An ophthalmic composition, its method of preparation and use

Abstract

The present application relates to the field of ophthalmic drugs, and particularly relates to an ophthalmic composition, a preparation method and application thereof, the ophthalmic composition comprising a compound as shown in formula I, an osmotic pressure regulator, a pH regulator and water for injection; the pH value of the ophthalmic composition is 4.0-6.0; the concentration of the compound as shown in formula I is 0.1-3.0% w / v, and the concentration of the osmotic pressure regulator is 0.3-10.0% w / v; the antibacterial activity against Streptococcus pneumoniae, Staphylococcus aureus and Staphylococcus epidermidis is 2-8 times that of levofloxacin and moxifloxacin hydrochloride; the antibacterial activity against Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli and Pseudomonas aeruginosa is also strong, and is equivalent to that of levofloxacin and moxifloxacin hydrochloride; the irritation is small, the light stability and high-temperature stability are good, the quality and drug safety are guaranteed, and the application value is good.

Description

Technical Field

[0001] This invention relates to the field of ophthalmic pharmaceutical technology, and particularly to an ophthalmic composition and its preparation method, as well as the use of the ophthalmic composition. Background Technology

[0002] Common ocular infections, such as conjunctivitis, keratitis, blepharitis, dacryocystitis, and endophthalmitis, are predominantly bacterial, with bacterial keratitis being the leading cause of blindness. Extensive clinical etiological analysis indicates that the main pathogens causing ocular infections are Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Pseudomonas aeruginosa, and Enterococcus faecalis. Due to the long treatment period and high recurrence rate of ocular infections, there is an increasing demand for clinically effective and broad-spectrum antibacterial drugs. Several quinolone ocular drugs are available for topical treatment, including ofloxacin, levofloxacin, ciprofloxacin, and moxifloxacin. However, currently marketed quinolone eye drops have relatively weak antibacterial activity, and the widespread clinical use of quinolone eye drops has led to a growing number of drug-resistant strains.

[0003] Compound (Formula I), as a novel non-fluoroquinolone drug, inhibits bacterial DNA replication by suppressing the activity of bacterial DNA gyrase and topoisomerase IV, thereby leading to bacterial death. Compound (Formula I) exhibits broad-spectrum antibacterial activity, effective against Gram-positive bacteria, Gram-negative bacteria, anaerobes, and atypical pathogens, particularly against streptococci and staphylococci, including multidrug-resistant Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA). Compound (Formula I) demonstrates concentration-dependent antibacterial activity, exhibiting slower and weaker in vitro resistance development against Streptococcus pneumoniae compared to other quinolones.

[0004] Currently, there is a need to develop an ophthalmic composition (Formula I) that can act directly on the eye, is non-irritating, and has good stability to meet clinical medication needs. Summary of the Invention

[0005] The purpose of this application is to provide an ophthalmic composition that exhibits low irritation during administration, good photostability and high-temperature stability, and demonstrates good preventative or therapeutic effects against ocular Gram-negative or Gram-positive bacterial infections. Furthermore, this invention provides a method for preparing the ophthalmic composition and its uses.

[0006] To achieve the above-mentioned objectives, the technical solution adopted in this application is as follows:

[0007] In a first aspect, this application provides an ophthalmic composition, characterized in that the ophthalmic composition comprises a compound as shown in Formula I, an osmotic pressure regulator, a pH regulator, and water for injection; the pH value of the ophthalmic composition is 4.0 to 6.0; the concentration of Formula II in the compound shown in Formula I of the ophthalmic composition is 0.1 to 3.0% w / v, and the concentration of the osmotic pressure regulator is 0.3 to 10.0% w / v;

[0008]

[0009] As one possible design, the osmotic pressure regulator is selected from at least one of sodium chloride, calcium chloride, magnesium chloride, boric acid, borax, mannitol, glycerol, propylene glycol, and polyethylene glycol.

[0010] As one possible design, the osmotic pressure regulator is selected from at least one of sodium chloride, boric acid, borax, glycerin, and polyethylene glycol.

[0011] As one possible design, the osmotic pressure regulator is selected from at least one of sodium chloride, boric acid, and glycerol, preferably sodium chloride.

[0012] As one possible design, the pH adjuster is selected from at least one of hydrochloric acid, sodium hydroxide, acetic acid, sodium acetate, citric acid, sodium citrate, sodium dihydrogen phosphate, and disodium hydrogen phosphate.

