CN109106684A - A kind of non-steroidal anti-inflammatory gel for eye use and preparation method thereof - Google Patents
A kind of non-steroidal anti-inflammatory gel for eye use and preparation method thereof Download PDFInfo
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- CN109106684A CN109106684A CN201811026040.8A CN201811026040A CN109106684A CN 109106684 A CN109106684 A CN 109106684A CN 201811026040 A CN201811026040 A CN 201811026040A CN 109106684 A CN109106684 A CN 109106684A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
It include following component: the water for injection of Flurbiprofen precursor medicine 0.01-0.1g, sodium hyaluronate 0.1-0.35g, natrium adetate 0.005-0.8g, sodium chloride 0.375-0.85g, thickener 0.3-1.6g and surplus in every 100mL gel for eye use the invention discloses a kind of non-steroidal anti-inflammatory gel for eye use；The Flurbiprofen precursor medicine is flurbiprofen axetil or Flurbiprofen pharmaceutically acceptable salt, and the present invention also provides the preparation methods of the gel for eye use.Gel for eye use of the invention has many advantages, such as that comfort is strong, nonirritant, good drug efficacy, and preparation method is easy to industrialized production.
Description
Technical field
The present invention relates to field of medicaments, more specifically to a kind of non-steroidal anti-inflammatory gel for eye use and preparation method thereof.
Background technique
Flurbiprofen precursor medicine is propionic non-steroid antiphlogistic (NSAIDs), and the mechanism of action is to inhibit epoxidation enzyme activity
Property block prostaglandin synthesis.Prostaglandin is the medium of certain intraocular inflammations, can cause blood aqueous barrier collapse, blood vessel dilatation,
Vasopermeability increase, leukocyte chemotaxis, cause the myosis unrelated with cholinergic mechanism.Clinical research shows that this product can
Inhibit myosis when cataract operation, intraocular pressure is had no significant effect, analgesic effect is than Ketoprofen, Indomethacin, naphthalene
General life is 10-20 times strong, works rapidly and has potent, balanced analgesia, anti-inflammatory, refrigeration function；Using safer, pro-drug disappears
It is low to change road adverse reaction rate, can take for a long time, Small side effects.Flurbiprofen precursor medicine listing dosage form has mouth both at home and abroad at present
Liquid, spansule, transdermal patch, gelling agent, cataplasm, gel for eye use are taken, is clinically mainly used for treating class
Rheumathritis, osteoarthritis, ankylosing spondylitis, trauma pain and other pain, due to blood-ocular barrier, fluorine ratio
The systemic medication of ibuprofen precursor medicine what effect no for the local inflammation of eye, moreover, the whole body of Flurbiprofen precursor medicine
Using can also generate a series of side effects.
In order to adapt to the needs of ophthalmic administration, people have done some researchs, promote drug by being arranged to gel or micro emulsion
In the residence time of agents area, and increase drug effect, such as:
The Chinese patent application file of Publication No. CN101385697A discloses a kind of ophthalmically acceptable nanometer of flurbiprofen axetil
Cream-in-situ gel preparation and preparation method thereof, the flurbiprofen axetil eye nano-emulsion in-situ gel preparation is by oil, emulsifier, increasing
Thick dose, osmotic pressure regulator, bacteriostatic agent, purified water be prepared；It mainly consists of the following compositions: flurbiprofen axetil 100-
500mg, oil 5-100g, emulsifier 1-50g, thickener 2-50g, appropriate osmotic pressure regulator, bacteriostatic agent 0.0-0.5g, pH are adjusted
Appropriate agent, purified water add to 1000mL, and obtained gelling agent can increase drug in the eye residence time, to extend drug work
With the time, heighten the effect of a treatment.
The Chinese patent application file of Publication No. CN102159186B discloses one kind and discloses a kind of flurbiprofen axetil
Eye nano-emulsion in-situ gel preparation and preparation method thereof, the flurbiprofen axetil eye nano-emulsion in-situ gel preparation by oil,
Emulsifier, thickener, osmotic pressure regulator, bacteriostatic agent, purified water are prepared；It mainly consists of the following compositions: Flurbiprofen
Ester 100-1000mg, oil 5-100g, emulsifier 1-50g, thickener 2-50g, appropriate osmotic pressure regulator, bacteriostatic agent 0.0-
0.5g, pH adjusting agent adjust pH value 4-9, purified water and add to 1000m, and obtained gelling agent can play nano-emulsion and gelling agent
Feature reduces medicine irritation, realizes long-acting drug release, stability is good.
