CN109833294A - A kind of Lomefloxacin Hydrochloride Eye-drops and its preparation process - Google Patents
A kind of Lomefloxacin Hydrochloride Eye-drops and its preparation process Download PDFInfo
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Abstract
The present invention discloses a kind of Lomefloxacin Hydrochloride Eye-drops and its preparation process, is related to ophthalmic pharmaceutical formulation field.The eye drops screens sodium alginate as thickening excipient, it is swollen to form clear solution with hydrotropy additive and water for injection, after mixing again with isotonic regulator glycerol, intraocular pressure-regulated dose of mannitol, biodegradable auxiliary agent, then by buffer adjusting pH, filtering, sterile packaged are obtained.Lomefloxacin Hydrochloride Eye-drops of the invention, preparation method is simply controllable, without harsh conditions, stability, homogeneity, absorbability are good, osmosis is strong when use, intraocular pressure is significantly reduced, the outer ocular infections such as acute and chronic bacterial conjunctivitis, blear-eye, sty, belephroadenitis, dacryocystitis, keratitis and ulcer of the cornea caused by sensitive pathogenic bacteria are significant in efficacy to treating.
Description
Technical field
The present invention relates to ophthalmic pharmaceutical formulation fields, and in particular to a kind of Lomefloxacin Hydrochloride Eye-drops and its preparation work
Skill, for treat acute and chronic bacterial conjunctivitis caused by sensitive pathogenic bacteria, blear-eye, sty, belephroadenitis, dacryocystitis,
The outer ocular infection such as keratitis and ulcer of the cornea.
Background technique
Chemical entitled 1- ethyl-6,8- bis- fluoro- 7- (3- methyl-1-piperazine)-4- oxo-3- quinoline carboxylic of Lomefloxacin
Acid.The pH value 3.5-4.5 of lomefloxacin hydrochloride, slightly soluble, almost insoluble in ethyl alcohol or chloroform in water；In sodium hydroxide test solution
In it is readily soluble, dissolved in ammonia solution；It is heated 5~10 minutes in 30~90 DEG C of water-bath with malonic acid and aceticanhydride, shows rufous,
Its chemical structural formula is as follows:
Lomefloxacin hydrochloride belongs to antibiotics, is two fluoroquinolones broad spectrum antibiotics, main by inhibiting thin
The DNA gyrase of bacterium and rise bactericidal effect, to the pseudomonas such as acinetobacter calcoaceticus, Pseudomonas aeruginosa, staphylococcus and pneumonia ball
Bacterium, hemolytic streptococcus etc. also have certain antibacterial action.Lomefloxacin hydrochloride is in 1985 first by Hokuriku, Japan pharmacy
Company and the production of Shionogi company, in Argentinian Initial Public Offering, are followed by the product of Searle company, the U.S. for 1989
City.
The Chinese patent of application number 201210159065.1 discloses a kind of Lomefloxacin Hydrochloride Eye-drops and its preparation side
Method and application, it further includes tackifier, buffer salt system, wetting agent, isotonic tune that active constituent accounts for 0.3% in terms of Lomefloxacin
Save agent, pH adjusting agent and its bacteriostatic agent；Said preparation be suitable for acute and chronic bacterial conjunctivitis caused by treating sensitive pathogenic bacteria,
The outer ocular infection such as blear-eye, sty, belephroadenitis, dacryocystitis, keratitis and ulcer of the cornea.This product improves hydrochloric acid Lome
The viscosity of husky star eye drops makes its fluidics property change, guarantees that drug fully absorbs, and improves bioavilability, improves
Patient's compliance, reaches therapeutic effect.The Chinese patent of application number 201510866019.9 discloses a kind of lomefloxacin hydrochloride
Injection and preparation method, the injection is by a certain proportion of lomefloxacin hydrochloride, salt forming agent, cosolvent, stabilizer, absorption
Agent, water for injection are prepared by raw material mixing, filtering, filling, inflated with nitrogen, sealing.The Lomefloxacin injection is given
Just, rapidly, stability is high for prescription, and preparation volume is small, and convenient transportation is at low cost.
In the prior art, Lomefloxacin eye drops have the following problems: 1, stability, homogeneity, absorbability are not sufficiently good；
2, osmosis is poor when using, and can not significantly reduce intraocular pressure, to acute and chronic bacillary conjunctiva caused by the sensitive pathogenic bacteria for the treatment of
The outer ocular infection curative effect such as inflammation, blear-eye, sty, belephroadenitis, dacryocystitis, keratitis and ulcer of the cornea also needs further to add
By force.
Summary of the invention
In order to solve the above technical problems, the purpose of the present invention is to provide a kind of Lomefloxacin Hydrochloride Eye-drops and its
Preparation process, screening sodium alginate are swollen to form clear solution with hydrotropy additive and water for injection as thickening excipient, then
After mixing with isotonic regulator glycerol, intraocular pressure-regulated dose of mannitol, biodegradable auxiliary agent, then pass through buffer adjusting pH, mistake
Filter, sterile packaged obtain.Preparation method is simply controllable, is not necessarily to harsh conditions, and stability, homogeneity, absorbability are good, when use
Osmosis is strong, significantly reduces intraocular pressure, to acute and chronic bacterial conjunctivitis, blear-eye, wheat caused by the sensitive pathogenic bacteria for the treatment of
The outer ocular infections such as grain is swollen, belephroadenitis, dacryocystitis, keratitis and ulcer of the cornea are significant in efficacy.
