CN110090294A - Ophthalmic composition with improved dry-run protection and reservation - Google Patents
Ophthalmic composition with improved dry-run protection and reservation Download PDFInfo
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Abstract
The present invention provides the ophthalmic composition with improved dry-run protection and reservation, belongs to field of pharmaceutical preparations, includes cyclosporin；Nano-micelle situ-gel；Hyaluronic acid or its pharmaceutically acceptable salt；The composition is liquid form in room temperature or low temperature, is hydrosol form in 35 DEG C of temperatures above, and still keep complete under the shear stress caused by being blinked by patient's eyelid.Preparation method includes providing the first solute and the second solute；And mix solute under conditions of using water as matrix, form the composition comprising gel dispersion.Composition bioavilability provided by the invention is high, will not cause eye-blurred, can improve patient compliance and/or reduce side effect, promotes ocular health, small to ocular pain and stimulation, has both antibacterial anti-corrosion；Preparation method can increase adhesiveness, promote gelation temperature, extend delay and effective acting time, improve Yield of Mitoxantrone, avoid autohemagglutination phenomenon, the effect of enhancing anti-oxidation protection and stability.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to the ophthalmic composition with improved dry-run protection and reservation.
Background technique
Mammiferous eyes, such as people and the eyes of other mammalitys (animal) provide preferably by sufficient lubrication for eyes
Comfortably, while more effectively provide, clearly eyesight.In general, this lubrication is natively obtained from tear film, tear film shape
On the exposed ocular of the outer layer in eye, which is usually to be answered by what lachrymal gland, Meibomian gland and other bodies of gland persistently supplemented
Collaborate body, complete Shi Kewei ocular provides required aquation and nutriment.In addition to covering fine ocular and to it
Outside being protected, tear film/Air Interface is alternatively arranged as the initial dioptric surface of eye.But in many cases, the tear film
It measures and inadequate, therefore just produces the illness of referred to as " dry eyes ".
Xerophthalmia, also known as angle xerosis of conjunctiva refer to that tear matter caused by any reason or amount exception or dynamics are abnormal, lead
Tear film stability decline is caused, with ophthalmic uncomfortable and/or the general name of a variety of diseases of ocular lesion tissue feature.In general, dry eyes
Disease is to cause tear can not holding eye appropriate since ocular tear secretory volume is insufficient, is unevenly distributed or tear excessive evaporation
Ball surface wet and caused by, common symptom is that eye is dry and astringent and foreign body sensation, other symptoms have burn feeling, gargalesthesia, photophobia,
Erythralgia, blurred vision, fatiguability, haircuts shape secretion etc..Xerophthalmia is the common ophthalmological disorder for influencing millions of people.With dry
The patient of eye disease can undergo the feeling and lasting stimulation of burn feeling, drying.In serious case, xerophthalmia can be seriously
Interfere the vision of patient.In addition, lachrymal gland in eye can produce less tears as people is ageing, eye is caused to become dry, hair
It is scorching, itch and have a sand sample sense, old man and 70~80% menopause after women since xerophthalmia is by ophthalmic uncomfortable.Although
Seem that xerophthalmia may be to cause to expose since a variety of incoherent causes of disease, the performance of all patient's condition have identical feature
Eye surface dehydration and the rupture of precorneal tear film outside.
For xerophthalmia there are the methods of many alleviations and treatment, a kind of common method is the artificial tears of whole day use instillation
Supplement eye tear film, the example of tear substitution approach includes using buffering, normal isotonic saline solution and molten comprising making
Liquid is more viscous and the aqueous solution of water-soluble polymer that therefore the more difficult cleaning action by tear flows out.It is serious dry
Eyeball must also be covered sometimes in addition to above method or impose tarsorrhaphy and cause it to avoid eyeball is over-drying by eye disease
Injury.Relatively large number of artificial tears compositions have been proposed to be used in treatment and processing dry eye syndrome, for example, artificial tears are
Function containing simulation natural tears or the substance with the Chemical composition that with natural tears identity function, and containing specific
The substance of the composition of lubricant (such as carboxymethyl cellulose).Since this artificial tears can lose from eyes quickly, it
Usually require fairly frequently use, although their wettable eyes, lubrication eyes value be lacking.
Summary of the invention
It to be hydrosol form in 35 DEG C of temperatures above that the purpose of the present invention is to provide one kind, and bioavilability is high, and
Will not cause eye-blurred, the compliance of patient can be improved and/or reduce side effect, promote ocular health, to ocular pain and
Stimulation is small, has both the ophthalmic composition with improved dry-run protection and reservation of antibacterial antiseptic property.
The object of the invention is also to provide a kind of increase adhesiveness, gelation temperature is promoted, extends residence time and effectively
Action time improves Yield of Mitoxantrone, promotes infiltration and promotees absorption, avoids autohemagglutination phenomenon, the effect of enhancing anti-oxidation protection and
Stability can be relieved the preparation method of the ophthalmic composition with improved dry-run protection and reservation of calcination stimulation.
The technical solution that the present invention is taken to achieve the above object are as follows:
Ophthalmic composition with improved dry-run protection and reservation includes:
A, cyclosporin, concentration are 0.05~1.15w/v%；
B, nano-micelle situ-gel, concentration are 0.5~5.0w/v%；
C, hyaluronic acid or its pharmaceutically acceptable salt, concentration are 0.1~3.0w/v%；The present composition is normal
It is liquid form when temperature or low temperature, is hydrosol form in 35 DEG C of temperatures above, and is cut caused by being blinked by patient's eyelid
Under shearing stress, composition keeps complete.The composition illustrates the effect with dry-run protection and ocular reservation, is conducive to alleviate
Scheroma and/or the rehabilitation from eye surgery, it is conventional to use the composition or the delivery vehicle as ophthalmically acceptable therapeutic agent, it can
Long-term lubricating action and low frequency administration mode are obtained, improves bioavilability, and eye-blurred will not be caused,
The compliance of patient can be improved after application and/or reduce side effect.
It also include a effective amount of tonicity component in composition of the invention, concentration is so that the composition has 260
The Osmolality of~630mOsmol/kg.Tonicity component is formed selected from least one of salt, sugar, sugar alcohol, glycol.
It preferably, include sugar alcohol in tonicity component, such as D-sorbite, mannitol or xylitol, the presence of sugar alcohol can assist to remove
Protein deposit.The tear film that is generally characterized by of scheroma cellular level is chronically at hypertonic environment, by isotonic or super infiltration group
Conjunction object adds to ocular and can be relieved symptom, this is because being combined with tensioned substances and gel in composition plays stimulation or maintenance
Effective protection substance takes in the effect intracellular to superficial keratectomy, so that composition lubricating action enhances, promotes ocular health.