The Chinese patent application file of Publication No. CN102920651A discloses a kind of flurbiprofen axetil micro emulsion gel system
Agent and preparation method thereof, including gel-type vehicle and drug containing micro emulsion, drug containing micro emulsion include oil phase substance 1-5%, surfactant 20-
35%, cosurfactant 7.5-15%, flurbiprofen axetil 0.5-1.5%, excess water；It is able to ascend drug effect and service efficiency.
The Chinese patent application file of Publication No. CN107157962A, disclose a kind of cataplasm by back sheet,
Drug-reservoir and protective layer composition, it is characterized in that the drug-reservoir consists of the following components in percentage by weight: as activity
The Flurbiprofen 0.2-0.5% of ingredient；Oil-phase component 5-10%, the oil-phase component by 1:0.08-0.12 castor oil and benzene
Methanol composition, the Flurbiprofen are redispersed in castor oil after being first dissolved in benzyl alcohol；Part as water-phase component neutralizes poly-
Sodium acrylate 5-10%, glycerine 15-20%, Dihydroxyaluminium Aminoacetate 0.2%-0.4%, mosatil 0.1-0.3, % carbomer
9341%-1.5%, sodium carboxymethylcellulose (CMC-Na) 1.5-3%, pH adjusting agent, gellan gum 0.05-0.1%, L- glycine
1%-1.5%；The water of filler 1-3% and surplus, water-phase component and water form hydrogel, and filler dispersed filler is in water-setting
In glue, oil-phase component emulsion dispersion forms drug-reservoir in hydrogel；Obtained flurbiprofen cataplasms can be taken into account quickly
With sustained release performance.
Above-mentioned technical proposal solves the time for solving medicine retention to a certain extent, but the use of oil is brought centainly
Discomfort in degree, while there are certain deficiencies for the stability of drug and scope of application Shanghai.
Summary of the invention
For existing non-steroidal anti-inflammatory gel for eye use medication comfort and in terms of insufficient problem, the present invention
Be designed to provide a kind of with good medication comfort, the gel for eye use that stability is strong, applied widely, while this hair
It is bright that the preparation method and application of the gel for eye use are also provided.
A kind of non-steroidal anti-inflammatory gel for eye use includes following component: Flurbiprofen precursor medicine in every 100mL gel for eye use
0.01-0.1g, sodium hyaluronate 0.1-0.35g, natrium adetate 0.005-0.8g, sodium chloride 0.375-0.85g, thickener 0.3-
The water for injection of 1.6g and surplus；The Flurbiprofen precursor medicine is that flurbiprofen axetil or Flurbiprofen are pharmaceutically acceptable
Salt.
The present invention also provides the preparation methods of non-steroidal anti-inflammatory gel for eye use, specifically comprise the following steps:
A. solvent swell will be thickened with appropriate water for injection, stirred evenly, and form gel-type vehicle；
B. it is dissolved, is obtained with appropriate water for injection and Flurbiprofen precursor medicine, sodium hyaluronate, natrium adetate, sodium chloride
Flurbiprofen precursor drug solns；
C. gel-type vehicle is mixed with Flurbiprofen precursor drug solns, water for injection constant volume is added, so that before Flurbiprofen
Body concentration be 0.1-1mg/mL, stir evenly, filter to get.
Gel for eye use of the invention is combined by the selection and proportion of raw material, so that eye liquid integrally has good eye
The advantages that interior bioavilability is higher, and penetration is strong, targeting is strong, toxic side effect is small, eye drip is comfortable；Suitable for treatment and in advance
External eyes caused by anti-non-infectious inflammation and anterior disease of eye and post-operation inflammatory；Raw material is easy to get, at low cost, and industry may be implemented
Change large-scale production, there is significant economic benefit.
