CN117562858A - Tosulfloxacin tosylate eye drops and preparation method thereof - Google Patents
Tosulfloxacin tosylate eye drops and preparation method thereof Download PDFInfo
- Publication number
- CN117562858A CN117562858A CN202311454617.6A CN202311454617A CN117562858A CN 117562858 A CN117562858 A CN 117562858A CN 202311454617 A CN202311454617 A CN 202311454617A CN 117562858 A CN117562858 A CN 117562858A
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- Prior art keywords
- eye drops
- tosylate
- thickening agent
- tosufloxacin
- composition
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
The invention belongs to the field of eye drops, relates to a technology for preparing eye drops in a laboratory, and particularly relates to tosufloxacin tosylate eye drops and a preparation method thereof, wherein the eye drops comprise a composition, a thickener, tosufloxacin mesylate, a PH regulator, a bacteriostatic agent, an osmotic pressure regulator and a solvent, and the specific method comprises the following steps: A. weighing a certain part of the composition, and putting the composition into an oven for sterilization; B. adding a solvent into the sterilized composition for ultrasonic dispersion to obtain a suspension; C. preparing a thickening agent, stirring the thickening agent, expanding the thickening agent after stirring, and sterilizing the thickening agent after expanding; D. sequentially adding the tosufloxacin mesylate, the PH regulator and the preservative into the thickener, dissolving, and filtering to obtain a product A; F. and adding the suspension into the product A, and uniformly stirring to obtain the final product of the eye drops. The product prepared by the invention not only can effectively solve the problem of infection, but also can treat inflammation.
Description
Technical Field
The invention belongs to the field of eye drops, relates to an eye drop preparation technology in a laboratory, and particularly relates to tosufloxacin tosylate eye drops and a preparation method thereof.
Background
The number of patients suffering from bacterial eye infection is increased, the number of myopia people in China, turkish and other developing countries is increased gradually, the incidence rate of wearing the contact lens is 10// 100-30/100 ten thousand, and if the incidence rate is calculated according to 2/10 ten thousand, 10 ten thousand patients suffering from bacterial keratitis are increased every year worldwide, and the patients become important causative factors of bacterial keratitis.
For eye diseases such as conjunctivitis, keratitis, iridocyclitis, etc. caused by bacterial infection of eye, anti-infection eye drops such as gentamicin, ofloxacin, ciprofloxacin, lomefloxacin, kanamycin, neomycin, polymyxin beta, etc. are commonly used. With the extension of clinical use time and the increase of use frequency, the medicine has drug resistance and cross drug resistance to certain bacteria such as staphylococcus aureus, pseudomonas aeruginosa, escherichia coli and the like, so that the clinical curative effect is greatly affected.
Fluoroquinolone eye drops or ophthalmic ointments such as lomefloxacin, ciprofloxacin and ofloxacin which are clinically used at home and abroad belong to third-generation fluoroquinolone medicines, wherein the antibacterial activity of lomefloxacin on pseudomonas aeruginosa is extremely weak, and the antibacterial activity of ciprofloxacin and ofloxacin on gram-positive bacteria is not very strong, so that the effects of infection on chlamydia, mycoplasma and the like are poorer. In addition, the three medicines have serious photosensitive side effects, and the use of lomefloxacin preparations is limited in the countries such as Germany, and phototoxic warning words are added in the use instructions and the labels.