It also include the Congestant that concentration is 0.01~0.5w/v% in composition of the invention.Congestant include but
It is not limited to the ophthalmically acceptable acceptable salt (such as tetrahydrozoline hydrochloride) of tetrahydrozoline, ephedrine, phenylephrine and above-mentioned substance.It is anti-
Congested agent is mainly to alleviate intraocular hyperemia.
Another aspect of the present invention provides the preparation method of above-mentioned ophthalmic composition, including,
A provides the first solute, and solute includes the nano-micelle situ-gel for carrying cyclosporin, wherein carrying cyclosporin
The average grain diameter of nano-micelle is 10~50nm；
B provides the second solute；
C mixes the first solute with the second solute under conditions of using water as matrix, to be formed comprising gel dispersion
Composition；Above-mentioned composition is liquid form in room temperature or low temperature, is hydrosol form in 35 DEG C of temperatures above.The combination
The preparation method of object utilizes nano-micelle system, improves the film transporting mechanism of drug and the permeability of biomembrane, improves drug
Stability, drug solubility and targeting increase drug adhesion, further increase drug in conjunction with situ-gel system
The residence time before cornea, more single drug delivery system are compared, before capable of providing good application efficiently to treat eye part disease
Scape.
In the preparation method of ophthalmic composition of the invention, provided second solute is hyaluronic acid or it pharmaceutically may be used
The salt of receiving, concentration in the composition are 0.1~3.0w/v%.Hyaluronic acid be ophthalmic community receive protect biology
Tissue or cell can work from the compound of compressing force basically as the shock absorber fluid of cell and tissue, also have phase
To big water suction and storage capacity.
It also include a effective amount of tension group in provided second solute in the preparation method of ophthalmic composition of the invention
Point and Congestant；The concentration of tonicity component is so that composition has the osmolality pressure of 260~630mOsmol/kg
Concentration；The concentration of Congestant in the composition is 0.01~0.5w/v%.
In the preparation method of ophthalmic composition of the invention, provided preparation method is in sterile and/or sterilized condition
Lower progress；Sterilising conditions are that made ophthalmic composition is exposed to γ to radiate lower 30~60s.This ophthalmic composition is suitble to be applied to
The mankind and/or animal eyes, it may be that sterile, to avoid infection, and composition has high stability under sterilising conditions.
In the preparation method of ophthalmic composition of the invention, the provided nano-micelle situ-gel for carrying cyclosporin
Offer scheme are as follows: after mixing Pluronic F127 and Pluronic F68 with ethylene oxide, glutaric acid, be dissolved in dehydrated alcohol
Then clarified solution is added in the nano micellar solution for carrying cyclosporin, stirs 30 at 60~80 DEG C by middle formation clarified solution
~60min obtains the nano-micelle situ-gel of liquid form then in 4 DEG C of 10~12h of refrigeration.By into nano-micelle
Situ-gel material is added, the drug release behavior of effective component can be made to reach unanimity, multi-component synchronous release is realized, avoid
The stimulation that mucous membrane local drug concentration is excessively high and generates, and it is able to extend mean residence time and the biological half-life of drug,
To improve the bioavilability of drug.
Preferably, the additive amount of Pluronic F127, Pluronic F68, ethylene oxide and glutaric acid is respectively glycerol
65~75%, 15~20%, 0.3~0.5% and the 0.5~1.5% of weight.During stirring in water bath, hydrophilic radical is
Ethylene oxide and glutaric acid, with continuing for shearing force, the two and the particle for the nano-micelle for carrying cyclosporin collide, and
Directly modification generates molecular film in nanoparticle surface, and the resistance for making cyclosporin release colloidal sol increases, and further slows down medicine
Object rate of release improves Yield of Mitoxantrone, and can promote antibacterial antiseptic property, after being applied to eye, molecular film and energy and mucus
Layer glycoprotein generates stronger intermolecular force, promotes the infiltration and absorption of cyclosporin；Another aspect situ-gel is cold
Nanoparticle surface is swollen and is coated in hiding, due to epoxy group and carboxyl intervention situ-gel molecule in, and with PEO block shape
At Hydrogenbond, charge and mutually exclusive power increase in system, so that the gelation temperature that final product is formed is risen, therefore
The phenomenon for causing the visual field fuzzy because of fast gelation is less prone to when being actually applied to eyes.
In the preparation method of ophthalmic composition of the invention, the offer scheme of the provided nano-micelle for carrying cyclosporin
Are as follows: take cyclosporin, glycerol and the poly- diethyl alcohol ester of 15- hydroxy stearic acid to mix, then at 80~95 DEG C stirring in water bath to molten
Solution, adds redistilled water, after 30~60s is stirred by ultrasonic under conditions of 100~300W of power, pulse 5s/10s, is down to room temperature,
And adjust gained micellar solution pH to 7~7.5 to obtain the final product.Preferably, cyclosporin, glycerol and the poly- diethanol of 15- hydroxy stearic acid
The weight ratio of ester is 1:3~5:4~8.Cyclosporin is lipophilic compound, after being loaded by nano-micelle, is conducive to cell suction
Receive and utilize, and the partial size of administration nano-drug administration system is smaller, easier to spread in corneal stroma, with ultrasonic energy accumulation and
Redistilled water environment cooperation, so that each material particle is further crushed and disperses more evenly, to form nano-micelle partial size and also become smaller, have
Conducive to the Yield of Mitoxantrone for improving situ-gel, while lesser partial size is conducive to deliver effective component to ocular region, simultaneously
The pain and stimulation to eye can be mitigated, correspondingly reduce the stress of eye, increase drug in eye
Stick residence time and effective acting time.
In the preparation method of ophthalmic composition of the invention, provided composition adjusts its pH to 6.5 using buffer
~7.8.Effective component is mainly exactly to be turned by the across cell that endocytosis and transcytosis mediate in made ophthalmic composition
Fortune approach enters cornea, and the interior environment of the endosome formed in endocytic processes and solvent body is in acid, and is received in composition
Rice glue beam situ-gel burst size in neutral medium is seldom, discharges rapidly in acid medium, this speciality not only improves group
The chemical stability for closing object can also be such that the drug loaded quick release after being absorbed comes out.
