CN108295072A - Nintedanib prevents the purposes of eye disease - Google Patents
Nintedanib prevents the purposes of eye disease Download PDFInfo
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- CN108295072A CN108295072A CN201510908457.7A CN201510908457A CN108295072A CN 108295072 A CN108295072 A CN 108295072A CN 201510908457 A CN201510908457 A CN 201510908457A CN 108295072 A CN108295072 A CN 108295072A
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- nintedanib
- ethanesulfonic acid
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Abstract
The invention discloses the purposes that Nintedanib prevents eye disease, application more particularly to Nintedanib and its salt or polymorph, Nintedanib hydrate or solvate as active constituent in the drug of prevention eye disease, Nintedanib relevant pharmaceutical composition of the present invention can be directed to the treatment that tri- kinds of angiogenesis receptors of VEGF, PDGF, FGF carry out ocular disorder, and access times are no more than 5 times daily, and it is capable of providing effective drug concentration, and then reaches preferable control effect.
Description
Technical field
The invention belongs to field of medicaments, and in particular to Nintedanib and its salt or polymorph, Nintedanib hydrate or molten
Application of the object as active constituent in the drug of prevention eye disease is closed in agent.
Background technology
Nintedanib, i.e. 3-Z- [1- (4- (N- ((4- thyl-piperazin -1- bases)-methyl carbonyl)-N- Methyl-aminos)-anilino-) -1-
Phenyi-methylene] -6- methoxycarbonyl -2- dihydroindolones, compound structure is shown in formula (I)：
Nintedanib is a kind of novel angiogenesis inhibitors, can be same
When vasoactive generating process involved in 3 kinds of key receptor families：Vascular endothelial growth factor receptor (VEGFR),
Platelet derived growth factor B (PDGFR) and fibroblast growth factor acceptor (FGFR).Nintedanib
It is also more by EMA approval joints for treating idiopathic pulmonary fibrosis (IPF) by FDA and EMA approval listings
Xi Tasai be applied to after First-line chemotherapy histodiagnosis be gland cancer, Locally Advanced or metastatic or local recurrence it is non-
Small Cell Lung Cancer (NSCLC) adult patients.
Age-related macular degeneration, also referred to as age-related macular degeneration (Age related macular degeneration,
AMD), 45 years old or more is mostly occurred in greatly, illness rate increases with the growth at age, is current middle-aged and the old's blinding
Important diseases.The disease is divided into dryness (being also nonexudativeage) and moist (also crying exudative) two types, dryness master
To be choroidal capillaries atrophy, glass-film is thickened to be denaturalized with macular area atrophy caused by retinal pigment epithelium atrophy；
The destruction of moist predominantly glass-film, choroidal artery, which invades, constitutes choroidal neovascularization (choroidal under retina
Neovascularization, CNV), and then occur serosity or to go out under macular area retinal pigment epithelium or under neural epithelium
Courageous and upright disciform detachment, eventually becomes machine scar.It can also be changed into exudative type according to clinical observation atrophic type.
VEGF (vascular endothelial growth factor receptor) is the angiogenesis signal path of classics, can be used for treating a variety of entities
Tumor and wet age related macular degeneration (AMD), what FDA had been approved by has for VEGF monoclonal antibody or fusion protein
Avastin (Avastin), Lucentis (Lucentis), VEGF Trap (Eylea), thunder not Lu Dankang (Cyramza), I
Western general (the trade name of Compaq of state's independent research：It is bright to wash one's hair) it has been listed in 2013.But it is directed to VEGF, PDGF, FGF
There are no launch for treating ocular disorder for the drug of three kinds of angiogenesis receptors, therefore better there is still a need for finding
Drug treats eye disease such as AMD, and the pharmaceutical composition it is also required to provide sufficient concentrations of activating agent and be controlled with reaching
Therapeutic effect, in addition daily access times are not to be exceeded 5 times, and the fewer number the better.
Invention content
In view of this, the purposes the purpose of the present invention is to provide Nintedanib as medicament for the eyes, is mainly to provide Nintedanib
Pharmaceutical composition, with enough stability and in eyes, particularly ocular region (for example, retina,
In Bruch films and choroidal region) it can realize the Nintedanib of effective concentration.