The toxacin tosylate belongs to a fourth-generation quinolone antibacterial agent, the raw materials of the toxacin tosylate and the eye drops are successfully developed and marketed in Japan, and the eye drops are not marketed in China because of the production of the raw materials. The tosufloxacin tosylate has obvious advantages over other medicines, firstly, the antibacterial spectrum is enlarged, the activity is increased, and the effect of the tosufloxacin tosylate on G bacillus is better than that of ofloxacin- +
Star, norfloxacin, is almost equivalent to ciprofloxacin, which has the highest antibacterial activity against G-bacilli. The antibacterial activity of the G bacteria is the strongest in all quinolone medicines on the international market at present, the antibacterial activity of the G bacteria on staphylococcus aureus and streptococcus pneumoniae is 4-8 times of that of ciprofloxacin and ofloxacin, the antibacterial activity of the G bacteria on mycoplasma, chlamydia and gonococcus is 8-10 times of that of the ciprofloxacin and ofloxacin, and the antibacterial activity of the toluene sulfonic acid of the T Shu Sha on chlamydia is almost equal to that of the span-sarcin. The antibacterial effect on gram-positive anaerobic bacteria is 2-4 times stronger than that of cyclopropyl Sha Xingjiang and 10 times stronger than that of tolnidazole; the tosufloxacin tosylate has stronger cell infiltration capacity; thirdly, the minimum antibacterial concentration of staphylococcus aureus, enterococcus faecalis, enterobacter and pseudomonas aeruginosa is equal to the minimum antibacterial concentration, other quinolone antibacterial effects belong to concentration dependence, and the tosulfloxacin tosylate is safer from a certain sense; finally, tosufloxacin tosylate is safer from a pharmaceutical design, which reduces the occurrence of tics.
Disclosure of Invention
The invention provides the tosufloxacin tosylate eye drops and the preparation method thereof.
In order to achieve the purpose, the technical scheme adopted by the invention is that the tosufloxacin tosylate eye drops are characterized by comprising the following components in detail:
| component (A) | Parts by weight |
| Composition and method for producing the same | 4-80 parts |
| Thickening agent | 20-300 parts |
| Tosulfloxacin mesylate | 12-15 parts |
| PH regulator | Proper amount of |
| Bacteriostatic agent | 0.5-1 part |
| Osmotic pressure regulator | Proper amount of |
| Solvent(s) | Allowance of |
Preferably, the composition comprises at least one of dexamethasone, fluorometholone, prednisolone acetate and sodium bromfenac.
Preferably, the thickener includes any one of sodium hyaluronate, hypromellose, polysorbate 20, carbomer, xanthan gum, polyethylene glycol, polyvinyl alcohol, and sodium carboxymethyl cellulose.
Preferably, the bacteriostatic agent comprises benzalkonium chloride, benzalkonium bromide, chlorobutanol, methylparaben and ethylparaben. The parts ratio is as follows: 1:1:1:1:1.
Preferably, the PH regulator is sodium hydroxide or/and hydrochloric acid.
Preferably, the osmotic pressure regulator is sodium chloride.
Preferably, the solvent is purified water.
8. A method for preparing tosufloxacin tosylate eye drops, which is characterized by comprising the following specific steps:
A. weighing a certain part of the composition, and putting the composition into an oven for sterilization;
B. adding a solvent into the sterilized composition for ultrasonic dispersion to obtain a suspension;
C. preparing a thickening agent, stirring the thickening agent, expanding the thickening agent after stirring, and sterilizing the thickening agent after expanding;
D. sequentially adding the tosufloxacin mesylate, the PH regulator and the preservative into the thickener, dissolving, and filtering to obtain a product A;
E. and adding the suspension into the product A, and uniformly stirring to obtain the final product of the eye drops.
Preferably, the temperature in the oven in the step A is 150 ℃, and the sterilization duration is as follows: 3h.
Preferably, the expansion time in the step C is 2-3h, and the sterilization is carried out in a sterilizing pot at 121 ℃ for 20-30min.
Preferably, the filtration in the step D is a secondary filtration, and the filtration is sequentially performed by 0.45 μm filtration and 0.22 μm filtration.
Compared with the prior art, the invention has the advantages and positive effects that:
the invention can not only effectively solve the problem of infection, but also treat inflammation by matching the formula and the preparation method, thereby greatly improving the treatment efficiency and effect, and besides, the invention has better protection and antibacterial capability on eyes.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the description of the embodiments will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings may be obtained according to these drawings without inventive effort to a person skilled in the art.