[0013] As one possible design, the pH adjuster is selected from at least one of hydrochloric acid, sodium hydroxide, acetic acid, sodium acetate, citric acid, and sodium citrate.

[0014] As one possible design, the pH adjuster is selected from at least one of hydrochloric acid, sodium hydroxide, acetic acid, and sodium acetate, preferably hydrochloric acid and / or sodium hydroxide.

[0015] Secondly, this application provides a method for preparing an ophthalmic composition, comprising:

[0016] The compound shown in Formula I, the osmotic pressure regulator, and water for injection are mixed to form a first solution, wherein the temperature of the water for injection is ≤70℃.

[0017] Add a pH adjuster to the first solution to adjust the pH to 4.0-6.0, thus obtaining the second solution;

[0018] The second solution is sterilized at 120–122°C for 8–15 minutes.

[0019] After aseptic dispensing, the product is capped and packaged.

[0020] Thirdly, this application provides the use of an ophthalmic composition in the preparation of a medicament for the prevention and / or treatment of infectious eye diseases.

[0021] Specifically, the ocular infectious diseases are infectious conjunctivitis, infectious keratitis, infectious blepharitis, infectious dacryocystitis, infectious endophthalmitis, infectious blepharitis, infectious meibomianitis, infectious dacryocystitis, infectious meibomianitis, infectious styes, and infectious corneal ulcers; preferably, the ocular infectious diseases are caused by infection with Gram-negative bacteria, Gram-positive bacteria, or anaerobic bacteria; more preferably, the ocular infectious diseases are caused by infection with Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis, or any combination thereof.

[0022] The beneficial effects of this invention are as follows:

[0023] Applying the compounds shown in Formula I to the treatment of eye diseases provides more medication options. Compared to levofloxacin and moxifloxacin, the compounds used in this invention exhibit stronger antibacterial activity against Streptococcus pneumoniae, Staphylococcus aureus, and Staphylococcus epidermidis, and comparable antibacterial activity against Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, and Pseudomonas aeruginosa. Furthermore, the drug combination described in this invention exhibits low irritation during administration, good photostability and high-temperature stability, ensuring the quality and safety of the formulation and demonstrating significant application value. Detailed Implementation

[0024] To make the technical problems, technical solutions, and beneficial effects of this application clearer, the following detailed description is provided in conjunction with embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the scope of this application.

[0025] The present invention comprises 13 embodiments and 2 comparative examples. The specific components of each embodiment and comparative example are detailed in Table 1.

[0026] It should be noted that the active ingredient of the compound shown in Formula I is the compound shown in Formula II; therefore, the compound shown in Formula II was used to calculate the concentration. The symbol "%" represents a percentage, i.e., w / v, calculated as the ratio between weight (g) and volume of the formulation (ml).

[0027] Table 1

[0028]

[0029]

[0030]

[0031] The preparation methods for each embodiment and comparative example are as follows:

[0032] S1. Place water for injection (temperature not exceeding 70℃) in a mixing tank, then add the compound shown in Formula I and the osmotic pressure regulator, and stir until completely dissolved to obtain solution A;

[0033] S2. Add a pH adjuster to solution A to adjust the pH value to the value required in each embodiment, to obtain solution B;

[0034] S3. Transfer solution B to a storage tank and maintain pressure, then sterilize at 121°C. The sterilization time is set according to the time required in each embodiment.

[0035] S4. After aseptic dispensing, the packaging is capped.

[0036] Experimental Example 1: Compound (Formula I) eye drops - Examples and comparative examples of influencing factors.

[0037] The products obtained in the examples and comparative examples were subjected to tests for the effects of high temperature and light exposure. The results are shown in Tables 2 and 3.

[0038] Table 2. Results of the investigation of influencing factors in the examples and comparative examples (high temperature 60℃)

[0039]

[0040]

[0041] Table 3. Results of the investigation of influencing factors in the examples and comparative examples (illuminance 4500 Lux)

[0042]

[0043]

[0044] According to the results in Tables 2 and 3:

[0045] (1) Under the same pH value, after being placed under high temperature and light conditions for 30 days, the total impurities of the example were lower than those of the comparative example, indicating that the stability of the example was significantly better than that of the comparative example.

