Lomefloxacin Hydrochloride Ear Drops Composition, Its Product, Preparation Method and Application

Abstract

The present invention provides a lomefloxacin hydrochloride ear drop composition, its product, preparation method and application, relating to the technical field of pharmaceutical preparations. The lomefloxacin hydrochloride ear drop composition of the present invention is prepared from the following raw materials in parts by weight: 3.0 - 6.7 parts of lomefloxacin hydrochloride, 30 - 50 parts of polyethylene glycol 200 - 300, 20 - 40 parts of propylene glycol, 3 - 6 parts of hydroxypropyl cellulose, 1 - 3 parts of polyvinylpyrrolidone, 0.5 - 2 parts of sodium acetate and 0.5 - 2 parts of disodium edetate; the lomefloxacin hydrochloride ear drop composition is prepared into lomefloxacin hydrochloride ear drops by a method of stepwise heating and ultrasonic mixing. The lomefloxacin hydrochloride ear drop composition of the present invention has a fast transdermal absorption rate and can quickly exert the drug effect of lomefloxacin hydrochloride in a short time; it still has high stability under strong light conditions and has high drug safety.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a lomefloxacin hydrochloride ear drop composition, its product, preparation method and application. Background Art

[0002] Otitis media, otitis externa, and tympanitis are common and frequently-occurring diseases in the otolaryngology department, mostly caused by fungal and bacterial infections, which can cause discomfort, swelling pain or strange itching in the ear canal, a feeling of stuffiness, and in severe cases, pain and even suppuration. Lomefloxacin hydrochloride is a third-generation broad-spectrum antibacterial drug of the quinolone class. It has high antibacterial activity against Enterobacteriaceae bacteria such as Escherichia coli, Shigella, Klebsiella, Proteus, Enterobacter, etc.; Lomefloxacin hydrochloride also has certain antibacterial effects on Acinetobacter, Pseudomonas aeruginosa and other Pseudomonas, Staphylococcus and Streptococcus pneumoniae, hemolytic streptococcus, etc.; Haemophilus influenzae, Neisseria gonorrhoeae, etc. are also highly sensitive to lomefloxacin hydrochloride.

[0003] Lomefloxacin hydrochloride has a long half-life, a long-lasting effect, and good permeability. Currently, the marketed dosage forms include eye drops, capsules, creams and ear drops.

[0004] To increase the solubility and penetration of lomefloxacin hydrochloride, ethanol is usually added to the lomefloxacin hydrochloride ear drops to help the drug act on the inflamed site. Wen Qiuju published an article in the journal "Chinese Journal of Modern Drug Application": Research on the preparation process of lomefloxacin hydrochloride ear drops (2015, 9(6): 274-275); the prescription of this lomefloxacin hydrochloride ear drops is: lomefloxacin hydrochloride 15.0 g, glycerol 1260 g, ethanol 1230 g, disodium edetate 5 g, and purified water is quantified to 5000 mL to make 1000 ear drops (5 mL / ear drop). This technical solution also increases the drug solubility and penetration through ethanol, and uses glycerol to relieve the irritation of ethanol to the mucosa and can prolong the residence time of the drug locally. However, ethanol has certain irritation. In addition, the currently marketed lomefloxacin hydrochloride ear drops have poor stability to light and heat and need to be stored in the dark, which not only increases the storage and transportation costs, but also easily causes quality problems of lomefloxacin hydrochloride ear drops.

[0005] The Chinese invention patent with the publication number CN109260152A discloses a lomefloxacin hydrochloride ear drop. Every 1000 mL of the ear drop contains: 2.5 - 3.5 g of lomefloxacin hydrochloride, 40 - 80 g of glycerol, 12 - 18 g of hydrogenated castor oil, 15 - 25 g of polyethylene glycol, and 0.6 - 1.4 g of disodium ethylenediaminetetraacetate. The lomefloxacin hydrochloride ear drop provided by this technical solution uses hydrogenated castor oil and polyethylene glycol as co-solvents, glycerol as a penetration enhancer, and disodium ethylenediaminetetraacetate as a buffer, which can make the lomefloxacin hydrochloride ear drop self-aggregate to form a micellar solution, reducing both the irritation of the ear drop and the discomfort of patients, prolonging the retention time in the ear, improving the bioavailability, and achieving a good therapeutic effect.

