CN107296791A - A kind of azithromycin micro emulsion eye drops - Google Patents
A kind of azithromycin micro emulsion eye drops Download PDFInfo
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- CN107296791A CN107296791A CN201710584619.5A CN201710584619A CN107296791A CN 107296791 A CN107296791 A CN 107296791A CN 201710584619 A CN201710584619 A CN 201710584619A CN 107296791 A CN107296791 A CN 107296791A
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- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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Abstract
The invention discloses a kind of azithromycin micro emulsion eye drops, it includes following component by raw material gross mass percentages：Azithromycin 0.1~5%, midchain oil 0.1~15%, emulsifying agent 0.5~30%, charge modifier 0.005~3%, adjustment auxiliary agent 0.26~27%, functional aid 0.01~7%, water for injection surplus.The present invention wraps up azithromycin using midchain oil as pharmaceutical carrier, it is scattered in the form of oil phase nano-liquid droplet in aqueous phase solution, and positive charge modification is carried out to oil phase nano-liquid droplet, so as to which micro emulsion eye drops is made, the micro emulsion eye drops is considerably increased to ocular cell permeability of the membrane, improve the stability in room temperature storage, the cost of reduction transport and storage, realize slow release of the azithromycin in eye simultaneously, mitigate the adverse reaction of the larger eye irritation of medicine, with good biocompatibility.The present invention can reduce drug wastage, not affect one's power of vision, and reduce administration number of times, be conducive to determining dosage administration, improve patient and use compliance.
Description
Technical field
The present invention relates to the field of putting drops in one's eyes, more particularly to a kind of azithromycin micro emulsion eye drops.
Background technology
Bacterial conjunctivitis is a kind of most common infection, and widespread is between country variant, race, age and sex
Contagious disease, is easily infected in the crowd City Regions such as kindergarten, school, although with self-healing property, but anti-infective therapy
Disease process can be shortened, prevent from infecting, reduce complication.Gram-positive staphylococcus, streptococcus pneumonia, influenza are bloodthirsty
Bacillus is most common pathogen.
Acute bacterial conjunctivitis is a kind of to be mainly in the extremely strong acute knot by pathogen of bacterium of summer and autumn infectiousness
Film inflammation, is that frequency highest eye part disease is met in daily ophthalmology first visit.Bacterial keratitis, conjunctivitis Chang Zhi ocular tissues are different
The infringement of degree, consequence is serious sometimes, endangers eyesight.The pathogenic bacteria species of bacterial conjunctivitis is a lot, corneal, conjunctival tissue
Degree of injury it is different.Acute bacterial conjunctivitis also belongs to the common ocular infection of children, clinical treatment antibiosis on children therapy
The optional leeway of element is smaller, and conventional selection only TOB is a kind of, although clinically there is multiple anti-infectious preparations, many not recommend to use
In children, wherein American Academy of Pediatrics clearly advises that the application of fluoroquinolones should be restricted.
In addition, trachoma is one of major reason of blinding caused by chlamydia trachomatis, the blind person of China more than 10% is
Caused by suffering from trachoma.And clinical treatment trachoma there is no particularly preferred eye-drops preparations at present.
Eye medicinal solution is instilled in eyes mainly to be absorbed by two approach of cornea and conjunctiva, and medicine is penetrated into first
Enter in cornea, therefore the permeability of medicine corneal is particularly important, for most drug, cornea is typically Medicated Permeation
Main barrier, limits medicine and reaches intraocular target tissue.In addition, the disadvantage of traditional eye-drops preparations is its holdup time
Short, bioavailability is extremely low, has the very effective protection mechanisms such as reflection of shedding tears and blink relevant with eyes, makes to be added dropwise to eye
Interior decoction is rapid to be eliminated from cornea forefoot area.In addition, substantial amounts of medicine enters nasal cavity through nasolacrimal duct or alimentary canal is finally complete
Body absorbs, and adds the risk for inducing side effect and toxicity.Therefore, it can effectively be alleviated using suitable medicine or control disease
The development of feelings, and select rational formulation, then it ensure that the safe and effective of ophthalmic administration and be willing to accept patient, be medicine
Important topic in thing treatment.