[0046] (2) The compositions of Examples 1 to 6 are consistent. When the pH value ranges from 3.0 to 4.5, the stability of the obtained samples under high temperature and light conditions increases with the increase of pH value. When the pH value ranges from 4.5 to 7.0, the stability of the obtained samples under high temperature and light conditions decreases with the increase of pH value. When the pH value is 4.5, the sample has the best stability under light and high temperature. When the pH value ranges from 3.5 to 6.0, the sample has good stability.

[0047] (3) When the pH value is constant (Examples 7-11), the higher the concentration of compound (Formula II), the worse the stability. In order to ensure the stability of the composition, the concentration range of compound (Formula II) is set to 0.1% to 3.0% (w / v).

[0048] (4) When the osmotic pressure regulator (Example 12) is replaced with calcium chloride, magnesium chloride, boric acid, borax, mannitol, glycerol, propylene glycol and polyethylene glycol, and the pH regulator (Example 13) is replaced with citric acid, sodium citrate, sodium dihydrogen phosphate and disodium hydrogen phosphate, the stability of the composition remains good.

[0049] In summary, the formulation composition (Formula II) determined by this invention exhibits excellent storage and transportation stability when the concentration range is 0.1% to 3.0% (w / v) and the pH value range is 3.5 to 6.0, effectively ensuring the quality of the formulation during storage and transportation.

[0050] Experimental Example 2: In vitro antibacterial activity test of compound (Formula I)

[0051] Various types of bacteria, such as Gram-positive bacteria (Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Streptococcus pneumoniae) and Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Haemophilus influenzae, Moraxella catarrhalis), were isolated from clinical samples. The microbroth dilution method recommended by the Clinical and Laboratory Standards Institute (CLSI) Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically (Approved Standard-Eleventh Edition, M07-A11, 2018) was used to determine the minimum inhibitory concentration (MIC) of each test drug against the test strains. This was also done in accordance with the Performance Standards for Antimicrobial Susceptibility Testing and the "Guidelines for Antimicrobial Pharmacodynamics" in the Compilation of Guidelines for Preclinical Research of New Drugs (Western Medicine) issued by the National Medical Products Administration.

[0052] Table 4. In vitro antibacterial activity (MIC) of compounds (Formula I) and positive control drugs against 43 bacterial strains.

[0053]

[0054]

[0055]

[0056] Note: "ECO" + "Escherichia coli producing ESBLs; "ECO - "Table of non-ESBL-producing Escherichia coli."

[0057] As shown in Table 4, the compound represented by Formula I (active ingredient of Formula II) exhibits strong antibacterial activity against the tested Streptococcus pneumoniae, Staphylococcus aureus, and Staphylococcus epidermidis, which is 2-8 times stronger than that of levofloxacin and moxifloxacin hydrochloride. It also shows strong antibacterial activity against the tested Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, and Pseudomonas aeruginosa, comparable to that of levofloxacin and moxifloxacin hydrochloride.

[0058] Experimental Example 3: Investigation of the eye irritation of compound (Formula I) eye drops

[0059] Experimental objective: To observe the irritant reactions of animals after administering compound (Formula I) eye drops via the eye.

[0060] Test animals: Selected qualified New Zealand rabbits, weighing 2.0-3.0 kg, both male and female, with no inflammatory reactions or eye damage in the test animals.

[0061] Test drugs: Examples 2, 3, 4, 5 and control drug levofloxacin eye drops.

[0062] Experimental Methods: A self-controlled left-right eye method was used, in which the test drug or a commercially available control drug was administered to the left eye of a New Zealand rabbit, while 0.9% sodium chloride injection was administered to the right eye. Four New Zealand rabbits were used in each group. Both eyes of each animal were examined within 24 hours before the experiment to ensure that there were no irritation symptoms, corneal defects, or conjunctival damage.

[0063] One drop was administered to the eyes every hour for six days, for a total of 14 days. The rabbit eyes were observed for fluorescein sodium staining before the first administration each day and at 0.25, 1, 2, 4, 6, 24, 48 and 72 hours after the last administration of the experiment.

[0064] Judgment criteria: According to Table 5, the irritation response scores of the cornea, iris, and conjunctiva of each animal at each observation time are added together to obtain the total score. The final score is obtained by dividing the total score of a group by the number of animals. The degree of irritation is judged according to Table 6.

[0065] The eye irritation data of each animal were statistically analyzed according to the scoring criteria in Table 8, and the experimental results are shown in Table 7.