The present invention reaches the purpose by following technical solution：
1. Nintedanib and its salt or polymorph, Nintedanib hydrate or solvate are as active constituent in prevention eye
Application in the drug of disease, the eye disease are age-related macular degeneration, choroidal neovascular formation, view
Film stripping, diabetic retinopathy, the atrophy change of retinal pigment epithelium tissue, retinal pigment epithelium tissue
Hypertrophy change, retinal vein occlusion, chorioretinal vein occlusion, macular edema, ocular region angiogenesis,
Corneal vessels generation, cystoid macular edema, regards pteryium conjunctiva, subretinal, choroidal neovascularization
Epiretinal membranes, macula hole, blood vessel striped, retinitis pigmentosa, recessive macular dystrophy, glaucoma, cataract, inflammation
In character condition, obstinate sexual abnormality, keratoconus, retinopathy of prematurity, intraretinal edema or high myopic eye
One or more.
It should be noted that solvate is that wherein solvent molecule forms solid stoichiometry compound and includes but unlimited
In the compound or its salt of ethyl alcohol and methanol.
Hydrate is the solvate of particular form, and wherein solvent molecule is water.The hydration of the compound of the present invention or its salt
Object is the compound or the coatings of stoichiometric composition of salt and water, such as semihydrate, monohydrate or dihydrate.
Salt is preferably the pharmaceutically acceptable salt of compound according to the present invention.Suitable pharmaceutically acceptable salt includes
The salt of inorganic acid and organic acid, including hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, Loprazolam, trifluoromethayl sulfonic acid, benzene
Sulfonic acid, p-methyl benzenesulfonic acid, 1-naphthalene sulfonic aicd, 2- naphthalene sulfonic acids, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid,
Lactic acid, ethanedioic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid.In addition,
Pharmaceutically acceptable salt includes the salt of inorganic base, such as containing base cations (such as Li+、Na+Or K+), alkaline earth sun from
Son (such as Mg2+、Ca2+Or Ba2+), the salt of ammonium cation；And the acid salt of organic base, including aliphatic and fragrance
Race is substituted ammonium and quaternary ammonium cation, such as from triethylamine, N, TMSDEA N diethylamine, N, N- dicyclohexyl amines, lysine, pyrrole
Pyridine, N, N- dimethyl aminopyridines (DMAP), 1,4- diazabicyclos [2.2.2] octane (DABCO), 1,5- diazas
The protonation of 11 carbon -7- alkene (DBU) of bicyclic [4,3,0] nonyl- 5- alkene (DBN) and 1,8- diazabicyclos [5.4.0] or full alkane
The salt of base.
Preferably, the active constituent is Nintedanib esilate, and the drug is the combination of Nintedanib esilate
The pH of object, composition is 6~9, and the mass fraction of Nintedanib esilate in the composition is 0.01~10%.
Preferably, the composition is eye drops, Eye ointments, eyewash, liposome, micro-capsule, microballoon or intraocular injection
Agent.
It should be noted that the ophthalmic pharmaceutical compositions as the present invention further include slow release intraocular implant, by activating agent
Matrix formulations obtained from mixing and be molded with the carrier containing polymer substance, with polymeric membrane coats activating agent and obtains
Preparation, by capsule preparations obtained from the enclosed tiny capsules comprising polymer substance of activating agent etc..
The macromolecule used in slow release intraocular implant can be hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyl
Propyl methocel phthalic acid ester, gelatin, collagen, lacks atelocollagen, hyaluronic acid, junket egg at pulullan polysaccharide
In vain, agar, Arabic gum, dextrin, ethyl cellulose, methylcellulose, chitin, chitosan, mannosan,
Carboxymethylethylcellulose, sodium carboxymethylcellulose, polyethylene glycol, sodium alginate, polyvinyl alcohol, cellulose ethanoate,
Polyvinylpyrrolidone, polysiloxanes, polyvinyl acetal diethyl amino yl acetate, albumin and lactic acid-ethanol
Copolymer etc..
2. a kind of eye drops, by Nintedanib or its polymorph or its salt or Nintedanib hydrate or solvate and medicine
Acceptable carrier and excipient composition, the excipient are surfactant, gelling agent, organic cosolvent anti-corrosion on
Agent, fungicide or antiseptic, pH adjusting agent, isotonic agent, chelating agent, buffer, stabilizer, antioxidant, thickener
One or more of；The carrier is oleoyl LABRAFIL M 1944CS, sub-oleoyl LABRAFIL M 1944CS, bay
Acyl group LABRAFIL M 1944CS, atoleine, light liquid paraffin, soft paraffin (vaseline), hard paraffin, castor oil,
Peanut oil, sesame oil, median chain triglyceride oil, cetostearyl alcohol, lanolin, glycerine, propylene glycol, polyethylene glycol (PEG),
One or more of water.