Azithromycin is 15 semi-synthetic member cyclic macrolide class antibiotic, i.e. first of nitrogen lactone (Azalides)
Kind.Its mechanism of action is by being combined with ribosomes 50S subunits in bacterial cell, hindering bacterium to turn peptide process, suppress to rely on
Synthesized in the protein of ribonucleic acid (RNA).The characteristics of azithromycin has more has a broad antifungal spectrum than erythromycin, to various grape balls
Bacterium, streptococcus, bacillus, mycoplasma, Chlamydia are sensitive, effective to the conjunctiva infection caused by various pathogens, by generation
Boundary's health organization is included in the emphasis medicine for preventing and treating the ocular infection disease such as trachomatous conjunctivitis.It bites influenza blood bacillus
Action intensity is higher than erythromycin and ROX 4~8 times, and stable to acid, better tolerance, it has also become the one for the treatment of infection at present
Line medicine.There is studies have shown that azithromycin with TOB in the experiment that suppurative bacterium membranous conjunctivitis is treated, total course for the treatment of is total to
Count 6 drops/trouble eye (azithromycin) suitable with 44 drops/trouble eye (TOB) therapeutic effect, illustrate that azithromycin is greatly facilitated
The use of patient, especially to child patient, using more simple and convenient, significantly improves the compliance of patient.It is husky in treatment
In terms of eye, inclusion conjunctivitis, oral medication is recommended compared with WHO, azithromycin eye water topical application advantage is more obvious, convenient,
Safety, easily by the whole body side reaction that oral drug is brought can be prevented effectively from, azithromycin eye water will turn into clinical trachoma treatment
Substitute the more favourable selection of oral drugs.
In April, 2007, U.S. FDA have approved 1% Azithromycin slow-release eye drops (business of InSite Vision companies production
Name of an article AzaSite) listing, for treating bacterial conjunctivitis, using noveltyOphthalmically acceptable medicine-releasing system exploitation, will
The azithromycin for being insoluble in water is prepared as eye drops, reduces administration number of times, increases the eye holdup time, and clinical test shows >=
Children can apply Azithromycin eye-drops within 1 year old, and without obvious toxic side effect.But in 2 III phase clinical researches,
The most common adverse reactions of AzaSite are Ocular irritations, are due to that sustained-release gel formulations reduce administration number of times, increase administration
Dosage, the eye holdup time is longer, and gel viscosity is big and easy microbiological contamination, and medicine and auxiliary material cause larger stimulation to eye, one
Determine to add the pain of patient in degree.When AzaSite extends delay of the medicine in conjunctival sac using cross-linked acrylic acid resin
Between, but be due to that the viscosity of cross-linked acrylic acid resin in itself is larger, mobility is poor, it is difficult to determine dosage administration；And the product chambers
Temperature stability is poor, it is necessary to be placed in refrigerator cold-storage storage.
Eye-drops preparations regular dosage form has eye drops, Eye ointments, gel for eye.Eye drops is instilled after intraocular, due to eye
Eyelid blink and tear secretion, the 0.1% of original concentration can be diluted to, it is necessary to increase administration number of times to improve in several minutes
Therapeutic effect.Eye ointment can provide the longer medicine retention time, but because its dosage is inaccurate, easily cause paste depending on and eyelid flake
Cause patient's poor compliance, and be typically only capable to use before sleeping.Gel is latex glop or semisolid, with preparation letter
It is single, with medicinal part especially mucosal tissue affinity is strong, holdup time length, toxic side effect is small the advantages of, be particularly suitable for it
Carrier as dosing eyes, but equally exist dosage and forbidden, the bad shortcoming of reappearance.
The content of the invention
It is an object of the invention to square in permeability, stability, excitant etc. for above-mentioned eye-drops preparations in the prior art
There is provided a kind of azithromycin micro emulsion eye drops for the deficiency in face.
In the past, the various drug delivery systems of design are attempted to increase absorption of the medicine in eye, are existed so as to improve medicine
The curative effect and bioavilability of eye.The purpose of solution focuses primarily upon the time of contact of extension medicine and eyeball surface, improves
Permeability of the medicine in cornea.CN104055729A discloses a kind of Archimycin gel for eye application, at the same using ion-sensitive and
Thermosensitive in situ gel matrix, with dual gelling characteristic, the preferential deacetylated gellan gum of ion-sensitive gel-type vehicle, temperature sensitivity is solidifying
The preferential poloxamer188 of gel matrix, can reduce loss, overcome the simple stability problem of aging using poloxamer188.
CN102824305A discloses a kind of Azithromycin eye-drops with proper viscosity, using sodium alginate as hydrophilic matrix,
It is in vitro half glue-like preparation under condition of storage.
Eye-drops preparations in above patent is mainly gel for eye use, although can extend the action time of medicine, reduces medication
Number of times, but amplification production difficulty is larger, is not easy to realize commercialization, dosage is difficult to control.Micro emulsion is one kind of nano-emulsion, and it is made
For the nano-dispersed delivery system of pharmaceutical carrier, there is safety non-toxic, while the biological natural cover for defense can be overcome, control
Drug release rate, reduces the adverse reaction of medicine, improves efficacy of drugs and utilization rate, however micro emulsion in eye-drops preparations not yet
There is preferable extensive use.
The technical solution used in the present invention is：A kind of azithromycin micro emulsion eye drops, it presses raw material gross mass percentage
Meter includes following component：
Wherein, the signified Azithromycin Raw Material mass percent of the present invention includes azithromycin being converted to azithromycin
Content.