Another aspect of the present invention provides the purposes of above-mentioned ophthalmic composition, i.e., in preparation for being controlled by local application
The purposes in the medicament of human or animal's scheroma is treated, facilitates the purposes from the medicament of rehabilitation in eye surgery in preparation,
And the purposes of the delivery vehicle as ophthalmically acceptable therapeutic agent；The composition will directly give the front of the eyes of human or animal.
The invention has the benefit that
1) ophthalmic composition of the present invention is liquid form in room temperature or low temperature, is hydrosol shape in 35 DEG C of temperatures above
Formula illustrates the effect with dry-run protection and ocular reservation, can get long-term lubricating action and low frequency administration
Mode improves bioavilability, and will not cause eye-blurred, can improve the compliance of patient after application and/or reduce secondary
Ocular health is promoted in effect；
2) ophthalmic composition of the present invention is prepared by nano-micelle system, improves the film transporting mechanism and biomembrane of drug
Permeability, improve stability, drug solubility and the targeting of drug, in conjunction with situ-gel system, it is viscous to increase drug
Attached property extends mean residence time and the biological half-life of drug, further increases drug effective acting time before cornea；
3) nano-micelle situ-gel Yield of Mitoxantrone provided in the present invention is high, energy small to ocular pain and stimulation
Effective component is promoted to permeate and absorb to ocular region, resulting composition gelation temperature is risen, and does not easily cause the visual field fuzzy
Phenomenon, and there is antibacterial antiseptic property；
4) ophthalmic composition of the present invention can be used for the delivery vehicle of ophthalmically acceptable therapeutic agent, also can be directly used for human or animal's
The medicament that eye therapy, such as preparation facilitate the rehabilitation from eye surgery for the medicament of scheroma and/or preparation.
The ophthalmic composition for having improved dry-run protection and reservation is provided present invention employs above-mentioned technical proposal, is made up
The deficiencies in the prior art, reasonable design, easy operation.
Specific embodiment
Technical solution of the present invention is described in further detail below in conjunction with specific embodiment:
Ophthalmic composition with improved dry-run protection and reservation includes:
A, cyclosporin, concentration are 0.05~1.15w/v%；
B, nano-micelle situ-gel, concentration are 0.5~5.0w/v%；
C, hyaluronic acid or its pharmaceutically acceptable salt, concentration are 0.1~3.0w/v%；The present composition is normal
It is liquid form when temperature or low temperature, is hydrosol form in 35 DEG C of temperatures above, and is cut caused by being blinked by patient's eyelid
Under shearing stress, composition keeps complete.The composition illustrates the effect with dry-run protection and ocular reservation, is conducive to alleviate
Scheroma and/or the rehabilitation from eye surgery, it is conventional to use the composition or the delivery vehicle as ophthalmically acceptable therapeutic agent, it can
Long-term lubricating action and low frequency administration mode are obtained, improves bioavilability, and eye-blurred will not be caused,
The compliance of patient can be improved after application and/or reduce side effect.
Composition cyclosporin of the invention can effectively treat xerophthalmia comprising cyclosporin A, Ala2-cyclosporine,
Cyclosporins C, the salt of Cyclosporin D and above-mentioned substance, derivative and two or more mixtures.Of the invention certain
In embodiment, preferred cyclosporin is cyclosporin A.
It also include a effective amount of tonicity component in composition of the invention, concentration is so that the composition has 260
The Osmolality of~630mOsmol/kg.Tonicity component is formed selected from least one of salt, sugar, sugar alcohol, glycol.
Suitable salt includes sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium lactate, Sodium Pyruvate, sodium ascorbate and two or more
Mixture, suitable sugar include glucose, sucrose, fructose, xylose, mannose and two or more mixtures, suitable two
Alcohol includes glycerine, propylene glycol and its mixture.Preferably, in tonicity component include sugar alcohol, as D-sorbite, mannitol,
Xylitol, maltitol and two or more mixtures, the presence of sugar alcohol can assist to remove protein deposit.It in addition or can
Alternatively, there can be the mixture of different types of tonicity component in the composition.The feature of scheroma cellular level is usual
It is that tear film is chronically at hypertonic environment, isotonic or super infiltration composition, which is added to ocular, can be relieved symptom, this is because composition
In be combined with tensioned substances and gel play stimulation or maintain effective protection substance take in the work intracellular to superficial keratectomy
With, so that composition lubricating action enhances, enhancement ocular health.
Term " isotonic ", " super to seep " are defined in the present invention, and isotonic composition has the other side for being substantially equal to semi-permeable membrane
Osmotic pressure, it is generally recognized that 0.8~1.0% sodium chloride with human tears be it is approximate isotonic, be equivalent to 274~342mOsmol/
" isotonic " definition is consistent in kg, with the present invention.FDA regulation, " 2% to 5% sodium chloride eye-drops preparations be it is hypertonic, its label
To be the OTC product met the requirements when ' hypertonic solution ' ".The range is equivalent to 684~1711mOsmol/kg.It is " super in the present invention
Seep " Osmolality is defined as in the range of 350~650mOsmol/kg, this super infiltration composition is sent into eyes
When middle, it is avoided that or is mitigated Ocular irritation, obtains bigger comfort.
It also include the Congestant that concentration is 0.01~0.5w/v% in composition of the invention.Congestant include but
It is not limited to the ophthalmically acceptable acceptable salt (such as tetrahydrozoline hydrochloride) of tetrahydrozoline, ephedrine, phenylephrine and above-mentioned substance.It is anti-
Congested agent is mainly to alleviate intraocular hyperemia.In embodiments of the invention, preferred Congestant be naphazoline or its
Ophthalmically acceptable acceptable salt, such as naphcon.
It can also include odorant in composition of the invention, concentration in the composition is 0.01~0.5w/v%,
Such as menthol.In certain embodiments of the invention, preferred odorant is levorotatory menthol or racemization menthol, it can be with
The peppermint fragrance for providing composition can assign cooling cooling effect when being applied to eyes.
It can also include tackifier in composition of the invention, concentration in the composition is 0.01~1.5w/v%,
Eyes can be promoted to increase the stability of composition to the absorption of effective component.Tackifier can be selected from natural products, such as alginic acid
Salt, pectin, guar gum, xanthan gum, carrageenan, agar or Arabic gum；Starch derivatives, such as starch acetate or hydroxypropyl
Starch；Synthetic product, such as polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxypropyl methyl cellulose, hydroxy ethyl fiber
Element, carboxymethyl cellulose, hydroxypropyl cellulose；And other reagents well-known to those skilled in the art or combinations thereof.
