CN108553407A - A kind of slow-release Linezolid eye-drops preparations and the preparation method and application thereof - Google Patents
A kind of slow-release Linezolid eye-drops preparations and the preparation method and application thereof Download PDFInfo
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Abstract
The present invention relates to a kind of slow-release Linezolid eye-drops preparations and the preparation method and application thereof.Its component includes Linezolid, polycarbophil, edetic acid disodium, auxiliary material and water for injection, and mass ratio is Linezolid：Polycarbophil：Edetic acid disodium=1：0.5~2：0.05~0.2, the mass fraction of Linezolid is 0.1%~1%.The dosage form of the preparation includes eye drops, eye ointment and eye gel.Drug effect of the present invention is significantly lasting, has good intraocular penetration, intraocular bioavilability is higher, and penetration is strong, targeting is strong, the small advantage of toxic side effect；Suitable for treating and preventing external eyes caused by non-infectious inflammation and anterior disease of eye and post-operation inflammatory, antibacterial and anti-inflammatory effects are good, and irritation is small, safe；Raw material is easy to get, and preparation process is simple, at low cost, and industrialization large-scale production may be implemented, and has significant economic benefit.
Description
Technical field
The present invention relates to a kind of ophthalmic pharmaceutical formulation for treating bacterial infection more particularly to a kind of slow-release Linezolids
Eye-drops preparations and preparation method thereof is in application.
Background technology
Linezolid is artificial synthesized (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides antibiotic, obtains within 2000 U.S. FDA approval, blue for treating leather
Positive (G+) coccigenic infection, including caused by MRSA it is doubtful or make a definite diagnosis nosocomial pneumonia (HAP), community obtains
Property pneumonia (CAP), complexity skin or skin soft-tissue infection (SSTI) and vancomycin-resistant enterococcus (VRE) infection.Profit
How azoles amine is a kind of oxazole ketone antimicrobial of completely new classification, covers gram positive bacteria-S. aureus L-forms/enterococcus/streptococcus comprehensively
Etc. antibody-resistant bacterium, be bacterio protein synthetic inhibitor, act on bacterium 50S ribosomal subunits, and closest to service portion
Position.Different from other medicines, Linezolid does not influence peptidyl transferase activity, only acts on the initial period of translation system,
Inhibit mRNA to be connect with ribosomes, the formation of 70S initiation complexes is prevented, to inhibit the synthesis of bacterio protein.Li Nai
The site of action and mode of azoles amine are unique, therefore in essential or acquired resistance feature positive bacteria, are all not easy
Crossing drug resistant occurs for the antimicrobial synthesized with other inhibition albumen, is not easy to the generation of Induction of bacterial drug resistance in vitro.
Only two kinds of dosage forms of intravenous fluid and oral tablet that the preparation of Linezolid lists at present, are systemic use
Medicine, it is diarrhea, headache and nausea to have the report of adverse reaction, most common adverse events, other adverse events have vomiting, lose
Dormancy, constipation, fash, dizziness, fever, thrush, vaginal candidiasis, fungal infection, local abdominal pain, indigestion,
Sense of taste change, tongue discoloration, itch etc..
For eye disease, local application has many benefits compared with systemic administration.It is noted under conjunctiva and in vitreum
Effective drug concentration can be reached in ocular tissue by penetrating medication, but intraocular injection administration is a kind of traumatic to prescription after all
Method, drug administration by injection, which is repeated several times, can greatly increase the incidence of infectious endophthalmitis.The best mode of ophthalmology local application is drop
Ocular fluid, and development ＆ production one kind providing good effect, few side effects, intraocular penetration power for vast eye bacterial infection disease patient
By force, property is stable, the novel eye-drops preparations of drug resistance is not always valuable research and development project.
Invention content
Technical problem to be solved by the present invention lies in a kind of good effect of offer, few side effects, intraocular penetration power by force, property
Stable, not drug resistance slow-release Linezolid eye-drops preparations.
The present invention is to solve above-mentioned technical problem one of by the following technical programs：A kind of slow-release Linezolid is ophthalmically acceptable
Preparation, including Linezolid, polycarbophil, edetic acid disodium, auxiliary material and water for injection, and mass ratio is Linezolid：It is poly-
Ka Bofei：Edetic acid disodium=1：0.5~2：0.05~0.2, the mass fraction of Linezolid is 0.1%~1%.