The purpose of the present invention can be achieved through the following technical solutions:
The present invention provides a kind of Lomefloxacin Hydrochloride Eye-drops, the eye drops by following mass percent substance preparation and
At: lomefloxacin hydrochloride 0.3-0.5%, hydrotropy additive 3.4-5.5%, propylparaben 0.05-0.12%, seaweed
Acid receives 0.04-0.08%, glycerol 0.12-0.19%, buffer 0.01-0.03%, mannitol 0.04-0.07%, biodegrade
Auxiliary agent 0.15-0.32%, surplus are water for injection；
The preparation method of the eye drops the following steps are included:
S1, it disperses Na-alginate, hydrotropy additive in suitable water for injection for being previously heated to 45-55 DEG C, makes
System is swelled into clear solution；
S2, it disperses lomefloxacin hydrochloride in suitable water for injection, is mixed with the clear solution for being preheated to 35-45 DEG C
After mixing evenly, glycerol, mannitol, biodegradable auxiliary agent and appropriate water for injection are added, after being stirred, buffer is added
PH is adjusted, and adds remaining water for injection；
S3, the micropore filtering film filtering for being passed through 0.22 μm, sterile packaged.
Lomefloxacin Hydrochloride Eye-drops of the invention, in order to reach good stability, absorbability, drug permeability, with
Lomefloxacin hydrochloride is main ingredient ingredient, has carried out a large amount of research and screening, discovery selection sea to other auxiliary materials, additive component
Mosanom as thickening excipient, with combination, lubrication, hydrotropy performance good hydrotropy additive and water for injection be swollen to be formed it is transparent
Solution, then after mix with isotonic regulator glycerol, intraocular pressure-regulated dose of mannitol, biodegradable auxiliary agent, then pass through buffer tune
PH is saved, filtering, sterile packaged obtain.Preparation method is simply controllable, is not necessarily to harsh conditions, and multiple auxiliary materials additive assists main ingredient salt
Lomefloxacin hydrochloride plays good stability, homogeneity, and absorbability is good, and osmosis is strong, reduces intraocular pressure, sensitive to treatment
Acute and chronic bacterial conjunctivitis caused by pathogenic bacteria, blear-eye, sty, belephroadenitis, dacryocystitis, keratitis and cornea are burst
The outer ocular infection such as ulcer is significant in efficacy.
As a further solution of the present invention, the biodegradable auxiliary agent the preparation method is as follows:
1) sodium hydroxide of the beta-cyclodextrin of 10.3g and 29.1g, 25wt% is put into flask, is added under stirring
1.15g sodium chloroacetate is stirred to react 4-5h at 45 DEG C, and hydrochloric acid is added dropwise by system pH and is adjusted to 7, system temperature is reduced to room temperature
Afterwards, methanol is added not to be further added by precipitation capacity, filters, filter cake is dry in 45 DEG C of driers, obtains powdered carboxyl and replaces
Beta-cyclodextrin；
2) 8.5g carboxyl Chagerdβcyclodextrins and the 1.26g n-hydroxysuccinimide distilled water of 50mL are dissolved, 2
It is stirred under DEG C water-bath, 2.1g EDC, insulation reaction 2h is added；It is slowly added to the chitosan of 11.2g, 1h is reacted at 2 DEG C, then room
Temperature reaction is for 24 hours；It is filtered to remove insoluble matter, bag filter dialysis 48h is put into low temperature quickly cooling in -15 DEG C of refrigerator, transfers to -25
DEG C vacuum freeze drier in carry out freezen protective.
Biodegradable auxiliary agent of the invention, beta-cyclodextrin is in coupling agent n-hydroxysuccinimide, carboxyl group activating reagents EDC
Under the action of, it is grafted on the polymer chain of chitosan, the antibacterial degradation synergistic hair of the package action and chitosan of cyclodextrin
It waves, effectively reduces the irritation of main ingredient lomefloxacin hydrochloride, extend drug in the residence time of eye, improve bactericidal antiphlogistic
Effect.In preparation process, -15 DEG C of low temperature quickly coolings and -25 DEG C of vacuum refrigerations after dialysis can make auxiliary agent surface and internal presentation
Loose porous shape, while heat source and bacterium in chitosan are sufficiently killed, ensure the gnotobasis and safety of biodegradable auxiliary agent
Property.
As a further solution of the present invention, the buffer is sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, boric acid-
One of borate buffer solution, acetic acid-ammonium acetate buffer, Acetic acid-sodium acetate buffer and citrate buffer are a variety of
Mixture.
As a further solution of the present invention, the hydrotropy additive the preparation method is as follows: the boiled-off silk of degumming is soaked
Moisten after ternary dissolution system 15-20min, be placed in 55-65 DEG C of baking oven and heat 3-4h, it is molten that dissolution obtains fibroin albumen completely
Liquid；Silk fibroin protein solution pours into bag filter, deionized water dialysis 3d；After dialysis under 10000-12000rpm revolving speed from
Heart separation removal insoluble matter impurity, is added the hydroxypropyl methyl cellulose of boiled-off silk quality 0.05-0.08%, pours into after mixing
Bag filter is dialysed for 24 hours with the polyglycol solution of molecular weight 20000,15wt%；Wherein, ternary dissolution system is by chlorination
Calcium, ethyl alcohol, water are formed according to molar ratio 1:2:8 mixed preparing.