[0066] Table 5. Scoring criteria for eye irritation response

[0067]

[0068]

[0069] Table 6. Evaluation Criteria for Eye Irritation

[0070]

[0071]

[0072] Table 7. Eye irritation effects of compound (Formula I) eye drops on rabbits.

[0073]

[0074] Experimental conclusion: According to Table 7, no eye irritation was observed in the animals of Examples 3-5 and the control drug at any time point, while Example 2 showed mild irritation. This indicates that a pH value that is too low will cause irritation, therefore the pH value of this product should not be too low.

[0075] Experimental Example 4: Ophthalmic pharmacodynamic test of compound (Formula I) eye drops (keratitis)

[0076] Experimental objective: To observe the therapeutic effect of compound (Formula I) eye drops on keratitis caused by Haemophilus influenzae and Enterococcus faecalis in rabbits.

[0077] Test animals: New Zealand rabbits, weighing 1.5–2.5 kg, both male and female, and the test animals showed no inflammatory reactions or eye damage.

[0078] Test drugs: Examples 3, 7-10 and positive control drug levofloxacin eye drops.

[0079] Establishment of a rabbit keratitis model: Healthy adult New Zealand rabbits were selected. After anesthesia, the eyes were rinsed with sterile PBS, followed by intrastromal injection of 10 μL of bacterial solution into both corneas (10 μL / 200ml). 7 (CFU / mL). Successful modeling was confirmed by gross observation after 24 hours. Each group consisted of 4 animals.

[0080] Judgment criteria: Corneal ocular clinical score.

[0081] Table 8 Animal grouping and dosage

[0082]

[0083] All animals were examined and recorded under a slit lamp every other day after the start of medication. Scoring was performed on days 1, 8, 15, and 22 after administration. The ocular stromal infiltration, corneal edema, ulcer diameter and margin, ulcer depth, time and height of hypopyon onset, time of corneal perforation, and ulcer healing time were recorded, and corresponding scores were given. The clinical scoring criteria are shown in Table 9.

[0084] The corneal inflammation status of each group of animals was statistically analyzed according to the scoring criteria in Table 9. The results are shown in Tables 10 and 11.

[0085] Table 9 Clinical Scoring Standards for Keratitis

[0086]

[0087]

[0088] Table 10 Daily Symptom Scoring Table for Different Groups of Haemophilus influenzae-Infected Rabbit Keratitis

[0089]

[0090] Table 11 Daily Symptom Scoring Table for Each Group of Rabbit Keratitis Infected by Enterococcus faecalis

[0091]

[0092] As can be seen from the keratitis symptom scores in Tables 10 and 11, all examples have therapeutic effects on keratitis caused by Haemophilus influenzae and Enterococcus faecalis. When the concentration of compound (Formula II) is 0.3% to 3.0% (w / v), the therapeutic effect of the composition is comparable to or better than that of the positive control drug.

[0093] Experimental Example 6: Ophthalmic pharmacodynamic test of compound (Formula I) eye drops (conjunctivitis)

[0094] Experimental objective: To observe the therapeutic effect of compound (Formula I) eye drops on conjunctivitis caused by Staphylococcus aureus and Staphylococcus epidermidis in rabbits.

[0095] Test animals: New Zealand rabbits, weighing 1.5–2.5 kg, both male and female, and the test animals showed no inflammatory reactions or eye damage.

[0096] Test drugs: Examples 3, 7-10, and the positive control drug levofloxacin eye drops.

[0097] Establishment of a rabbit conjunctivitis model: Healthy adult New Zealand rabbits were selected, and after anesthesia, the eyeballs were rinsed with sterile PBS. 20 μL of bacterial solution (10 μL / 100ml) was injected into the conjunctival sac of both lower eyelids. 8 (CFU / mL). Successful modeling was confirmed by gross observation after 24 hours. Each group consisted of 4 animals.

[0098] Table 1 Animal grouping and drug dosage

[0099]

[0100] Scoring was conducted on D1 (confirmation of successful modeling), D5 (3 days after drug administration), D9 (1 week after drug administration), D12 (10 days after drug administration), and D16 (2 weeks after drug administration) before the experimental endpoint. Judgment criteria: Observations and scores were conducted at each time point, and all scores were accumulated. 0-2 points indicated no conjunctivitis symptoms, 3-4 points indicated mild conjunctivitis symptoms, 5-6 points indicated moderate conjunctivitis symptoms, and 7-9 points indicated severe conjunctivitis symptoms.