Preferably, composed of the following components per 100mL：
Ethanesulfonic acid Nintedanib 1g, median chain triglyceride oil 15g, Tween 80 or Emulsifier EL-60 0.1g, soybean ovum
Phosphatidase 1 .5g, cholesterol 0.4g, glycerine 2g, benzalkonium chloride or benzalkonium bromide 0.01g, vitamin E 0.03g use hydrochloric acid
Or pH is adjusted to 6.5~7.5 by sodium hydroxide solution, surplus is water for injection.
Preferably, the eye drops pH is 6.8.
3. the preparation method of eye drops, includes the following steps：
By the Tween 80 of the median chain triglyceride oil of proportional quantity, soybean lecithin, glycerine and half proportional quantity or gather
Ethylene oxide castor oil, which is mixed and heated, to be stirred evenly, and the cholesterol mixing of proportional quantity is added, and A liquid is obtained after filtering；By proportional quantity
Ethanesulfonic acid Nintedanib be dissolved in A liquid；Meanwhile by the vitamin E of proportional quantity, benzalkonium chloride or benzalkonium bromide and
The Emulsifier EL-60 or Tween 80 of half proportional quantity obtain B liquid after being added to the water filtering, by B liquid at 1000 turns
/ timesharing emulsifying adds A liquid after ten minutes, adjusts pH to 6.5~7.5 with hydrochloric acid or sodium hydroxide solution, finally
The emulsifying 30 minutes at 3000 revs/min, 121 DEG C of moist heat sterilization 30min.
4. the application for the drug that the eye drops is formed as prevention age-related macular degeneration or choroidal neovascular.
5. a kind of ethanesulfonic acid Nintedanib eye ointment, composed of the following components per 100g：Ethanesulfonic acid Nintedanib 1g, liquid stone
Wax 10g, wool grease 10g, benzalkonium chloride 0.01g, surplus are vaseline.
6. a kind of preparation method of ethanesulfonic acid Nintedanib eye ointment, includes the following steps：
By the ethanesulfonic acid Nintedanib of the micronizing of proportional quantity, benzalkonium chloride and after the atoleine of sterilising filtration mixes
It is ground into thin paste, No. six sieves is crossed, adds the lanolin and vaseline of proportional quantity, stir evenly.
7. a kind of ethanesulfonic acid Nintedanib liposome eye drops, by ethanesulfonic acid Nintedanib, soybean lecithin, cholesterol and benzene
Oronain composition is pricked, the weight percent of each component is ethanesulfonic acid Nintedanib：Soybean lecithin：Cholesterol：Benzalkonium chloride
=2:10:4:0.02.
8. a kind of preparation method of ethanesulfonic acid Nintedanib liposome eye drops, includes the following steps：
Ethanesulfonic acid Nintedanib, soybean lecithin, cholesterol and the benzalkonium chloride of the micronizing of proportional quantity are dissolved in 10ml
In ether, the sodium chloride solution 10ml that pH value is 6.8, mass fraction 0.9% is added, interval is 30 minutes ultrasonic after mixing
Form stable water-in-oil emulsion；Then by the ether evaporative removal in emulsion, and continue to be evaporated to obtain uniform fat
Plastid suspension, by 0.45 μm of filtering with microporous membrane degerming of suspension.
Preferably, described to be evaporated to reduction vaporization, evaporating temperature is 30 DEG C.
The beneficial effects of the present invention are：Nintedanib relevant pharmaceutical composition of the present invention can be directed to VEGF,
Tri- kinds of angiogenesis receptors of PDGF, FGF carry out the treatment of ocular disorder, and access times are no more than 5 times daily, and
And it is capable of providing effective drug concentration, and then reach preferable control effect.
Specific implementation mode
The preferred embodiment of the present invention is described in detail below.Test method without specific conditions in embodiment,
Usually according to conventional conditions or according to the manufacturer's recommendations.