Fibroin albumen is the natural polymer fibrin extracted from silk, and content accounts for about the 70%~80% of silk,
With excellent physicochemical property, nontoxic, nonirritant, good biocompatibility, and meanwhile it is biodegradable, can largely it expire
The demand of sufficient biomaterial.Fibroin albumen has excellent processing performance simultaneously, can prepare filmogen, gel, microballoon, more
Hole bracket etc., can be applied to pharmaceutical carrier.The present invention is by being dissolved in the ternary that calcium chloride, ethyl alcohol, water form for fibroin albumen
It in dissolution system, dialysed, be centrifuged at a high speed, the fiber impurity of other good water solubilities can be removed, it is fine to improve fibroin albumen
The purity of dimension after mixing with the common lubricant hydroxypropyl methyl cellulose of ophthalmology, dialyses to obtain hydrotropy addition through polyethylene glycol
Agent.The additive has both the combination of fibroin albumen and the lubricating action of hydroxypropyl methyl cellulose, and water solubility, alcohol-soluble are equal
Poor lomefloxacin hydrochloride passes through the hydrophobic forces combination of hydrophobic region between silk fibroin molecular, reaches in ophthalmic administration
Slow releasing function, while any toxic side effect will not be generated.
The present invention also provides the preparation processes of above-mentioned Lomefloxacin Hydrochloride Eye-drops, comprising the following steps:
S1, it disperses Na-alginate, hydrotropy additive in suitable water for injection for being previously heated to 45-55 DEG C, makes
System is swelled into clear solution；
S2, it disperses lomefloxacin hydrochloride in suitable water for injection, is mixed with the clear solution for being preheated to 35-45 DEG C
After mixing evenly, glycerol, mannitol, biodegradable auxiliary agent and appropriate water for injection are added, after being stirred, buffer is added
PH is adjusted, and adds remaining water for injection；
S3, the micropore filtering film filtering for being passed through 0.22 μm, sterile packaged.
Beneficial effects of the present invention:
1, Lomefloxacin Hydrochloride Eye-drops of the invention, using lomefloxacin hydrochloride as main ingredient ingredient, to other auxiliary materials, addition
Agent ingredient has carried out a large amount of research and screening, and discovery selects sodium alginate as thickening excipient, with combination, lubrication, hydrotropy
The good hydrotropy additive of performance and water for injection are swollen to form clear solution, then with isotonic regulator glycerol, intraocular pressure-regulated dose
After mannitol, biodegradable auxiliary agent mixing, then by buffer adjusting pH, filtering, sterile packaged are obtained.Preparation method simply may be used
Control is not necessarily to harsh conditions, and multiple auxiliary materials additive assists main ingredient lomefloxacin hydrochloride, plays good stability, homogeneity, inhales
The property received is good, and osmosis is strong, reduces intraocular pressure, to acute and chronic bacterial conjunctivitis, margo palpebrae caused by the sensitive pathogenic bacteria for the treatment of
The outer ocular infection such as inflammation, sty, belephroadenitis, dacryocystitis, keratitis and ulcer of the cornea is significant in efficacy.
2, biodegradable auxiliary agent of the invention, by grafted by beta cyclodextrin on the polymer chain of chitosan, the packet of cyclodextrin
It wraps up in effect and the antibacterial degradation synergistic of chitosan plays, effectively reduce the irritation of main ingredient lomefloxacin hydrochloride, extend medicine
Object improves the effect of bactericidal antiphlogistic in the residence time of eye；Low temperature quickly cooling and vacuum refrigeration after dialysis make auxiliary agent surface and
Loose porous shape is presented in inside, while sufficiently killing heat source and the bacterium in chitosan, ensures the asepsis ring of biodegradable auxiliary agent
Border and safety.
3, hydrotropy additive of the invention, by the ternary dissolution that fibroin albumen is dissolved in calcium chloride, ethyl alcohol, water composition
It in system, dialysed, be centrifuged at a high speed, the fiber impurity of other good water solubilities can be removed, improve fibroin fiber
Purity dialyses to obtain hydrotropy additive through polyethylene glycol after mixing with the common lubricant hydroxypropyl methyl cellulose of ophthalmology.It should
Additive has both the combination of fibroin albumen and the lubricating action of hydroxypropyl methyl cellulose, and water solubility, alcohol-soluble are poor
Lomefloxacin hydrochloride combined by the hydrophobic forces of hydrophobic region between silk fibroin molecular, reach the sustained release in ophthalmic administration
Effect, while any toxic side effect will not be generated.
Specific embodiment
Below in conjunction with the embodiment of the present invention, technical scheme in the embodiment of the invention is clearly and completely described,
Obviously, described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.Based in the present invention
Embodiment, all other embodiment obtained by those of ordinary skill in the art without making creative efforts, all
Belong to the scope of protection of the invention.
Embodiment 1
A kind of Lomefloxacin Hydrochloride Eye-drops of the present embodiment, are prepared: hydrochloric acid by the substance of following mass percent
Lomefloxacin 0.36%, hydrotropy additive 4.2%, propylparaben 0.07%, Na-alginate 0.05%, glycerol
0.16%, buffer 0.016%, mannitol 0.046%, biodegradable auxiliary agent 0.25%, surplus is water for injection.
