CN116270662A - Moxifloxacin and dexamethasone hydrochloride sodium phosphate eye drops - Google Patents

Abstract

The invention discloses moxifloxacin dexamethasone sodium phosphate eye drops, which comprise the following components in parts by weight: moxifloxacin hydrochloride 0.544-0.546%; dexamethasone sodium phosphate 0.011-0.0275%; 0.02 to 0.1 percent of tyloxapol/poloxamer; boric acid 0.2-0.4%; sorbitol 0.1-0.4%; 0.01 to 0.1 percent of edetate disodium; sodium chloride 0.59-0.68%; sodium hydroxide in an amount sufficient to bring the eye drops to a pH of 7.5 to 8.5; water for injection. The eye drop provided by the invention has the advantages of high efficiency, broad antibacterial spectrum, good stability and high safety, can effectively prevent ocular inflammation, and reduces the content of dexamethasone, thereby effectively reducing and even avoiding the problems of increased intraocular pressure, optic nerve damage, reinfection, cornea perforation, subclinical conjunctivitis reaction and secondary subcapsular cataract caused by long-term use of high-concentration glucocorticoid.

Description

Moxifloxacin and dexamethasone hydrochloride sodium phosphate eye drops

Technical Field

The application relates to the technical field of biological medicines, in particular to moxifloxacin dexamethasone sodium phosphate eye drops.

Background

Cataract surgery is a common ophthalmic surgery and is one of the most widely performed ophthalmic surgeries at present. Post-operative infections are rare but potentially damaging complications of cataract surgery. Inflammation after cataract surgery manifests itself as proteolysis and inflammatory cells in the anterior chamber, congestion, pupil constriction, oedema, leukocyte migration, fibroblast proliferation and scar formation, and other localized reactions to the released pro-inflammatory cytokines.

In order to exert better effects of preventing postoperative ocular inflammation and infection and treating ocular infection caused by microorganisms, the administration of the drugs is usually carried out in a combined mode, and particularly, antibiotics are used for preventing and treating the ocular infection by combining steroid hormones. Furthermore, because fluoroquinolone antibiotics have strong intraocular penetrability and glucocorticoid is helpful for reducing inflammatory reaction, fluoroquinolone antibiotics and glucocorticoid eye drops are often used for preventing ocular inflammation and infection after cataract surgery after operation.

However, the above combination administration has the following disadvantages due to limited eye space, blinking eye movement, etc: 1. the absorption of the front drop of medicine is generally not facilitated due to the influence of dilution or blocking of the rear drop of medicine when in use, and the absorption of the front drop of medicine is locally influenced due to the cleaning of the rear drop of medicine; 2. there is a potential for overdosing; 3. the dripping dosage is easy to be wrong, and the conditions of leakage, wrong dripping, multiple dripping and the like exist.

Therefore, in order to provide a simple and convenient administration mode to increase the compliance of patients, several fluoroquinolones and antibiotics combined hormone compound eye drops are developed clinically for preventing postoperative infection and inflammation of eyes, and the common use is mainly tobramycin dexamethasone eye drops.

However, long-term use of tobramycin dexamethasone eye drops can lead to corneal fungal infection or drug-resistant strains, and double infection occurs; meanwhile, the concentration of dexamethasone in the tobramycin dexamethasone eye drops is higher.

However, prolonged use of high concentrations of glucocorticoids by the eye may occur as follows: ocular hypertension, optic nerve damage, reinfection and corneal perforation. Whereas elevated ocular pressure is the most common adverse effect in ophthalmic clinics, severe cases can lead to glucocorticoid-like glaucoma. The mechanism by which it causes ocular pressure elevation is quite complex, and it is thought to be probably related to factors including accumulation of small Liang Xi extracellular matrix, affected expression of cytoaquaporin-1, altered cytoskeleton, decreased expression of cell surface glucocorticoid beta receptor, and inhibited expression of epidermal growth factor. In addition, high concentrations of glucocorticoids can also lead to subclinical conjunctivitis responses and secondary post-subcapsular cataracts.

For ocular inflammation with bacterial ocular infection risk after cataract operation, development of a low-concentration fluoroquinolone antibiotic combined hormone eye drop is very necessary for preventing postoperative infectious ocular inflammation.

Disclosure of Invention

The application provides moxifloxacin dexamethasone sodium phosphate eye drops, which are used for solving the problem that the following phenomenon can occur when the high-concentration glucocorticoid is used for a long time in eyes: increased ocular pressure, impaired optic nerve, reinfection and corneal perforation, and high concentrations of glucocorticoids can also lead to problems with subclinical conjunctivitis and secondary subcapsular cataracts.

The technical scheme adopted by the application is as follows:

the invention provides moxifloxacin dexamethasone sodium phosphate eye drops, which comprise the following components in parts by weight:

sodium hydroxide in an amount sufficient to provide the eye drops with a pH of 7.5 to 8.5; and

water for injection.

In one embodiment, the composition comprises the following components in parts by weight:

sodium hydroxide in an amount sufficient to provide the eye drops with a pH of 7.5 to 8.5; and

water for injection.

In one embodiment, the composition comprises the following components in parts by weight:

sodium hydroxide in an amount sufficient to provide the eye drops with a pH of 7.5 to 8.5; and

water for injection.

The technical scheme of the application has the following beneficial effects:

the eye drop provided by the invention has the advantages of high efficiency, broad antibacterial spectrum, good stability and high safety, can effectively prevent ocular inflammation, and reduces the content of dexamethasone, thereby effectively reducing and even avoiding the problems of intraocular pressure increase, optic nerve damage, reinfection, cornea perforation, subclinical conjunctivitis reaction and secondary subcapsular cataract caused by long-term use of high-concentration glucocorticoid.

Drawings

In order to more clearly illustrate the technical solutions of the present application, the drawings that are needed in the embodiments will be briefly described below, and it will be obvious to those skilled in the art that other drawings can be obtained from these drawings without inventive effort.