[0006] In order to further improve the storage stability of the lomefloxacin hydrochloride ear drop, the Chinese invention patent with the publication number CN118978426A discloses a method for acidifying glycerol. The glycerol is processed with acidified activated carbon, and the obtained acidified glycerol is used in the preparation of the lomefloxacin hydrochloride ear drop, which can improve the stability of the drug. However, the stability of the ear drop obtained by the above patent technology still needs to be further improved.

[0007] In view of this, there is a need to provide an ear drop with safe excipient components, stable combined effects, without using ethanol and without additional modification of the excipients, which can significantly improve the penetration rate and storage stability of lomefloxacin hydrochloride. Summary of the Invention

[0008] In view of the problems existing in the prior art, the present invention provides a lomefloxacin hydrochloride ear drop composition, its product, preparation method, and application. In the composition of the present invention, by reasonably using excipient components, the transdermal absorption of lomefloxacin hydrochloride is improved, and the efficacy of lomefloxacin hydrochloride can be rapidly exerted in a short time; the lomefloxacin hydrochloride ear drop of the present invention still has high stability under strong light conditions and high drug safety.

[0009] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0010] First of all, the present invention provides a lomefloxacin hydrochloride ear drop composition, which is made from the following raw materials by weight: 3.0 - 6.7 parts of lomefloxacin hydrochloride, 30 - 50 parts of polyethylene glycol 200 - 300, 20 - 40 parts of propylene glycol, 3 - 6 parts of hydroxypropyl cellulose (HPC), 1 - 3 parts of polyvinylpyrrolidone (PVP), 0.5 - 2 parts of sodium acetate, and 0.5 - 2 parts of disodium ethylenediaminetetraacetate.

[0011] Preferably, the lomefloxacin hydrochloride ear drops composition is made from the following raw materials by weight: 3.8 parts of lomefloxacin hydrochloride, 30 - 50 parts of polyethylene glycol 200 - 300, 20 - 40 parts of propylene glycol, 3 - 6 parts of hydroxypropyl cellulose, 1 - 3 parts of polyvinylpyrrolidone, 0.5 - 2 parts of sodium acetate, and 0.5 - 2 parts of disodium ethylenediaminetetraacetate.

[0012] Preferably, the lomefloxacin hydrochloride ear drops composition is made from the following raw materials by weight: 3.3 - 6.0 parts of lomefloxacin hydrochloride, 35 - 45 parts of polyethylene glycol 200 - 300, 25 - 35 parts of propylene glycol, 4 - 5 parts of hydroxypropyl cellulose, 1.5 - 2.5 parts of polyvinylpyrrolidone, 1 - 1.5 parts of sodium acetate, and 0.6 - 1.4 parts of disodium ethylenediaminetetraacetate.

[0013] More preferably, the lomefloxacin hydrochloride ear drops composition is made from the following raw materials by weight: 3.8 parts of lomefloxacin hydrochloride, 35 - 45 parts of polyethylene glycol 200 - 300, 25 - 35 parts of propylene glycol, 4 - 5 parts of hydroxypropyl cellulose, 1.5 - 2.5 parts of polyvinylpyrrolidone, 1 - 1.5 parts of sodium acetate, and 0.6 - 1.4 parts of disodium ethylenediaminetetraacetate.

[0014] Even more preferably, the lomefloxacin hydrochloride ear drops composition is made from the following raw materials by weight: 3.8 parts of lomefloxacin hydrochloride, 40 parts of polyethylene glycol 200 - 300, 30 parts of propylene glycol, 4.5 parts of hydroxypropyl cellulose, 2 parts of polyvinylpyrrolidone, 1.3 parts of sodium acetate, and 1 part of disodium ethylenediaminetetraacetate.

[0015] Preferably, the polyethylene glycol 200 - 300 is polyethylene glycol with a molecular weight of 200 - 300.

[0016] Furthermore, the present invention provides a lomefloxacin hydrochloride ear drops, the components of which include the lomefloxacin hydrochloride ear drops composition and water.