As the further improvement of such scheme, the particle diameter of oil phase drop is below 50nm in the micro emulsion eye drops, i.e., originally
Invention belongs to O/W formulations.Using micro emulsion dosing eyes can be increased with the dissolubility of insoluble drug such as azithromycin, so as to improve
The drugloading rate of preparation, and medicine improves the stability of medicine while avoiding medicine and biological mucosa due to being wrapped in oil droplet
Directly contact, so as to reduce the excitant that medicine is produced in eye；On the other hand, due to for the relative aqueous solution micro emulsion it is viscous
Degree is increased, while showing tension force reduction, slow release effect and utilization ratio of drug can be improved applied to dosing eyes.
Wherein the species of oil phase plays vital effect in the prescription of microemulsion, and different types of oil phase is to micro emulsion
The physicochemical properties and stability of agent have a great impact.Medium chain triglyceride molecular weight is smaller, have larger water solubility and
The solubility of relatively low pKa value, wherein medium chain triglyceride in water is 100 times of long chain triglycerides.With long-chain glycerine three
Ester is compared, and medium chain triglyceride can improve the solubilising power for medicine.Found according to research, azithromycin is in soybean oil, red
Solubility very little during the long-chain such as caul-fat, castor oil glycerine three is cruel, and have larger solubility in midchain oil.In addition, ophthalmically acceptable
The optimum viscosity scope of preparation should be 2~3cP, so not only can guarantee that higher utilization ratio of drug but also patient can have been made to have preferably
Compliance.As a further improvement on the present invention, described midchain oil is selected from CapteX355, Miglyol 812, Miglyol
At least one of 840.The preferred Miglyol 812 of midchain oil of the present invention.The special of midchain oil of the present invention is improved from further
Its envelop rate to azithromycin.
To make oil phase fully be mixed with aqueous phase, homogeneous system is formed, it is necessary to use emulsifying agent, it is nano-emulsion formation institute
Required material.The main function of emulsifying agent is reduction interfacial tension formation interfacial film, promotes nano-emulsion to be formed.Meanwhile, emulsification
Agent can increase the dissolubility of medicine, it is ensured that the stability of preparation.Nano-emulsion particle diameter is smaller to be accomplished by more energy or need
Emulsifying agent that will be more, needs to overcome emulsion droplet surface tension by higher energy because big particle becomes smaller particle
Or reduce surface tension by increasing emulsifier concentration.Therefore, the determination of emulsifying agent is a most important step for nano-emulsion formula,
The consumption of emulsifying agent is more preferably 1~10% in the present invention.
The species of emulsifying agent is a lot, but not all surface activating agent can be used in preparing nano-emulsion, the selection of emulsifying agent
Depending on the characteristic and application target of the nano-emulsion formed, while the problems such as considering security, economy.Typically, it is newborn
The consumption of agent is bigger, and the nano-emulsion of formation is more stable, but consumption crosses conference and produces excitant and other adverse reactions.So should
The compound emulsifying agent of the small toxicities such as nonionic surface active agent is selected as far as possible.The selection of emulsifying agent must consider its hydrophilic parent
Oily equilibrium valve (HLB value).Research also found that, when preparing O/W type emulsions, the increase of emulsifier hlb value can reduce particle diameter, one
As think that HLB value forms O/W type nano-emulsions when 8~18, be used as the further improvement of such scheme, breast of the present invention
Agent is selected from Tween 80, polysorbas20, span80, egg yolk lecithin, soybean lecithin, poloxamer188, PLURONICS F87, poly-
At least one of oxygen ethylene castor oil, sapn, PEG, polyglycerol stearate, Unigly GO 102S.Further, it is of the invention
It is preferred that Tween 80 is used as emulsifying agent.
Emulsifying agent is used alone in the microemulsion of the present invention easily makes interfacial tension and fluid boundary film unstable, therefore logical
Addition assistant for emulsifying agent reduction surface tension, increase interface membrane fluidity are crossed, makes interfacial film that there is enough bendabilities, assists emulsification
Agent adjusts HLB value, is that stable microemulsion is more readily formed in the eye drip formula of liquid.Middle short chain alcohol can increase into newborn area, but due to
Its toxicity and excitant, which greatly limit, to be used, and for example ethanol is just not suitable as the assistant for emulsifying agent of dosing eyes, and it is removed to eye
It is irritant outer, it is also volatile, it is difficult to maintain the stabilization of interfacial film, easily occur the phenomenons such as demulsification.It is of the present invention to help emulsification
Agent is selected from least one of Emulsifier EL-60, glycerine, propane diols, ethylene glycol.By research screening, find Tween 80 with
After Emulsifier EL-60 compounding use, microemulsion particle diameter can be made smaller and had good stability, therefore the present invention preferably polyoxy second
Alkene castor oil is used as assistant for emulsifying agent.