The dosage form of the preparation includes gel, eye drops, and described any type is suitable for eye part on eye ointment or pharmacy
Other dosage forms of external application.
Further, the dosage form of the eye-drops preparations is eye drops, and mass ratio is Linezolid：Auxiliary material=1：0.102~
1. 5；
The auxiliary material includes bacteriostatic agent and thickener, and the pH value of the eye drops is 5.5~7.5；
Further, the bacteriostatic agent is thimerosal, quaternary ammonium salt, Domiphen, Xian Bitai, anesin, nipalgin
One or more arbitrary combinations in class, three pears acid；And the mass ratio of bacteriostatic agent and Linezolid is Linezolid：Bacteriostatic agent=
1.0：0.002~0.5；
Further, the thickener is hydroxypropyl methylcellulose, methylcellulose, sodium hyaluronate, polyvinyl alcohol, polyethylene
One or more arbitrary combinations in pyrrolidones；The mass ratio of thickener and Linezolid is Linezolid：Thickener=
1.0:0.1~1.0.
Further, the osmotic pressure molar density of the eye drops is adjusted using sodium chloride and/or mannitol, eye drops
Osmotic pressure molar density is 250~350mOsmol/kg.
Further, the pH value of the eye drops is using sodium hydroxide, hydrochloric acid, sodium citrate, the minor official acid of Chinese holly, boric acid, borax
In one or more adjustings.
The beneficial effects of the present invention are：Drug effect of the present invention is significantly lasting, has good intraocular penetration, intraocular biology
Availability is higher, and penetration is strong, targeting is strong, the small advantage of toxic side effect；Draw suitable for treating and preventing non-infectious inflammation
The external eyes and anterior disease of eye and post-operation inflammatory risen, antibacterial and anti-inflammatory effects are good, and irritation is small, safe；Raw material is easy to get, system
Standby process is simple, at low cost, and industrialization large-scale production may be implemented, and has significant economic benefit.
Convenient drug administration of the present invention, liquid have delay and slow releasing function on eye mask surface.Because Linezolid is insoluble in water, in water
It is unstable in solution, therefore mucoadhesive polymer medicine-releasing system (Polycarbophil, edetic acid disodium) is used to prepare slow-release profit
How azoles amine eye drops, water and active constituent Linezolid is embedded therein, form stable aqueous gel shape eye drops, from
And solve the problems, such as that Linezolid dissolubility and stability in simple aqueous solutions are poor, administration frequency can be reduced, patient is increased
Compliance.
Its ophthalmology indication is at home and abroad declared for the first time, and the present invention has filled up Linezolid treatment eye bacterial infection disease
The blank of disease has huge economic benefit and social benefit.
Below just in conjunction with the embodiments, the embodiment of the present invention is described in further detail, so that the technology of the present invention
Scheme is more readily understood, grasps.
Specific implementation mode
A kind of slow-release Linezolid eye-drops preparations, including Linezolid, polycarbophil, edetic acid disodium, auxiliary material and
Water for injection；The dosage form of eye-drops preparations is that any type in eye drops, gel for eye use, spongarion or pharmacy is suitable for eye part
The dosage form of external application.
When the dosage form of eye-drops preparations is eye drops, mass ratio is Linezolid：Polycarbophil：Edetic acid disodium：Auxiliary material
=1：0.5~2：0.05~0.2：0.102~1.5, the mass fraction of Linezolid is 0.1%~1%, i.e., every 100 parts by weight
Eye-drops preparations in, the content of Linezolid is 0.1~1 parts by weight.
Auxiliary material includes bacteriostatic agent and thickener, and the osmotic pressure molar density of eye drops is 250~350mOsmol/kg；It is antibacterial
Agent is one or more in thimerosal, quaternary ammonium salt, Domiphen, Xian Bitai, anesin, parabens, three pears acid
Meaning combination；And the mass ratio of bacteriostatic agent and Linezolid is Linezolid：Bacteriostatic agent=1.0：0.002~0.5；Thickener is hydroxyl
One or more arbitrary combinations in third methylcellulose, methylcellulose, sodium hyaluronate, polyvinyl alcohol, polyvinylpyrrolidone；
The mass ratio of thickener and Linezolid is Linezolid：Thickener=1.0:0.1~1.0.The pH value of eye drops uses hydrogen-oxygen
Change one or more adjustings in sodium, hydrochloric acid, sodium citrate, the minor official acid of Chinese holly, boric acid, borax；The osmotic pressure molar density of eye drops
It is adjusted using sodium chloride and/or mannitol, and the pH value of eye drops is 5.5~7.5.
