Levofloxacin eye drops and preparation method thereof

Abstract

The invention relates to levofloxacin eye drops and a preparation method thereof. The levofloxacin eye drops comprise the following components in percentage by mass: 0.4-0.5% of levofloxacin; 0.005% to 0.05% of a bacteriostatic agent; 1%-2% of citric acid; 1%-2% of potassium citrate; 0.2%-0.25% of a pH regulator; 94%-95% of water; the pH (Potential of Hydrogen) of the levofloxacin eye drops is 6 to 7. According to the levofloxacin eye drops disclosed by the invention, the antibacterial activity of the eye drops is remarkably improved by optimizing the bacteriostatic agent and the ratio of the bacteriostatic agent; by screening and optimizing the pH buffer pair and the ratio thereof, the color of the eye drops reaches the lightest, and the eye drops better meet the market requirements. The ratio of domiphen to citric acid to potassium citrate is further optimized, and the stability of the levofloxacin eye drop system is remarkably improved, so that the viscosity of the eye drop is not remarkably increased under the environment of high temperature and strong ultraviolet irradiation, other auxiliaries such as a stabilizer and an inhibitor are not added, and the eye drop can be stored for a long time.

Description

Technical Field

[0001] The invention relates to levofloxacin eye drops and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. Background Art

[0002] Levofloxacin is a type of quinolone drug with a broad-spectrum antibacterial effect. It has strong antibacterial activity against most Enterobacteriaceae, such as Escherichia coli, Klebsiella, Proteus, Salmonella, Shigella, and Gram-negative bacteria such as Haemophilus influenzae, Legionella pneumophila, and Neisseria gonorrhoeae; it also has antibacterial activity against Gram-positive bacteria such as Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and Mycoplasma pneumoniae and Chlamydia pneumoniae, but has poorer effects on anaerobic bacteria and enterococci.

[0003] Eye drops with levofloxacin as the main active ingredient can be used to treat blepharitis, hordeolum, dacryocystitis, conjunctivitis, tarsal glanditis, keratitis, and for aseptic chemotherapy during perioperative ophthalmic surgery.

[0004] The existing levofloxacin eye drops have limited antibacterial effects, especially against Aspergillus niger, if no additional antibacterial agent is added. In addition, due to the different selection of buffer pairs of pH adjusters, they may form a colloidal phase with levofloxacin; the inventors have found in a large number of practices that if the eye drops are exposed to high temperatures and strong ultraviolet rays for a long time, the viscosity of the eye drops may increase significantly, the eye drops become "thick", and the experience becomes worse. Some commercially available levofloxacin eye drops use brown plastic bottles as packaging bottles, mainly to absorb ultraviolet rays. In addition, the general storage temperature is 15-25°C.

[0005] Based on this, the present invention is proposed. Summary of the invention

[0006] In view of the deficiencies in the prior art, the present invention provides a levofloxacin eye drop and a preparation method thereof. The specific technical scheme is as follows:

[0007] A levofloxacin eye drop, comprising the following components in percentage by mass:

[0008]

[0009] The sum of the mass percentages of the above components is 100%;

[0010] The pH of the levofloxacin eye drops is 6-7.

[0011] A further improvement is a levofloxacin eye drop, comprising the following components in percentage by weight:

[0012]

[0013] In a further improvement, the mass ratio of citric acid to potassium citrate is 1:1.

[0014] In a further improvement, the pH regulator is one or more of hydrochloric acid and sodium hydroxide.

[0015] In a further improvement, the antibacterial agent is one or more of domiphene, benzalkonium chloride, and benzalkonium bromide.

[0016] In a further improvement, the mass ratio of domiphene, citric acid and potassium citrate is 1:400:400.

[0017] In a further improvement, the mass ratio of domiphene to levofloxacin is 488:5.