It can also include preservative in composition of the invention, concentration in the composition is 0.01~0.5w/v%.
Preservative component includes but is not limited to persalt, such as perborate, percarbonate；Peroxide, such as hydrogen peroxide；Alcohols, such as
Benzyl alcohol, chlorobutanol；Sorbic acid and its salt for eye and its mixture.Preservative is mainly used for saving the activity of composition,
Prevent the growth of storage life microorganism and infection.In certain embodiments of the invention, antiseptic ingredient can be contained in composition,
For the composition after preparing and saving 6 months, effective component maintains an average of at least 94% (by weight).Of the invention another
In some embodiments, antiseptic ingredient can be free of in composition, the composition without antiseptic ingredient is preparing and saving 6
After month, effective component maintains an average of at least 93% (by weight).
It can also combined comprising acceptable antioxidant composition on one or more ophthalmology in composition of the invention
Concentration in object is 0.01~0.5w/v%.The chemical stability of composition can be enhanced in antioxidant composition, extends composition
Shelf-life.Antioxidant composition includes but is not limited to ascorbic acid, methionine, sodium thiosulfate, sodium pyrosulfite, gallic acid
Propyl ester, metal-chelator, the compound containing mercaptan and other stabilizers well-known to those skilled in the art or combination.
Another aspect of the present invention provides the preparation method of above-mentioned ophthalmic composition, including,
A provides the first solute, and solute includes the nano-micelle situ-gel for carrying cyclosporin, wherein carrying cyclosporin
The average grain diameter of nano-micelle is 10~50nm；
B provides the second solute；
C mixes the first solute with the second solute under conditions of using water as matrix, to be formed comprising gel dispersion
Composition；Above-mentioned composition is liquid form in room temperature or low temperature, is hydrosol form in 35 DEG C of temperatures above.The combination
The preparation method of object utilizes nano-micelle system, improves the film transporting mechanism of drug and the permeability of biomembrane, improves drug
Stability, drug solubility and targeting increase drug adhesion, further increase drug in conjunction with situ-gel system
The residence time before cornea, more single drug delivery system are compared, before capable of providing good application efficiently to treat eye part disease
Scape.
In the preparation method of ophthalmic composition of the invention, provided second solute is hyaluronic acid or it pharmaceutically may be used
The salt of receiving, concentration in the composition are 0.1~3.0w/v%.Hyaluronic acid be ophthalmic community receive protect biology
Tissue or cell from compressing force compound.The viscoelastic properties of hyaluronic acid (is hard elastics in the quiescent state, but in small shearing
It is less sticky under power) hyaluronic acid is worked basically as the shock absorber fluid of cell and tissue, hyaluronic acid also has
There are relatively large water suction and storage capacity.If Sodium Hyaluronate is added, the temperature of solution is warming to not less than 70 DEG C
Temperature, Sodium Hyaluronate is then added, the solution of warm is stirred into 20~30min, until Sodium Hyaluronate is completely dissolved.
It also include a effective amount of tension group in provided second solute in the preparation method of ophthalmic composition of the invention
Point and Congestant；The concentration of tonicity component is so that composition has the osmolality pressure of 260~630mOsmol/kg
Concentration；The concentration of Congestant in the composition is 0.01~0.5w/v%.
In the preparation method of ophthalmic composition of the invention, provided preparation method is in sterile and/or sterilized condition
Lower progress；Sterilising conditions are that made ophthalmic composition is exposed to γ to radiate lower 30~60s.This ophthalmic composition is suitble to be applied to
The mankind and/or animal eyes, it may be that sterile, to avoid infection, and composition has high stability under sterilising conditions.
In the preparation method of ophthalmic composition of the invention, the provided nano-micelle situ-gel for carrying cyclosporin
Offer scheme are as follows: after mixing Pluronic F127 and Pluronic F68 with ethylene oxide, glutaric acid, be dissolved in dehydrated alcohol
Then clarified solution is added in the nano micellar solution for carrying cyclosporin, stirs 30 at 60~80 DEG C by middle formation clarified solution
~60min obtains the nano-micelle situ-gel of liquid form then in 4 DEG C of 10~12h of refrigeration.By into nano-micelle
Situ-gel material is added, the drug release behavior of effective component can be made to reach unanimity, multi-component synchronous release is realized, avoid
The stimulation that mucous membrane local drug concentration is excessively high and generates, and it is able to extend mean residence time and the biological half-life of drug,
To improve the bioavilability of drug.
Preferably, the additive amount of Pluronic F127, Pluronic F68, ethylene oxide and glutaric acid is respectively glycerol
65~75%, 15~20%, 0.3~0.5% and the 0.5~1.5% of weight.During stirring in water bath, hydrophilic radical is
Ethylene oxide and glutaric acid, with continuing for shearing force, the two and the particle for the nano-micelle for carrying cyclosporin collide, and
Directly modification generates molecular film in nanoparticle surface, and the resistance for making cyclosporin release colloidal sol increases, and further slows down medicine
Object rate of release improves Yield of Mitoxantrone, and can promote antibacterial antiseptic property, after being applied to eye, molecular film and energy and mucus
Layer glycoprotein generates stronger intermolecular force, promotes the infiltration and absorption of cyclosporin；Another aspect situ-gel is cold
Nanoparticle surface is swollen and is coated in hiding, due to epoxy group and carboxyl intervention situ-gel molecule in, and with PEO block shape
At Hydrogenbond, charge and mutually exclusive power increase in system, so that the gelation temperature that final product is formed is risen, therefore
The phenomenon for causing the visual field fuzzy because of fast gelation is less prone to when being actually applied to eyes.
In the preparation method of ophthalmic composition of the invention, the offer scheme of the provided nano-micelle for carrying cyclosporin
Are as follows: take cyclosporin, glycerol and the poly- diethyl alcohol ester of 15- hydroxy stearic acid to mix, then at 80~95 DEG C stirring in water bath to molten
Solution, adds redistilled water, after 30~60s is stirred by ultrasonic under conditions of 100~300W of power, pulse 5s/10s, is down to room temperature,
And adjust gained micellar solution pH to 7~7.5 to obtain the final product.15-hydroxy polyethylene glycol stearate is widely used in dissolution insoluble medicine,
May also suppress p- glycoprotein, influence permeability of cell membrane, influence the close connection between epithelial cell, so as to increase drug across
Cell traffic and diffusion through cell bypass.