FIG. 1 is a photograph of a slit lamp sodium fluorescein stain of the present invention-specific embodiment-during the treatment of a first experimental bacterial keratitis model,
wherein the first row is a model group, the second row is a positive control group, and the third row is a test sample group;
FIG. 2 is a photograph showing the result of cornea-drawing culture after the first test of mouse bacterial keratitis model 7d according to the present invention,
wherein the first small graph is a model group; the second panel is a positive control group; the third panel is the test set;
FIG. 3 is a photograph showing the H & E staining results of a first test according to the present invention,
wherein the first small graph is a model group; the second panel is a positive control group; the third panel is the test set;
figure 4 is a graph of the invention-embodiment-a second experimental animal model of staphylococcus aureus keratitis,
wherein A is 30min after bacterial inoculation, bacterial vesicles (indicated by arrows) disappear. The white plaque (indicated by the arrow) was about 3mm 12 hours after bacterial inoculation. 24 hours after bacterial inoculation, white bacterial plaque (indicated by arrow) is about 5mm;
FIG. 5 is a photograph of a slit lamp for clinical observation of a second test, according to the present invention, wherein A is a model group before molding, B is a model group after administration, C is a positive control group, and D is a test sample group;
FIG. 6 is a photograph showing the pathological microscopic observation (HE, ×400) of the second test of the present invention,
a is model control group, B is positive control group, C is test sample group, black arrow shows cornea stroma, blue arrow shows cornea epithelium.
Description of the embodiments
In order that the above objects, features and advantages of the invention will be more clearly understood, a further description of the invention will be rendered by reference to the appended drawings and examples. It should be noted that, in the case of no conflict, the embodiments of the present application and the features in the embodiments may be combined with each other.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, however, the present invention may be practiced otherwise than as described herein, and therefore the present invention is not limited to the specific embodiments of the disclosure that follow.
The tosufloxacin tosylate eye drops comprise a composition, a thickener, tosufloxacin mesylate, a PH regulator, a bacteriostat, an osmotic pressure regulator and a solvent, namely the eye drops can be prepared according to a certain proportion, and the following components are prepared according to the proportion relation:
the specific components and parts of the product and the proportioning relationship among the components are clearly described.
1.1 Example 1
1) Weighing 100mg of fluorometholone (25 mg of dexamethasone and 1g of prednisolone acetate), placing in a small oven for sterilization at 150 ℃ for 3 hours, cooling to room temperature, adding water, and performing ultrasonic dispersion for 20min;
2) Preparing 1g of sodium hyaluronate by using a batching keg, stirring by using a stirring rod, then swelling (2-3) for 2-3 hours, and sterilizing in a sterilizing pot at 121 ℃ for 20-30min;
3) Weighing 300mg of toxacin mesylate, dissolving auxiliary materials of sodium hydroxide, benzalkonium chloride 2mg (benzalkonium bromide 2mg, chlorbutanol 2 mg) and the like in a dosing barrel, and filtering after 0.45 and 0.22 mu m;
4) Adjusting the pH value of the 3) to 7.4, and adding the dispersed 1) suspension into an ultra-clean bench;
5) The suspension of 4) is stirred and mixed evenly and filled into a polyester medicinal eye drop bottle, and prepared samples have batch numbers of SE-2023-003-20230301-1 to SE-2023-003-20230301-9.
1.2 Example 2
1) Weighing 100mg of fluorometholone (25 mg of dexamethasone and 1g of prednisolone acetate), placing in a small oven for sterilization at 150 ℃ for 3 hours, cooling to room temperature, adding water, and performing ultrasonic dispersion for 20min;
2) Preparing 400mg carbomer with a batching keg, stirring with a stirring rod, swelling (2-3) for 2-3 hours, sterilizing in a sterilizing pot at 121deg.C for 20-30min;
3) Weighing 300mg of toxacin mesylate, dissolving auxiliary materials of sodium hydroxide, benzalkonium chloride 2mg (benzalkonium bromide 2mg, chlorbutanol 2 mg) and the like in a dosing barrel, and filtering after 0.45 and 0.22 mu m;
4) Adjusting the pH value of the 3) to 7.4, and adding the dispersed 1) suspension into an ultra-clean bench;
5) The suspension of 4) is stirred and mixed evenly and filled into a polyester medicinal eye drop bottle, and prepared samples have batch numbers of SE-2023-003-20230302-1 to SE-2023-003-20230302-9.