Specific embodiment
A kind of non-steroidal anti-inflammatory gel for eye use, including following component: including following component: fluorine in every 100mL gel for eye use
Than ibuprofen precursor medicine 0.01-0.1g, sodium hyaluronate 0.1-0.35g, natrium adetate 0.005-0.8g, sodium chloride 0.375-
The water for injection of 0.85g, thickener 0.3-1.6g and surplus；The Flurbiprofen precursor medicine is flurbiprofen axetil or Flurbiprofen
Pharmaceutically acceptable salt.
Non-steroidal anti-inflammatory gel for eye use of the invention, in order to enable medication is more comfortable, it can also include that osmotic pressure is adjusted
Agent and pH adjusting agent；Wherein osmotic pressure regulator and pH adjusting agent can select the acceptable various corresponding originals of ophthalmic administration
Material；The specific osmotic pressure regulator can be sodium chloride and/or mannitol；The pH adjusting agent can be hydroxide
The combination of one or more of the minor official acid of sodium, hydrochloric acid, sodium citrate, Chinese holly, boric acid, borax.
In order to enable gel for eye use is more stable and safe, the gel for eye use may also include bacteriostatic agent；The bacteriostatic agent
With the weight ratio of Flurbiprofen precursor medicine: for Flurbiprofen precursor medicine: bacteriostatic agent=1:0.02-1；Bacteriostatic agent can select eye
The acceptable various bacteriostatic agents of medication；Specifically, can select the bacteriostatic agent is thimerosal, quaternary ammonium salt, Domiphen, Xian Bi
The combination of one or more of Thailand, anesin, parabens and sorbic acid.
Thickener of the invention can select acceptable each thickener of ophthalmic administration and combinations thereof；The thickener is
Hydroxypropyl methylcellulose and/or carbomer；In order to enable drug effect is more preferable, more stable, the thickener is hydroxypropyl methylcellulose or card
Wave nurse, wherein the hydroxypropyl methylcellulose methoxyl value 19.0%-30.0%, hydroxypropyl base value 4%-12%；The carbomer
Model 910,934,934P, 940,941.
In order to use medicine more comfortable, the pH value of the gel for eye use is 5.5-7.5；The osmol of the gel for eye use
Your concentration is 250-350mOsmol/kg.
The present invention also provides the preparation methods of the non-steroidal anti-inflammatory gel for eye use, include the following steps:
A. solvent swell will be thickened with appropriate water for injection, stirred evenly, and form gel-type vehicle；
B. it is dissolved, is obtained with appropriate water for injection and Flurbiprofen precursor medicine, sodium hyaluronate, natrium adetate, sodium chloride
Flurbiprofen precursor drug solns；
C. gel-type vehicle is mixed with Flurbiprofen precursor drug solns, water for injection constant volume is added, so that before Flurbiprofen
Body concentration be 0.1-1mg/mL, stir evenly, filter to get.
Further, dissolving bacteriostatic agent, pH adjusting agent and osmotic pressure respectively using appropriate water for injection in step
Then regulator is added in gel-type vehicle, the pH value for adjusting gel-type vehicle is 5.5-7.5, adjusts the osmol of gel-type vehicle
Your concentration is 250-350mOsmol/kg, and the gel-type vehicle viscosity in the step A is that measured value is 3.0- at 30 ± 0.1 DEG C
30.0mm2/s；The weight average molecular weight of sodium hyaluronate in the step C should be not less than 400,000, and dispersion of distribution Mw/Mn should be less than 3.
Eye drops of the invention, being added to thickener makes hydrophobic main chain and surrounding water molecules by hydrogen bond association, improves
The fluid volume of this product reduces the movable space of Particle free, so that system viscosity is improved, before maintaining flurbiprofen sodium
The stability of body medicine, while the lubricity of this product is increased, eye drip is comfortable；In addition, the present invention is only appropriate to be added to eye drops
Necessary auxiliary material avoids excessive auxiliary material for the drug effect interference of Flurbiprofen precursor medicine, the toxic side effect of reduction preparation；It seeps
This product can be adjusted to isotonic and suitable pH value by the addition of pressure regulator and pH adjusting agent thoroughly, and eye drip is more comfortable；Bacteriostatic agent
Can pathogen be killed or be inhibited its growth, breeding；Compared with other prior arts, present invention process is more compared with the prior art
It is simple and easy, it is at low cost, industrialization large-scale production may be implemented.