[0018] A further improvement is a method for preparing levofloxacin eye drops, comprising the following steps:

[0019] Step 1, weighing levofloxacin, antibacterial agent, citric acid, potassium citrate, pH regulator and water according to the formula amount;

[0020] Step 2, dissolving levofloxacin in a portion of water, filtering, and obtaining a levofloxacin solution;

[0021] Step 3, dissolving the antibacterial agent, citric acid and potassium citrate in a portion of water to obtain a base solution, pouring the levofloxacin solution into the base solution and mixing evenly, and then stopping when the pH value is adjusted to 6.0-7.0 with a pH adjuster;

[0022] Step 4: Finally, add the remaining water to make up the volume, and package to obtain the levofloxacin eye drops.

[0023] Beneficial effects of the present invention:

[0024] 1. The levofloxacin eye drops of the present invention significantly improve the antibacterial property of the eye drops by optimizing the antibacterial agent and its ratio.

[0025] 2. By screening and optimizing the pH buffer pairs and their ratios, the color of the eye drops can be made lightest, which is more in line with market demand.

[0026] 3. Further optimize the ratio of domiphene, citric acid, and potassium citrate, significantly improve the stability of the levofloxacin eye drops system, so that the viscosity of the eye drops will not increase significantly under high temperature and strong ultraviolet irradiation, and no other stabilizers, inhibitors, or other auxiliary agents will be added, and the levofloxacin eye drops can be stored for a long time.

[0027] 4. The preparation method of the levofloxacin eye drops is simple in process and easy to produce in large quantities. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is a color comparison photo of the eye drops described in Formula 1 and Formulas 16 to 19;

[0029] Figure 2 This is a curve graph of the changes in x and y. DETAILED DESCRIPTION

[0030] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0031] Example 1

[0032] Recipe 1 is as follows:

[0033]

[0034] The preparation method comprises the following steps:

[0035] Step 1, weigh levofloxacin, antibacterial agent (domiphene), citric acid, potassium citrate, pH regulator (hydrochloric acid and sodium hydroxide) and water according to the above formula;

[0036] Step 2, dissolving levofloxacin in a portion of water, filtering, and obtaining a levofloxacin solution;

[0037] Step 3, dissolving the antibacterial agent, citric acid and potassium citrate in a portion of water to obtain a base solution, pouring the levofloxacin solution into the base solution and mixing evenly, and then stopping when the pH value is adjusted to 6.0-7.0 with a pH adjuster;

[0038] Step 4. Finally, add the remaining water to make up the volume and divide into portions to obtain the eye drops.

[0039] Example 2

[0040] Recipe 2 is as follows:

[0041]

[0042] The preparation method comprises the following steps:

[0043] Step 1, weigh levofloxacin, citric acid, potassium citrate, pH adjuster (hydrochloric acid and sodium hydroxide) and water according to the above formula;

[0044] Step 2, dissolving levofloxacin in a portion of water, filtering, and obtaining a levofloxacin solution;

[0045] Step 3, dissolving the antibacterial agent, citric acid and potassium citrate in a portion of water to obtain a base solution, pouring the levofloxacin solution into the base solution and mixing evenly, and then stopping when the pH value is adjusted to 6.0-7.0 with a pH adjuster;

[0046] Step 4: Finally, add the remaining water to make up the volume and divide the mixture into portions to obtain reference preparation 1 (without antibacterial agents such as domiphene, benzalkonium chloride, and benzalkonium bromide).

[0047] Example 3

[0048] Recipe 3 is as follows:

[0049]

[0050] The preparation method is the same as that in Example 1.

[0051] Example 4

[0052] Recipe 4 is as follows:

[0053]

[0054] The preparation method is the same as that in Example 1.

[0055] Example 5

[0056] Recipe 5 is as follows:

[0057]

[0058]

[0059] The preparation method is the same as that in Example 1.

[0060] Example 6

[0061] Recipe 6 is as follows:

[0062]

[0063] The preparation method is the same as that in Example 1.

[0064] Example 7

[0065] Recipe 7 is as follows:

[0066]

[0067]

[0068] The preparation method is the same as that in Example 1.