FIG. 1 is a schematic representation of model set HE staining of a test example of the invention;

FIG. 2 is a schematic illustration of HE staining of moxifloxacin group according to the test example of the present invention;

FIG. 3 is a schematic representation of HE staining of dexamethasone sodium phosphate group according to the test example of the present invention;

FIG. 4 is a schematic representation of HE staining in the low dose group of the test examples of the invention;

FIG. 5 is a schematic representation of HE staining in the high dose group of the test examples of the invention.

Detailed Description

Reference will now be made in detail to the embodiments, examples of which are illustrated in the accompanying drawings. When the following description refers to the accompanying drawings, the same numbers in different drawings refer to the same or similar elements, unless otherwise indicated. The implementations described in the examples below are not representative of all implementations consistent with the present application. Merely examples of systems and methods consistent with some aspects of the present application as detailed in the claims.

In order to facilitate understanding of the technical solutions of the application, some of the components referred to in the present application will be described below first.

Moxifloxacin: fourth-substituted fluoroquinolone antibiotics. The DNA topoisomerase inhibitor can be used for preventing eye inflammation caused by gram positive bacteria, gram negative bacteria, anaerobic bacteria, acid-fast bacteria, mycoplasma, chlamydia and Legionella, and moxifloxacin has wider antibacterial activity of eye bacteria and lower incidence of adverse reaction.

Dexamethasone sodium phosphate (dexamethasone): the adrenocortical hormone medicine has pharmacological actions such as anti-inflammatory and antiallergic, and can effectively reduce and avoid the reaction of tissues to inflammation and reduce the expression of inflammation. In addition, the composition has antiallergic and immunity inhibiting effects, and can prevent or inhibit cell mediated immune reaction, delayed allergic reaction, and relieve primary immune reaction expansion. Dexamethasone has wide clinical application, and can be administered by oral administration, intravenous injection, intramuscular injection, inhalation, ocular administration and topical application, for treating various diseases such as autoimmune diseases, allergy, inflammation, asthma, and dermatological and ophthalmic diseases.

Tyloxapol/poloxamer: the nonionic surfactant is used as a multifunctional ophthalmic pharmaceutical adjuvant, and has effects in improving solubility of medicine, prolonging residence time before cornea, and enhancing cornea permeabilityHigh bioavailability potential. Nonionic surfactants are generally less toxic, less hemolytic, less irritating to the ocular surface, and remain in solution toward a near physiological pH. The polyoxyethylated nonionic surfactant has important application value in ophthalmology and has wide application in nonionic surfactants. These surfactants are commonly referred to as polymeric ethers because they all contain a common hydrophilic portion of the polyoxyethylene or polyethylene glycol molecule, with repeating (CH ₂ CH ₂ O) _n The ether structure, n, is typically between 10 and 100 units. Tyloxapol is an amber viscous liquid, sometimes slightly turbid, slightly aromatic. The relative density is about 1.072. Stable at sterilization temperature, stable in the presence of acid and alkali, and can be oxidized by metal. Is slowly miscible with water and is soluble in acetic acid, chloroform, carbon tetrachloride, carbon disulfide, benzene, toluene and other organic solvents. The product is nontoxic and has no irritation to skin and mucous membrane. Poloxamer is soluble in water or ethanol, soluble in absolute ethanol, ethyl acetate, chloroform, and hardly soluble in diethyl ether or petroleum ether, and has a certain foamability. The pH value of the 2.5% aqueous solution is between 5.0 and 7.5, and the pH value for injection is between 6.0 and 7.0. The aqueous solution is stable in air, and the pH value is reduced when the aqueous solution meets light. Is stable to acid-base aqueous solution and metal ions. Poloxamers are often used in formulations as emulsifiers, stabilizers, and also as solubilisers, solid dispersants and the like. Tyloxapol/poloxamer is used as a pharmaceutical adjuvant mainly as an emulsifier and detergent. Both the tension and the surface tension can be reduced. Has good solubilization and dispersion effects, and is widely used for liquid preparations such as eye drops, nose drops and the like. Both are reported to have good detergency and cleaning effect for prescriptions for eye cleaners (eyewashes). According to the physicochemical properties of the medicine and the characteristics of the product, tyloxapol/poloxamer is selected to be used as an eyeball cleaning agent for the prescription.

Boric acid is colorless, slightly bright and crystalline or white loose powder with greasy feeling. Dissolving the product in ethanol or water; is easily dissolved in boiling water or boiling ethanol. Taking 1.0g of boric acid, adding 30ml of water for dissolution, and then adjusting the pH value to be in the range of 3.5-4.8. The compound is used as a pharmaceutic adjuvant, mainly used as a buffering agent and has a certain antibacterial effect. The principle of selecting the buffer solution is determined according to the physicochemical property of the drug, which is favorable for the stability of the drug and the therapeutic effect of the drug. Boric acid is selected as a buffering agent for the prescription according to the physicochemical properties of the medicine and the characteristics of the product.

Sorbitol is a white crystalline powder. Is soluble in water, slightly soluble in ethanol, and insoluble in chloroform or diethyl ether. Sorbitol is widely used as an adjuvant in pharmaceutical preparations, and in the preparation of liquid preparations, sorbitol can be used as a carrier for sugarless preparations and as a stabilizer for pharmaceutical, vitamin and antacid suspensions. Can also be used for injection and topical preparation. Sorbitol is chemically stable and compatible with most of the excipients. Sorbitol is selected as a stabilizer for the prescription according to the physicochemical properties of the medicine and the characteristics of the product.