Embodiment 1
The preparation of ethanesulfonic acid Nintedanib eye ointment：
Preparation method：In C grades of clean area clean bench (sterile cabinet), by the ethanesulfonic acid Ni Dani of the micronizing of recipe quantity
Cloth and benzalkonium chloride are added to by aseptic manipulation in appropriate vessel, add the liquid stone of recipe quantity cooled down by sterilising filtration
Wax after being ground into thin paste, crosses No. six sieves, then is added gradually to lanolin, the vaseline base of the recipe quantity of sterilizing filtration
It in matter, stirs evenly, lets cool to obtain the final product.
Embodiment 2
The preparation of ethanesulfonic acid Nintedanib liposome eye drops：
Preparation method：In C grades of clean area clean bench (sterile cabinet), by the ethanesulfonic acid Ni Dani of the micronizing of recipe quantity
Cloth, soybean lecithin, cholesterol and benzalkonium chloride are dissolved in by aseptic manipulation in 10ml ether, as oil phase.It prepares
0.9% sodium chloride solution 10ml, hydrochloric acid or sodium hydroxide adjust pH to 6.8, as water phase.Above-mentioned two solution is mixed,
Interval ultrasound 30 minutes, until forming stable water/oil (W/O) emulsion.The emulsion is steamed in decompression on Rotary Evaporators
Hair removes organic solvent (30 DEG C of bath temperature, rotating speed 75r/min), and after forming gel in bottle wall, continuing rotary evaporation makes
Gel falls off aquation, obtains uniform liposome turbid liquor, close in 4 DEG C after 0.45 μm of filtering with microporous membrane degerming
Envelope preserves.
Embodiment 3
The preparation of ethanesulfonic acid Nintedanib emulsion-type eye drops：
Hydrochloric acid or sodium hydroxide adjust pH to 7.5, and water for injection adds to 100mL.
Preparation method：In C grades of clean area clean bench (sterile cabinet), by the median chain triglyceride oil of recipe quantity, soybean
The Emulsifier EL-60 of lecithin, glycerine and half recipe quantity, heating stir evenly, then cholesterol is added thereto makes
Dissolving is used as oil phase after filtering.The ethanesulfonic acid Nintedanib of the micronizing of recipe quantity is dissolved in by aseptic manipulation in oil phase,
Prescription is added in the Emulsifier EL-60 of the vitamin E of recipe quantity, the benzalkonium chloride of recipe quantity and half recipe quantity
In the water of amount, water phase is used as after filtering, by water phase at 1000 revs/min emulsifying 10 minutes, then oil phase is added rapidly
Enter in water phase, using hydrochloric acid or sodium hydroxide adjusting pH and osmotic pressure, the emulsifying 30 minutes at 3000 revs/min,
Moist heat sterilization (121 DEG C, 30min) in the aseptic subpackaged container to installation eye drops.
Embodiment 4
The preparation of ethanesulfonic acid Nintedanib emulsion-type eye drops：
Hydrochloric acid or sodium hydroxide adjust pH to 6.8, and water for injection adds to 100mL.
Preparation method：In C grades of clean area clean bench (sterile cabinet), by the median chain triglyceride oil of recipe quantity, soybean
The Tween 80 of lecithin, glycerine and half recipe quantity, heating stir evenly, then cholesterol is added thereto makes dissolving, mistake
Oil phase is used as after filter.The ethanesulfonic acid Nintedanib of the micronizing of recipe quantity is dissolved in by aseptic manipulation in oil phase.By prescription
The Tween 80 of the vitamin E of amount, the benzalkonium chloride of recipe quantity and half recipe quantity is added in the water of recipe quantity, filtering
Be used as water phase afterwards, by water phase at 1000 revs/min emulsifying 10 minutes, then oil phase is rapidly added in water phase, is utilized
Hydrochloric acid and/or sodium hydroxide adjust pH and osmotic pressure, the emulsifying 30 minutes at 3000 revs/min, aseptic subpackaged to holding
Fill moist heat sterilization (121 DEG C, 30min) in the container of eye drops.
Embodiment 5
The preparation of ethanesulfonic acid Nintedanib emulsion-type eye drops：
Hydrochloric acid or sodium hydroxide adjust pH to 6.5, and water for injection adds to 100mL.