Because intraocular has physiological electrical potential difference, eyeball front end is positive pole, and it is one small that rear end forms intraocular for negative pole
Electric microfield environment.In addition, compared with neutral or negatively charged particle, positively charged particle can be intended to posterior segment
Retinal surface.And it is furthermore interesting that, the macromolecule (such as chitosan) of positively charged proves reversibly open intercellular tight
Close connection, it is easy to enter retina deep layer.So, the present invention modifies oil phase nano-liquid droplet, the electric charge modification by positive charge
Agent is selected from hyaluronic acid, carboxyl chitosan, sodium carboxymethylcellulose, carbomer, sodium alginate, amphotericin B, polyamine, tristearin
At least one of amine, arginine.Electrostatic force that the present invention is shown in using these cationic substances and eye cornea surface charge etc.
Factor helps lend some impetus to medicine and specifically bound with mucous membrane, so that extend holdup time of the azithromycin in cornea, it is saturating beneficial to its
Barrier is crossed, uptake ratio of the cornea to azithromycin is improved.Wherein chitosan is the derivative of chitin deacetylate.It is certainly
The alkaline polysaccharide of unique lotus positive electricity, can be degraded by the enzyme lysozyme, with nontoxic, good biology in vivo present in right boundary
The series of characteristics such as compatibility, low immunological rejection, bioadhesive and cross-cell membrane transduction potential.Thus, the present invention is excellent
Select carboxyl chitosan as charge modifier, it is wrapped in the nano-liquid droplet table containing azithromycin by electrostatic adsorption
Face, to overturn the electrical of nano-liquid droplet, improves transparency and targeting to each subgrade of the nano-liquid droplet to retina, and then
Improve curative effect of medication.
As the further improvement of such scheme, micro emulsion eye drops of the invention is adjusted as described in raw material gross mass percentages
Agent aid includes following component：
Tackifier 0.01~2%；
Cosolvent and its buffer salt 0.05~5%；
Osmotic pressure regulator 0.1~10%.
Eye-drops preparations has certain viscosity to have preferable effect to improving bioavilability, therefore adds and have in prescription
Prepared by the high molecular crosslink polymer hydroxypropyl methyl cellulose of bioadhesive, increase viscosity and bioadhesive, instills
With the viscous Glycoprotein binding covered before cornea after eye, more extend the medicine eye holdup time, reach the effect of increase curative effect.This
Preferred hydroxypropyl methyl cellulose is invented as tackifier.
Wherein, the cosolvent in cosolvent and its buffer salt of the present invention is organic acid, and selected from lactobionic acid, rich horse
One of which in acid, maleic acid, citric acid, malic acid, L-aminobutanedioic acid, L-aminobutanedioic acid, boric acid, acetic acid, hydrochloric acid, sulfuric acid.Through
Research screening, preferably citric acid-sodium citrate buffer of the present invention is as the cosolvent and its buffer salt in the present invention, to enter one
Step improves envelop rate of the oil phase drop to azithromycin.
Osmotic pressure regulator of the present invention is selected from electrolytes sodium chloride, potassium chloride, sodium dihydrogen phosphate, phosphoric acid hydrogen two
At least one of sodium, boric acid, borax, in addition to non-electrolyte class material glucose, mannitol, sorbierite, glycerine, propane diols
At least one of, screened through research, the present invention preferably mannitol is used as osmotic pressure regulator.
As the further improvement of such scheme, the micro emulsion eye drops of the invention work(as described in raw material gross mass percentages
Energy property auxiliary agent includes following component：
Antioxidant 0.01~5%；
Preservative 0.001~2%.
Wherein, antioxidant of the present invention may be selected from sodium ethylene diamine tetracetate, natrium adetate, vitamin E, vitamin
C, Cys, sodium sulfite, sodium hydrogensulfite, sodium pyrosulfite, sodium thiosulfate, citric acid, Tea Polyphenols, thimerosal,
At least one of propane diols, glycerine, boric acid.That is antioxidant of the invention can be fat soluble antioxidants and water soluble antioxidants,
Wherein fat soluble antioxidants preferred vitamin E, the preferred Cys of water soluble antioxidants or vitamin C.
Preservative of the present invention is selected from benzalkonium chloride, benzalkonium bromide, Metagin, second or propyl ester, sorbic acid, hydroxyl
At least one of methyl benzoate, nipagin A, nipasol, anesin.Screened through research, this
Preferred benzalkonium chloride is invented as preservative.
The beneficial effects of the invention are as follows：
(1) present invention wraps up azithromycin using midchain oil as pharmaceutical carrier, is disperseed in the form of oil phase nano-liquid droplet
Positive charge modification is carried out in aqueous phase solution, and to oil phase nano-liquid droplet, so that micro emulsion eye drops is made, this is considerably increased micro-
Emulsion droplet ocular fluid improves the stability in room temperature storage, reduction transport and the cost stored to ocular cell permeability of the membrane,
Slow release of the azithromycin in eye is realized simultaneously, mitigates the adverse reaction of the larger eye irritation of medicine, with good
Biocompatibility.The present invention can reduce drug wastage, not affect one's power of vision, and reduce administration number of times, be conducive to determining dosage administration, improve
Patient uses compliance.