Wherein, the component of the ophthalmically acceptable eye drops of slow-release Linezolid in each embodiment 1-7 and proportioning situation such as 1 institute of table
Show：
The component and proportioning situation of the 1 ophthalmically acceptable eye drops of slow-release Linezolid of table
The preparation method of the ophthalmically acceptable eye drops of slow-release Linezolid is as follows in above example：
1), according to the component and proportioning of embodiment 1-7 in table one, prepare raw material respectively；It takes at 20% water for injection dissolving
The polycarbophil and edetic acid disodium just measured dissolve the Linezolid of recipe quantity after mixing, spare；
2), thickener is disperseed to let cool with 10% water for injection, adds bacteriostatic agent, stir evenly filtering, be added to step 1 institute
The Linezolid solution obtained；
3) pH adjusting agent, is dissolved with 10% water for injection, is slowly added in the Linezolid solution obtained by step 2, adjusts
PH values are 5.5~7.5 i.e. stopping；The pH adjusting agent is in sodium hydroxide, hydrochloric acid, sodium citrate, the minor official acid of Chinese holly, boric acid, borax
It is one or more.
4) conditioning agent, is pressed with water for injection solution pervasion, is slowly added in step 3 acquired solution, osmol(e) is adjusted
Concentration stops adding to 250~350mOsmol/kg；The osmotic pressure regulator is sodium chloride and/or mannitol, to adjust
Save solution osmotic pressure molar density.
5), adding water for injection constant volume so that a concentration of 0.5~5mg/ml of Linezolid in eye drops is filtered, packing,
To obtain the final product.
A kind of oxazole ketone antimicrobial of the Linezolid as completely new classification covers gram positive bacteria-S. aureus L-forms/intestines comprehensively
Coccus/streptococcus, including the drug resistances such as methicillin-resistant staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE)
Bacterial strain.With unique mechanism of action and higher penetration into tissue, ensure that enough drug reaches infection site and other classifications
There is no cross resistance between antibiotic.
(1) 8 pharmacokinetic trial of embodiment
With healthy new zealand rabbit (half male and half female) be experimental animal, Linezolid eye drops single (20 after administration, 40,
60,80,100,120,150,210,270,360,480min extracts 30 μ l of aqueous humor) and repeatedly (successive administration 7 days, 4 times a day,
Every 6 hours primary.30 μ l of aqueous humor, the 3rd administration are taken before last 1 administration in the 6th day, before being administered for the 7th day the 1st time and the 2nd time
Afterwards in 20,40,60,80,100,120,150,210,270,360,480min extract 30 μ l of aqueous humor) after administration, Aqueous humor samples warp
HPLC-MS is measured.
The Cmax of Linezolid is 38.754 ± 9.426g/ml in single-dose aqueous humor；Tmax is 102.00 ± 12.55
min；T1/2 is 81.52 ± 13.64min；AUC0-t be 5179.60 ± 1881.16gminml-1, AUC0- be 5374.01 ±
2056.85gminml-1；Ke is 0.01 ± 0.001min-1.After multiple eye drop administration, the Tmax of Linezolid is in aqueous humor
94.00 ± 13.32min, T1/2 be 84.46 ± 14.02min, Ke be 0.01 ± 0.002min-1, AUC0-t be 6014.86 ±
1428.17gminml-1, AUC0- be 6085.50 ± 1458.94gminml-1, Css max be 47.73 ±
11.25gml-1, Css min are 2.8 ± 0.76gml-1, and Cavg is 10.79 ± 3.92 gml-1, and FI (%) is
95.7% ± 9.5%.Compare the pharmacokinetic parameter repeatedly with single-dose, the difference on Ke, T1/2 are not statistically significant,
The release rate substantially constant for showing two methods Linezolid ophthalmic administration, does not change with successive administration.The fluctuation hundred of drug
Score is larger, Css min are very low, it was demonstrated that Linezolid is not accumulated substantially in aqueous humor.In single and multiple dosing main medicine generation, are dynamic
The comparison of mechanics parameter see the table below 2.