[0069] 《Bacterial inhibition test》

[0070] According to the antibacterial efficacy test method of the 2020 edition of the Chinese Pharmacopoeia, antibacterial tests were conducted on Gram-positive bacteria (Staphylococcus aureus), Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa), vegetative yeast (Candida albicans) and fungi (Aspergillus niger and Aspergillus sphaeroides). The results are shown in Table 1:

[0071] Table 1

[0072]

[0073] The levofloxacin eye drops of the present invention have strong antibacterial activity against Gram-positive bacteria (Staphylococcus aureus), Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa), vegetative yeast (Candida albicans) and fungi (Aspergillus niger and Aspergillus sphaeroides), and have good antibacterial and antibacterial effects.

[0074] In addition, in some embodiments, if the levofloxacin in formula 1 is replaced with water to prepare an antibacterial solution of corresponding concentration, the antibacterial solution is used to perform the "Antibacterial Test" and it is found that a 0.01% domiphene solution can completely inhibit the growth of Aspergillus niger, but cannot completely inhibit the growth of Aspergillus sphaeroides. In other words, a low concentration of domiphene solution alone cannot completely inhibit the growth of Aspergillus niger and Aspergillus sphaeroides. The combination of levofloxacin and a low concentration of domiphene can completely inhibit the growth of Aspergillus niger and Aspergillus sphaeroides.

[0075] "Eye Drop pH Adjustment Test"

[0076] In the process of adjusting the pH of eye drops using different pH buffers, it was found that different pH buffers have a great influence on the color of eye drops. According to the requirements of the 2020 edition of the Chinese Pharmacopoeia, the color should not exceed yellow-green No. 6 ( Figure 1 Ampoule YG-6, ampoule YG-4, ampoule YG-1 and ampoule YG-2 are respectively the YG yellow-green colorimetric solutions specified in the Chinese Pharmacopoeia.

[0077] Based on the formula 1 of Example 1, the citric acid and potassium citrate in the formula 1 were all replaced with sodium dihydrogen phosphate to obtain the formula 16. The color of the eye drops finally obtained was as shown in FIG. Figure 1 Medium size 1 ampoule.

[0078] Based on the formula 1 of Example 1, the citric acid and potassium citrate in the formula 1 were all replaced by boric acid and borax to obtain the formula 17. The color of the eye drops finally obtained is shown in FIG. Figure 1 Medium size 2 ampoule.

[0079] Based on the formula 1 of Example 1, the citric acid and potassium citrate in the formula 1 were all replaced with disodium hydrogen phosphate to obtain the formula 18. The color of the final eye drops is shown in FIG. Figure 1 Medium size 3 ampoule.

[0080] Based on the formula 1 of Example 1, the citric acid and potassium citrate in the formula 1 were all replaced with dipotassium hydrogen phosphate to obtain the formula 19. The color of the final eye drops is shown in FIG. Figure 1 Medium size 4 ampoule.

[0081] The above test results are shown in Table 2:

[0082] Table 2

[0083] Serial number formula Color comparison results Figure 1 Medium No. 1 Ampoule Eye drops (formula 16, sodium dihydrogen phosphate) qualified Figure 1 Medium No. 2 Ampoule Eye drops (Formula 17, Boric acid & Borax) qualified Figure 1 Medium No. 3 Ampoule Eye drops (formula 18, disodium hydrogen phosphate) qualified Figure 1 Medium No. 4 Ampoule Eye drops (formula 19, dipotassium hydrogen phosphate) qualified Figure 1 Medium No. 5 Ampoule Eye drops (Formula 1, citric acid & potassium citrate) Optimal

[0084] Depend on Figure 1 It can be seen that the eye drops corresponding to Formula 1 in Example 1 use citric acid and potassium citrate as a buffer pair, which not only meets the requirement that the pH of the eye drops is 6 to 7, but also has the lightest color.

[0085] 《Eye Drop Viscosity Stability Test》

[0086] Condition 1: Place the eye drop sample at 40°C and under strong ultraviolet light from a 200W ultraviolet disinfection lamp for 0 and 2 months to compare the kinematic viscosity of the eye drops (20°C). Kinematic viscosity growth rate = (kinematic viscosity after 2 months - kinematic viscosity at 0 month) / kinematic viscosity at 0 month.