Preparation method：In C grades of clean area clean bench (sterile cabinet), by the median chain triglyceride oil of recipe quantity, soybean
The Emulsifier EL-60 of lecithin, glycerine and half recipe quantity, heating stir evenly, then cholesterol is added thereto makes
Dissolving is used as oil phase after filtering.The ethanesulfonic acid Nintedanib of the micronizing of recipe quantity is dissolved in by aseptic manipulation in oil phase.
Prescription is added in the Emulsifier EL-60 of the vitamin E of recipe quantity, the benzalkonium bromide of recipe quantity and half recipe quantity
In the water of amount, water phase is used as after filtering, by water phase at 1000 revs/min emulsifying 10 minutes, then oil phase is added rapidly
Enter in water phase, using hydrochloric acid and/or sodium hydroxide adjusting pH and osmotic pressure, the emulsifying 30 minutes at 3000 revs/min,
Moist heat sterilization (121 DEG C, 30min) in the aseptic subpackaged container to installation eye drops.
Ethanesulfonic acid Nintedanib emulsion-type eye drops prepared by embodiment 3~5 is measured into pH, osmotic pressure, viscosity, clear respectively
Lightness detects and average grain diameter, and carries out accelerated test, the results are shown in Table 1.
The dependence test result of 1 eye drops of table
| Embodiment 3 | Embodiment 4 | Embodiment 5 | |
| pH | 7.5 | 6.8 | 6.5 |
| Osmotic pressure (mOsm) | 290 | 270 | 270 |
| Viscosity (cPa.s) | 4.43 | 4.08 | 3.90 |
| Clarity detects | Without visible foreign matters | Without visible foreign matters | Without visible foreign matters |
| Average grain diameter (nm) | 422 | 380 | 475 |
| 0 day | Yellow emulsion | Yellow emulsion | Yellow emulsion |
| 40 DEG C, RH75%5 days | Yellow emulsion | Yellow emulsion | Yellow emulsion |
| 40 DEG C, RH75%10 days | Yellow emulsion | Yellow emulsion | Yellow emulsion |
| 40 DEG C, RH75%30 days | Yellow emulsion | Yellow emulsion | Yellow emulsion |
As seen from the results in Table 1：Eye drip formula of liquid of the present invention has good under accelerated test (40 DEG C, RH75%)
Stability, and pH, osmotic pressure, viscosity, clarity and average grain diameter meet the requirement of eye drops.
It is that ethanesulfonic acid Nintedanib emulsion-type eye drops of the present invention causes the correlation of cornea rebirth blood vessel to grind alkali burn below
Study carefully.
Object of this investigation is to determine that the ethanesulfonic acid Nintedanib emulsion-type eye drops of the present invention causes cornea rebirth in alkali burn
Whether corneal neovascularization can be caused to reduce in the rabbit model of blood vessel research.
For this purpose, taking the healthy new zealand rabbit 18 without eye illness, claim its weight, is anaesthetized with 3% yellow Jackets
(1ml/kg), and local anaesthetics lidocaine hydrochloride is bestowed in ocular surface, dosage is 20 μ l/；Prepare the filter of 9mm diameters
The scraps of paper are soaked in about 10s in 1mol/L sodium hydroxide solutions, and filter paper is positioned on dry filter paper with tweezers and is sucked
Extra sodium hydroxide solution is removed after the filter paper for being soaked with sodium hydroxide is hit exactly 60s as rabbit eyes cornea,
Wash bottle about 20ml normal saline flushing corneas are taken rapidly, and give prevention antibiotic to prevent infection (aureomycin hydrochloride eye
Cream), 2 times/day.
It is divided into burn, A (ethanesulfonic acid Nintedanib emulsion-type eye drops (is prepared) 10mg/ml by embodiment 1) after modeling immediately,
B (ethanesulfonic acid Nintedanib emulsion-type eye drops (is prepared) 5mg/ml by embodiment 1), C (is free of ethanesulfonic acid Ni Dani
The pharmaceutical base (being prepared by embodiment 1) of cloth) four groups, it is 0 day on the day of modeling, since the 1st day, A, B, C
Group gives relative medicine respectively, and 5 times/day of administration frequency, 50 μ l/, successive administration 10 days separately take dosage every time
2 new zealand rabbits are normal group.Simultaneously, observing eye cornea rebirth blood vessel (NV) growth conditions and eye are for daily administration
It is no separately to have inflammatory reaction.