2 single of table and multiple dosing main pharmacokinetic parameter
| Parameters | Single-dose | Multiple-dose |
| Trough 1 | 2.16±0.55 | |
| Trough 2 | 2.24±1.03 | |
| Trough 3 | 2.13±0.70 | |
| Tmax(min) | 102.00±12.55 | 94.00±13.32 |
| T1/2(min) | 81.52±13.64 | 84.46±14.02 |
| Ke(min-1) | 0.01±0.001 | 0.01±0.002 |
| AUCo-t(μg·min·ml-1) | 5179.60±1881.16 | 6014.86±1428.17 |
| AUC0-∞(μg·min·ml-1) | 5374.01±2056.85 | 6085.50±1458.94 |
| Css max(μg·ml-1) | 31.40±9.32 | 47.73±11.25 |
| Css min(μg·ml-1) | 2.8±0.76 | |
| Cavg(μg·ml-1) | 10.79±3.92 | |
| FI (%) | 95.7±9.5 |
The preparation of tissue samples：Animal is put to death with gas embolism method within 2.5 hours after last time eye drip, then use blade
Corneal epithelium is struck off, normal saline flushing conjunctival sac extracts aqueous humor, the moisture of conjunctival sac blotted with cotton swab, with micro- clip portion
Then bulb separation conjunctiva, cornea, iris, retina, vitreum and sclera are used normal saline flushing, are placed on after filter paper suck dry moisture
It in 1.5ml test tubes, closes the lid, is placed on scales/electronic balance weighing as early as possible, be then transferred into 8ml teat glass, add methylene chloride
5ml fully crushes tissue with microscissors.After ten minutes with centrifuge, take bottom dichloromethane 4.5ml in another test tube
In, it is dried up with nitrogen.Closed test tube mouth, in 4 DEG C of preservations.Compare ophthalmically acceptable same method processing.
Linezolid is distributed widely in each Main Tissues of intraocular, with concentration highest in conjunctiva, cornea and iris.Administration 60
After min, 120min and 240min, the concentration in cornea is respectively 673.59 ± 388.78g/g, 519.32 ± 289.80 g/g and
265.75±51.67g/g.The distributed density of eye Main Tissues see the table below after Linezolid eye drops single-dose.
Following table shows using the eye drops single and multiple eye drip prepared by this method, the profit in each Main Tissues of intraocular
How azoles amine concentration is relatively high, especially with concentration highest in conjunctiva, cornea and iris, illustrates this eye drops eye inner tissue penetrability
Preferably, concentration is higher, and effective bacteriocidal concentration is fully achieved for treating intraocular bacterial infection disease.
The distributed density of eye Main Tissues after 3 Linezolid eye drops single-dose of table
| Tissue | 60min | 120min | 240min |
| Cornea (μ g/g) | 673.59±388.78 | 519.32±289.80 | 265.75±51.67 |
| Conjunctiva (μ g/g) | 699.58±398.76 | 349.31±153.49 | 319.84±189.2 |
| Iris (μ g/g) | 260.08±116.64 | 109.42±26.10 | 207.36±169.28 |
| Retina (μ g/g) | 131.25±123.22 | 87.79±53.82 | 15.73±8.49 |
| Vitreum (μ g/g) | 3.04±2.91 | 3.61±2.94 | 2.07±1.25 |
| Sclera (μ g/g) | 75.88±32.54 | 46.50±20.01 | 19.15±17.62 |
(2) comparative example 1
The ophthalmically acceptable eye drops of slow-release Linezolid and Levofloxacin Eye drop inside and outside antibacterial tests
Purpose：By observing the ophthalmically acceptable eye drops of eye surface application slow-release Linezolid to staphylococcus aureus, epidermis
Staphylococcus, enterococcus, streptococcus pneumonia etc. carry out inside and outside antibacterial tests, and are compareed with Levofloxacin Eye drop, with
Study the antibacterial action of Linezolid eye drops.
Control is commercially available product, trade name with Levofloxacin Eye drop：Cravit, specification 25mg：5ml.