Gel for eye use of the invention, be suitable for treating and prevention non-infectious inflammation caused by external eyes and anterior disease of eye with
And post-operation inflammatory.
In the following, being described further in conjunction with specific embodiment to the present invention:
Embodiment 1-10
The raw material and proportion situation of 1 gel for eye use of table
Embodiment 1
It will stock up first by being formulated shown in table 1；
Step A, it is penetrated with water with three times quality by the static swelling of sodium carboxymethylcellulose 12 hours, stirs evenly, form gel base
Matter；Bacteriostatic agent is dissolved with appropriate water for injection, filtering is stirred evenly, is mixed with gel-type vehicle；Separately pH is dissolved with water for injection in right amount
Regulator is slowly added in gel-type vehicle obtained by step, and adjusting pH value is 7.5 i.e. stopping；It is pressed and is adjusted with water for injection solution pervasion
Agent is saved, is slowly added in gel-type vehicle obtained by step, adjusts osmotic pressure molar density to the i.e. stopping addition of 250mOsmol/kg；
Step B), with sodium hyaluronate, natrium adetate and sodium chloride dissolve flurbiprofen sodium precursor medicine, obtain Flurbiprofen
Precursor drug solns；
Step C), in the resulting gel-type vehicle of step A be added the resulting Flurbiprofen precursor drug solns of step B, add surplus
Remaining water for injection constant volume 100mL, stirs evenly filtering, packing to get.
Bacteriostatic agent thimerosal, thickener carbomer, pH adjusting agent are sodium hydroxide solution and/or hydrochloric acid solution；It seeps
Pressure regulator is sodium chloride and/or mannitol thoroughly, to adjust solution osmotic pressure molar density.
Embodiment 2
It will stock up first by being formulated shown in table 1；
Step A, it is penetrated with water with three times quality by the static swelling of sodium carboxymethylcellulose 15 hours, stirs evenly, form gel base
Matter；Bacteriostatic agent is dissolved with appropriate water for injection, filtering is stirred evenly, is mixed with gel-type vehicle；Separately pH is dissolved with water for injection in right amount
Regulator is slowly added in gel-type vehicle obtained by step, and adjusting pH value is 5.5 i.e. stopping；It is pressed and is adjusted with water for injection solution pervasion
Agent is saved, is slowly added in gel-type vehicle obtained by step, adjusts osmotic pressure molar density to the i.e. stopping addition of 350mOsmol/kg；
Step B), with sodium hyaluronate, natrium adetate and sodium chloride dissolve flurbiprofen sodium precursor medicine, obtain Flurbiprofen
Precursor drug solns；
Step C), in the resulting gel-type vehicle of step A be added the resulting Flurbiprofen precursor drug solns of step B, add surplus
Remaining water for injection constant volume 100mL, stirs evenly filtering, packing to get.
Bacteriostatic agent benzalkonium chloride, thickener hydroxypropyl methylcellulose, pH adjusting agent are sodium citrate and the minor official acid of Chinese holly；Infiltration
Pressure regulator is mannitol, to adjust solution osmotic pressure molar density；
Embodiment 3
It will stock up first by being formulated shown in table 1；
Step A, it is penetrated with water with three times quality by the static swelling of sodium carboxymethylcellulose 12 hours, stirs evenly, form gel base
Matter；Bacteriostatic agent is dissolved with appropriate water for injection, filtering is stirred evenly, is mixed with gel-type vehicle；Separately pH is dissolved with water for injection in right amount
Regulator is slowly added in gel-type vehicle obtained by step, and adjusting pH value is that 5.5-7.5 stops；With water for injection solution pervasion
Regulator is pressed, is slowly added in gel-type vehicle obtained by step, osmotic pressure molar density is adjusted and stops adding to 300mOsmol/kg
Add；
Step B), with sodium hyaluronate, natrium adetate and sodium chloride dissolve flurbiprofen sodium precursor medicine, obtain Flurbiprofen
Precursor drug solns；
Step C), in the resulting gel-type vehicle of step A be added the resulting Flurbiprofen precursor drug solns of step B, add surplus
Remaining water for injection constant volume 100mL, stirs evenly filtering, packing to get.