In administration the 10th day, 3% yellow Jackets anesthetized animal (1ml/kg), and local anaesthetics hydrochloric acid is bestowed in ocular surface
Lidocaine, dosage is 20 μ l/, in 10 times of hour directions object microscopic observation rabbit cornea NV of slit-lamp, while
It takes a picture under 10 times and 16 times of object lens.It acquires image and carries out hour number correction in Photoshop CS, cornea rebirth area is adopted
With Image Pro Plus processing；Area formula：S=C/12 × 3.1416 × [R2-(R-L)2], C indicates the cornea side in picture
Edge indicates in picture from the hour number having shared by NV to no NV growth time points, R from the edge that cornea is contacted with sclera
To the length of corneal center, L indicates the end of cornea and NV in the root to cornea of sclera engagement edge NV in picture
NV length takes a longest length of vessel in each hour.All data statistic analysis are analyzed using T variance tests.
Data withIt indicates,It is average value, s is standard deviation.It the results are shown in Table 2.
2 ethanesulfonic acid Nintedanib emulsion-type eye drops of table causes cornea rebirth blood vessel result of study to alkali burn
Cornea rebirth blood vessel area effect：Cornea NV area data analysis results are shown in Table 2 within 10th day, as shown in Table 2,
Compared with alkali burn group and pharmaceutical base without ethanesulfonic acid Nintedanib, ethanesulfonic acid Nintedanib 5mg/ml and ethanesulfonic acid
Nintedanib 10mg/ml can obviously inhibit cornea NV to grow, and reduce NV areas, have statistical significance (P
＜ 0.05), and 10mg/ml inhibitions are better than 5mg/ml.Although the pharmaceutical base unrestraint without ethanesulfonic acid Nintedanib
Cornea rebirth blood vessel growth, and NV areas are more than burn group, but there was no significant difference.
The total amount that eye drops of the present invention is administered to the activating agent in eyes is usually application every time, and each eyes are about
0.01-50mg, preferably 0.02-10mg, more preferably 0.05-5mg ranges, apply once or more daily, preferably extremely
More 5 times, most preferably up to 3 times.
Eye drops chemical stability of the present invention be more than 24 months, the chemical stabilization refer to activating agent during storage not
It can significantly degrade.
Finally illustrate, preferred embodiment above is merely illustrative of the technical solution of the present invention and unrestricted, although passing through
Above preferred embodiment is described in detail the present invention, however, those skilled in the art should understand that, can be
Various changes are made to it in form and in details, without departing from claims of the present invention limited range.
Claims (10)
1. Nintedanib and its salt or polymorph, Nintedanib hydrate or solvate are as active constituent in prevention eye disease
Application in the drug of disease, which is characterized in that the eye disease is age-related macular degeneration, choroidal neovascular is formed,
Detached retina, diabetic retinopathy, the atrophy change of retinal pigment epithelium tissue, retinal pigment epithelium tissue
Hypertrophy change, retinal vein occlusion, chorioretinal vein occlusion, macular edema, the angiogenesis of ocular region, angle
Before film angiogenesis, pteryium conjunctiva, subretinal, choroidal neovascularization, cystoid macular edema, retina
It is film, macula hole, blood vessel striped, retinitis pigmentosa, recessive macular dystrophy, glaucoma, cataract, inflammatory condition, stupid
One or more of solidity exception, keratoconus, retinopathy of prematurity, intraretinal edema or high myopic eye.
2. Nintedanib and its salt or polymorph, Nintedanib hydrate or solvate are as work according to claim 1
Property ingredient prevention eye disease drug in application, which is characterized in that the active constituent be Nintedanib esilate,
The drug is the composition of Nintedanib esilate, and the pH of composition is 6~9, and Nintedanib esilate is in the composition
Mass fraction be 0.01~10%；The composition is eye drops, Eye ointments, eyewash, liposome, micro-capsule, microballoon or eye
Interior injection.
3. a kind of eye drops, which is characterized in that by Nintedanib or its polymorph or its salt or Nintedanib hydrate or solvent
Close object and pharmaceutically acceptable carrier and excipient composition, the excipient is surfactant, gelling agent, organic molten altogether
Agent preservative, fungicide or antiseptic, pH adjusting agent, isotonic agent, chelating agent, buffer, stabilizer, antioxidant, thickening
One or more of agent；The carrier is oleoyl LABRAFIL M 1944CS, sub-oleoyl LABRAFIL M 1944CS, lauroyl
Base LABRAFIL M 1944CS, atoleine, light liquid paraffin, vaseline, hard paraffin, castor oil, peanut oil, sesame oil,
One or more of median chain triglyceride oil, cetostearyl alcohol, lanolin, glycerine, propylene glycol, polyethylene glycol, water.