(2) by Detection of Stability of the present invention, placing and exceeding still transparent shape after June, do not crystallize precipitation, show it
Storge quality does not change, and micro emulsion eye drops is accredited as, than what is reported at present《Azithromycin Submicron Emulsion eye drops is ground
Study carefully》In Submicron Emulsion particle diameter (about 200nm) it is smaller, the present invention have excellent corneal osmosis performance.
Brief description of the drawings
Accompanying drawing 1 is the pattern in kind of the gained azithromycin micro emulsion eye drops of the embodiment of the present invention 1；
Accompanying drawing 2 is the In-vitro release curves of azithromycin micro emulsion eye drops in the present invention；
Accompanying drawing 3 is the particle diameter distributed number figure of azithromycin micro emulsion eye drops in the present invention；
Accompanying drawing 4 is the particle diameter intensity distribution of azithromycin micro emulsion eye drops in the present invention.
Embodiment
The present invention is specifically described with reference to embodiment, in order to art personnel to the present invention
Understand.It is necessary that herein the present invention will be further described it is emphasized that embodiment is only intended to, it is impossible to be interpreted as to this
The limitation of invention protection domain, art person skilled in the art, the non-intrinsically safe made according to foregoing invention content to the present invention
The modifications and adaptations of property, should still fall within protection scope of the present invention.Simultaneously following mentioned raw materials are unspecified, are
Commercially available prod；The processing step or preparation method not referred in detail be processing step known to a person skilled in the art or
Preparation method.
Embodiment 1
A kind of azithromycin micro emulsion eye drops, it includes such as the following group by the gross mass percentages of Azithromycin eye-drops
Point：
Preparation method：
1) after Miglyol 812, Tween 80, Emulsifier EL-60 mixed dissolution, 40~50 DEG C are stirred continuously, and are formed
Solution I；
2) citric acid and sodium citrate of recipe quantity are dissolved with water for injection, water for injection consumption is recipe quantity 50%
(amount for calculating water), then adds azithromycin, Cys, mannitol and BZK, 40~50 DEG C constantly
Stirring, pH to 6.5 is adjusted with pH adjusting agent, forms solution II；
3) solution I is slowly injected and is added dropwise into solution II, while 40~50 DEG C are constantly stirred, is stirred, and is formed
Solution III；
4) carboxyl chitosan is weighed, water for injection (water consumption is total amount 20%) is placed in, after carboxyl chitosan dissolves, plus
Enter solution III, then 0.22 μm of membrane filtration is degerming, form solution IV；
5) 1% hydroxypropyl methylcellulose solution is prepared (first to heat 20ml water, be slowly added into 1g hydroxypropyl methylcelluloses, stir
40min, cooling), after high-temperature sterilization, whole Gonaks (i.e. 20ml) are added toward solution IV, stirring,
And constant volume, packing, the micro emulsion eye drops finished product of embodiment 1 is obtained, its pattern is as shown in Figure 1.
Embodiment 2
A kind of azithromycin micro emulsion eye drops, it includes such as the following group by the gross mass percentages of Azithromycin eye-drops
Point：
Preparation method is identical with the preparation method of embodiment 1, obtains the micro emulsion eye drops finished product of embodiment 2.
Embodiment 3
A kind of azithromycin micro emulsion eye drops, it includes such as the following group by the gross mass percentages of Azithromycin eye-drops
Point：
Preparation method is identical with the preparation method of embodiment 1, obtains the micro emulsion eye drops finished product of embodiment 3.
Embodiment 4
A kind of azithromycin micro emulsion eye drops, it includes such as the following group by the gross mass percentages of Azithromycin eye-drops
Point：
Preparation method：
1) after Miglyol 812, Tween 80, Emulsifier EL-60, vitamin E mixed dissolution, 40~50 DEG C constantly
Stirring, forms solution I；
2) citric acid and sodium citrate water for injection are dissolved, water for injection consumption is that recipe quantity 50% (is calculated
The amount of water), azithromycin, mannitol and BZK are then added, 40~50 DEG C are constantly stirred, pH is adjusted with pH adjusting agent
To 6.5, solution II is formed；
3) solution I is slowly injected and is added dropwise into solution II, while 40~50 DEG C are constantly stirred, is stirred, and is formed
Solution III；
4) carboxyl chitosan is weighed, water for injection (water consumption is total amount 20%) is placed in, after carboxyl chitosan dissolves, plus
Enter solution III, then 0.22 μm of membrane filtration is degerming, form solution IV；
5) 1% hydroxypropyl methylcellulose solution is prepared (first to heat 20ml water, be slowly added into 1g HPMC, stir 40min, cooling
), after high-temperature sterilization, whole hydroxypropyl methylcellulose solution (i.e. 20ml) are added toward solution IV, are stirred, and constant volume, dispense, obtain
The micro emulsion eye drops finished product of embodiment 4.