The preparation method of the eye drops the following steps are included:
S1, it disperses Na-alginate, hydrotropy additive in suitable water for injection for being previously heated to 52 DEG C, makes system
It is swelled into clear solution；
S2, it disperses lomefloxacin hydrochloride in suitable water for injection, mixes and stir with the clear solution for being preheated to 38 DEG C
After mixing uniformly, glycerol, mannitol, biodegradable auxiliary agent and appropriate water for injection are added, after being stirred, buffer tune is added
PH is saved, and adds remaining water for injection；
S3, the micropore filtering film filtering for being passed through 0.22 μm, sterile packaged.
Wherein, the biodegradable auxiliary agent the preparation method is as follows:
1) sodium hydroxide of the beta-cyclodextrin of 10.3g and 29.1g, 25wt% is put into flask, is added under stirring
1.15g sodium chloroacetate is stirred to react 4.6h at 45 DEG C, and hydrochloric acid is added dropwise by system pH and is adjusted to 7, system temperature is reduced to room temperature
Afterwards, methanol is added not to be further added by precipitation capacity, filters, filter cake is dry in 45 DEG C of driers, obtains powdered carboxyl and replaces
Beta-cyclodextrin；
2) 8.5g carboxyl Chagerdβcyclodextrins and the 1.26g n-hydroxysuccinimide distilled water of 50mL are dissolved, 2
It is stirred under DEG C water-bath, 2.1g EDC, insulation reaction 2h is added；It is slowly added to the chitosan of 11.2g, 1h is reacted at 2 DEG C, then room
Temperature reaction is for 24 hours；It is filtered to remove insoluble matter, bag filter dialysis 48h is put into low temperature quickly cooling in -15 DEG C of refrigerator, transfers to -25
DEG C vacuum freeze drier in carry out freezen protective.
The buffer is sodium dihydrogen phosphate-disodium hydrogen phosphate buffer.
The hydrotropy additive the preparation method is as follows: the boiled-off silk of degumming is infiltrated on ternary dissolution system 18min after,
It is placed in 62 DEG C of baking ovens and heats 3.5h, dissolution obtains silk fibroin protein solution completely；Silk fibroin protein solution pours into bag filter, go from
Sub- water dialysis 3d；Centrifuge separation removes insoluble matter impurity under 11000rpm revolving speed after dialysis, and boiled-off silk quality is added
0.06% hydroxypropyl methyl cellulose, pours into bag filter after mixing, with molecular weight 20000, the polyethylene glycol of 15wt%
Solution is dialysed for 24 hours；Wherein, ternary dissolution system is formed by calcium chloride, ethyl alcohol, water according to molar ratio 1:2:8 mixed preparing.
Embodiment 2
A kind of Lomefloxacin Hydrochloride Eye-drops of the present embodiment, are prepared: hydrochloric acid by the substance of following mass percent
Lomefloxacin 0.42%, hydrotropy additive 4.5%, propylparaben 0.09%, Na-alginate 0.06%, glycerol
0.17%, buffer 0.017%, mannitol 0.058%, biodegradable auxiliary agent 0.28%, surplus is water for injection.
The preparation method of the eye drops the following steps are included:
S1, it disperses Na-alginate, hydrotropy additive in suitable water for injection for being previously heated to 53 DEG C, makes system
It is swelled into clear solution；
S2, it disperses lomefloxacin hydrochloride in suitable water for injection, mixes and stir with the clear solution for being preheated to 43 DEG C
After mixing uniformly, glycerol, mannitol, biodegradable auxiliary agent and appropriate water for injection are added, after being stirred, buffer tune is added
PH is saved, and adds remaining water for injection；
S3, the micropore filtering film filtering for being passed through 0.22 μm, sterile packaged.
Wherein, the biodegradable auxiliary agent the preparation method is as follows:
1) sodium hydroxide of the beta-cyclodextrin of 10.3g and 29.1g, 25wt% is put into flask, is added under stirring
1.15g sodium chloroacetate is stirred to react 4.8h at 45 DEG C, and hydrochloric acid is added dropwise by system pH and is adjusted to 7, system temperature is reduced to room temperature
Afterwards, methanol is added not to be further added by precipitation capacity, filters, filter cake is dry in 45 DEG C of driers, obtains powdered carboxyl and replaces
Beta-cyclodextrin；
2) 8.5g carboxyl Chagerdβcyclodextrins and the 1.26g n-hydroxysuccinimide distilled water of 50mL are dissolved, 2
It is stirred under DEG C water-bath, 2.1g EDC, insulation reaction 2h is added；It is slowly added to the chitosan of 11.2g, 1h is reacted at 2 DEG C, then room
Temperature reaction is for 24 hours；It is filtered to remove insoluble matter, bag filter dialysis 48h is put into low temperature quickly cooling in -15 DEG C of refrigerator, transfers to -25
DEG C vacuum freeze drier in carry out freezen protective.
The buffer is boric acid-borate buffer solution, acetic acid-ammonium acetate buffer is mixed according to 1:1.
The hydrotropy additive the preparation method is as follows: the boiled-off silk of degumming is infiltrated on ternary dissolution system 20min after,
It is placed in 63 DEG C of baking ovens and heats 3.2h, dissolution obtains silk fibroin protein solution completely；Silk fibroin protein solution pours into bag filter, go from
Sub- water dialysis 3d；Centrifuge separation removes insoluble matter impurity under 12000rpm revolving speed after dialysis, and boiled-off silk quality is added
0.07% hydroxypropyl methyl cellulose, pours into bag filter after mixing, with molecular weight 20000, the polyethylene glycol of 15wt%
Solution is dialysed for 24 hours；Wherein, ternary dissolution system is formed by calcium chloride, ethyl alcohol, water according to molar ratio 1:2:8 mixed preparing.
