the cellulose derivative class, and polyvinyl alcohol, polyvidone etc.The PH regulator be sodium hydrogen phosphate-sodium dihydrogen phosphate buffering to, boric acid-Borax buffering to, Borax-disodiumedetate buffering to and acid and alkali substances such as hydrochloric acid, sodium hydroxide or carbonate.
The preparation method of eye medicinal preparation of the present invention can adopt conventional eye medicinal technology of preparing preparation.Particularly use the technology of preparing of ophthalmic solution formulations, as: glass acid or its sodium salt are dissolved in the water for injection.Get the material of appropriate hydrochloric acid dissolving erythromycin series,, regulate pH to 6.0～7.0,, stir to wherein adding antiseptic or isotonic agent as azithromycin.Two kinds of solution are mixed, add the injection water, stir to 100ml.With the sterilization of 0.25um membrane filtration, packing, promptly.
The present invention preferably fills a prescription to form and is listed in the embodiment of the invention.
Following data declaration beneficial effect of the present invention by experiment:
Purpose: the Azithromycin eye-drops of the investigating embodiment 1 preparation delay situation in the lagophthalmos of being in.
Material and method:
1, material
1) medicine: (1) sees embodiment 1
(2) contain the Azithromycin eye-drops (seeing prescription) of HPMC
Prescription:
Azithromycin 1g
HPMC(K100M) 1g
Hydrochloric acid is an amount of
Sodium chloride is an amount of
Benzalkonium chloride 0.005g
Sodium hydroxide is an amount of
Water for injection adds to 100ml
2) animal: New Zealand white rabbit, healthy no ophthalmic, 2.0～3.0Kg, male and female dual-purpose.
2, method
1) administration: drip above-mentioned three kinds of eye drop 50ul respectively in rabbit right and left eyes conjunctival sac, the rabbit eyelid is pulled into cup-shaped, push down nasolacrimal duct simultaneously, medicine is dripped in the middle part in palpebra inferior then.After dripping medicine, press eyes to make its closure, push down nasolacrimal duct simultaneously, unclamp behind the 1min and let alone from overflowing with have gentle hands.Take a sample in 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2.0h behind the eye drip.
2) sampling: during sampling, accurately draw the tear of constant weight, record tear weight with filter paper.
3) sample treatment: after treating that the filter paper bar volatilizes, be placed in the 1.5ml centrifuge tube, to wherein adding 0.2ml mobile phase, behind the vortex 2.5min, centrifugal 10min under the 100000rpm condition gets supernatant 20ul sample introduction.
4) chromatographic condition:
Chromatographic column: the C18 analytical column (150mm * 4.6mm, 5um)
Mobile phase: acetonitrile-isopropyl alcohol-0.002mol/L dipotassium hydrogen phosphate 60: 15: 25
Flow velocity: 1.0ml/min
Detect wavelength: 210nm
Sample size: 20ul
Column temperature: 30 ℃
Sensitivity: 0.005AUFS
3, result and discussion
1) result
Table 1 is for containing azithromycin concentration in each time tear of HPMC Azithromycin eye-drops; Table 2 is an azithromycin concentration in each time tear of Azithromycin eye-drops of embodiment 1 preparation; Fig. 1 be in two kinds of eye drop rabbit tears concentration through the time change.
Table 1, contain azithromycin concentration in each time tear of HPMC Azithromycin eye-drops
Azithromycin concentration in each time tear of Azithromycin eye-drops of table 2, embodiment 1 preparation
2) discuss
After the ordinary eye drops administration, big in 5 minutes 90% drug wastage.Therefore, bioavailability of medicament is very low.From experimental result, we as can be seen: after in eye drop, adding HPMC, can make medicine holdup time in eye extend to 3 hours, and concentration still is higher than MIC.Illustrate that HPMC has certain effect to prolonging the holdup time of eye drop in eye.But by contrast, SH more has superiority than HPMC.We can visually see from Fig. 1: at each time point, contain the concentration of SH Azithromycin eye-drops in tear and be higher than all the time and contain the concentration of HPMC Azithromycin eye-drops in tear.Simultaneously, SH solution has the characteristic of the not available non-Newtonian fluid of synthesising macromolecule copolymer solution, does not blink even SH concentration also can not influence eyelid up to 1%.Therefore we think that the various salt with glass acid and glass acid thereof are carrier, can improve the bioavailability of MA ophthalmic administration, have the good patient compliance simultaneously.
The present invention finds through experiment, preparation of the present invention, and effects such as lubrication, antiinflammatory and short reparation that part tissue of eye is preserved moisture reduce the eye local excitation, increase patient's comfort; Medicinal liquid is long in the eye holdup time simultaneously, can bring into play drug effect fully enduringly.
Description of drawings:
Fig. 1, contain in the eye drop rabbit tear of HPMC (1%) and SH (1%) concentration through the time change
The specific embodiment:
Be the embodiment of this patent below, but following embodiment does not limit the interest field of this patent.