4. eye drops according to claim 3, which is characterized in that composed of the following components per 100mL：
Ethanesulfonic acid Nintedanib 1g, median chain triglyceride oil 15g, Tween 80 or Emulsifier EL-60 0.1g, soybean lecithin
1.5g, cholesterol 0.4g, glycerine 2g, benzalkonium chloride or benzalkonium bromide 0.01g, vitamin E 0.03g, with hydrochloric acid or hydroxide
PH is adjusted to 6.5~7.5 by sodium solution, and surplus is water for injection.
5. the preparation method of the eye drops of claim 3 or 4, which is characterized in that include the following steps：
By the Tween 80 or polyoxy second of the median chain triglyceride oil of proportional quantity, soybean lecithin, glycerine and half proportional quantity
Alkene castor oil, which is mixed and heated, to be stirred evenly, and the cholesterol mixing of proportional quantity is added, and A liquid is obtained after filtering；By the ethanesulfonic acid of proportional quantity
Nintedanib is dissolved in A liquid；Meanwhile the vitamin E of proportional quantity, benzalkonium chloride or benzalkonium bromide and half being matched
The Emulsifier EL-60 or Tween 80 of amount are added to the water after filtering to obtain B liquid, the emulsifying 10 at 1000 revs/min by B liquid
A liquid is added after minute, adjusts pH to 6.5~7.5 with hydrochloric acid or sodium hydroxide solution, finally the homogenized milk at 3000 revs/min
Change 30 minutes, 121 DEG C of moist heat sterilization 30min.
6. the drug that the eye drops of claim 3 or 4 is formed as prevention age-related macular degeneration or choroidal neovascular
Application.
7. a kind of ethanesulfonic acid Nintedanib eye ointment, which is characterized in that composed of the following components per 100g：Ethanesulfonic acid Nintedanib 1g,
Atoleine 10g, wool grease 10g, benzalkonium chloride 0.01g, surplus are vaseline.
8. a kind of preparation method of ethanesulfonic acid Nintedanib eye ointment described in claim 7, which is characterized in that include the following steps：
It is ground by the ethanesulfonic acid Nintedanib of the micronizing of proportional quantity, benzalkonium chloride and after the atoleine of sterilising filtration mixes
At thin paste, No. six sieves are crossed, the lanolin and vaseline of proportional quantity is added, stirs evenly.
9. a kind of ethanesulfonic acid Nintedanib liposome eye drops, which is characterized in that by ethanesulfonic acid Nintedanib, soybean lecithin,
The weight percent of cholesterol and benzalkonium chloride composition, each component is ethanesulfonic acid Nintedanib：Soybean lecithin：Cholesterol：Benzene
Prick oronain=2:10:4:0.02.
10. a kind of preparation method of ethanesulfonic acid Nintedanib liposome eye drops described in claim 9, which is characterized in that including such as
Lower step：
Ethanesulfonic acid Nintedanib, soybean lecithin, cholesterol and the benzalkonium chloride of the micronizing of proportional quantity are dissolved in 10ml ether,
The sodium chloride solution 10ml that pH value is 6.8, mass fraction 0.9% is added, interval ultrasound forms stable oil in 30 minutes after mixing
Water-in type emulsion；Then by the ether evaporative removal in emulsion, and continue to be evaporated to obtain uniform liposome turbid liquor, will mix
0.45 μm of filtering with microporous membrane degerming of suspension.