[0017] Preferably, in the lomefloxacin hydrochloride ear drops, the concentration of the active ingredient lomefloxacin hydrochloride is 3.0 - 6.7 g / L, and the solution of the liquid preparation is water.

[0018] More preferably, in the lomefloxacin hydrochloride ear drops, the concentration of the active ingredient lomefloxacin hydrochloride is 3.3 - 6.0 g / L.

[0019] Even more preferably, in the lomefloxacin hydrochloride ear drops, the concentration of the active ingredient lomefloxacin hydrochloride is 3.8 g / L.

[0020] Then, the present invention provides a preparation method of the above - mentioned lomefloxacin hydrochloride ear drops, including the steps:

[0021] (1) Preheat water to 40 - 50 °C, add lomefloxacin hydrochloride, and stir to dissolve; sequentially add polyethylene glycol 200 - 300, sodium acetate, disodium ethylenediaminetetraacetate, and 1 / 4 - 1 / 2 of the formulated amount of propylene glycol under the condition of maintaining the temperature at 40 - 50 °C, and perform ultrasonic treatment to obtain solution A;

[0022] (2) Mix solution A with hydroxypropyl cellulose, polyvinylpyrrolidone, and the remaining formulated amount of propylene glycol, stir, and perform ultrasonic treatment to obtain solution B;

[0023] (3) Make up the volume of solution B with water to obtain lomefloxacin hydrochloride ear drops.

[0024] Preferably, in step (1), the temperature for preheating the water is 45 °C.

[0025] Preferably, in step (1), the dosage of propylene glycol is 1 / 3 of the formulated amount of propylene glycol.

[0026] Preferably, in step (1), there is no special limitation on the amount of water added, as long as it can dissolve the added components. Generally, the amount of water added in this step is 30% - 90% of the total water addition volume.

[0027] Preferably, in step (2), the temperature for mixing is 40 - 50 °C; more preferably 45 °C.

[0028] Preferably, in steps (1) and (2), the ultrasonic treatment time is 5 - 15 min, and the ultrasonic frequency is 140 - 160 Hz.

[0029] More preferably, in step (1), the ultrasonic treatment time is 10 - 15 min, and the ultrasonic frequency is 160 Hz.

[0030] More preferably, in step (2), the ultrasonic treatment time is 5 - 10 min, and the ultrasonic frequency is 140 Hz.

[0031] Preferably, in step (3), when the lomefloxacin hydrochloride ear drop composition is prepared as a liquid preparation, the concentration of the active ingredient lomefloxacin hydrochloride is 3.0 - 6.7 g / L.

[0032] Finally, the present invention provides the application of the above - mentioned lomefloxacin hydrochloride ear drop composition in the preparation of drugs for treating otitis media, otitis externa, tympanitis, and / or restoring hearing.

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] 1. Through research, the inventors unexpectedly found that the simultaneous use of hydroxypropyl cellulose, polyvinylpyrrolidone, and sodium acetate can significantly improve the stability of pharmaceutical preparations. The three work synergistically to endow the lomefloxacin hydrochloride ear drop composition with excellent photo-thermal stability.

[0035] 2. In the composition of the present invention, ethanol is not used as a solvent, which ensures high drug safety and improves patient compliance. Moreover, as a penetration enhancer, propylene glycol can interact with disodium ethylenediaminetetraacetate and small-molecule polyethylene glycol while improving the stability of the composition, thereby enhancing the transdermal absorption rate of lomefloxacin hydrochloride, improving the efficacy, and shortening the treatment time. Detailed Embodiments

[0036] The following non-limiting examples can enable those of ordinary skill in the art to more comprehensively understand the present invention, but do not limit the present invention in any way. The following content is merely an exemplary illustration of the scope claimed by the present invention. Those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, and such changes and modifications should also fall within the scope claimed by the present invention.

[0037] When the examples give a numerical range, it should be understood that unless otherwise specified in the present invention, any value between the two endpoints of each numerical range and either of the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present invention belongs.

[0038] The present invention will be further described below by way of specific examples. All chemical reagents used in the examples of the present invention are obtained through conventional commercial channels unless otherwise specified.