Bacteriostatic agent Domiphen, thickener methylcellulose, pH adjusting agent are boric acid and borax；Osmotic pressure regulator is
Sodium chloride and/or mannitol, to adjust solution osmotic pressure molar density；
Embodiment 4-10
It will stock up first by being formulated shown in table 1；
Step A, it is penetrated with water with three times quality by the static swelling of sodium carboxymethylcellulose 12 hours, stirs evenly, form gel base
Matter；Bacteriostatic agent is dissolved with appropriate water for injection, filtering is stirred evenly, is mixed with gel-type vehicle；Separately pH is dissolved with water for injection in right amount
Regulator is slowly added in gel-type vehicle obtained by step, and adjusting pH value is 5.5 i.e. stopping；It is pressed and is adjusted with water for injection solution pervasion
Agent is saved, is slowly added in gel-type vehicle obtained by step, adjusts osmotic pressure molar density to the i.e. stopping addition of 350mOsmol/kg；
The pH adjusting agent is sodium citrate and the minor official acid of Chinese holly；Osmotic pressure regulator is sodium chloride and/or mannitol, to adjust
Save solution osmotic pressure molar density.
The pharmacokinetics of 1 embodiment of experimental example, 3 gel for eye use
Commercially available 0.03% flurbiprofen sodium eye drops (trade name Ocufen, the Ireland Ai Ligen are compareed with 3 eye ointment of embodiment
Drugmaker) pharmacokinetic is carried out, new zealand rabbit right and left eyes are administered simultaneously, and dosage is 50 μ L,.Respectively at administration
20,40,60,80,100,120,150,210,270,360,480min extraction 30 μ l of aqueous humor detection afterwards；Aqueous humor samples are through LC-MS
Measurement, the results are shown in Table 2:
Table 2: the main medicine of new zealand rabbit eye single dose embodiment 3 eye ointment and 0.03% flurbiprofen sodium eye drops
For kinetic parameter
The preparation of tissue samples: animal is put to death with gas embolism method after single dose administration, then strikes off cornea with blade
Epithelium, normal saline flushing conjunctival sac, extract aqueous humor, the moisture of conjunctival sac is blotted with cotton swab, with micro- clip part bulbar conjunctiva,
Then cornea, iris, retina, vitreum and sclera use normal saline flushing, are placed on 1.5ml test tube after filter paper suck dry moisture
In, it closes the lid, is placed on electronic balance weighing as early as possible, is then transferred into 8ml teat glass, add methylene chloride 5ml, and use is micro-
It cuts and sufficiently crushes tissue.After ten minutes with centrifuge centrifugation, it takes bottom methylene chloride 4.5ml in another test tube, is blown with nitrogen
It is dry.Closed test tube mouth is saved in 4 DEG C.Experiment shows that Flurbiprofen precursor medicine is distributed widely in intraocular each Main Tissues, with knot
Concentration highest in film, cornea and iris.The Flurbiprofen precursor medicine distributed density of eye Main Tissues is shown in Table 3-4 after administration.
Table 3: new zealand rabbit gives the concentration of Flurbiprofen precursor medicine in ocular tissue after embodiment 3
Table 4: new zealand rabbit gives the concentration of flurbiprofen sodium in ocular tissue after 0.03% flurbiprofen sodium eye drops
| Tissue | 60min | 120min | 240min |
| Conjunctiva (μ g/g) | 660.18±218.78 | 410.25±90.68 | 312.90±192.47 |
| Cornea (μ g/g) | 607.47±198.19 | 505.44±179.90 | 298.90±30.78 |
| Iris (μ g/g) | 275.11±125.19 | 101.23±49.97 | 102.67±96.76 |
| Retina (μ g/g) | 142.52±65.33 | 100.08±26.50 | 21.58±6.12 |
| Vitreum (μ g/g) | 4.17±1.98 | 3.67±2.00 | 2.78±1.12 |
| Sclera (μ g/g) | 67.28±27.68 | 50.78±12.98 | 20.35±18.56 |
The result shows that Flurbiprofen precursor medicine gel for eye use of the invention, intraocularly before the Flurbiprofen in each Main Tissues
Body concentration is relatively high, especially with concentration highest in conjunctiva, cornea and iris, illustrates Flurbiprofen precursor medicine eye of the invention
More preferable with gel intraocular penetration, concentration is high, for treat intraocular noninfectious disease fully achieve effectively treat it is dense
Degree.