Embodiment 3
A kind of Lomefloxacin Hydrochloride Eye-drops of the present embodiment, are prepared: hydrochloric acid by the substance of following mass percent
Lomefloxacin 0.45%, hydrotropy additive 5.3%, propylparaben 0.10%, Na-alginate 0.07%, glycerol
0.18%, buffer 0.023%, mannitol 0.055%, biodegradable auxiliary agent 0.28%, surplus is water for injection.
The preparation method of the eye drops the following steps are included:
S1, it disperses Na-alginate, hydrotropy additive in suitable water for injection for being previously heated to 49 DEG C, makes system
It is swelled into clear solution；
S2, it disperses lomefloxacin hydrochloride in suitable water for injection, mixes and stir with the clear solution for being preheated to 42 DEG C
After mixing uniformly, glycerol, mannitol, biodegradable auxiliary agent and appropriate water for injection are added, after being stirred, buffer tune is added
PH is saved, and adds remaining water for injection；
S3, the micropore filtering film filtering for being passed through 0.22 μm, sterile packaged.
Wherein, the biodegradable auxiliary agent the preparation method is as follows:
1) sodium hydroxide of the beta-cyclodextrin of 10.3g and 29.1g, 25wt% is put into flask, is added under stirring
1.15g sodium chloroacetate is stirred to react 4.6h at 45 DEG C, and hydrochloric acid is added dropwise by system pH and is adjusted to 7, system temperature is reduced to room temperature
Afterwards, methanol is added not to be further added by precipitation capacity, filters, filter cake is dry in 45 DEG C of driers, obtains powdered carboxyl and replaces
Beta-cyclodextrin；
2) 8.5g carboxyl Chagerdβcyclodextrins and the 1.26g n-hydroxysuccinimide distilled water of 50mL are dissolved, 2
It is stirred under DEG C water-bath, 2.1g EDC, insulation reaction 2h is added；It is slowly added to the chitosan of 11.2g, 1h is reacted at 2 DEG C, then room
Temperature reaction is for 24 hours；It is filtered to remove insoluble matter, bag filter dialysis 48h is put into low temperature quickly cooling in -15 DEG C of refrigerator, transfers to -25
DEG C vacuum freeze drier in carry out freezen protective.
The buffer is sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, Acetic acid-sodium acetate buffer according to mass ratio 1:
2 mixed preparings form.
The hydrotropy additive the preparation method is as follows: the boiled-off silk of degumming is infiltrated on ternary dissolution system 20min after,
It is placed in 62 DEG C of baking ovens and heats 3.6h, dissolution obtains silk fibroin protein solution completely；Silk fibroin protein solution pours into bag filter, go from
Sub- water dialysis 3d；Centrifuge separation removes insoluble matter impurity under 11500rpm revolving speed after dialysis, and boiled-off silk quality is added
0.07% hydroxypropyl methyl cellulose, pours into bag filter after mixing, with molecular weight 20000, the polyethylene glycol of 15wt%
Solution is dialysed for 24 hours；Wherein, ternary dissolution system is formed by calcium chloride, ethyl alcohol, water according to molar ratio 1:2:8 mixed preparing.
Embodiment 4
A kind of Lomefloxacin Hydrochloride Eye-drops of the present embodiment, are prepared: hydrochloric acid by the substance of following mass percent
Lomefloxacin 0.46%, hydrotropy additive 5.3%, propylparaben 0.11%, Na-alginate 0.072%, glycerol
0.18%, buffer 0.025%, mannitol 0.062%, biodegradable auxiliary agent 0.31%, surplus is water for injection.
The preparation method of the eye drops the following steps are included:
S1, it disperses Na-alginate, hydrotropy additive in suitable water for injection for being previously heated to 53 DEG C, makes system
It is swelled into clear solution；
S2, it disperses lomefloxacin hydrochloride in suitable water for injection, mixes and stir with the clear solution for being preheated to 42 DEG C
After mixing uniformly, glycerol, mannitol, biodegradable auxiliary agent and appropriate water for injection are added, after being stirred, buffer tune is added
PH is saved, and adds remaining water for injection；
S3, the micropore filtering film filtering for being passed through 0.22 μm, sterile packaged.
Wherein, the biodegradable auxiliary agent the preparation method is as follows:
1) sodium hydroxide of the beta-cyclodextrin of 10.3g and 29.1g, 25wt% is put into flask, is added under stirring
1.15g sodium chloroacetate is stirred to react 4-5h at 45 DEG C, and hydrochloric acid is added dropwise by system pH and is adjusted to 7, system temperature is reduced to room temperature
Afterwards, methanol is added not to be further added by precipitation capacity, filters, filter cake is dry in 45 DEG C of driers, obtains powdered carboxyl and replaces
Beta-cyclodextrin；
2) 8.5g carboxyl Chagerdβcyclodextrins and the 1.26g n-hydroxysuccinimide distilled water of 50mL are dissolved, 2
It is stirred under DEG C water-bath, 2.1g EDC, insulation reaction 2h is added；It is slowly added to the chitosan of 11.2g, 1h is reacted at 2 DEG C, then room
Temperature reaction is for 24 hours；It is filtered to remove insoluble matter, bag filter dialysis 48h is put into low temperature quickly cooling in -15 DEG C of refrigerator, transfers to -25
DEG C vacuum freeze drier in carry out freezen protective.