Embodiment 1
Prescription: (in the 100ml eye drop)
Azithromycin 1g
Hyaluronic acid sodium (SH) 1g
Hydrochloric acid is an amount of
Sodium chloride is an amount of
Benzalkonium chloride 0.005g
Sodium hydroxide is an amount of
Water for injection adds to 100ml
Technology: the 1g hyaluronic acid sodium is dissolved in about 40ml water for injection in advance.Get appropriate hydrochloric acid dissolving azithromycin,,, stir to wherein adding benzalkonium chloride, sodium chloride with using sodium hydroxide to regulate pH to 6.0～7.0.Two kinds of solution are mixed, add the injection water, stir to 100ml.With the sterilization of 0.25um membrane filtration, packing, promptly.
Embodiment 2
Prescription: (in the 100ml eye drop)
Clarithromycin 1g
Hyaluronic acid sodium (SH) 1g
Hydrochloric acid is an amount of
Sodium chloride is an amount of
Benzalkonium chloride 0.005g
Sodium hydroxide is an amount of
Water for injection adds to 100ml
Technology: the 1g hyaluronic acid sodium is dissolved in about 40ml water for injection in advance.Get appropriate hydrochloric acid dissolving clarithromycin,,, stir to wherein adding benzalkonium chloride, sodium chloride with using sodium hydroxide to regulate pH to 6.0～7.0.Two kinds of solution are mixed, add the injection water, stir to 100ml.With the sterilization of 0.25um membrane filtration, packing, promptly.
Embodiment 3
Prescription: (in the 100ml eye drop)
Erythromycin 1g
Hyaluronic acid sodium (SH) 1g
Hydrochloric acid is an amount of
Sodium chloride is an amount of
Benzalkonium chloride 0.005g
Sodium hydroxide is an amount of
Water for injection adds to 100ml
Technology: the 1g hyaluronic acid sodium is dissolved in about 40ml water for injection in advance.Get appropriate hydrochloric acid dissolving erythromycin,,, stir to wherein adding benzalkonium chloride, sodium chloride with using sodium hydroxide to regulate pH to 6.0～7.0.Two kinds of solution are mixed, add the injection water, stir to 100ml.With the sterilization of 0.25um membrane filtration, packing, promptly.
Embodiment 4
Prescription: (in the 100ml eye drop)
Azithromycin 2g
Hyaluronic acid sodium (SH) 0.5g
Hydrochloric acid is an amount of
Sodium chloride is an amount of
Benzalkonium chloride 0.005g
Sodium hydroxide is an amount of
Water for injection adds to 100ml
Preparation technology is with embodiment 1
Embodiment 5
Prescription: (in the 100ml eye drop)
Azithromycin 1g
Hyaluronic acid sodium (SH) 0.1g
Hydrochloric acid is an amount of
Sodium chloride is an amount of
Benzalkonium chloride 0.005g
Sodium hydroxide is an amount of
Water for injection adds to 100ml
Preparation technology is with embodiment 1
Embodiment 6
Prescription: (in the 100ml eye drop)
Erythromycin 1g
Hyaluronic acid sodium (SH) 0.1g
Hydrochloric acid is an amount of
Sodium chloride is an amount of
Benzalkonium chloride 0.005g
Sodium hydroxide is an amount of
Water for injection adds to 100ml
Preparation technology is with embodiment 1
Embodiment 7
Prescription: (in the 100ml eye drop)
Roxithromycin 1g
Hyaluronic acid sodium (SH) 0.1g
Hydrochloric acid is an amount of
Sodium chloride is an amount of
Benzalkonium chloride 0.005g
Sodium hydroxide is an amount of
Water for injection adds to 100ml
Preparation technology is with embodiment 1
Embodiment 8
Prescription: (in the 100ml eye drop)
Erythromycin 1g
Hyaluronic acid sodium (SH) 0.5g
Hydrochloric acid is an amount of
Sodium chloride is an amount of
Benzalkonium chloride 0.005g
Sodium hydroxide is an amount of
Water for injection adds to 100ml
Preparation technology is with embodiment 1
Embodiment 9
Prescription: (in the 100ml eye drop)
Azithromycin 0.5g
Hyaluronic acid sodium (SH) 0.1g
Hydrochloric acid is an amount of
Sodium chloride is an amount of
Benzalkonium chloride 0.005g
Sodium hydroxide is an amount of
Water for injection adds to 100ml
Preparation technology is with embodiment 1.
Claims (1)
1. an eye medicinal preparation is characterized in that, contains glass acid or its salt and azithromycin, and it consists of:
Azithromycin 1g
Hyaluronic acid sodium 1g
Hydrochloric acid is an amount of
Sodium chloride is an amount of
Benzalkonium chloride 0.005g
Sodium hydroxide is an amount of
Water for injection adds to 100ml.
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| CN112791050B (en) * | 2019-11-13 | 2022-11-18 | 湖北远大天天明制药有限公司 | Azithromycin eye drops |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1410071A (en) * | 2002-11-28 | 2003-04-16 | 吴文耀 | Archimycin gel for eye application |
| CN1514735A (en) * | 2001-06-08 | 2004-07-21 | 诺瓦提斯公司 | Ophthalmic composition comprising hyaluronic acid |
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| CN1514735A (en) * | 2001-06-08 | 2004-07-21 | 诺瓦提斯公司 | Ophthalmic composition comprising hyaluronic acid |
| CN1410071A (en) * | 2002-11-28 | 2003-04-16 | 吴文耀 | Archimycin gel for eye application |
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