Embodiment 5
A kind of azithromycin micro emulsion eye drops, it includes such as the following group by the gross mass percentages of Azithromycin eye-drops
Point：
Preparation method is identical with the preparation method of embodiment 1, obtains the micro emulsion eye drops finished product of embodiment 5.
Embodiment 6
A kind of azithromycin micro emulsion eye drops, it includes such as the following group by the gross mass percentages of Azithromycin eye-drops
Point：
Preparation method：
1) after Miglyol 812, Tween 80, Emulsifier EL-60 mixed dissolution, 40~50 DEG C are stirred continuously, and are formed
Solution I；
2) citric acid and sodium citrate water for injection are dissolved, water for injection consumption is that recipe quantity 50% (is calculated
The amount of water), azithromycin, Cys, mannitol and BZK are then added, 40~50 DEG C are constantly stirred, and use pH
Conditioning agent adjusts pH to 6.5, forms solution II；
3) solution I is slowly injected and is added dropwise into solution II, while 40~50 DEG C are constantly stirred, is stirred, and is formed
Solution III；
4) 0.22 μm of membrane filtration of the progress of solution III is degerming, forms solution IV；
5) 1% hydroxypropyl methylcellulose solution is prepared (first to heat 20ml water, be slowly added into 1g hydroxypropyl methyl celluloses, stir
Mix 40min, cooling), after high-temperature sterilization, whole hydroxypropyl methylcellulose solution (i.e. 20ml) are added toward solution IV, stirring, and
Constant volume, packing, obtains the micro emulsion eye drops finished product of embodiment 6.
Embodiment 7
A kind of azithromycin micro emulsion eye drops, it includes such as the following group by the gross mass percentages of Azithromycin eye-drops
Point：
Preparation method is identical with the preparation method of embodiment 1, obtains the micro emulsion eye drops finished product of embodiment 7.
Embodiment 8
A kind of azithromycin micro emulsion eye drops, it includes such as the following group by the gross mass percentages of Azithromycin eye-drops
Point：
Preparation method：
1) after Miglyol 812, Tween 80, Emulsifier EL-60 mixed dissolution, 40~50 DEG C are stirred continuously, and are formed
Solution I；
2) citric acid and sodium citrate water for injection are dissolved, water for injection consumption is that recipe quantity 50% (is calculated
The amount of water), azithromycin, Cys, mannitol and BZK are then added, 40~50 DEG C are constantly stirred, and use pH
Conditioning agent adjusts pH to 6.5, forms solution II；
3) solution I is slowly injected and is added dropwise into solution II, while 40~50 DEG C are constantly stirred, is stirred, and is formed
Solution III；
4) carboxyl chitosan is weighed, water for injection (water consumption is total amount 20%) is placed in, after carboxyl chitosan dissolves, plus
Enter solution III, and constant volume, then 0.22 μm of membrane filtration is degerming, dispense, obtain the micro emulsion eye drops finished product of embodiment 8.
Embodiment 9
A kind of azithromycin micro emulsion eye drops, it includes such as the following group by the gross mass percentages of Azithromycin eye-drops
Point：
Preparation method is identical with the preparation method of embodiment 1, obtains the micro emulsion eye drops finished product of embodiment 9.
Embodiment 10
A kind of azithromycin micro emulsion eye drops, it includes such as the following group by the gross mass percentages of Azithromycin eye-drops
Point：
Preparation method is identical with the preparation method of embodiment 1, obtains the micro emulsion eye drops finished product of embodiment 10.
Embodiment 11
A kind of azithromycin micro emulsion eye drops, it includes such as the following group by the gross mass percentages of Azithromycin eye-drops
Point：
Preparation method is identical with the preparation method of embodiment 1, obtains the micro emulsion eye drops finished product of embodiment 11.
Embodiment 12
A kind of azithromycin micro emulsion eye drops, it includes such as the following group by the gross mass percentages of Azithromycin eye-drops
Point：
Preparation method：
1) after Miglyol 8122, Tween 80, Emulsifier EL-60, glycerine mixed dissolution, 40~50 DEG C are constantly stirred
Mix, form solution I；
2) citric acid and sodium citrate water for injection are dissolved, water for injection consumption is that recipe quantity 50% (is calculated
The amount of water), azithromycin, Cys, mannitol and BZK are then added, 40~50 DEG C are constantly stirred, and use pH
Conditioning agent adjusts pH to 6.5, forms solution II；
3) solution I is slowly injected and is added dropwise into solution II, while 40~50 DEG C are constantly stirred, is stirred, and is formed
Solution III；
4) carboxyl chitosan is weighed, water for injection (water consumption is total amount 20%) is placed in, after carboxyl chitosan dissolves, plus
Enter solution III, then 0.22 μm of membrane filtration is degerming, form solution IV；
5) 1% hydroxypropyl methylcellulose solution is prepared (first to heat 20ml water, be slowly added into 1g hydroxypropyl methylcelluloses, stir
40min, cooling), after high-temperature sterilization, whole hydroxypropyl methylcellulose solution (i.e. 20ml) are added toward solution IV, are stirred, and calmly
Hold, packing obtains the micro emulsion eye drops finished product of embodiment 12.