Preferably, the weight ratio of cyclosporin, glycerol and the poly- diethyl alcohol ester of 15- hydroxy stearic acid is 1:3~5:4~8.Ring
Spore rhzomorph is lipophilic compound, after being loaded by nano-micelle, is conducive to cell and absorbs and utilize, and the grain of administration nano-drug administration system
Diameter is smaller, easier to spread in corneal stroma, as the accumulation of ultrasonic energy and redistilled water environment cooperate, so that each substance grain
Son is further crushed and disperses more evenly, to form nano-micelle partial size and also become smaller, and is conducive to the Yield of Mitoxantrone for improving situ-gel,
Lesser partial size is conducive to deliver effective component to ocular region simultaneously, while can mitigate and make to the pain of eye and stimulation
With correspondingly reducing the stress of eye, increase drug in eye and stick residence time and effective acting time.
In the preparation method of ophthalmic composition of the invention, provided composition adjusts its pH to 6.5 using buffer
~7.8.Effective component is mainly exactly to be turned by the across cell that endocytosis and transcytosis mediate in made ophthalmic composition
Fortune approach enters cornea, and the interior environment of the endosome formed in endocytic processes and solvent body is in acid, and is received in composition
Rice glue beam situ-gel burst size in neutral medium is seldom, discharges rapidly in acid medium, this speciality not only improves group
The chemical stability for closing object can also be such that the drug loaded quick release after being absorbed comes out.
Preferably, buffer include but is not limited to acetic acid, lactic acid, diethylamine, three-(methylol) aminomethane hydrochlorides,
Citrate, phosphate, borate, bicarbonate, sodium salt, sylvite.In certain embodiments of the invention, preferred buffering
Agent citrate.
Another aspect of the present invention provides the purposes of above-mentioned ophthalmic composition, i.e., in preparation for being controlled by local application
The purposes in the medicament of human or animal's scheroma is treated, facilitates the purposes from the medicament of rehabilitation in eye surgery in preparation,
And the purposes of the delivery vehicle as ophthalmically acceptable therapeutic agent；The composition will directly give the front of the eyes of human or animal.
Composition of the invention is delivered to eyes with topical liquid form, is such as delivered by eye drops, it is also possible to make ophthalmically acceptable therapeutic agent
Drug delivery medium, give composition to cornea and/or be slowly dropped into the front of eyes, to reach other portions to eyes
Point treatment benefit, such as the treatment benefit to goblet cell, lachrymal gland, oil gland and/or nasolacrimal duct, it helps eyes are from eye
Rehabilitation in surgical operation, can at a point prior to the surgical procedure, during and/or after effectively use, surgical procedure include but is not limited to will
Eye exposure is in laser energy, such as in LASIK postoperative infection, drying and the treatment of other ocular complication.
Ophthalmic composition is being helped improve by directly application or the composition prepared as delivery vehicle in the present invention
The Heterosis of the compliance of patient is in the following areas: 1) low frequency administration reduces application administration frequency to deliver a effective amount of substance
Rate；2) there is high osmosis, conducive to the delivering to ocular region；3) after being applied to eyes and during eyelid blinks,
Composition is at least a partially formed the hydrosol, is effectively trapped in the ocular sufficiently long time, to improve the intake of superficial keratectomy cell.
Hereinafter, in order to help to understand the present invention, following embodiment is provided.However, following embodiment is only used for making
The present invention is easier to understand, and the scope of the present invention is not restricted in the following example.
Embodiment 1:
Ophthalmic composition with improved dry-run protection and reservation is respectively as follows: the ring spore bacterium of 0.5w/v% including concentration
The nano-micelle situ-gel of plain A, 1.0w/v%, the hyaluronic acid of 0.5w/v%, the naphazoline of 0.05w/v% are added slow
Electuary sodium citrate regulation composition pH is 7.5, and the sodium ascorbate and D-sorbite mixture of equal proportion is added, so that group
Polymer weight osmolarity is adjusted to 300mOsmol/kg.
The preparation method of ophthalmic composition with improved dry-run protection and reservation, comprising the following steps:
1) take cyclosporin A, glycerol and the poly- diethyl alcohol ester of 15- hydroxy stearic acid mixed by weight the ratio for 1:3.5:5
Even, then stirring in water bath adds the redistilled water of 2 times of amounts, in the condition of power 200W, pulse 5s/10s to dissolving at 85 DEG C
After lower ultrasonic agitation 40s, it is down to room temperature, and adjusts gained micellar solution pH to 7 to get the nano-micelle of cyclosporin is carried；
2) it after mixing Pluronic F127 and Pluronic F68 with ethylene oxide, glutaric acid, is dissolved in dehydrated alcohol
Clarified solution is formed, then clarified solution is added in the nano micellar solution for carrying cyclosporin, 45min is stirred at 70 DEG C, so
Afterwards in 4 DEG C of refrigeration 10h, obtain the nano-micelle situ-gel of liquid form, above-mentioned Pluronic F127, Pluronic F68,
The additive amount of ethylene oxide and glutaric acid is respectively 70%, 18%, 0.4% and the 0.8% of glycerin weight；
3) hyaluronic acid, naphazoline, sodium ascorbate and D-sorbite are added into the water of half amount, stirring is until complete
Fully dissolved is to get solute liquid；
4) solute liquid and nano-micelle situ-gel are added into the water of the other half amount, after being sufficiently stirred, is added
Buffer adjusts pH, is subsequently placed in γ and radiates lower 30s, obtains transparent, clear liquid form ophthalmic composition.
Embodiment 2:
The present embodiment difference from example 1 is that: gulose in step 1) in redistilled water containing 0.05mM and
The cyclohexanol of 0.08mM；After cyclosporin A is linked with glycerol, in conjunction with the hydrophobic grouping of the poly- diethyl alcohol ester of 15- hydroxy stearic acid,
And the hydrophilic radical of the poly- diethyl alcohol ester of 15- hydroxy stearic acid be exposed to it is outer, in ultrasonic energy transmitting, gulose and cyclohexanol with
Hydrophilic radical combines, since the addition of the two is so that steric hindrance increases between the nanoparticle formed, so that small particle is received
Repulsive interaction enhances rice corpuscles in systems, avoids and is become smaller the autohemagglutination phenomenon of initiation by partial size, while enhancing composition
Anti-oxidation protection effect and stability, hydrophilic radical both on the other hand can increase the hydrophily in composition, assist to increase
Its strong osmosis to eye mask can be relieved drug fever stress when composition is applied to eye, mitigate burning sensation and thorn
Swash property.