[0101] Table 2 Clinical scoring criteria for conjunctivitis

[0102]

[0103]

[0104] Table 3 Daily symptom scoring table for each group of rabbit conjunctivitis infected with Staphylococcus aureus.

[0105]

[0106] Table 4 Daily Symptom Scoring Table for Each Group of Staphylococcus epidermidis Infected Conjunctivitis

[0107]

[0108]

[0109] As can be seen from the conjunctivitis symptom scores in Tables 14 and 15, all examples have therapeutic effects on conjunctivitis caused by Staphylococcus aureus and Staphylococcus epidermidis. When the concentration of compound (Formula II) is 0.3% to 3.0% (w / v), the therapeutic effect of the composition is comparable to or better than that of the positive control drug.

[0110] Pharmaceutical and pharmacodynamic studies of the compositions of the present invention have shown that the compositions and preparation methods determined by the present invention can produce ophthalmic preparations with good photostability and high-temperature stability. Moreover, these preparations have good therapeutic effects on keratitis and conjunctivitis caused by bacterial infections and have good application value.

[0111] The above description is merely a specific embodiment of the present invention, enabling those skilled in the art to understand or implement the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit and scope of the invention. Therefore, the essential scope of the invention will be defined by the appended claims and their equivalents.

Claims

1. An ophthalmic composition, characterized in that, The ophthalmic composition comprises a compound as shown in Formula I, an osmotic pressure regulator, a pH regulator, and water for injection; the pH value of the ophthalmic composition is 4.0 to 6.0; the concentration of Formula II in the compound shown in Formula I of the ophthalmic composition is 0.1 to 3.0% w / v, and the concentration of the osmotic pressure regulator is 0.3 to 10.0% w / v; 2. The ophthalmic composition according to claim 1, characterized in that, The osmotic pressure regulator is selected from at least one of sodium chloride, calcium chloride, magnesium chloride, boric acid, borax, mannitol, glycerol, propylene glycol, and polyethylene glycol.

3. The ophthalmic composition according to claim 2, characterized in that, The osmotic pressure regulator is selected from at least one of sodium chloride, boric acid, borax, glycerin, and polyethylene glycol.

4. The ophthalmic composition according to claim 3, characterized in that, The osmotic pressure regulator is selected from at least one of sodium chloride, boric acid, and glycerol, with sodium chloride being preferred.

5. The ophthalmic composition according to claim 1, characterized in that, The pH adjuster is selected from at least one of hydrochloric acid, sodium hydroxide, acetic acid, sodium acetate, citric acid, sodium citrate, sodium dihydrogen phosphate, and disodium hydrogen phosphate.

6. The ophthalmic composition according to claim 5, characterized in that, The pH adjuster is selected from at least one of hydrochloric acid, sodium hydroxide, acetic acid, sodium acetate, citric acid, and sodium citrate.

7. The ophthalmic composition according to claim 6, characterized in that, The pH adjuster is selected from at least one of hydrochloric acid, sodium hydroxide, acetic acid, and sodium acetate, preferably hydrochloric acid and / or sodium hydroxide.

8. A method for preparing the ophthalmic composition according to any one of claims 1-7, characterized in that, The preparation method includes: The compound shown in Formula I, the osmotic pressure regulator, and water for injection are mixed to form a first solution, wherein the temperature of the water for injection is ≤70℃. Add a pH adjuster to the first solution to adjust the pH to 4.0-6.0, thus obtaining the second solution; The second solution is sterilized at 120–122°C for 8–15 minutes. After aseptic dispensing, the product is capped and packaged.

9. Use of the ophthalmic composition according to any one of claims 1-7 in the preparation of a medicament for the prevention and / or treatment of infectious diseases of the eye.

10. The use according to claim 9, characterized in that, The ocular infectious diseases are infectious conjunctivitis, infectious keratitis, infectious blepharitis, infectious dacryocystitis, infectious endophthalmitis, infectious blepharitis, infectious meibomianitis, infectious dacryocystitis, infectious meibomianitis, infectious styes, and infectious corneal ulcers; preferably, the ocular infectious diseases are caused by infection with Gram-negative bacteria, Gram-positive bacteria, or anaerobic bacteria; more preferably, the ocular infectious diseases are caused by infection with Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis, or any combination thereof.

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