The zoopery of experimental example 1, inventive embodiments are also repeated in the gel for eye use of embodiment 1-2,4-10 by inventor
The effect of gel for eye use of 1-2,4-10, is approximate with embodiment 3, it can also be used to which treating intraocular noninfectious disease can reach completely
To effective treatment concentration.
The release of 2 embodiment of experimental example, 3 gel for eye use
According to drug release determination method (" Chinese Pharmacopoeia " version the 4th in 2015) to 3 gel for eye use of embodiment and commercially available
0.03% flurbiprofen sodium eye drops (trade name Ocufen, the Ireland Ai Ligen drugmaker) carries out release inspection.Using
Ultraviolet-visible spectrophotometry (UV method) carries out drug release determination；Eye drops 10g is measured, bottom of the beaker is set, it is raw to be carefully added into 100ml
Salt water is managed, is kept the temperature in 37 DEG C, as drug release determination solution.Supernatant 5ml was taken to carry out release respectively at 1,3,7,12 hour
Measurement, while supplementing the physiological saline of equivalent volumes.Measuring method: it takes supernatant 5ml to be placed in 50ml volumetric flask, adds
0.1mol/L hydrochloric acid solution shakes up and constant volume；The accurate each 5ml of the solution that measures is respectively placed in 10ml volumetric flask again, adds sulfuric acid
Solution 5ml shakes up, in being stored at room temperature 30min.Solution after taking above-mentioned colour developing, using 0.1mol/L hydrochloric acid solution as blank, according to point
Light photometry measures trap at the wavelength of 482nm, calculates the content and release of nepafenac.It the results are shown in Table 5.
5 drug release determination result (%) of table
| Lot number | 1 hour | 3 hours | 7 hours | 12 hours |
| 3 gel for eye use of embodiment | 56 | 64 | 80 | 96 |
| 0.03% flurbiprofen sodium eye drops | 85 | 95 | 96 | 97 |
The result shows that commercially available flurbiprofen sodium eye drops release is very fast, about 85% is just released within 1 hour, and it is of the invention
The release of 3 eye ointment of embodiment is slower, and is gradually to discharge, and can keep higher drug concentration for a long time in eye surface,
To greatly improve Flurbiprofen precursor medicine in the bioavilability of eye.
3 embodiment of experimental example, 3 gel for eye use tests the anti-inflammatory effect of acute chemosis
Healthy SD rat 40 are taken, is randomly divided into 4 groups: 4 gel for eye use group of embodiment, commercially available flurbiprofen sodium eye drops
Group.The acute chemosis model of Rat Experimental is made with arachidonic acid in each group.Each group lagophthalmos is without anterior chamber of eye before being film-made
15,30min each group, 1 ocular administration after inflammation, film preceding 60,45,30,15min and film, Second eye is physiological saline.With poly-
The variation of photoelectricity cylinder and slit lamp observation lagophthalmos leading portion inflammation.The result shows that 4 gel for eye use of embodiment can inhibit arachidonic
The acute chemosis of Rat Experimental caused by acid, but the curative effect of 3 gel for eye use of embodiment is substantially better than commercially available Flurbiprofen
Sodium eye drops, and side effect is less.
Experiment shows gel for eye use of the present invention to the acute conjunctiva water of Rat Experimental caused by arachidonic acid
It is swollen that there is apparent anti-inflammatory effect.