It prepares that each component content in other steps and composition of composition is consistent in embodiment 1, liquid is made
Ophthalmic composition.
Embodiment 3:
The present embodiment difference from example 1 is that: in ophthalmic composition also containing concentration be 0.3w/v% mountain
As preservative, and in the preparation, preservative is dissolved in solute liquid potassium sorbate.
In composition other components content and prepare composition other steps it is consistent in embodiment 1, be made liquid
Ophthalmic composition.
Embodiment 4:
The present embodiment difference from example 1 is that: in ophthalmic composition also containing concentration be 0.1w/v% a left side
Menthol is revolved as odorant, and in the preparation, and odorant is dissolved in solute liquid.
In composition other components content and prepare composition other steps it is consistent in embodiment 1, be made liquid
Ophthalmic composition.
Embodiment 5:
The present embodiment difference from example 1 is that: in step 1) use convention stir, not using ultrasonic agitation.
It prepares that each component content in other steps and composition of composition is consistent in embodiment 1, liquid is made
Ophthalmic composition.
Embodiment 6:
The present embodiment and embodiment 2 the difference is that: convention stir is used in step 1), not using ultrasonic agitation.
It prepares that each component content in other steps and composition of composition is consistent in embodiment 2, liquid is made
Ophthalmic composition.
Embodiment 7:
The present embodiment difference from example 1 is that: ethylene oxide and glutaric acid are not added in step 2).
It prepares that each component content in other steps and composition of composition is consistent in embodiment 1, liquid is made
Ophthalmic composition.
Embodiment 8:
Ophthalmic composition with improved dry-run protection and reservation is respectively as follows: the ring spore bacterium of 1.0w/v% including concentration
The nano-micelle situ-gel of plain A, 2.5w/v%, the Sodium Hyaluronate of 1.5w/v%, the naphcon of 0.2w/v%,
Buffer sodium citrate tune is added in the levorotatory menthol of 0.1w/v%, the guar gum of 0.5w/v%, the ascorbic acid of 0.3w/v%
Saving composition pH is 6.5, and the propylene glycol and mannitol mixture of equal proportion is added, so that composition weight osmolarity
It is adjusted to 450mOsmol/kg.
The preparation method of above-mentioned ophthalmic composition, comprising the following steps:
1) cyclosporin A, glycerol and the poly- diethyl alcohol ester of 15- hydroxy stearic acid are taken by weight for the ratio of 1:4.5:6.5
It mixes, then stirring in water bath adds the redistilled water of 2 times of amounts, in the item of power 300W, pulse 5s/10s to dissolving at 80 DEG C
After 30s is stirred by ultrasonic under part, it is down to room temperature, and adjusts gained micellar solution pH to 7.5 to get the nanometre glue of cyclosporin is carried
Beam；
2) it after mixing Pluronic F127 and Pluronic F68 with ethylene oxide, glutaric acid, is dissolved in dehydrated alcohol
Clarified solution is formed, then clarified solution is added in the nano micellar solution for carrying cyclosporin, 35min is stirred at 75 DEG C, so
Afterwards in 4 DEG C of refrigeration 12h, obtain the nano-micelle situ-gel of liquid form, above-mentioned Pluronic F127, Pluronic F68,
The additive amount of ethylene oxide and glutaric acid is respectively 72%, 16%, 0.45% and the 1.2% of glycerin weight；
3) Sodium Hyaluronate is added into the water of half amount, stirs at a temperature of 80 DEG C to being completely dissolved, salt is then added
Sour naphazoline, levorotatory menthol, guar gum, ascorbic acid, propylene glycol and mannitol continue to stir up to being completely dissolved,
Up to solute liquid；
4) solute liquid and nano-micelle situ-gel are added into the water of the other half amount, after being sufficiently stirred, is added
Buffer adjusts pH, is subsequently placed in γ and radiates lower 40s, obtains transparent, clear liquid form ophthalmic composition.
Embodiment 9:
The present embodiment and embodiment 8 the difference is that: the sorbic acid for being also 0.3w/v% containing concentration in composition
As preservative, and in the preparation, preservative is dissolved in solute liquid potassium.
In composition other components content and prepare composition other steps it is consistent in embodiment 8, be made liquid
Ophthalmic composition.
Embodiment 10:
The ophthalmic composition of the made liquid form of embodiment 8 is given to the eye for the human patients that will carry out surgical operation
Eyeball, the eyes will be exposed to laser energy, specifically LASIK surgical operation in above-mentioned surgical operation.
Surgical site infections, relative to living through same surgical procedure and give without the identical of nano-micelle situ-gel
The patient of composition, patient's Eye irritation reduce and/or quickly from surgical rehabilitations.
Embodiment 11:
The ophthalmic composition of the made liquid form of embodiment 8 is given to the eye for the human patients for carrying out surgical operation
Eyeball, the eyes will be exposed to laser energy, specifically LASIK surgical operation in above-mentioned surgical operation.
Surgical site infections, relative to living through same surgical procedure and give without the identical of nano-micelle situ-gel
The patient of composition, patient's Eye irritation reduce and/or quickly from surgical rehabilitations.
Embodiment 12:
The ophthalmic composition of the made liquid form of embodiment 8 is almost given immediately after patient experienced surgical operation
To the eyes of patient, the eyes will be exposed to laser energy, specifically LASIK surgical operation in above-mentioned surgical operation.
Surgical site infections, relative to living through same surgical procedure and give without the identical of nano-micelle situ-gel
The patient of composition, patient's Eye irritation reduce and/or quickly from surgical rehabilitations.
Test example 1:
The gelation temperature of nano-micelle situ-gel is tested
Made nano-micelle situ-gel, is set to test group 1 and 2 in Example 1 and 7；With identical weight ratio
Example takes Pluronic F127 and Pluronic F68, using situ-gel made from identical preparation condition as blank group, carries out glue
The measurement of solidifying temperature: measuring its gelation temperature using II+Pro type viscosity of U.S. Brookfiled DV, and revolving speed is set as 1rpm,
It uprushes temperature when reaching 5000cp in viscosity, that is, is considered its gelation temperature.Its result is as shown in table 1 below.