The buffer is sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, boric acid-borate buffer solution, acetic acid-ammonium acetate are slow
One of fliud flushing, Acetic acid-sodium acetate buffer and citrate buffer or a variety of mixtures.
The hydrotropy additive the preparation method is as follows: the boiled-off silk of degumming is infiltrated on ternary dissolution system 20min after,
It is placed in 63 DEG C of baking ovens and heats 3.5h, dissolution obtains silk fibroin protein solution completely；Silk fibroin protein solution pours into bag filter, go from
Sub- water dialysis 3d；Centrifuge separation removes insoluble matter impurity under 11500rpm revolving speed after dialysis, and boiled-off silk quality is added
0.068% hydroxypropyl methyl cellulose, pours into bag filter after mixing, with molecular weight 20000, the polyethylene glycol of 15wt%
Solution is dialysed for 24 hours；Wherein, ternary dissolution system is formed by calcium chloride, ethyl alcohol, water according to molar ratio 1:2:8 mixed preparing.
Embodiment 5
A kind of Lomefloxacin Hydrochloride Eye-drops of the present embodiment, are prepared: hydrochloric acid by the substance of following mass percent
Lomefloxacin 0.47%, hydrotropy additive 5.3%, propylparaben 0.12%, Na-alginate 0.055%, glycerol
0.18%, buffer 0.025%, mannitol 0.06%, biodegradable auxiliary agent 0.30%, surplus is water for injection.
The preparation method of the eye drops the following steps are included:
S1, it disperses Na-alginate, hydrotropy additive in suitable water for injection for being previously heated to 55 DEG C, makes system
It is swelled into clear solution；
S2, it disperses lomefloxacin hydrochloride in suitable water for injection, mixes and stir with the clear solution for being preheated to 42 DEG C
After mixing uniformly, glycerol, mannitol, biodegradable auxiliary agent and appropriate water for injection are added, after being stirred, buffer tune is added
PH is saved, and adds remaining water for injection；
S3, the micropore filtering film filtering for being passed through 0.22 μm, sterile packaged.
Wherein, the biodegradable auxiliary agent the preparation method is as follows:
1) sodium hydroxide of the beta-cyclodextrin of 10.3g and 29.1g, 25wt% is put into flask, is added under stirring
1.15g sodium chloroacetate is stirred to react 5h at 45 DEG C, and hydrochloric acid is added dropwise by system pH and is adjusted to 7, after system temperature is reduced to room temperature,
Methanol is added not to be further added by precipitation capacity, filters, filter cake is dry in 45 DEG C of driers, obtains powdered carboxyl substituted beta-ring
Dextrin；
2) 8.5g carboxyl Chagerdβcyclodextrins and the 1.26g n-hydroxysuccinimide distilled water of 50mL are dissolved, 2
It is stirred under DEG C water-bath, 2.1g EDC, insulation reaction 2h is added；It is slowly added to the chitosan of 11.2g, 1h is reacted at 2 DEG C, then room
Temperature reaction is for 24 hours；It is filtered to remove insoluble matter, bag filter dialysis 48h is put into low temperature quickly cooling in -15 DEG C of refrigerator, transfers to -25
DEG C vacuum freeze drier in carry out freezen protective.
The buffer is sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, boric acid-borate buffer solution, acetic acid-ammonium acetate are slow
One of fliud flushing, Acetic acid-sodium acetate buffer and citrate buffer or a variety of mixtures.
The hydrotropy additive the preparation method is as follows: the boiled-off silk of degumming is infiltrated on ternary dissolution system 16min after,
It is placed in 62 DEG C of baking ovens and heats 3.8h, dissolution obtains silk fibroin protein solution completely；Silk fibroin protein solution pours into bag filter, go from
Sub- water dialysis 3d；Centrifuge separation removes insoluble matter impurity under 12000rpm revolving speed after dialysis, and boiled-off silk quality is added
0.08% hydroxypropyl methyl cellulose, pours into bag filter after mixing, with molecular weight 20000, the polyethylene glycol of 15wt%
Solution is dialysed for 24 hours；Wherein, ternary dissolution system is formed by calcium chloride, ethyl alcohol, water according to molar ratio 1:2:8 mixed preparing.
Comparative example 1
This comparative example the difference from embodiment 1 is that, be not added with Na-alginate.
Comparative example 2
This comparative example the difference from embodiment 1 is that, be not added with mannitol.
Comparative example 3
This comparative example the difference from embodiment 1 is that, be not added with hydrotropy additive.
Comparative example 4
This comparative example the difference from embodiment 1 is that, be not added with biodegradable auxiliary agent.
Comparative example 5
The Lomefloxacin Hydrochloride Eye-drops that in the patent of reference application number 201210159065.1 prepared by embodiment 3, prescription
For lomefloxacin hydrochloride 3.32g, sodium hyaluronate 0.8g, sodium dihydrogen phosphate-disodium hydrogen phosphate 0.20g, benzalkonium chloride 0.20g, sweet
Oily 2.00g, sodium chloride 6.80g, water for injection are settled to 1000mL.The preparation method comprises the following steps: (1) disperses the sodium hyaluronate of recipe quantity
In appropriate 40 DEG C of -55 DEG C of waters for injection, makes to be swollen, clear solution is made；(2) the main ingredient lomefloxacin hydrochloride of recipe quantity is molten
In appropriate 60 DEG C of -70 DEG C of waters for injection, be added sodium dihydrogen phosphate-disodium hydrogen phosphate of recipe quantity, sodium chloride, benzalkonium chloride,
The mixed solution of glycerol after being stirred, then is transferred in (1), adjusts pH to 6.0, filling with 0.1mol/L sodium hydroxide solution
Penetrate the full dose with water, sterile packaged with 0.22 μm of filtering with microporous membrane, after passed examination to obtain the final product.