Method：Nutrient broth dilution method, fresh strain inoculation nutrient broth culture 18h is used to make original bacteria liquid, take in vitro
0.1mL surveys viable count adjustment bacterium solution 1010CFU/L.Linezolid eye drip is diluted with 0.1mol/L phosphate buffers (PBS)
Agent, 4 DEG C of filtration sterilization save backup, and nutrient broth doubling dilution is first used when experiment, often the profit of pipe plus 1.0mL various concentrations how azoles
Amine eye drops is separately added into 1010CFU/L staphylococcus aureuses, staphylococcus epidermis, enterococcus, streptococcus pneumonia 0.1mL,
Streptococcus pneumonia adds rabbit blood 1 to drip, the every pipe 109CFU/L of final inoculated bacteria amount.Set blank control and positive control pipe (no simultaneously
Dosing).37 DEG C of cultures 18~for 24 hours, minimum inhibitory concentration (MIC) is measured, followed by selects and has no liquid in bacterial growth pipe
0.1mL is inoculated on agar medium tablet (streptococcus pneumonia inoculation blood agar culture plate) and further does minimum bactericidal concentration
(MBC) it measures.
In vivo studies will be inoculated in the staphylococcus aureus on plain agar culture medium flat plate, staphylococcus epidermis, intestines
Coccus and the streptococcus pneumonia of blood agar culture plate are scraped with oese, are made into 2 × 1012CFU/L (light respectively with physiological saline
Electricity is than turbid instrument measured concentration).Rabbit cornea is caused to damage (eyes) with corneal trephine, rabbit is per ocular infections bacterium 0.1mL, 2d nothing
Bacterium brine cotton swab takes eye discharge, is put into 4mL sterile saline bottles, and bacterium is done to its liquid with agar plate method
Culture.It is carried out at the same time inflammatory score, 0 grade：Eye is bright without secretion；0.5 grade：No secretion covering, eye are slightly red and swollen；1 grade：
Secretion covering is less than 6mm；2 grades：Secretion covering is full of 6mm；3 grades：Secretion covering is more than 6mm.According to standards of grading with
Machine is grouped：Treatment group's (bacterial infection+Linezolid eye drops), treatment control group (bacterial infection+Levofloxacin Eye drop),
Control group (bacterial infection+drop physiological saline), 6 rabbit of each group are not treated.Normal group (not modeling, not bacterial infection, drop
Physiological saline) 2.Every 0.1mL, 4 times/d, continuity point medicine 7d.It is once scored every eyes for 24 hours, 7d is observed continuously, commented
Point result, which takes statistics, learns t inspections processing.And the 1d before administration, 1 after administration, 3,5,7d take discharge of eye with Sterile Saline cotton swab
Make Bacteria Culture, judges yin and yang attribute result.D8 puts to death rabbit, takes cornea to be put into fixation in 40g/L formaldehyde and makees pathological section, HE
Chromoscopy.
As a result：In vitro test shows Linezolid to staphylococcus aureus, staphylococcus epidermis, enterococcus, pneumonia chain
The minimum bactericidal concentration (MBC) of coccus is respectively 2.0,1.0,2.0,1.0 μ g/mL, and minimum inhibitory concentration (MIC) range is respectively
0.25~8,0.06~8,0.5~>8,0.12~2 μ g/mL.Antibacterial tests are shown in vivo, rabbit ocular infections Staphylococcus aureus
After bacterium, staphylococcus epidermis, enterococcus, streptococcus pneumonia, Linezolid and lavo-ofloxacin are in treatment 3d appraisal results and not
Treating control group, relatively there were significant differences, and Linezolid group 5d Bacteria Culture negative conversion rates are 100%, and lavo-ofloxacin 5d is thin
It is 100% that bacterium culture negative conversion rate, which is 98%, 7d Bacteria Culture negative conversion rates,.Cornea pathological examination shows that the healing of wound spot is good
It is good.
In vivo studies：There is inflammatory symptoms, less serious case's conjunctiva redness bloodshot eyes, severe one whole body shape afterwards for 24 hours in 4 kinds of bacterium infection lagophthalmos
It is red and swollen congested with conjunctiva that state is not good enough, and corneal edema thickens, and a large amount of secretion are in yellow-white, upper palpebra inferior are clung, eyes close.