1.3 Example 3
1) Weighing 100mg of fluorometholone (25 mg of dexamethasone and 1g of prednisolone acetate), placing in a small oven for sterilization at 150 ℃ for 3 hours, cooling to room temperature, adding water, and performing ultrasonic dispersion for 20min;
2) Preparing polysorbate 20 (PEG-20) 1g with a batching keg, stirring with a stirring rod, swelling (2-3) for 2-3 hours, sterilizing at 121deg.C for 20-30min;
3) Weighing 300mg of toxacin mesylate, dissolving auxiliary materials of sodium hydroxide, benzalkonium chloride 2mg (benzalkonium bromide 2mg, chlorbutanol 2 mg) and the like in a dosing barrel, and filtering after 0.45 and 0.22 mu m;
4) Adjusting the pH value of the 3) to 7.4, and adding the dispersed 1) suspension into an ultra-clean bench;
5) The suspension of 4) is stirred and mixed evenly and filled into a polyester medicinal eye drop bottle, and prepared samples have batch numbers of SE-2023-003-20230303-1 to SE-2023-003-20230303-9.
1.4 Example 4
1) Weighing 100mg of fluorometholone (25 mg of dexamethasone and 1g of prednisolone acetate), placing in a small oven for sterilization at 150 ℃ for 3 hours, cooling to room temperature, adding water, and performing ultrasonic dispersion for 20min;
2) Preparing 1g of xanthan gum by using a batching keg, stirring by using a stirring rod, then swelling (2-3) for 2-3 hours, and sterilizing in a sterilizing pot at 121 ℃ for 20-30min;
3) Weighing 300mg of toxacin mesylate, dissolving auxiliary materials of sodium hydroxide, benzalkonium chloride 2mg (benzalkonium bromide 2mg, chlorbutanol 2 mg) and the like in a dosing barrel, and filtering after 0.45 and 0.22 mu m;
4) Adjusting the pH value of the 3) to 7.4, and adding the dispersed 1) suspension into an ultra-clean bench;
5) The suspension of 4) is stirred and mixed evenly and filled into a polyester medicinal eye drop bottle, and prepared samples have batch numbers of SE-2023-003-20230304-1 to SE-2023-003-20230304-9.
The products prepared in the above examples were tested as follows:
according to the developed products, the invention provides two groups of targeted tests, and the specific tests are as follows:
1. animal selection and group administration
Adult C57BL/6 male mice (SPF grade) were selected as subjects, 6-8 weeks old, and 20-25 weight g, supplied by Ji Nanny laboratory animal Breeding Co. The mice live under 12-h normal light daily, the room temperature is 20-26 ℃, the relative humidity is 40-70%, and the mice are fed for one week to adapt to laboratory environment before experiments.
A bacterial keratitis model is established by using staphylococcus aureus infected mice, and 24h of the mice after infection are divided into a model group, a levofloxacin positive control group and a test sample group according to the grading balance group. Each group of 10 mice is divided into groups, and then administration is started, a test group is treated by SE-IP-2023-003, a positive control group is treated by levofloxacin eye drops, a model group is treated by normal saline, 3 groups are simultaneously administered, three times a day, and 5 mu L of one administration is dripped on the right eye part, and the left eye is not treated. And (5) subsequently observing the illness state, recording, photographing and scoring, and verifying the materials until the mice in the experimental group heal.
Model building
A trephine labeling method is used for establishing a bacterial keratitis model of the mice. The method comprises the following steps: the mice were anesthetized by intraperitoneal injection with chloral hydrate (10%, 4 mL/kg), the beard was cut off with scissors, the periphery of the eyes was sterilized with iodophor, and local anesthesia was performed by eye drops with obucaine hydrochloride. The central right eye cornea of the mice was marked under a surgical microscope using a trephine (d=2 mm), then the marked sites were scraped using a 45 ° knife, and corneal epithelium was scraped off to a shallow stroma. The sterilized toothpick is used for picking up the cultured staphylococcus aureus and uniformly wiping the staphylococcus aureus on the scraping part. After the molding is finished, the mice are placed into a culture room for continuous feeding, and all used equipment is sterilized by a sterilizing pot before and after the experiment in the experimental process.