Disodium edentate is a white or off-white crystalline powder. The product is soluble in water and hardly soluble in methanol, ethanol or trichloromethane. Edetic acid and edetate are used as stabilizers in pharmaceutical formulations, cosmetics and foods; they form stable water-soluble complexes (stabilizers) with alkaline earth metals and heavy metal ions. The nature of the ions in the chelate is almost free of ions, so stabilizers are often described as being able to "remove" ions from solution; this process may also be referred to as chelation. The stability of the edetate complex is related to the metal ion being complexed and also to the pH of the solution. Edetic acid and edetate are mainly used as antioxidants, synergists and chelate trace metal ions such as copper, iron, manganese and the like which can catalyze autoxidation, and the edetic acid and edetate can be used singly or in combination with the antioxidants, and the concentration is 0.005-0.1% w/v. Edetic acid and edetate have a certain antibacterial activity due to chelation. According to the physicochemical property of the medicine and the characteristics of the product, a proper amount of metal ion stabilizer is added to improve the stability of the preparation, and disodium edentate is selected as the stabilizer of the prescription.

Sodium chloride is colorless, transparent cubic crystals or white crystalline powder. Is easily soluble in water and hardly soluble in ethanol. As a pharmaceutical adjuvant, mainly used as an osmotic pressure regulator. The eye drops should be selected for proper osmotic pressure, and should be generally isotonic with tears, and sodium chloride, which is a common osmotic pressure regulator, is selected as an isotonic regulator in the prescription.

The solubility, stability, irritation and efficacy of the drug are all related to the pH of the eye drop solution. The pH of normal human tears is 7.2-7.5, and the tolerable pH of eyes is 5.0-9.0. The research result before the prescription process shows that the moxifloxacin hydrochloride and dexamethasone sodium phosphate bulk drugs are mixed in a medium with low pH value to generate precipitation, and different liquid medicine pH values have obvious influence on the dissolution of the bulk drugs. Therefore, the pH is set to 7.5 to 8.5.

Examples

Moxifloxacin and dexamethasone sodium phosphate eye drops, as shown in table 1, comprise the following components in parts by weight:

example a

The moxifloxacin dexamethasone sodium phosphate eye drops comprise the following components in parts by weight:

sodium hydroxide in an amount sufficient to bring the eye drops to a pH of 7.5; and

water for injection.

Specifically, as shown in Table 1 above, namely (5 ml: moxifloxacin 25mg and dexamethasone phosphate 0.5 mg).

Example b

The moxifloxacin dexamethasone sodium phosphate eye drops comprise the following components in parts by weight:

sodium hydroxide in an amount sufficient to bring the eye drops to a pH of 7.8; and

water for injection.

Specifically, as shown in Table 1 above, namely (5 ml: moxifloxacin 25mg and dexamethasone phosphate 0.5 mg).

Example c

The moxifloxacin dexamethasone sodium phosphate eye drops comprise the following components in parts by weight:

sodium hydroxide in an amount sufficient to provide the eye drops with a pH of 8.0; and

water for injection.

Specifically, as shown in Table 1 above, namely (5 ml: moxifloxacin 25mg and dexamethasone phosphate 0.5 mg).

Example d

The moxifloxacin dexamethasone sodium phosphate eye drops comprise the following components in parts by weight:

sodium hydroxide in an amount sufficient to bring the eye drops to a pH of 7.5; and

water for injection.

Specifically, as shown in Table 1 above, namely (5 ml: moxifloxacin 25mg and dexamethasone phosphate 0.5 mg).

Example e

The moxifloxacin dexamethasone sodium phosphate eye drops comprise the following components in parts by weight:

sodium hydroxide in an amount sufficient to provide the eye drops with a pH of 8.0; and

water for injection.

Specifically, as shown in Table 1 above, namely (5 ml: moxifloxacin 25mg and dexamethasone phosphate 1.25 mg).

Example f

The moxifloxacin dexamethasone sodium phosphate eye drops comprise the following components in parts by weight:

sodium hydroxide in an amount sufficient to bring the eye drops to a pH of 7.8; and

water for injection.

Specifically, as shown in Table 1 above, namely (5 ml: moxifloxacin 25mg and dexamethasone phosphate 1.25 mg).

Example g

The moxifloxacin dexamethasone sodium phosphate eye drops comprise the following components in parts by weight:

sodium hydroxide in an amount sufficient to provide the eye drops with a pH of 8.5; and

water for injection.

Specifically, as shown in Table 1 above, namely (5 ml: moxifloxacin 25mg and dexamethasone phosphate 1.25 mg).

Example h

The moxifloxacin dexamethasone sodium phosphate eye drops comprise the following components in parts by weight:

sodium hydroxide in an amount sufficient to provide the eye drops with a pH of 8.0; and

water for injection.

Specifically, as shown in Table 1 above, namely (5 ml: moxifloxacin 25mg and dexamethasone phosphate 1.25 mg).

Test examples

Based on a model of inducing rabbit eye inflammation by injecting LPS in a puncture combined anterior chamber, the treatment is carried out by taking a test medicament of moxifloxacin hydrochloride, dexamethasone sodium phosphate eye drops (the test medicament high dose group contains 25mg of moxifloxacin per 5ml, and 1.25mg of dexamethasone phosphate per 5ml, the test medicament low dose group contains 25mg of moxifloxacin and 0.5mg of dexamethasone phosphate) with the same concentration for 4 times per day, the control substance of moxifloxacin hydrochloride eye drops and the control substance of dexamethasone sodium phosphate eye drops, and the inhibition curative effect of the test medicament on eye inflammation is evaluated through inflammation scoring, inflammatory factor detection in aqueous humor and pathological examination of eyeball slices.

In the evaluation of inflammation indexes of a pathological model, typical ophthalmic surgery postoperative symptoms such as conjunctival edema, congestion, corneal edema, turbidity, iris congestion, vasodilation, vitreous cavity turbidity, red light reflection disappearance and the like of rabbit eyes can be obviously induced by combining mechanical puncture with LPS injection.

The experimental rabbits were scored for ocular signs and rated on a scale (ocular inflammation scoring table) by two independent clinicians.