Standards of grading are at 1.5~3 grades.Bacteria cultivation results：It is the positive, Linezolid that cornea 4 kinds of Bacteria Cultures of secretion, which are administered,
The cornea secretion Bacteria Culture negative conversion rate that eye drops treats 5d is 100%, and Levofloxacin Eye drop treats the training of 7d bacteriums
Foster negative conversion rate is 100%.Rabbit eyes appraisal result, compared with not treating control group, Linezolid eye drops is to golden yellow Portugal
4,5d has notable difference (P after grape coccus, staphylococcus epidermis, enterococcus, the administration of streptococcus pneumoniae infection group<0.01), left
It is apparent poor that ofloxacin eye drops have 4,5d after staphylococcus aureus, staphylococcus epidermis, the administration of enterococcal infection group
Different (P<0.01) all variant (P of 4,5d after, streptococcus pneumoniae infection group is administered<0.05).Pathological section：Linezolid eye drip
Each layer structure of the cornea of agent treatment group and Levofloxacin Eye drop is substantially complete, and wound surface is covered by stratified squamous epithelium,
Wound has proliferation of fibrous tissue, the scarring healing of wound to have no cell infiltration；Control group is not treated infects rabbit after 4 kinds of bacterium
Eye shows corneal edema, and blood vessel dilatation is congested, and wound is not more associated with ulcer, there is a large amount of cell infiltrations and slough.
Normal group cornea is excellent.
In vitro, in internal antibacterial tests, the effect of Linezolid, is significantly better than that Levofloxacin Eye drop.
Conclusion：Linezolid eye drops is quick to staphylococcus aureus, staphylococcus epidermis, enterococcus, streptococcus pneumonia
Perception is relatively strong, and caused rabbit cornea inflammation therapeutic effect is preferable.
(3) comparative example 2
Linezolid drop is made with the ophthalmically acceptable medicine-releasing systems of DuraSite in the ophthalmically acceptable eye drops of slow-release Linezolid in embodiment 7
The pharmacokinetic trial of eye agent
New zealand rabbit right and left eyes are administered simultaneously, and dosage is 50 μ L.20 after administration, 40,60,80,100,
120,150,210,270,360,480min extracts 30 μ l detections of aqueous humor；Aqueous humor samples are measured through LC-MS, as a result see the table below 4：
Table 4：The ophthalmically acceptable eye drops of slow-release Linezolid and DuraSite in new zealand rabbit eye single dose embodiment 7
The main pharmacokinetic parameter of Linezolid eye drops
(4) comparative example 3
New zealand rabbit eye gives the ophthalmically acceptable eye drops of slow-release Linezolid in embodiment 7
Controlling at Linezolid in the ocular tissue of Linezolid eye drops concentration tests
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, 1.5ml test tubes are placed on after filter paper suck dry moisture
In, it closes the lid, is placed on scales/electronic balance weighing as early as possible, be then transferred into 8ml teat glass, add methylene chloride 5ml, and use is micro-
It cuts and fully crushes tissue.After ten minutes with centrifuge, it takes bottom dichloromethane 4.5ml in another test tube, is blown with nitrogen
It is dry.Closed test tube mouth, in 4 DEG C of preservations.Experiment shows that Linezolid is distributed widely in each Main Tissues of intraocular, with conjunctiva, cornea
And concentration highest in iris.The Linezolid distributed density of eye Main Tissues is shown in Table 5-6 after administration.
Table 5：New zealand rabbit gives the concentration of Linezolid in ocular tissue after embodiment 7
Table 6：New zealand rabbit gives the concentration of Linezolid in ocular tissue after DuraSite Linezolid eye drops
The result shows that Linezolid eye drops of the invention, the Linezolid concentration in each Main Tissues of intraocular all compares
Height illustrates that the Linezolid eye drops intraocular penetration of the present invention is more preferable especially with concentration highest in conjunctiva, cornea and iris,
Concentration is high, and effective treatment concentration is fully achieved for treating intraocular bacterial infection disease.
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, it is other it is any without departing from the spirit and principles of the present invention made by changes, modifications, substitutions, combinations, simplifications,
Equivalent substitute mode is should be, is included within the scope of the present invention.
Claims (9)
1. a kind of slow-release Linezolid eye-drops preparations, it is characterised in that：Its component includes Linezolid, polycarbophil, according to him
Acid disodium, auxiliary material and water for injection, and mass ratio is Linezolid：Polycarbophil：Edetic acid disodium=1：0.5~2：0.05
~0.2, the mass fraction of Linezolid is 0.1%~1%.
2. slow-release Linezolid eye-drops preparations as described in claim 1, it is characterised in that：The dosage form of the preparation includes solidifying
Described any type is suitable for other dosage forms of eye local topical in glue, eye drops, eye ointment or pharmacy.
3. the ophthalmically acceptable eye drops of slow-release Linezolid as claimed in claim 2, it is characterised in that：Slow-release Linezolid is ophthalmically acceptable
In eye drops, the mass ratio of Linezolid and auxiliary material is：Linezolid：Auxiliary material=1：0.102~1.5.