The gelation temperature test result of 1 nano-micelle situ-gel of table
| Test group 1 | Test group 2 | Blank group | |
| Gelation temperature DEG C | 35.3 | 33.5 | 32.3 |
By upper table data it is found that blank group gelation temperature is minimum；The gelation temperature of gel after nano-micelle is added all has
Risen, and the temperature of test group 1 rises more, so that test group 1 is more dominant in actual use, is easier in higher temperature
Under steadily save in liquid form, be also beneficial to ocular delivery.
Test example 2:
The encapsulation rate of nano-micelle situ-gel is tested
The nano-micelle and nano-micelle situ-gel of cyclosporin are carried with the intermediate product of embodiment 1,2,5,6,7 respectively
For test material, correspondence is set as test group 1~5.
The nano-micelle for carrying cyclosporin is taken, after being diluted with methanol, carries out HPLC analysis (chromatographic column: Waters X-
Bridge C18,3.5mm, 3.0mm × 150.0mm) mobile phase be water: methanol=8:92；Flow velocity is 0.7ml/min；Column temperature is set
It is 40 DEG C；Detection wavelength is 224nm；Sample volume: then 20 μ l measure the total concentration (C of solution cyclosporinAlways).Then it takes
Nano-micelle situ-gel solution is placed in ultrafilter (Ultra-4, molecular cut off 50kDa, Merck Millipore, Ai Er
It is blue), 10min is centrifuged with 4000rpm.Filtrate mixes with isometric methanol, and 12000rpm is centrifuged 8min after oscillation, takes supernatant
Liquid, HPLC method measure the concentration (C of free cyclosporinIt is free), the encapsulation rate (%) of cyclosporin is calculated according to the following formula:
Encapsulation rate (%)=(CAlways-CIt is free)/CAlways×100
Final calculation result is as shown in table 2 below.
The encapsulation rate test result of 2 nano-micelle situ-gel of table
| Total concentration mg/ml | Free concentration μ g/ml | Encapsulation rate % | |
| Test group 1 | 5.36 | 0.094 | 100 |
| Test group 2 | 5.32 | 0.089 | 100 |
| Test group 3 | 5.41 | 0.554 | 99.0 |
| Test group 4 | 5.34 | 0.562 | 98.9 |
| Test group 5 | 5.37 | 0.752 | 98.6 |
By upper table data it is found that the encapsulation rate of test group 1 and 2 can reach 100%, and the encapsulation rate of test group 3,4 and 5 is slightly
The case where difference is the preparation condition defect due to test group 3~5, and encapsulation rate is less than 100%, is unfavorable for composition
Subsequent preservation is easy in prolonged save, reveals effective component, reduce the activity and bioavailability of composition.
Test example 3:
The stability test of ophthalmic composition
The made ophthalmic composition of same amount of embodiment 1,3,8,9 is taken respectively, and correspondence is set as test group 1~4, by various samples
After product store 6 months at room temperature, active quantities measurement is carried out to effective component in composition (in terms of cyclosporin), as a result such as
Shown in the following table 3.
3 ophthalmic composition stability test result of table
| W/v% before storing | W/v% after storage | Change rate % | |
| Test group 1 | 0.5 | 0.46 | -8 |
| Test group 2 | 0.5 | 0.47 | -7 |
| Test group 3 | 1.0 | 0.93 | -7 |
| Test group 4 | 1.0 | 0.95 | -5 |
As seen from the above table, test group can keep higher stability in storage phase, and wherein test group 1 and 3 compares 2 and 4
Contain preservative in group, therefore show better stability, but group containing preservative and without preservative group stability difference not
Greatly, it is contemplated that the risk of the Ocular irritation as caused by preservative can not add preservative in actual production in composition.
Test example 4:
The dry-run protection and retention test of ophthalmic composition
The made ophthalmic composition of Example 1,2,3,8,9 respectively, is set as test group 1~5；Take exclusive use hyaluronic acid
For contrast groups, protection and retention test is dried.
1) human transforming corneal epithelial cell dry-run protection test method: is taped against glue with 0.09 × 106 cell/mL painting
On former 48 orifice plate of application type, and it is made to grow to remittance in the EpiLife culture medium for being supplemented with human corneal growth supplement
Conjunction continues 48 hours.By cell test compositions-treated 30 minutes at 37 DEG C, then rinsed with the culture medium of no supplement
1X(250μL).It gently removes all solution and 30 points is dried to cell at 45% humidity, 37 DEG C in the drying chamber
Clock.Cell viability is measured using MTS test (Promega#G5421), to calculate the protective rate compareed relative to culture medium.As a result
As shown in table 4 below.
The dry-run protection test result of 4 ophthalmic composition of table
| Protective rate % before washing | Protective rate % after washing | Dry-run protection rate % | |
| Test group 1 | 58.6 | 54.1 | 92.3 |
| Test group 2 | 58.2 | 53.3 | 91.5 |
| Test group 3 | 58.9 | 54.0 | 91.7 |
| Test group 4 | 59.5 | 54.0 | 90.8 |
| Test group 5 | 59.4 | 54.9 | 92.4 |
| Contrast groups | 18.6 | 12.8 | 68.8 |
As seen from the above table, test group illustrates preferable dry-run protection ability, can all reach 90% or more protective rate,
The relatively transparent matter acid of dry-run protection ability is strong, and significant difference.
2) retention test method: the fluorescein-labeled dextran tracer of 70kD is added to the concentration of 0.1w/v%
In each test composition.Carry out monitoring signals using scanning fluophotometer to decay, correspond to the elimination of composition, is come pair with this
Solution Cell surface stick effect is assessed.Test result is as shown in table 5 below.
The retention test result of 5 ophthalmic composition of table
As seen from the above table, test group illustrates preferable reserve capability, retains relatively transparent matter acid by force, and significant difference.
Test example 5:
The eye irritation of ophthalmic composition is tested
Test specimen: the made ophthalmic composition of embodiment 1 and 8
Experimental animal: take 5 New Zealand White Rabbit are interior for 24 hours before experiment to carry out eye examination and scoring, appearance is without any different
Often, fluorescein sodium dyeing is given, with cobalt blue light illumination, hand slit lamp checks that corneal epithelium is not damaged, conjunctiva, cornea structure
Without exception, iris texture is clear, no inflammation reaction.
Test setting: " Chemical induced irritation, anaphylaxis and the guidance of hemolytic investigative technique are former for eye irritation experimental evidence
Method in the 4.1st " eye irritant test " in then " carries out.Using androgynous left and right sides self-contrast method.Use microscale sampler
50 μ L of sample liquids, the intracapsular physiology that same dose is given in a single dose of conjunctiva of left eye is given in a single dose to animal subject conjunctiva of right eye is intracapsular
Salt water is lightly closed eyelid 30 seconds as control after administration.1,2,4 and 8h carries out examination of eyes upon administration and stimulation is commented
Valence, as a result as shown in table 6 below.