Table 2 ocular inflammation scoring table

Wherein, table 3.1 below shows the effect of each administration group on the overall score of rabbit ocular inflammation on day 0, table 3.2 shows the effect of each administration group on the overall score of rabbit ocular inflammation on day 3, and table 3.3 shows the effect of each administration group on the overall score of rabbit ocular inflammation on day 5.

Referring to the average value of the inflammation scores, the lower the score, the more responsive the improvement; SD index level difference, discrete degree of response data, for determining stability of scoring valueThe method comprises the steps of carrying out a first treatment on the surface of the The smaller the P value is, the more likely it is that the hypothesis test result will occur, i.e., the more significant.

Table 3.1 effect of dosing group on overall score of rabbit ocular inflammation (day 0, n=8)

Table 3.2 effect of dosing group on overall score of rabbit ocular inflammation (day 3, n=8)

Table 3.3 effect of dosing group on overall score of rabbit ocular inflammation (day 5, n=8)

As shown in Table 3.1, the test group rabbit eyes were scored for inflammatory symptoms 24 hours after molding

A value of 12 refers to the sum of the highest 3 minutes per conjunctiva, cornea, iris, vitreous cavity.

As shown in Table 3.2, after three days of eye drop treatment, each treatment drug was able to improve ocular inflammatory symptoms caused by the model, from the score evaluation model group, moxifloxacin group, dexamethasone sodium phosphate group, low dose group of the test drug, and high dose group of the test drug

The gradual decrease in value can be seen: the dexamethasone sodium phosphate group, the low-dose group and the high-dose group can improve pathological damage of iris more effectively, while the moxifloxacin group is not remarkably improved.

As shown in Table 3.3, the drugs were administeredFive days after eye drop treatment, each therapeutic drug further relieves the symptoms of ocular inflammation caused by the model, and the model group, the moxifloxacin group, the dexamethasone sodium phosphate group, the low-dose group and the high-dose group of the test drug are evaluated according to the scores

The gradual decrease in value can be seen: the low-dose group and the high-dose group of the test drugs can improve the overall pathological damage of the eyes more effectively, and the improvement effect on conjunctiva and cornea is better than that of a moxifloxacin group and a dexamethasone sodium phosphate group.

The moxifloxacin group was not significantly improved by ELISA to detect the concentrations of inflammatory factors in aqueous humor of each of the third and fifth days. Under normal conditions, the content of tumor necrosis factor-alpha (tumor necrosisfactor-alpha, TNF-alpha), interleukin (IL) -1 beta and interferon-gamma (IFN-gamma) in the aqueous humor of the rabbit is very low and is smaller than or close to the detection limit. After modeling, the levels of TNF-alpha, IL-1 beta and IFN-gamma in aqueous humor can be obviously induced, the tested drugs, especially the high-dose group, can obviously reduce inflammatory factors, and under the experimental condition, the tested drugs are obviously superior to single use of moxifloxacin, and the effect of reducing the TNF-alpha at the middle time point of treatment is superior to that of single use of dexamethasone sodium phosphate although the tested drugs are not obviously different from single use of dexamethasone sodium phosphate in the later period of treatment, namely the tested drugs, especially the high dose group, have the potential of accelerating the improvement process of inflammatory diseases.

The eye fixation was taken after euthanasia of animals on the sixth day after dosing, and the overall pathological changes were assessed by HE staining, as can be seen in connection with fig. 1 to 5: the color of the staining part of the model group, the moxifloxacin group, the dexamethasone sodium phosphate group, the low-dose group and the high-dose group of the test medicament gradually decreases, which shows that the model group (4/8) and the moxifloxacin group (3/8) are all possible individuals with local retinal edema, and no possible sample of the local retinal edema is found in the dexamethasone sodium phosphate group, the high-dose group and the low-dose group of the test medicament.

From the overall inflammation score, each drug group had an effect on alleviating inflammation, and dexamethasone sodium phosphate group and each test drug group had a better effect with prolonged administration time (tables 3.1-3.3). The high dose group of the test drug had significantly reduced inflammatory symptoms compared to the moxifloxacin group (p=0.009) on day 3, but no significant difference compared to the dexamethasone sodium phosphate group; the low-dose group of the test drug had significantly reduced inflammatory symptoms compared to the moxifloxacin group (p=0.0158) but no significant differences compared to the dexamethasone sodium phosphate group, and no significant differences between the high-dose group of the test drug and the low-dose group of the test drug (table 3.2); the high dose group of the test drug had significant relief of inflammatory symptoms at day 5 compared to the dexamethasone sodium phosphate group (p=0.0009) and moxifloxacin group (p < 0.001); the low dose group of the test drug had significant relief of inflammatory symptoms compared to the moxifloxacin group (p < 0.001) but no significant differences compared to the dexamethasone sodium phosphate group; there was no significant difference between the test drug high dose group and the test drug low dose group (table 3.3).

The test examples show that the moxifloxacin dexamethasone sodium phosphate eye drops with different specifications can play a role in preventing and treating postoperative ocular inflammation according to the non-clinical pharmacodynamic research results of mechanical injury and bacterial lipopolysaccharide-induced ocular inflammation models.

Comparative example one

External antibacterial study on moxifloxacin dexamethasone sodium phosphate eye drops:

MIC values of all strains are measured by a CLSI recommended plate double dilution method, and the external antibacterial effects of the moxifloxacin and dexamethasone sodium phosphate eye drops with different proportions are compared (high-dose group of the test medicament-5 ml: moxifloxacin 25mg, dexamethasone phosphate 1.25mg; low-dose group of the test medicament-5 ml: moxifloxacin 25mg and dexamethasone phosphate 0.5 mg).

The results show that: the MIC values of the moxifloxacin hydrochloride dexamethasone sodium phosphate eye drops in each proportion on each strain of standard bacteria and clinical isolate bacteria are basically consistent, and the in-vitro antibacterial effect is not obviously different.