Stability test
The Lomefloxacin Hydrochloride Eye-drops of Example 1-5 and the preparation of comparative example 1-5 group, in 40 DEG C of temperature, relative humidity
It places 6 months under conditions of 65%, separately sampled is once examined 1st month, 2 months, 3 months, 6 months time points
It surveys.Wherein, face shaping is pistac supernatant liquid, has carried out the detection of pH value, viscosity, impurity content, specific to test
It the results are shown in Table 1.
1. stability test result of table
As can be seen from the above table, the Lomefloxacin Hydrochloride Eye-drops of the embodiment of the present invention have good compared with comparative example
PH stability, stability of viscidity, impurity content stability, illustrate ingredient stable uniform, buffer, thickener proportion are suitable
When.Comparative example 1 reduces significantly due to being not added with thickener Na-alginate as the time increases viscosity.Comparative example 3 is not added with hydrotropy
Additive, so that the compatibility, binding force between main ingredient and other compositions are deteriorated, impurity content increases significant.
The test of lagophthalmos irritation
Healthy rabbits 10 are taken, every respectively corresponds embodiment 1-5 group, comparative example 1-5 group, and conjunctiva of left eye capsule instills
0.1mL physiological saline is to compare, the intracapsular instillation 0.1mL Lomefloxacin Hydrochloride Eye-drops of conjunctiva of right eye, is gently closed eye after eye drip
Eyelid 10s, 4 times a day, continuous 7 days, before daily administration and last time be administered after 1h, for 24 hours, 48h and 72h examine eye
Look into, according to State Food and Drug Administration 2005 " Eye irritation reaction evaluating standard " score record, as the result is shown with it is right
Ratio group is compared, and embodiment group corneal transparency, iris is clear, and conjunctiva is hyperemia, no oedema and secretion, and flashlight is equipped with magnifying glass
Check lesion, scoring is 0, is illustrated safe and non-stimulating.
Lomefloxacin Hydrochloride Eye-drops of the invention, stability, homogeneity, absorbability are good, and osmosis is strong when use,
Intraocular pressure is significantly reduced, to acute and chronic bacterial conjunctivitis, blear-eye, sty, Meibomian gland caused by the sensitive pathogenic bacteria for the treatment of
The outer ocular infection such as inflammation, dacryocystitis, keratitis and ulcer of the cornea is significant in efficacy.
In the description of this specification, the description of reference term " one embodiment ", " example ", " specific example " etc. means
Particular features, structures, materials, or characteristics described in conjunction with this embodiment or example are contained at least one implementation of the invention
In example or example.In the present specification, schematic expression of the above terms may not refer to the same embodiment or example.
Moreover, particular features, structures, materials, or characteristics described can be in any one or more of the embodiments or examples to close
Suitable mode combines.
Above content is only citing made for the present invention and explanation, affiliated those skilled in the art are to being retouched
The specific embodiment stated does various modifications or additions or is substituted in a similar manner, and without departing from invention or surpasses
More range defined in the claims, is within the scope of protection of the invention.
Claims (5)
1. a kind of Lomefloxacin Hydrochloride Eye-drops, which is characterized in that the eye drops by following mass percent substance preparation and
At: lomefloxacin hydrochloride 0.3-0.5%, hydrotropy additive 3.4-5.5%, propylparaben 0.05-0.12%, seaweed
Acid receives 0.04-0.08%, glycerol 0.12-0.19%, buffer 0.01-0.03%, mannitol 0.04-0.07%, biodegrade
Auxiliary agent 0.15-0.32%, surplus are water for injection；
The preparation method of the eye drops the following steps are included:
S1, it disperses Na-alginate, hydrotropy additive in suitable water for injection for being previously heated to 45-55 DEG C, makes system
It is swelled into clear solution；
S2, it disperses lomefloxacin hydrochloride in suitable water for injection, is mixed with the clear solution for being preheated to 35-45 DEG C
After uniformly, glycerol, mannitol, biodegradable auxiliary agent and appropriate water for injection are added, after being stirred, buffer is added and adjusts
PH, and add remaining water for injection；
S3, the micropore filtering film filtering for being passed through 0.22 μm, sterile packaged.
2. Lomefloxacin Hydrochloride Eye-drops according to claim 1, which is characterized in that the preparation of the biodegrade auxiliary agent
Method is as follows:
1) sodium hydroxide of the beta-cyclodextrin of 10.3g and 29.1g, 25wt% is put into flask, 1.15g is added under stirring
Sodium chloroacetate is stirred to react 4-5h at 45 DEG C, and hydrochloric acid is added dropwise by system pH and is adjusted to 7, after system temperature is reduced to room temperature, is added
Methanol is not further added by precipitation capacity, and filtering, filter cake is dry in 45 DEG C of driers, obtains powdered carboxyl substituted beta-ring paste
Essence；
2) 8.5g carboxyl Chagerdβcyclodextrins and the 1.26g n-hydroxysuccinimide distilled water of 50mL are dissolved, 2 DEG C of water
The lower stirring of bath, is added 2.1g EDC, insulation reaction 2h；It is slowly added to the chitosan of 11.2g, 1h is reacted at 2 DEG C, then room temperature is anti-
It should for 24 hours；It is filtered to remove insoluble matter, bag filter dialysis 48h is put into low temperature quickly cooling in -15 DEG C of refrigerator, transfers to -25 DEG C
Freezen protective is carried out in vacuum freeze drier.