The eye irritation result of 6 ophthalmic composition of table
As seen from the above table, all there is a small amount of secretion when the test of two groups is up to 8h in left eye, it may be possible to which animal is from status
Caused by secretion deposition；There is slight oedema after 1h is administered in animal in the group of embodiment 8, and subsequent symptom disappears, occurs after 8h
A small amount of secretion, in addition to this equal corneal transparency of remaining animal subject, without muddiness, conjunctiva is without congested, oedema, no secretion,
Significant Ocular irritation reaction is not observed.It follows that made ophthalmic composition is nonirritant to lagophthalmos in embodiment, no
It is fuzzy to will cause the visual field.
The prior art of routine techniques dawn known to those skilled in the art in above-described embodiment, therefore herein no longer in detail
It repeats.
The above embodiments are only used to illustrate the present invention, and not limitation of the present invention, the ordinary skill people of this field
Member can also make a variety of changes and modification without departing from the spirit and scope of the present invention.Therefore, all equivalent
Technical solution also belong to scope of the invention, scope of patent protection of the invention should be defined by the claims.
Claims (10)
1. the ophthalmic composition with improved dry-run protection and reservation, it is characterised in that: include:
A, cyclosporin, concentration are 0.05~1.15w/v%；
B, nano-micelle situ-gel, concentration are 0.5~5.0w/v%；
C, hyaluronic acid or its pharmaceutically acceptable salt, concentration are 0.1~3.0w/v%；
The composition is liquid form in room temperature or low temperature, is hydrosol form in 35 DEG C of temperatures above, and by suffering from
Under shear stress caused by person's eyelid blinks, the composition keeps complete.
2. the ophthalmic composition according to claim 1 with improved dry-run protection and reservation, it is characterised in that: described
It also include a effective amount of tonicity component in composition, concentration is so that the composition has 260~630mOsmol/kg
Osmolality.
3. the ophthalmic composition according to claim 1 with improved dry-run protection and reservation, it is characterised in that: described
It also include the Congestant that concentration is 0.01~0.5w/v% in composition.
4. the preparation method of ophthalmic composition as claimed in any one of claims 1 to 3, it is characterised in that: including,
A provides the first solute, and the solute includes the nano-micelle situ-gel for carrying cyclosporin, the load cyclosporin
The average grain diameter of nano-micelle is 10~50nm；
B provides the second solute；
C mixes first solute with second solute under conditions of using water as matrix, includes gel dispersion to be formed
The composition of body；
The composition is liquid form in room temperature or low temperature, is hydrosol form in 35 DEG C of temperatures above.
5. the preparation method of ophthalmic composition according to claim 4, it is characterised in that: second solute is hyalomitome
Acid or its pharmaceutically acceptable salt, concentration in the composition are 0.1~3.0w/v%.
6. the preparation method of ophthalmic composition according to claim 4, it is characterised in that: also include in second solute
A effective amount of tonicity component and Congestant；The concentration of the tonicity component be so that the composition have 260~
The Osmolality of 630mOsmol/kg；The concentration of the Congestant in the composition be 0.01~
0.5w/v%.
7. the preparation method of ophthalmic composition according to claim 4, it is characterised in that: the preparation method is sterile
And/or it is sterilized under the conditions of carry out；The sterilising conditions are that made ophthalmic composition is exposed to γ to radiate lower 30~60s.
8. the preparation method of ophthalmic composition according to claim 4, it is characterised in that: the nanometer for carrying cyclosporin
The offer scheme of micella situ-gel are as follows: mix Pluronic F127 and Pluronic F68 with ethylene oxide, glutaric acid
Afterwards, it is dissolved in dehydrated alcohol and forms clarified solution, then clarified solution is added in the nano micellar solution for carrying cyclosporin, is stirred
It mixes, and in 4 DEG C of 10~12h of refrigeration, obtains the nano-micelle situ-gel of liquid form.
9. the preparation method of the ophthalmic composition according to claim 4 or 8, it is characterised in that: the load cyclosporin
The offer scheme of nano-micelle are as follows: take cyclosporin, glycerol and the poly- diethyl alcohol ester of 15- hydroxy stearic acid to mix, then 80~
Stirring in water bath adds redistilled water, is stirred by ultrasonic under conditions of 100~300W of power, pulse 5s/10s to dissolving at 95 DEG C
Afterwards, it is down to room temperature, and adjusts gained micellar solution pH to 7~7.5 to obtain the final product.
10. the purposes of ophthalmic composition as claimed in any one of claims 1 to 3, it is characterised in that: in preparation for passing through office
Purposes in the medicament of portion's application treatment human or animal's scheroma, facilitates from the medicament of rehabilitation in eye surgery in preparation
Purposes, and the purposes of the delivery vehicle as ophthalmically acceptable therapeutic agent；The composition will directly give the human or animal
Eyes front.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021032073A1 (en) * | 2019-08-18 | 2021-02-25 | IVIEW Therapeutics (Zhuhai) Co., Ltd. | In-situ gel containing cyclosporine micelles as sustained ophthalmic drug delivery system |
| CN112516084A (en) * | 2020-09-16 | 2021-03-19 | 艾威药业(珠海)有限公司 | In situ gel containing cyclosporine micelles as sustained release ophthalmic drug delivery system |
| CN114364372A (en) * | 2019-09-09 | 2022-04-15 | 株式会社泰俊制药 | Nanoemulsion ophthalmic compositions comprising cyclosporin and menthol and methods of making the same |
-
2019
- 2019-04-09 CN CN201910281040.0A patent/CN110090294A/en not_active Withdrawn
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021032073A1 (en) * | 2019-08-18 | 2021-02-25 | IVIEW Therapeutics (Zhuhai) Co., Ltd. | In-situ gel containing cyclosporine micelles as sustained ophthalmic drug delivery system |
| CN114364372A (en) * | 2019-09-09 | 2022-04-15 | 株式会社泰俊制药 | Nanoemulsion ophthalmic compositions comprising cyclosporin and menthol and methods of making the same |
| CN112516084A (en) * | 2020-09-16 | 2021-03-19 | 艾威药业(珠海)有限公司 | In situ gel containing cyclosporine micelles as sustained release ophthalmic drug delivery system |
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