3. Scoring photographing
From 1, 4, 7, d after dosing, visual lesions of mice were observed using slit lamp recordings, using white light mode; judging the edema, perforation and focus depth of the cornea by using a fracture mode; cobalt blue mode lesion size and corneal epithelial repair were used. The treatment effect was scored according to keratitis scoring criteria.
TABLE 1 clinical scoring criteria for bacterial keratitis
4. Staining of material sections
Mice were sacrificed by intraperitoneal injection with chloral hydrate (10%), and the eyeballs were collected using sterilized forceps and stored in FAS eye-fixing solution, embedded in paraffin, and cut into slices at one third of the cornea. Subsequent partial sections were stained for H & E, examined for corneal tissue lesions using a fluorescence microscope, partial sections were gram stained, and fluorescence microscopy was used to determine bacterial invasion into corneal tissue.
5. Corneal bacterium culture
After the treatment of 7d, the mice were euthanized, the eyeballs were dissected aseptically, washed with physiological saline, and the washing solution was collected and incubated at 36℃for 24 hours to determine the bacterial culture results.
6. Statistical analysis of data
Experimental data are expressed by mean ± standard deviation (x±sd), using SPSS Statistics25
Statistical software data analysis was performed by One-way anova (One-way anova) between different groups. P < 0.05 is statistically significant as the difference.
Test results
Clinical scoring
According to the slit lamp photographing results of 1, 4 and 7d, compared with the clinical evaluation of bacterial keratitis, the symptoms of different treatment time periods are evaluated, and as shown in the following table, the mice in the model group have higher and higher scores along with time, which indicates that the symptoms are more and more serious, and the cornea infection is continuously developed and worsened. The scores of the positive control group and the tested product treatment group are continuously reduced, and the scores of the 4d and 7d of the administration are remarkably reduced compared with the model group (p is less than 0.05 or p is less than 0.01), which indicates that the cornea infection is continuously repaired and healed. The test sample group is basically consistent with the positive control group, and the treatment effect is equivalent.
TABLE 2 influence of test samples on clinical scores of bacterial keratitis mice±S ，n=10）
Note that: * p < 0.05, p < 0.01, compared to model group
Fluorescein examination results:
as shown in fig. 1, the size of the lesion can be seen according to the staining area, the staining area of the model group can be seen to be gradually increased, the cornea is perforated finally, the staining areas of the positive control group and the test sample group are gradually reduced, and finally, no obvious staining exists, so that the bacterial keratitis of the mice is proved to be cured. The slit lamp photo shows that the effect of the test sample group on treating bacterial keratitis is basically consistent with that of the positive control group, the treatment period is short, the effect is quick, and the test sample has good application potential when being used for in vivo infection treatment.
Results of corneal bacterial culture:
as shown in fig. 2, a photograph of cornea obtained for bacterial culture after modeling and drug intervention at 7d is shown. The positive control group and the test sample group are obtained from the re-culture result, and no colony grows, so that the bacteria are completely killed by the drug administration group. The results of the model group cornea re-culture showed that there was still significant staphylococcus aureus growth.
Pathological examination results:
as shown in the H & E staining results in FIG. 3, 7 th d after administration, model group had severe corneal edema and massive inflammatory cell infiltration, while positive control group and test group had no obvious edema and inflammatory cell infiltration. The results show that the keratitis of the animals in the positive control group and the test sample group is basically cured.