Embodiment 13
A kind of azithromycin micro emulsion eye drops, it includes such as the following group by the gross mass percentages of Azithromycin eye-drops
Point：
Preparation method：
1) after Miglyol 812, Tween 80, Emulsifier EL-60 mixed dissolution, 40~50 DEG C are stirred continuously, and are formed
Solution I；
2) citric acid and sodium citrate water for injection are dissolved, water for injection consumption is that recipe quantity 50% (is calculated
The amount of water), azithromycin, Cys, mannitol and BZK are then added, 40~50 DEG C are constantly stirred, and use pH
Conditioning agent adjusts pH to 6.5, forms solution II；
3) solution I is slowly injected and is added dropwise into solution II, while 40~50 DEG C are constantly stirred, is stirred, and is formed
Solution III；
4) stearylamine is weighed, water for injection (water consumption is total amount 20%) is placed in, after after stearic amine solvent, adds solution
III, then 0.22 μm of membrane filtration is degerming, forms solution IV；
5) 1% hydroxypropyl methylcellulose solution is prepared (first to heat 20ml water, be slowly added into 1g hydroxypropyl methylcelluloses, stir
40min, cooling), after high-temperature sterilization, whole hydroxypropyl methylcellulose solution (i.e. 20ml) are added toward solution IV, are stirred, and calmly
Hold, packing obtains the micro emulsion eye drops finished product of embodiment 13.
Embodiment 14
A kind of azithromycin micro emulsion eye drops, it includes such as the following group by the gross mass percentages of Azithromycin eye-drops
Point：
Preparation method：
1) Miglyol 812 is stirred continuously at 40~50 DEG C, forms solution I；
2) citric acid and sodium citrate water for injection are dissolved, water for injection consumption is that recipe quantity 50% (is calculated
The amount of water), then azithromycin, Tween 80, Emulsifier EL-60 35, Cys, mannitol and BZK, 40~
50 DEG C are constantly stirred, and pH to 6.5 is adjusted with pH adjusting agent, form solution II；
3) solution I is slowly injected and is added dropwise into solution II, while 40~50 DEG C are constantly stirred, is stirred, and is formed
Solution III；
4) carboxyl chitosan is weighed, water for injection (water consumption is total amount 20%) is placed in, after carboxyl chitosan dissolves, plus
Enter solution III, then 0.22um membrane filtrations are degerming, form solution IV；
5) 1% hydroxypropyl methylcellulose solution is prepared (first to heat 20ml water, be slowly added into 1g hydroxypropyl methylcelluloses, stir
40min, cooling), after high-temperature sterilization, whole hydroxypropyl methylcellulose solution (i.e. 20ml) are added toward solution IV, are stirred, and calmly
Hold, packing obtains the micro emulsion eye drops finished product of embodiment 14.
Embodiment 15
A kind of azithromycin micro emulsion eye drops, it includes such as the following group by the gross mass percentages of Azithromycin eye-drops
Point：
Preparation method：
1) Miglyol 812 is stirred continuously at 40~50 DEG C, forms solution I；
2) citric acid and sodium citrate water for injection are dissolved, water for injection consumption is total consumption 50%, is then added
Azithromycin or its salt, Tween 80, Emulsifier EL-60,40~50 DEG C are constantly stirred, and form solution II；
3) carboxyl chitosan, mannitol and benzalkonium chloride are dissolved with water for injection, water for injection consumption is total consumption
40%, 40~50 DEG C are constantly stirred, and form solution III；
4) solution I is slowly injected and is added dropwise into solution II, while 40~50 DEG C are constantly stirred, is finally slowly added to molten
Liquid III, pH to 6.5 is adjusted with sodium hydroxide pH adjusting agent, degerming by 0.22 μm of filtering with microporous membrane, forms solution IV；
5) 1% hydroxypropyl methylcellulose solution is prepared (first to heat 20ml water, be slowly added into 1g hydroxypropyl methylcelluloses, stir
40min, cooling), after high-temperature sterilization, whole hydroxypropyl methylcellulose solution (i.e. 20ml) are added toward solution IV, are stirred, and calmly
Hold, packing obtains the micro emulsion eye drops finished product of embodiment 15.
Embodiment 16：Performance detection
The gained micro emulsion eye drops finished product of embodiment 1~15 is subjected to every detection respectively, its physical and chemical property determining result is such as
Shown in table 1 below, as shown in Figure 2, particle diameter distributed number is as shown in figure 3, particle diameter intensity distribution such as Fig. 4 institutes for In-vitro release curves
Show.Wherein, its average grain diameter can be obtained for 7.265nm according to the data of table 1, zeta potential is 30.20mV, and content is 99.8%, envelop rate
Up to 70%.And long-term 25 DEG C with accelerating 40 DEG C of stability tests, 6 months every physicochemical properties not have significant changes, all in qualified model
In enclosing.Items detection shows that the micro emulsion eye drops obtained by the present invention has good stability, and does not coalesce, it is adaptable to work
Industry production and transportation.