Comparative example two

Regarding pharmacodynamics study of moxifloxacin dexamethasone hydrochloride sodium phosphate eye drops on rabbit pseudomonas aeruginosa keratitis:

by constructing a new zealand rabbit pseudomonas aeruginosa keratitis model, taking the moxifloxacin dexamethasone sodium phosphate eye drops with different specifications and the reference moxifloxacin hydrochloride eye drops as test substances by eye drops, and observing the curative effect of the rabbit pseudomonas aeruginosa keratitis.

The results show that: 2 specification moxifloxacin hydrochloride dexamethasone sodium phosphate eye drops and moxifloxacin eye drops have antibacterial effect and equivalent effect; the moxifloxacin dexamethasone sodium phosphate eye drops and the moxifloxacin eye drops with 2 specifications have the effect of improving cornea symptoms in rabbit pseudomonas aeruginosa keratitis and have the same effect; the improvement of 2-specification moxifloxacin dexamethasone hydrochloride sodium phosphate eye drops on edema and conjunctival congestion is superior to that of moxifloxacin eye drops, but no obvious difference is found among 2-specification test object groups; compared with the moxifloxacin hydrochloride control group, the moxifloxacin hydrochloride dexamethasone sodium phosphate eye drops with 2 specifications have obvious epithelial repair and obviously reduced other pathological changes.

Comparative example three

Pharmacodynamics study of moxifloxacin dexamethasone sodium phosphate eye drops on rabbit pseudomonas aeruginosa conjunctivitis:

by constructing a New Zealand rabbit pseudomonas aeruginosa conjunctivitis model, taking moxifloxacin dexamethasone sodium phosphate eye drops with different concentrations, a reference moxifloxacin hydrochloride eye drop and a reference dexamethasone sodium phosphate eye drop as eye drops by eye drops, and observing the antibacterial curative effect of the rabbit pseudomonas aeruginosa conjunctivitis.

The results show that: in the pathological aspect, the improvement degree of dexamethasone on the membrane tissue lesion is positively related to the specification concentration, and the main content is as follows:

1) The 2 standard test objects and the moxifloxacin eye drops have antibacterial effect and equivalent effect;

2) The 2-specification test substances, the moxifloxacin eye drops and the dexamethasone sodium phosphate eye drops have an improvement effect on conjunctival symptoms in rabbit pseudomonas aeruginosa conjunctivitis, and the 3-specification test substances are superior to the moxifloxacin eye drops and the dexamethasone sodium phosphate eye drops in improvement on symptoms of edema and conjunctival congestion;

3) The eye drops of 2 specifications of the test substances, moxifloxacin and dexamethasone sodium phosphate improve conjunctival tissue lesions in rabbit pseudomonas aeruginosa conjunctivitis; among them, the decrease of the test object 1 group (specification: 5ml: moxifloxacin 25mg and dexamethasone phosphate 1.25 mg) was most remarkable, and the decrease of the lesion degree of the test object 2 group (specification: 5ml: moxifloxacin 25mg and dexamethasone phosphate 0.5 mg), and the moxifloxacin control group and dexamethasone control group was worst.

Comparative example four

Pharmacodynamics study of moxifloxacin dexamethasone hydrochloride sodium phosphate eye drops on ocular inflammation:

based on a rabbit ocular inflammation model induced by puncturing combined with anterior chamber injection LPS, 3 standard test substances, a reference substance moxifloxacin hydrochloride eye drop and a reference substance dexamethasone sodium phosphate eye drop are administered, treatment is carried out 4 times per day, and the inhibiting curative effect of the test substances on ocular inflammation is evaluated through inflammation scoring, detection of inflammatory factors in aqueous humor and pathological examination of eyeball sections.

Under the experimental conditions: the test object 1 group (specification: 5ml: moxifloxacin 25mg and dexamethasone phosphate 1.25 mg) and the test object 2 group (specification: 5ml: moxifloxacin 25mg and dexamethasone phosphate 0.5 mg) remarkably accelerate the improvement of inflammation scores, reduce the inflammatory factor level in aqueous humor and reduce pathological damage to a certain extent, and the effect is generally superior to that of a moxifloxacin control group and a dexamethasone control group.

Comparative example five

For single-administration pharmacokinetic experiments in rabbits:

after the compound preparation is dripped into the rabbit for single eye, the time-varying process of the compound preparation in animal plasma, tears, aqueous humor, cornea and conjunctiva is examined, and compared with the single preparation, and reference information is provided for deeply clarifying the mechanism of action of the medicine, designing and optimizing the pre-clinical and clinical test dosing schemes.

After the compound/single formulation is administrated by dropping eyes for 10min, 1h, 6h and 24h, the moxifloxacin/dexamethasone at each time point has the highest content in tears and the lowest plasma content. After the compound/single preparation is applied to rabbit eyes by dripping, the change trend of moxifloxacin in cornea, conjunctiva and aqueous humor is similar, the content of moxifloxacin is highest 10min after the administration, and the moxifloxacin is gradually reduced along with time; tear fluid varies with time due to large individual differences. After the compound single preparation is applied to rabbit eyes by dripping, the variation trend of dexamethasone in cornea, conjunctiva and aqueous humor is similar, the content of dexamethasone is highest 10min after the cornea and conjunctiva are applied, and the dexamethasone is gradually reduced along with time; the content of the aqueous humor is highest for 1h, then the aqueous humor is rapidly reduced, and the lower limit of quantification is lower than the lower limit of quantification in 24 h; tear fluid has a large individual difference and a different trend with time.

The results show that: after the compound/single formulation is applied to rabbits by eye drops, no obvious sex difference is found among the contents of plasma, tear, aqueous humor, desmopressin and dexamethasone in the cornea of female animals and male animals at various time points; the content of moxifloxacin/dexamethasone in plasma, tear, aqueous humor, conjunctiva and cornea at each time point after the compound group administration is not obviously different from that of the single preparation.