4 embodiment of experimental example, 3 gel for eye use tests the anti-inflammatory effect of allergic conjunctivitis
Extracting male Wistar rat 40, it is randomly divided into 4 groups: 4 gel for eye use group of embodiment, commercially available flurbiprofen sodium eye drip
Liquid group.Ovalbumin sensitization liquid is injected intraperitoneally in each group in advance, and (100 μ g ovalbumins and 20mg aluminum aluminum sulfate are dissolved in 1ml phosphate
Buffer, pH7.4), after two weeks with the attack of 10% ovalbumin liquid (being dissolved in phosphate buffer), 10 μ l eye drip, cause conjunctiva fast
Allergy reaction.15min makees eye pretreatment with bis- mercapto threitol of 1moll-1DL-, 20 μ l before attacking, vein when facing attack
Inject blue (EB) solution (about 2mg/100g) of Evans；15,30min each group, 1 eye after attack preceding 60,45,30,15min and attack
Administration, Second eye is physiological saline.1h puts to death all animals after attack, measures each eye EB seepage discharge, is compared, and calculates drug
Inhibiting rate.The result shows that each group drug therapy eye EB volumes of extravasation result is below saline therapy eye, 3 gel for eye use group of embodiment
Showing that statistics has a significant meaning with commercially available flurbiprofen sodium eye drops group, 3 gel for eye use inhibiting rate of embodiment is 54.56% ±
10.36%, it is significantly higher than commercially available flurbiprofen sodium eye drops (30.21% ± 23.16%, P=0.036).Show institute of the present invention
The gel for eye use stated has good anti-inflammatory effect.
Experiment shows gel for eye use of the present invention for experimental allergic membranous conjunctivitis caused by antibody antiserum
With apparent anti-inflammatory effect.
Inventor has also carried out pharmacodynamics verifying to embodiment 3 and commercially available flurbiprofen sodium eye drops gel for eye use, right
The therapeutic effect of the inflammation such as inflammation, acute chemosis is compared with comparative example, without notable difference or even effect
More excellent, more preferable for treating and preventing non-infectious inflammation effect, safety is higher.
The zoopery of experimental example 2,3 and 4 is also repeated in the gel for eye use of embodiment 1-2,4-10 by inventor, and invention is real
The effect of applying the gel for eye use of 1-2,4-10 is approximate with embodiment 3, they have been fully achieved for treating intraocular inflammation
The treatment of effect, and safety is higher.
5 stability test of experimental example
By gel for eye use made from embodiment 1-10 by the 4th microorganism limitation inspection technique of pharmacopeia in 2015 check bacterium,
Mould, saccharomycete, are as a result not detected.
The test of 6 Ocular irritation of experimental example
Eye irritation test takes healthy rabbits 12, is randomly divided into two groups of blank groups, tested group, checks for 24 hours before experiment dynamic
Object eyes, selection eye is normal, no inflammation, zero defect, the corneal injury rabbit without oldness.Two groups of rabbit right eyes are given respectively
Physiological saline, embodiment gel for eye use 0.1ml, left eye is not dealt with, as control.3 times a day, 3d is administered, in last dose
It 1,24,48,72h is observed afterwards respectively under slit-lamp, score by dermoreaction score criteria table and records appraisal result, be shown in Table 6.
Daily every animal average integral (stimulus index) is calculated according to the following formula.
Daily every animal average integral=∑ (erythema and oedema total mark of every animal 14d)/(animal subject number ×
14)。
The scoring of 6 rabbit skin irritation of table
| Group | Stimulus index | Group | Stimulus index |
| Embodiment 1 | 0 | Embodiment 6 | 0 |
| Embodiment 2 | 0 | Embodiment 7 | 0 |
| Embodiment 3 | 0 | Embodiment 8 | 0 |
| Embodiment 4 | 0 | Embodiment 9 | 0 |
| Embodiment 5 | 0 | Embodiment 10 | 0 |
It will be apparent to those skilled in the art that can make various other according to the above description of the technical scheme and ideas
Corresponding change and deformation, and all these changes and deformation all should belong to the protection scope of the claims in the present invention
Within.
Claims (10)
1. a kind of non-steroidal anti-inflammatory gel for eye use, it is characterised in that include following component: Flurbiprofen in every 100mL gel for eye use
Precursor medicine 0.01-0.1g, sodium hyaluronate 0.1-0.35g, natrium adetate 0.005-0.8g, sodium chloride 0.375-0.85g, thickening
The water for injection of agent 0.3-1.6g and surplus；The Flurbiprofen precursor medicine is that flurbiprofen axetil or Flurbiprofen can pharmaceutically connect
The salt received.