The gained finished product physical and chemical property determining of 1 embodiment of the present invention of table 1~15
Above-described embodiment is the preferred embodiments of the present invention, all with similar technique of the invention and the equivalence changes made,
The protection category of the present invention all should be belonged to.
Claims (10)
1. a kind of azithromycin micro emulsion eye drops, it is characterised in that：Include following component by raw material gross mass percentages：
2. a kind of azithromycin micro emulsion eye drops according to claim 1, it is characterised in that：Oil phase in the micro emulsion eye drops
The particle diameter of drop is below 50nm.
3. a kind of azithromycin micro emulsion eye drops according to claim 1, it is characterised in that：By raw material gross mass percentage
The meter adjustment auxiliary agent includes following component：
Tackifier 0.01~2%；
Cosolvent and its buffer salt 0.05~5%；
Osmotic pressure regulator 0.1~10%.
4. a kind of azithromycin micro emulsion eye drops according to claim 1, it is characterised in that：By raw material gross mass percentage
Counting the functional aid includes following component：
Antioxidant 0.01~5%；
Preservative 0.001~2%.
5. a kind of azithromycin micro emulsion eye drops according to any one of claim 1, it is characterised in that：Described midchain oil
Selected from least one of CapteX355, Miglyol 812, Miglyol 840.
6. a kind of azithromycin micro emulsion eye drops according to any one of claim 1, it is characterised in that：Described emulsifying agent
Selected from Tween 80, polysorbas20, span80, egg yolk lecithin, soybean lecithin, poloxamer188, PLURONICS F87, polyoxy second
At least one of alkene castor oil, sapn, PEG, polyglycerol stearate, Unigly GO 102S.
7. a kind of azithromycin micro emulsion eye drops according to any one of claim 1, it is characterised in that：Described electric charge is repaiied
Adorn agent be selected from hyaluronic acid, chitosan, sodium carboxymethylcellulose, carbomer, sodium alginate, amphotericin B, polyamine, stearylamine,
At least one of arginine.
8. a kind of azithromycin micro emulsion eye drops according to claim 1, it is characterised in that：Described assistant for emulsifying agent is selected from
At least one of Emulsifier EL-60, glycerine, ethanol, propane diols, ethylene glycol；Described tackifier are selected from PVP, Huang
Virgin rubber, HPMC, sodium alginate, carbomer, poloxamer, Sodium Hyaluronate, methylcellulose, polyvinyl
At least one of alcohol, sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, dextran.
9. a kind of azithromycin micro emulsion eye drops according to claim 3, it is characterised in that：Described cosolvent and its slow
The cosolvent rushed in salt is organic acid.
10. a kind of azithromycin micro emulsion eye drops according to claim 4, it is characterised in that：Described oxidant is selected from
Sodium ethylene diamine tetracetate, natrium adetate, vitamin E, vitamin C, Cys, sodium sulfite, sodium hydrogensulfite, Jiao Ya
At least one of sodium sulphate, sodium thiosulfate, citric acid, Tea Polyphenols, thimerosal, propane diols, glycerine, boric acid.
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| CN201710584619.5A CN107296791A (en) | 2017-07-18 | 2017-07-18 | A kind of azithromycin micro emulsion eye drops |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710584619.5A CN107296791A (en) | 2017-07-18 | 2017-07-18 | A kind of azithromycin micro emulsion eye drops |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022058325A1 (en) * | 2020-09-16 | 2022-03-24 | Santen Sas | Oil-in-water emulsions for intravitreal administration |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1344541A (en) * | 2001-08-04 | 2002-04-17 | 安徽省新药研究院 | Water soluble Azithromycin salt and its eye drop |
| CN101077352A (en) * | 2006-05-22 | 2007-11-28 | 沈阳市兴齐制药有限责任公司 | Eye preparation containing lactose-azithromycin |
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2017
- 2017-07-18 CN CN201710584619.5A patent/CN107296791A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1344541A (en) * | 2001-08-04 | 2002-04-17 | 安徽省新药研究院 | Water soluble Azithromycin salt and its eye drop |
| CN101077352A (en) * | 2006-05-22 | 2007-11-28 | 沈阳市兴齐制药有限责任公司 | Eye preparation containing lactose-azithromycin |
Non-Patent Citations (1)
| Title |
|---|
| 刘妍: "阿奇霉素亚微乳滴眼液的研究", 《中国优秀硕士论文全文数据库 医药卫生科技辑》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022058325A1 (en) * | 2020-09-16 | 2022-03-24 | Santen Sas | Oil-in-water emulsions for intravitreal administration |
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Application publication date: 20171027 |