3. Lomefloxacin Hydrochloride Eye-drops according to claim 1, which is characterized in that the buffer is biphosphate
Sodium-disodium hydrogen phosphate buffer, boric acid-borate buffer solution, acetic acid-ammonium acetate buffer, Acetic acid-sodium acetate buffer and citron
One of acid buffer or a variety of mixtures.
4. Lomefloxacin Hydrochloride Eye-drops according to claim 1, which is characterized in that the preparation side of the hydrotropy additive
Method is as follows: after the boiled-off silk of degumming is infiltrated on ternary dissolution system 15-20min, it is placed in 55-65 DEG C of baking oven and heats 3-4h,
Dissolution obtains silk fibroin protein solution completely；Silk fibroin protein solution pours into bag filter, deionized water dialysis 3d；After dialysis
Centrifuge separation removal insoluble matter impurity, is added the hydroxypropyl first of boiled-off silk quality 0.05-0.08% under 10000-12000rpm revolving speed
Base cellulose, pours into bag filter after mixing, is dialysed for 24 hours with the polyglycol solution of molecular weight 20000,15wt%；
Wherein, ternary dissolution system is formed by calcium chloride, ethyl alcohol, water according to molar ratio 1:2:8 mixed preparing.
5. a kind of preparation process of Lomefloxacin Hydrochloride Eye-drops, which comprises the following steps:
S1, it disperses Na-alginate, hydrotropy additive in suitable water for injection for being previously heated to 45-55 DEG C, makes system
It is swelled into clear solution；
S2, it disperses lomefloxacin hydrochloride in suitable water for injection, is mixed with the clear solution for being preheated to 35-45 DEG C
After uniformly, glycerol, mannitol, biodegradable auxiliary agent and appropriate water for injection are added, after being stirred, buffer is added and adjusts
PH, and add remaining water for injection；
S3, the micropore filtering film filtering for being passed through 0.22 μm, sterile packaged.
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| CN112618480A (en) * | 2020-11-10 | 2021-04-09 | 南昌大学 | Preparation method of novel ocular drug delivery system |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0938896A1 (en) * | 1998-01-15 | 1999-09-01 | Novartis AG | Autoclavable pharmaceutical compositions containing a chelating agent |
| US20110263587A1 (en) * | 2003-10-31 | 2011-10-27 | Wakamoto Pharmaceutical Co., Ltd. | Reversibly heat-gelable aqueous composition |
| CN102670493A (en) * | 2012-05-22 | 2012-09-19 | 宁夏康亚药业有限公司 | Lomefloxacin hydrochloride eye drops and preparation method and application thereof |
| CN106822914A (en) * | 2017-01-10 | 2017-06-13 | 安徽师范大学 | A kind of carboxymethyl beta cyclodextrin grafted chitosan ionomer nanoparticle, preparation method and applications |
| CN107105724A (en) * | 2014-08-20 | 2017-08-29 | 蚕丝科技有限公司 | Protein compositions derived from fibroin |
| US20170266345A1 (en) * | 2014-08-19 | 2017-09-21 | Industrial Cooperation Foundation Chonbuk National University | Ultra-thin film silk fibroin/collagen composite implant and manufacturing method therefor |
-
2019
- 2019-04-19 CN CN201910318888.6A patent/CN109833294B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0938896A1 (en) * | 1998-01-15 | 1999-09-01 | Novartis AG | Autoclavable pharmaceutical compositions containing a chelating agent |
| US20110263587A1 (en) * | 2003-10-31 | 2011-10-27 | Wakamoto Pharmaceutical Co., Ltd. | Reversibly heat-gelable aqueous composition |
| CN102670493A (en) * | 2012-05-22 | 2012-09-19 | 宁夏康亚药业有限公司 | Lomefloxacin hydrochloride eye drops and preparation method and application thereof |
| US20170266345A1 (en) * | 2014-08-19 | 2017-09-21 | Industrial Cooperation Foundation Chonbuk National University | Ultra-thin film silk fibroin/collagen composite implant and manufacturing method therefor |
| CN107105724A (en) * | 2014-08-20 | 2017-08-29 | 蚕丝科技有限公司 | Protein compositions derived from fibroin |
| CN106822914A (en) * | 2017-01-10 | 2017-06-13 | 安徽师范大学 | A kind of carboxymethyl beta cyclodextrin grafted chitosan ionomer nanoparticle, preparation method and applications |
Non-Patent Citations (2)
| Title |
|---|
| KHALIL, RM 等: "Design and evaluation of proniosomes as a carrier for ocular delivery of lomefloxacin HCl", 《JOURNAL OF LIPOSOME RESEARCH》 * |
| 刘祖雄等: "盐酸洛美沙星缓释滴眼液的研制", 《中国药业》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112618480A (en) * | 2020-11-10 | 2021-04-09 | 南昌大学 | Preparation method of novel ocular drug delivery system |
| CN112618480B (en) * | 2020-11-10 | 2022-07-12 | 南昌大学 | Preparation method of eye drug delivery system |
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