Comparative example six

For the rabbit multiple dosing pharmacokinetic assay:

after the compound preparation is dripped into normal cornea or damaged cornea of rabbit for many times, the time-varying process of the compound preparation in animal plasma, tear, aqueous humor, cornea and conjunctiva is examined, and compared with the single preparation, and reference information is provided for deeply clarifying the mechanism of the drug action, designing and optimizing the pre-clinical and clinical test dosing scheme.

After the rabbits were given with single formulation by eye drop, the concentration of the other component in plasma, tears, aqueous humor, conjunctiva, cornea was lower than LLOQ except for individual tissues. The detection results of tears and blood plasma of the animals D4, 5 and 6 in the groups A1, B1 and C1 show that moxifloxacin/dexamethasone can be detected in the tears in the compound/single group, and only trace moxifloxacin can be detected in blood plasma, so that the medicine content in blood plasma is low even if the medicine is administrated by eye drops for 4 times every day. After the compound/single preparation is administrated for 10min, 1h, 6h and 24h by multiple times of eye drops, the moxifloxacin/dexamethasone at each time point has the highest content in tears and the lowest blood plasma content. After the compound/single formulation is applied to rabbit eyes, the change trend of moxifloxacin/dexamethasone in tears, cornea and conjunctiva is similar, the content of moxifloxacin/dexamethasone is highest after the administration for 10min, and the content is gradually reduced along with time; the aqueous humor changes slightly differently, the content of 10min and 1h after the last administration are similar, and the content of 1h after the administration at a specific time point is highest.

The results show that: after the compound/single formulation is administrated by dropping eyes for many times, the contents of the moxifloxacin/dexamethasone in the plasma, tear, aqueous humor, conjunctiva and cornea of normal cornea and damaged cornea animals at various time points are not obviously different, and the damage of the cornea has no obvious influence on the distribution of the moxifloxacin/dexamethasone in eye tissues. After the compound preparation is applied to rabbit eyes, the contents of moxifloxacin/dexamethasone in normal cornea/damaged cornea animal plasma, tear, aqueous humor, conjunctiva and cornea at each time point are not obviously different from those of the single preparation.

Comparative example seven

For single-dose pharmacokinetic experiments in monkeys:

after the compound preparation is dripped into the monkey for single eye, the time-varying process of the compound preparation in animal blood plasma and tears is examined, and compared with the single preparation, and reference information is provided for deeply clarifying the mechanism of action of the medicine, designing and optimizing the pre-clinical and clinical test dosing schemes.

After the compound/single formulation is administrated by eye drops, no obvious sex difference is found in the pharmacokinetic parameters of dexamethasone and moxifloxacin in the blood plasma and tear of male and female animals; compound group plasma, dexamethasone, moxifloxacin AUC in tear _(0-t) 、AUC _(0-∞) 、MRT _(0-t) 、MRT _(0-∞) 、t _1/2 、C _max The differences between the pharmacokinetic parameters and the single component groups are not statistically significant.

The exposure of dexamethasone and moxifloxacin in the plasma is extremely low, and the content of the dexamethasone in the plasma at most time points is lower than LLOQ, so that parameters such as the exposure and the like cannot be calculated; compound and unilateral group moxifloxacin plasma exposure (AUC _(0-t) ) Only about 0.01% of tear.

Comparative example eight

Toxicity study on rabbit ocular repeat dosing for 4 weeks:

the method comprises the steps of continuously administering a test object to the eyes of a rabbit for 4 weeks, detecting potential toxicity of the test object, and predicting possible clinical adverse reactions including the properties, degree, dose-effect and aging relation, reversibility and the like of the adverse reactions through observation in a 4-week recovery period; providing indexes or toxic and side effects which need to be monitored in a clinical test; provides reference for detoxification or rescue measures in clinical trials. Furthermore, the toxicity study results are explained by the pharmacokinetic (TK) profile of the test sample in the animal.

None of the animals in each group had died during the entire trial. The rabbits of each group generally had good performance, and neither behavioural nor fecal form had any toxic response associated with administration of the test subjects. Body weight results showed that the body weight of rabbits in each dose group grew normally during dosing and recovery. The subjects at each dose level had no significant effect on the animal feed intake. The clinical pathology results show that the indexes such as the animal hematology, the hematogenesis chemistry, the coagulation, the electrolyte and the urine of the tested animals do not find abnormal changes obviously related to the administration. The anatomical pathology results show that: the weight and coefficient of each organ were not found to be significantly abnormal in relation to the administration of the subject, and the pathological changes associated with the administration of the subject were not found either under general observation or under a microscope.

The toxicological dynamic results show that the peak time of moxifloxacin in a clinical concentration group, a 2 x clinical concentration group and a 4 x clinical concentration group after the first and last administration has a trend of being prolonged along with the increase of the administration dosage. Peaks were reached 10min after administration of the clinical concentration group, except for individual animals. The peak time of the 2X clinical concentration group and the 4X clinical concentration group is between 10min and 2h. The peak time of the plug Mi Songda of each dose group after the first and last administration fluctuates greatly, and there is a prolonged trend with the increase of the administration dose. The peak time of the clinical concentration group plug Mi Songda is 10min-2h; the peak time of the 2X clinical concentration group is between 10min and 4h; the peak time of the 4X clinical concentration group is between 0.5h and 4h. Analysis of first and last toxicological kinetic parameters shows that no obvious sex difference is found in moxifloxacin and dexamethasone parameters in male and female animals.

After rabbits were continuously given with eye drops for 4 weeks, moxifloxacin was used in animals in clinical concentration group and 2 x clinical concentration groupExposure in (C) _max 、AUC _(0-t) ) The number is obviously increased compared with the first time; AUC after last dose _(0-t) About 1.3 times, 1.9 times, 1.2 times, C _max About 1.4 times, 2.1 times, 1.3 times the first time, and is considered to be caused by ocular administration absorption saturation after analysis. Exposure of dexamethasone to animals in the 4 Xclinical concentration group (C _max 、AUC _(0-t) ) The reduction of the degree of difference occurs for the first time; AUC after last dose _(0-t) About 0.8 times, 0.9 times, 0.5 times, C _max About 1.0 times, 0.5 times for the first time. After eye drop administration of rabbits, the AUC of moxifloxacin and dexamethasone in the plasma of each dose group at the first and last times _(0-t) 、C _max All increase disproportionately to the dose, exhibiting non-linear kinetics.