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| CN201510908457.7A CN108295072A (en) | 2015-12-09 | 2015-12-09 | Nintedanib prevents the purposes of eye disease |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107865821A (en) * | 2016-09-26 | 2018-04-03 | 瑞阳(苏州)生物科技有限公司 | A kind of preparation for preventing or treating CNV and formed |
| CN109475506A (en) * | 2016-06-02 | 2019-03-15 | 拨云生物医药科技(广州)有限公司 | The composition and method of the eye disease formed with aberrant nascent vessels are treated using Nintedanib |
| CN111789842A (en) * | 2020-08-07 | 2020-10-20 | 南开大学 | Application of nintedanib in preparation of medicine for treating inflammatory bowel disease |
| CN112654345A (en) * | 2018-09-10 | 2021-04-13 | 台湾微脂体股份有限公司 | Sustained-release ophthalmic pharmaceutical composition and use thereof |
| CN114340618A (en) * | 2019-09-10 | 2022-04-12 | 克劳德布雷克医疗有限责任公司 | Method for mitigating pterygium-related eye appearance concerns |
| CN116139145A (en) * | 2022-09-09 | 2023-05-23 | 中南民族大学 | New application of nintedanib ethanesulfonate in preventing and treating type II diabetes |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102295640A (en) * | 2011-06-29 | 2011-12-28 | 南京工业大学 | 3-heterocycle schiff base-5-fluorine-indole-2-ketone compounds, preparation method thereof and application thereof |
| CN104003925A (en) * | 2013-06-05 | 2014-08-27 | 四川大学 | Indolone compounds or derivatives thereof and applications thereof |
| WO2015029948A1 (en) * | 2013-08-26 | 2015-03-05 | リンク・ジェノミクス株式会社 | Prophylactic or therapeutic agent for retinal disease caused by retinal pigment epithelium disorder |
| CN104884049A (en) * | 2012-11-08 | 2015-09-02 | 克莱尔塞德生物医学股份有限公司 | Methods and devices for the treatment of ocular diseases in human subjects |
| CN105001143A (en) * | 2015-07-24 | 2015-10-28 | 南京正大天晴制药有限公司 | Method for preparing high-purity ethanesulfonic acid nintedanib |
| CN107708664A (en) * | 2015-06-22 | 2018-02-16 | 新源生物科技股份有限公司 | The ophthalmically acceptable composite of tyros kinase inhibitor, its application method, and preparation method thereof |
-
2015
- 2015-12-09 CN CN201510908457.7A patent/CN108295072A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102295640A (en) * | 2011-06-29 | 2011-12-28 | 南京工业大学 | 3-heterocycle schiff base-5-fluorine-indole-2-ketone compounds, preparation method thereof and application thereof |
| CN104884049A (en) * | 2012-11-08 | 2015-09-02 | 克莱尔塞德生物医学股份有限公司 | Methods and devices for the treatment of ocular diseases in human subjects |
| CN104003925A (en) * | 2013-06-05 | 2014-08-27 | 四川大学 | Indolone compounds or derivatives thereof and applications thereof |
| WO2015029948A1 (en) * | 2013-08-26 | 2015-03-05 | リンク・ジェノミクス株式会社 | Prophylactic or therapeutic agent for retinal disease caused by retinal pigment epithelium disorder |
| CN107708664A (en) * | 2015-06-22 | 2018-02-16 | 新源生物科技股份有限公司 | The ophthalmically acceptable composite of tyros kinase inhibitor, its application method, and preparation method thereof |
| CN105001143A (en) * | 2015-07-24 | 2015-10-28 | 南京正大天晴制药有限公司 | Method for preparing high-purity ethanesulfonic acid nintedanib |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109475506A (en) * | 2016-06-02 | 2019-03-15 | 拨云生物医药科技(广州)有限公司 | The composition and method of the eye disease formed with aberrant nascent vessels are treated using Nintedanib |
| CN107865821A (en) * | 2016-09-26 | 2018-04-03 | 瑞阳(苏州)生物科技有限公司 | A kind of preparation for preventing or treating CNV and formed |
| CN107865821B (en) * | 2016-09-26 | 2021-07-02 | 瑞阳(苏州)生物科技有限公司 | A preparation for preventing or treating choroidal neovascularization |
| CN112654345A (en) * | 2018-09-10 | 2021-04-13 | 台湾微脂体股份有限公司 | Sustained-release ophthalmic pharmaceutical composition and use thereof |
| CN114340618A (en) * | 2019-09-10 | 2022-04-12 | 克劳德布雷克医疗有限责任公司 | Method for mitigating pterygium-related eye appearance concerns |
| CN111789842A (en) * | 2020-08-07 | 2020-10-20 | 南开大学 | Application of nintedanib in preparation of medicine for treating inflammatory bowel disease |
| CN116139145A (en) * | 2022-09-09 | 2023-05-23 | 中南民族大学 | New application of nintedanib ethanesulfonate in preventing and treating type II diabetes |
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