[0087] Condition 2: Place the eye drop samples at 40°C for 0 and 2 months to compare the kinematic viscosity of the eye drops (20°C).

[0088] Condition 3: Place the eye drop samples under strong ultraviolet light from a 200W ultraviolet disinfection lamp for 0 and 2 months to compare the kinematic viscosity of the eye drops (20°C).

[0089] The eye drops corresponding to Formula 1, Formula 6, Formula 7, Formula 17 and Reference Preparation 2 were tested according to the above conditions. The results are shown in Table 3:

[0090] Table 3

[0091]

[0092] Reference preparation 2 is levofloxacin hydrochloride eye drops with national medicine approval number H20020327.

[0093] As shown in Table 3, domiphene + citric acid + potassium citrate and levofloxacin construct a stable system in water, which has good stability. Even in such harsh environments as high temperature and strong ultraviolet radiation, the kinematic viscosity of the eye drops will not increase excessively; while the eye drops of other systems will increase their kinematic viscosity exponentially in such harsh environments as high temperature and strong ultraviolet radiation; due to the excessive kinematic viscosity, it is easy to cause discomfort to the user. In addition, it should be noted that for levofloxacin eye drops, the single factors of high temperature and strong ultraviolet rays have limited effects on the kinematic viscosity of the eye drops. The combination of the two and long-term action can easily cause physical changes in the eye drop system.

[0094] Test example

[0095] In Example 1, the mass ratio of domiphene, citric acid and potassium citrate is 1:400:x, and x varies from 350 to 450. The change curve of the kinematic viscosity growth rate y under the corresponding conditions is shown in FIG. Figure 2 .

[0096] Depend on Figure 2 It can be seen that the mass ratio of domiphene, citric acid and potassium citrate is 1:400:400.

[0097] The outer packaging bottle of levofloxacin hydrochloride eye drops with national medicine approval number H20020327 is a brown plastic bottle with good UV resistance.

[0098] In addition, some special groups of people (such as breeders and pet owners) may be infected with a small amount of fecal fungi due to unclean eye habits, and the levofloxacin eye drops of the present invention can be used to alleviate the symptoms. Because the levofloxacin eye drops of the present invention also have a good antibacterial effect on fecal fungi such as Sphaerotheca sphaerocephala.

[0099] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A levofloxacin eye drop, characterized in that: The components include the following mass percentages: The sum of the mass percentages of the above components is 100%; The pH of the levofloxacin eye drops is 6-7.

2. A levofloxacin eye drop according to claim 1, characterized in that: The components include the following mass percentages:

3. A levofloxacin eye drop according to claim 1, characterized in that: The mass ratio of citric acid to potassium citrate is 1:

1.

4. A levofloxacin eye drop according to claim 1, characterized in that: The pH regulator is one or more of hydrochloric acid and sodium hydroxide.

5. A levofloxacin eye drop according to claim 1, characterized in that: The antibacterial agent is one or more of domiphene, benzalkonium chloride and benzalkonium bromide.

6. A levofloxacin eye drop according to claim 1, characterized in that: The mass ratio of domiphene, citric acid and potassium citrate is 1:400:

400.

7. A levofloxacin eye drop according to claim 1, characterized in that: The mass ratio of domiphene to levofloxacin is 488:

5.

8. A method for preparing levofloxacin eye drops according to any one of claims 1 to 7, characterized in that: The following steps are involved: Step 1, weighing levofloxacin, antibacterial agent, citric acid, potassium citrate, pH regulator and water according to the formula amount; Step 2, dissolving levofloxacin in a portion of water, filtering, and obtaining a levofloxacin solution; Step 3, dissolving the antibacterial agent, citric acid and potassium citrate in a portion of water to obtain a base solution, pouring the levofloxacin solution into the base solution and mixing evenly, and then stopping when the pH value is adjusted to 6.0-7.0 with a pH adjuster; Step 4: Finally, add the remaining water to make up the volume, and package to obtain the levofloxacin eye drops.

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