4. the ophthalmically acceptable eye drops of slow-release Linezolid as claimed in claim 2, it is characterised in that：The auxiliary material includes bacteriostatic agent
And thickener；The bacteriostatic agent is thimerosal, quaternary ammonium salt, Domiphen, Xian Bitai, anesin, parabens, three pears acid
In one or more arbitrary combinations；And the mass ratio of bacteriostatic agent and Linezolid is Linezolid：Bacteriostatic agent=1.0：0.002
~0.5.
5. the ophthalmically acceptable eye drops of slow-release Linezolid as claimed in claim 4, it is characterised in that：The thickener is hydroxypropyl first
One or more arbitrary combinations in cellulose, methylcellulose, sodium hyaluronate, polyvinyl alcohol, polyvinylpyrrolidone；Thickening
The mass ratio of agent and Linezolid is Linezolid：Thickener=1.0:0.1~1.0.
6. the ophthalmically acceptable eye drops of slow-release Linezolid as claimed in claim 2, it is characterised in that：The pH value of the eye drops is
5.5~7.5；Use pH adjusting agent to be one or more in sodium hydroxide, hydrochloric acid, sodium citrate, the minor official acid of Chinese holly, boric acid, borax
It adjusts.
7. the ophthalmically acceptable eye drops of slow-release Linezolid as claimed in claim 2, it is characterised in that：The osmotic pressure of the eye drops
Molar concentration is 250~350mOsmol/kg；It is adjusted using sodium chloride and/or mannitol.
8. the preparation method of the ophthalmically acceptable eye drops of slow-release Linezolid described in claim 2, its step are as follows:
1), prepare raw material respectively according to component and proportioning；The polycarbophil and edetic acid disodium of water for injection dissolving recipe quantity are taken,
The Linezolid of recipe quantity is dissolved after mixing, it is spare；
2), the dispersion of thickener water for injection is let cool, adds bacteriostatic agent, stirs evenly filtering, is added to the Li Nai obtained by step 1
Azoles amine aqueous solution；
3), dissolve pH adjusting agent with water for injection, be added in the Linezolid solution obtained by step 2, adjust pH value be 5.5~
7.5 stop；
4) conditioning agent, is pressed with water for injection solution pervasion, is added in the solution obtained by step 3, adjusts osmotic pressure molar density
Stop addition to 250~350mOsmol/kg.
5), constant volume so that a concentration of 0.5~5mg/ml of Linezolid in eye drops, filtering, packing to get.
9. the sustained release described in any one of slow-release Linezolid eye-drops preparations described in claim 1 and claim 2-8
Application of the ophthalmically acceptable eye drops of type Linezolid in ophthalmology disease.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810291136.0A CN108553407A (en) | 2018-04-03 | 2018-04-03 | A kind of slow-release Linezolid eye-drops preparations and the preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810291136.0A CN108553407A (en) | 2018-04-03 | 2018-04-03 | A kind of slow-release Linezolid eye-drops preparations and the preparation method and application thereof |
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| CN101766628A (en) * | 2010-01-20 | 2010-07-07 | 广东宏盈科技有限公司 | Ophthalmic bacterial-infection resisting medicine for external use |
| WO2011066260A2 (en) * | 2009-11-25 | 2011-06-03 | Michael Zasloff | Formulations comprising aminosterols |
| CN102283799A (en) * | 2011-08-17 | 2011-12-21 | 北京乐维生物技术有限公司 | Azithromycin gel eye drops and preparation process thereof |
| CN102670499A (en) * | 2012-06-09 | 2012-09-19 | 广东宏盈科技有限公司 | Slow-release sirolimus ophthalmic preparation |
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2018
- 2018-04-03 CN CN201810291136.0A patent/CN108553407A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011066260A2 (en) * | 2009-11-25 | 2011-06-03 | Michael Zasloff | Formulations comprising aminosterols |
| CN101766628A (en) * | 2010-01-20 | 2010-07-07 | 广东宏盈科技有限公司 | Ophthalmic bacterial-infection resisting medicine for external use |
| CN102283799A (en) * | 2011-08-17 | 2011-12-21 | 北京乐维生物技术有限公司 | Azithromycin gel eye drops and preparation process thereof |
| CN102670499A (en) * | 2012-06-09 | 2012-09-19 | 广东宏盈科技有限公司 | Slow-release sirolimus ophthalmic preparation |
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