In summary, under the present test conditions, rabbits were administered 4 times per day with 1 drop (about 50 μl) of each, and clinical concentrations, 2×clinical concentrations, and 4×clinical concentrations of the eye drops were administered in consecutive 4-week eye drops, and drug withdrawal was resumed for 4 weeks. None of the dose groups were examined for general status, body weight and food intake, hematology, blood biochemistry, urine convention, organ coefficients, and histopathology for toxic response associated with the test subjects.

Comparative example nine

Regarding eye irritation test:

the reversible inflammatory reaction and other possible stimulating reactions generated on the front surface of the eyes of rabbits are observed to provide reference for clinical experiments after the products are administrated through eyes.

Eye examination results: prior to day 12 dosing, a small amount of secretions were found in the left eye of individual rabbits (ear number T4799) at regular ocular examination and the cornea was examined for sodium fluorescein. D12 left eye irritation average score was 0.17 and right eye was normal. No other abnormalities were found during the observation period, and the eye irritation scores were in the range of 0-3 for both the left and right rabbits, and the eye irritation results were judged to be non-irritating.

Pathological examination results: after the administration, epithelial cells at each part of conjunctiva at the left side and the right side of the rabbit eyes are not denatured and necrotized, interstitial blood vessels are not dilated, engorged, and inflammatory cell infiltration and other lesions are avoided; the corneal epithelial cells are free from denaturation and necrosis, the collagen fibers of the stroma layer are free from swelling and fracture, the inflammatory cells are free from infiltration, and the corneal endothelial cells are free from necrosis and proliferation; the tissue structure of the iris ciliary body is clear, the interstitium is free from congestion and inflammatory cell infiltration; the haemand gland and lacrimal gland epithelial cells are normal, and the interstitium is free of congestion, edema and inflammatory cell infiltration. No obvious pathological changes were seen in the convalescence.

In conclusion, the test object has no irritation to conjunctiva, cornea, iris, hashimoto gland, lacrimal gland and the like of rabbit eyes.

Comparative example ten

Regarding the guinea pig skin allergy test (Buehler test):

the clinical test is provided with reference by observing whether local allergic reaction is generated after the product is subjected to initial contact through skin and re-excitation contact.

The results showed that neither the animals in the test group nor the negative control group had erythema and edema during the entire sensitization and challenge period of the test; the positive control animals are observed 1h after sensitization, most of guinea pig skin is slightly visible to moderate erythema, individual animals are severe with mild edema, dander and split are visible, erythema is obviously relieved after 24h, and edema is eliminated; observed 24h after challenge, most animals appeared with slightly visible erythema, which disappeared after 48 h. The sensitization rate of the positive control animals is 100% during sensitization and excitation, and the allergic reaction intensity is extremely strong sensitization.

Under GLP laboratory conditions, the skin allergy result of the test object is negative.

Comparative example eleven

Comparative experiments on different dexamethasone content:

by using different amounts of dexamethasone phosphate (0.5 mg, 1.25mg, 5 mg) and moxifloxacin dexamethasone sodium phosphate eye drops to 100 postoperative patients, 8 cases that can be matched with the atrial angle examination were wide angles among 11 cases of glaucoma patients, wherein the content was 5mg of the most obvious, 1.25mg of the lighter, and 0.5mg of the no wide angle. In 9 of the cases, ocular tension was restored to normal after deactivation and no further elevation was found at 12 months of follow-up. In 2 cases, the eye pressure of the patient who uses 5mg of the moxifloxacin dexamethasone hydrochloride sodium phosphate eye drops cannot be recovered to be normal. Among them, it can be understood that: the pathogenesis of the dermatosteroid glaucoma is hormonal glaucoma, which is that hormone prevents a solution enzyme from contacting mucopolysaccharide in the angle of the house, and the latter is accumulated on trabeculae due to the inability of the solution enzyme to be decomposed by retrogressive metabolism, so that the outflow resistance of aqueous humor is increased, and the intraocular pressure is increased. The clinical manifestations of hormonal glaucoma are similar to primary open angle glaucoma, characterized by elevated intraocular pressure and open angle, with concomitant visual field defects. The ocular pressure elevation response caused by topical corticosteroid application is related to the susceptibility of the individual, the concentration of the drug used, the frequency and duration of use, etc.

Meanwhile, the 100 postoperative patients use the moxifloxacin dexamethasone sodium phosphate eye drops with different contents of dexamethasone phosphate (0.5 mg, 1.25mg and 5 mg), and the content of the moxifloxacin dexamethasone sodium phosphate eye drops is most obvious when the content of the moxifloxacin dexamethasone sodium phosphate eye drops is 5mg, and the patients with cataract are lighter when the content of the moxifloxacin dexamethasone sodium phosphate eye drops is 1.25mg and the content of the moxifloxacin dexamethasone sodium phosphate eye drops is 0.5 mg. It can be seen that the high content of dexamethasone phosphate can induce cataract after long-term use, and the longer the treatment course, the higher the content, the higher the cataract degree, and the more likely the local administration of the medicine causes GIC, whether the medicine is used in whole body, local or inhaled through respiratory tract.

It can be seen that in the comparative experiments with dexamethasone phosphate content of 0.5, 1.25 and 5mg, the greater the dexamethasone phosphate content, the greater the damage to human body, especially the 5mg damage to human body.

To sum up, as described in comparative examples one to eleven, moxifloxacin hydrochloride + dexamethasone can prevent infection and improve inflammation more quickly.