2. non-steroidal anti-inflammatory gel for eye use according to claim 1, it is characterised in that: the gel for eye use further includes infiltration
Press regulator and pH adjusting agent.
3. non-steroidal anti-inflammatory gel for eye use according to claim 2, it is characterised in that: the osmotic pressure regulator is chlorination
Sodium and/or mannitol；The pH adjusting agent is one of sodium hydroxide, hydrochloric acid, sodium citrate, the minor official acid of Chinese holly, boric acid, borax
Or two or more combination.
4. non-steroidal anti-inflammatory gel for eye use according to claim 1, it is characterised in that: the gel for eye use further includes antibacterial
Agent；The weight ratio of the bacteriostatic agent and Flurbiprofen precursor medicine: for Flurbiprofen precursor medicine: bacteriostatic agent=1:0.02-1.
5. non-steroidal anti-inflammatory gel for eye use according to claim 4, it is characterised in that: the bacteriostatic agent is thimerosal, season
The combination of one or more of ammonium salt class, Domiphen, Xian Bitai, anesin, parabens and sorbic acid.
6. non-steroidal anti-inflammatory gel for eye use according to claim 1, it is characterised in that: the thickener is hypromellose
Element and/or carbomer.
7. non-steroidal anti-inflammatory gel for eye use according to claim 1, it is characterised in that: the pH value of the gel for eye use is
5.5-7.5。
8. non-steroidal anti-inflammatory gel for eye use according to claim 1, it is characterised in that: the osmol of the gel for eye use
Your concentration is 250-350mOsmol/kg.
9. the preparation method of non-steroidal anti-inflammatory gel for eye use according to claim 1-8, it is characterised in that including
Following steps:
A. solvent swell will be thickened with appropriate water for injection, stirred evenly, and form gel-type vehicle；
B. it is dissolved with appropriate water for injection and Flurbiprofen precursor medicine, sodium hyaluronate, natrium adetate, sodium chloride, obtains fluorine ratio
Ibuprofen precursor drug solns；
C. gel-type vehicle is mixed with Flurbiprofen precursor drug solns, water for injection constant volume is added, so that Flurbiprofen precursor medicine
Concentration is 0.1-1mg/mL, stir evenly, filter to get.
10. the preparation method of non-steroidal anti-inflammatory gel for eye use according to claim 9, it is characterised in that: adopt in step
Bacteriostatic agent, pH adjusting agent and osmotic pressure regulator are dissolved respectively with appropriate water for injection, is then added in gel-type vehicle, are adjusted
The pH value of gel-type vehicle is 5.5-7.5, and the osmotic pressure molar density for adjusting gel-type vehicle is 250-350mOsmol/kg, the A
Gel-type vehicle viscosity in step is that measured value is 3.0-30.0mm at 30 ± 0.1 DEG C2/s；Hyaluronic Acid in the step C
The weight average molecular weight of sodium should be not less than 400,000, and dispersion of distribution Mw/Mn should be less than 3.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101385697A (en) * | 2008-10-30 | 2009-03-18 | 中国科学院上海药物研究所 | Flurbiprofen axetil eye nano-emulsion in-situ gel preparation and preparation method thereof |
| CN101564374A (en) * | 2008-04-25 | 2009-10-28 | 北京和润创新医药科技发展有限公司 | Medicinal in situ forming eye gel |
| CN106913518A (en) * | 2017-03-10 | 2017-07-04 | 广州奥博医药科技有限公司 | A kind of precursor type non-steroidal anti-inflammatory gel for eye use and preparation method thereof |
-
2018
- 2018-09-04 CN CN201811026040.8A patent/CN109106684A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101564374A (en) * | 2008-04-25 | 2009-10-28 | 北京和润创新医药科技发展有限公司 | Medicinal in situ forming eye gel |
| CN101385697A (en) * | 2008-10-30 | 2009-03-18 | 中国科学院上海药物研究所 | Flurbiprofen axetil eye nano-emulsion in-situ gel preparation and preparation method thereof |
| CN106913518A (en) * | 2017-03-10 | 2017-07-04 | 广州奥博医药科技有限公司 | A kind of precursor type non-steroidal anti-inflammatory gel for eye use and preparation method thereof |
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Application publication date: 20190101 |