Model preparation
The test was performed using New Zealand rabbits. The preoperative slit lamp was used to examine rabbit eyes, and the conjunctiva, cornea and appendages of each rabbit eye were observed, and the examination qualifiers were used in the experiments. The method comprises the steps of fixing rabbits in a rabbit box, disinfecting eyes by 75% alcohol before operation for three times, flushing conjunctival sac by 0.1% iodophor diluent, flushing iodophor diluent by sterile physiological saline, dripping 50ul of 0.6% eye drops into the conjunctival sac, lightly massaging for 10 seconds, sucking 10ul of 1×105CFU staphylococcus aureus bacterial suspension by using a 100ul microinjector under an operation microscope after cornea reflection disappears, injecting a needle from the pupil margin of a nasal cornea, injecting the prefabricated staphylococcus aureus bacterial suspension into a central matrix of a cornea of a model animal to form bacterial vesicles with a certain volume, and feeding the bacterial vesicles in a single cage after the injection depth is about 1/3 depth of the cornea matrix. The clinical observation indexes and the scoring standards in the table are adopted for observation and scoring, two observers observe the clinical observation indexes and the scoring standards simultaneously by adopting a double-blind method, and the sum of the scores obtained by the two observers is divided by 2 to obtain the final total score.
TABLE 3 clinical observations and scoring criteria
Grouping and administration of animals
24h after modeling, balanced grouping was performed according to rabbit keratitis observation scores. The model group, the positive control group and the SE-IP-2023-003 group are respectively provided, and each group comprises 12 rabbits, and the total number is 36. The subjects were administered after the grouping, and the left eyes of the animals of each group were administered the corresponding subjects or controls 3 times per day, 2 drops each time, and 7d continuously, except for the model control group, which was administered an equal volume of physiological saline.
Index detection
And (3) carrying out microscopic examination by using a slit lamp for 7d administration, grading corresponding indexes, carrying out euthanasia on all the experimental rabbits after 7d administration, randomly selecting 6 rabbits for picking eyeballs from each group, removing soft tissues carried on the eyeballs, fixing the eyeballs by 4% formaldehyde immediately to prevent tissue cells from autolysis and putrefaction, simultaneously preventing enzyme in the tissues from decomposing protein, fixing the 4% formaldehyde for 24 hours, preparing paraffin sections, carrying out HE staining, and observing the inflammation condition of the cornea. In addition, 6 ophthalmic forceps and surgical blades are taken for separating cornea, after flushing with sterile physiological saline, liquid nitrogen is added for rapid grinding and smashing of tissues, the tissues are put into a tissue grinder with 1ml of sterile physiological saline, grinding and homogenizing are carried out, the homogenate is taken and diluted in 10-time concentration gradient and inoculated into beef extract peptone culture medium, and CFU counting is carried out after culture for 24 hours at 37 ℃.
4. Test results
1. Post-film formation observation before drug administration
Immediately after injection (PI) the surface of the cornea appeared about 3mm of milky bacterial vesicles, and after injection the bacterial vesicles disappeared for 30min, and the cornea was restored to transparency. White bacterial plaque of about 3mm appears on the surface of the cornea at 12 hours, and experimental rabbit eyes slightly redise, photophobia and lacrimation increase. At 24 hours, white bacterial plaque on the surface of the cornea developed to 5mm, and the symptoms of classical bacterial keratitis were manifested by photophobia, lacrimation, secretion of a small amount of secretion, conjunctival congestion, slight edema of cornea, blepharospasm. The inflammation score was between 6 and 10 at 24h in 36 rabbits, and photophobia, lacrimation, blepharospasm, small amounts of secretions, conjunctival edema, congestion, cornea forming an off-white infiltration focus about 5mm in diameter were seen in each rabbit eye. The preparation of the staphylococcus aureus keratitis animal model is successful. The performance at each time point is shown in fig. 4.
2. Post-administration observations (slit lamp inspection)
On day 7, the clinical symptoms of bacterial keratitis in the model group eye were further exacerbated: plaque enlargement, corneal stroma infiltration and edema exacerbation, and partial eye appearance of anterior chamber purulence. The bacterial cornea inflammation of the levofloxacin hydrochloride eye drops and the in-situ formed gel of the levofloxacin hydrochloride eye is obviously reduced: reduced corneal plaque, reduced conjunctival congestion and edema, reduced corneal stroma infiltration and edema, and increased corneal transparency. The clinical index observation slit lamp photograph is shown in fig. 5.