Pharmacodynamic in-vitro antibacterial tests prove that the in-vitro antibacterial effects of the 2 specifications are equivalent; the results of the acute bacterial infectious conjunctivitis model for rabbits show that: the 2 standard test objects have the effect of improving conjunctival symptoms and tissue lesions in the rabbit pseudomonas aeruginosa conjunctivitis, and the improvement of symptoms of edema and conjunctival congestion is superior to that of a single preparation; the results of the acute bacterial infectious keratitis model of the rabbit show that: the 2 standard test objects have the effect of improving cornea symptoms in rabbit pseudomonas aeruginosa keratitis, the improvement on symptoms of edema and conjunctival congestion is superior to that of single preparation, the epithelial repair is obvious, and the other pathological changes are obviously relieved; pharmacodynamics of ocular inflammation shows that: the compound preparation obviously accelerates the improvement of inflammation scores, reduces the level of inflammatory factors in aqueous humor and reduces pathological damage to a certain extent.

After the compound/single formulation is applied to rabbits and monkeys by eye drops, no obvious sex difference is found in the content of moxifloxacin and dexamethasone in tissues of the male and female animals at each time point; the concentration of moxifloxacin/dexamethasone in each tissue of plasma, tear, aqueous humor, conjunctiva and cornea at each time point after the compound group is dosed is not obviously different from that of a single preparation, and the plasma exposure is only about 0.01% of tear, so that the plasma exposure of the compound preparation is low, and the possibility of systemic exposure caused by clinical use is estimated to be extremely low.

According to non-clinical local tolerance test data, the 2-specification preparations are presumed to be free from special harm to human bodies under the clinical dose of local administration.

Comparative tests with dexamethasone phosphate content of 0.5, 1.25, 5mg showed that: the higher the content of dexamethasone in the compound preparation is, the more damage is caused to human body. Specific control measures (1) avoiding the use of high-content dexamethasone sodium phosphate eye drops, the minimum strength and the minimum frequency of moxifloxacin hydrochloride dexamethasone sodium phosphate eye drops are given according to the reaction and tolerance of patients. (2) For patients who need to repeatedly use the moxifloxacin dexamethasone hydrochloride sodium phosphate eye drops for postoperative prevention, the patients should be informed of the potential complications of glucocorticoid treatment, and ordered to take medicines according to medical orders, and regularly follow-up, such as headache, nausea, vomiting, iridescence, vision decline and the like. (3) Baseline eye pressure was measured and the eye pressure, dilated pupil, was periodically reviewed to assess whether cataract and glaucoma occurred. (4) Once hormonal glaucoma appears, moxifloxacin dexamethasone sodium phosphate eye drops are immediately deactivated, ocular tension is closely monitored, and ocular tension lowering treatment is given if necessary. (5) performing trabeculectomy if necessary. If the treatment such as hormone deactivation is carried out, the intraocular pressure cannot be recovered to be normal, and conventional trabeculectomy is carried out.

The invention carries out systematic research on pharmacodynamics, pharmacokinetics and toxicology on moxifloxacin dexamethasone sodium phosphate eye drops with different specifications. The product has definite efficacy, safety and reliability, and provides sufficient basis for clinical practical application.

It can be appreciated that: the fourth-generation quinolone antibiotic moxifloxacin has broad-spectrum antibacterial activity, and shows broad-spectrum antibacterial activity on gram-positive bacteria, gram-negative bacteria, anaerobic bacteria, acid-fast bacteria, and atypical microorganisms such as mycoplasma, chlamydia and army bacteria in vitro; the moxifloxacin hydrochloride eye drops have better treatment effect on conjunctivitis caused by the bacterial infection. Meanwhile, the adverse reaction rate is lower when the medicine is clinically used for a long time.

Dexamethasone is an adrenocortical hormone medicine, and has various pharmacological actions such as anti-inflammatory, antiallergic and immunity inhibiting. The main mechanism of the glucocorticoid can be anti-inflammatory action, and the glucocorticoid can reduce and prevent the reaction of tissues to inflammation, so that the manifestation of the inflammation can be reduced. In addition, the composition has antiallergic and immunosuppressive effects, and can prevent or inhibit cell mediated immune reaction, delayed allergic reaction, and relieve primary immune reaction expansion. Dexamethasone sodium phosphate as a derivative of dexamethasone improves stability and solubility of dexamethasone.

Therefore, in combination with the use condition of the existing ophthalmic antibiotics, the novel compound preparation is developed by selecting the antibiotic moxifloxacin hydrochloride with wide antibacterial spectrum and relatively short service life of eyes and the dexamethasone sodium phosphate, which has long clinical application time and safety, and is used for preventing bacterial infection of eyes after operation, in particular for preventing infection and preventing infection of uncertain pathogenic bacteria types, and has important clinical value.

It should be noted that terms such as "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that an article or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Without further limitation, an element defined by the phrase "comprising one does not exclude the presence of other like elements in a process, method, article, or apparatus that comprises an element.

The foregoing is merely a specific embodiment of the application to enable one skilled in the art to understand or practice the application. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the application. Thus, the present application is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims (3)

1. The moxifloxacin dexamethasone sodium phosphate eye drops are characterized by comprising the following components in parts by weight:

sodium hydroxide in an amount sufficient to provide the eye drops with a pH of 7.5 to 8.5; and

water for injection.

2. The moxifloxacin dexamethasone hydrochloride sodium phosphate eye drop as claimed in claim 1, comprising the following components in parts by weight:

sodium hydroxide in an amount sufficient to provide the eye drops with a pH of 7.5 to 8.5; and

water for injection.

3. The moxifloxacin dexamethasone hydrochloride sodium phosphate eye drop as claimed in claim 1, comprising the following components in parts by weight:

sodium hydroxide in an amount sufficient to provide the eye drops with a pH of 7.5 to 8.5; and

water for injection.

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