Clinical observation scoring
The clinical scores of the groups are basically consistent before administration, and no obvious difference exists; after 7d of administration, the scores of the model group are obviously increased, the symptoms are heavier, and the scores of the positive control group and the test sample group are obviously reduced compared with the scores of the model group (p is less than 0.05). The cornea score of the test sample group is smaller than that of the positive control group, but the cornea score and the cornea score have no statistical significance. See table 4.
TABLE 4 influence of test samples on clinical scores of bacterial keratitis rabbits±S ，n=12）
Note that: * P < 0.01, compared with model group
Cornea colony count
Compared with the model group, the cornea colony count of the positive control group and the cornea colony count of the test sample group are greatly reduced, and the cornea colony count of the positive control group and the cornea colony count of the test sample group are obviously different (P is less than 0.05). While the positive control group and the test group have no significant difference in cornea colony count. See table 5.
TABLE 5 influence of test sample on bacterial keratitis rabbit cornea colony count±S ，n=6）
Note that: * P < 0.01, compared with model group
Pathological examination
The model group has obvious edema of cornea epithelium and stroma, massive inflammatory cell infiltration, cornea epithelium defect and stroma layer structure disorder. The positive control group had slight edema of corneal epithelium and stroma, and decreased inflammatory cell infiltration. The cornea of the test sample group has no edema, inflammatory cell infiltration is reduced, and the stroma is complete. The pathological microscope observations of each group are shown in fig. 6.
The present invention is not limited to the above-mentioned embodiments, and any equivalent embodiments which can be changed or modified by the technical content disclosed above can be applied to other fields, but any simple modification, equivalent changes and modification made to the above-mentioned embodiments according to the technical substance of the present invention without departing from the technical content of the present invention still belong to the protection scope of the technical solution of the present invention.
Claims (10)
1. The tosufloxacin tosylate eye drops are characterized by comprising the following components in detail:
2. The tosulfloxacin tosylate eye drops according to claim 1 wherein the composition comprises at least one of dexamethasone, fluorometholone, prednisolone acetate and sodium bromfenate.
3. The tosulfloxacin tosylate eye drops according to claim 2 wherein the thickening agent comprises any one of sodium hyaluronate, hypromellose, polysorbate 20, carbomer, xanthan gum, polyethylene glycol, polyvinyl alcohol and sodium carboxymethyl cellulose.
4. A tosufloxacin tosylate eye drop according to claim 3 wherein the bacteriostat comprises benzalkonium chloride, benzalkonium bromide, chlorobutanol, methylparaben, ethylparaben. The parts ratio is as follows: 1:1:1:1:1.
5. The toxacin tosylate eye drops according to claim 4 wherein the PH modifier is sodium hydroxide or/and hydrochloric acid.
6. The toxacin tosylate eye drops according to claim 5 wherein the osmotic pressure regulator is sodium chloride.
7. The toxacin tosylate eye drops according to claim 6 wherein the solvent is purified water.
8. A process for the preparation of the tosufloxacin tosylate eye drops according to claims 1-7 characterized in that the specific process is as follows:
weighing a certain part of the composition, and putting the composition into an oven for sterilization;
adding a solvent into the sterilized composition for ultrasonic dispersion to obtain a suspension;
preparing a thickening agent, stirring the thickening agent, expanding the thickening agent after stirring, and sterilizing the thickening agent after expanding;
sequentially adding the tosufloxacin mesylate, the PH regulator and the preservative into the thickener, dissolving, and filtering to obtain a product A;
and adding the suspension into the product A, and uniformly stirring to obtain the final product of the eye drops.
9. The method for preparing the tosufloxacin tosylate eye drops according to claim 8, wherein the temperature in the oven in the step a is 150 ℃ and the sterilization time is as follows: 3h.
10. The method for preparing the tosufloxacin tosylate eye drops according to claim 9 wherein the expansion time in the step C is 2-3 hours and the sterilization is performed in a sterilizing pot at 121 ℃ for 20-30min; the filtration in the step D is secondary filtration, and the filtration is sequentially carried out by 0.45 μm filtration and 0.22 μm filtration.
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