[0039] In the following examples, the lomefloxacin hydrochloride is purchased from Yichang Humanwell Pharmaceutical Co., Ltd.; the hydroxypropyl cellulose is purchased from Adamas; the polyvinylpyrrolidone is polyvinylpyrrolidone k30, purchased from BASF New Materials Co., Ltd. Products from different manufacturers have no significant impact on the effect.

[0040] Example 1

[0041] A lomefloxacin hydrochloride ear drop composition has the following formula: 3.8 g of lomefloxacin hydrochloride, 40 g of polyethylene glycol 200, 30 g of propylene glycol, 4.5 g of hydroxypropyl cellulose, 2 g of polyvinylpyrrolidone, 1.3 g of sodium acetate, and 1 g of disodium ethylenediaminetetraacetate;

[0042] (1) Preheat 700 mL of water to 45 °C, add 3.8 g of lomefloxacin hydrochloride, and stir well to dissolve; under the condition of keeping warm at 45 °C, add 40 g of polyethylene glycol 200, 1.3 g of sodium acetate, 1 g of disodium ethylenediaminetetraacetate, and 10 g of propylene glycol in sequence, and perform ultrasonic treatment at 160 Hz for 10 min to obtain solution A;

[0043] (2) At a temperature of 45 °C, mix solution A with 4.5 g of hydroxypropyl cellulose, 2 g of polyvinylpyrrolidone, and 20 g of propylene glycol, stir evenly, and perform ultrasonic treatment at 140 Hz for 10 min to obtain solution B;

[0044] (3) Dilute solution B with water to a volume of 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0045] Example 2

[0046] A lomefloxacin hydrochloride ear drop composition, with the formula: 3.8 g of lomefloxacin hydrochloride, 35 g of polyethylene glycol 200, 25 g of propylene glycol, 4 g of hydroxypropyl cellulose, 1.5 g of polyvinylpyrrolidone, 1 g of sodium acetate, and 0.6 g of disodium ethylenediaminetetraacetate;

[0047] (1) Preheat 700 mL of water to 45 °C, add 3.8 g of lomefloxacin hydrochloride, and stir well to dissolve; under the condition of keeping warm at 45 °C, add 35 g of polyethylene glycol 200, 1 g of sodium acetate, 0.6 g of disodium ethylenediaminetetraacetate, and 8 g of propylene glycol in sequence, and perform ultrasonic treatment at 160 Hz for 10 min to obtain solution A;

[0048] (2) At a temperature of 45 °C, mix solution A with 4 g of hydroxypropyl cellulose, 1.5 g of polyvinylpyrrolidone, and 17 g of propylene glycol, stir evenly, and perform ultrasonic treatment at 140 Hz for 10 min to obtain solution B;

[0049] (3) Dilute solution B with water to a volume of 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0050] Example 3

[0051] A lomefloxacin hydrochloride ear drop composition, with the formula: 3.8 g of lomefloxacin hydrochloride, 45 g of polyethylene glycol 200, 35 g of propylene glycol, 5 g of hydroxypropyl cellulose, 2.5 g of polyvinylpyrrolidone, 1.5 g of sodium acetate, and 1.4 g of disodium ethylenediaminetetraacetate;

[0052] (1) Preheat 600 mL of water to 45 °C, add 3.8 g of lomefloxacin hydrochloride, and stir well to dissolve; under the condition of keeping warm at 45 °C, add 45 g of polyethylene glycol 200, 1.5 g of sodium acetate, 1.4 g of disodium ethylenediaminetetraacetate, and 12 g of propylene glycol in sequence, and perform ultrasonic treatment at 160 Hz for 10 min to obtain solution A;

[0053] (2) At a temperature of 45 °C, solution A was mixed with 5 g of hydroxypropyl cellulose, 2.5 g of polyvinylpyrrolidone, and 21 g of propylene glycol, stirred evenly, and sonicated at 140 Hz for 10 min to obtain solution B;

[0054] (3) Solution B was made up to 1000 mL with water to obtain lomefloxacin hydrochloride ear drops.

[0055] Example 4

[0056] A lomefloxacin hydrochloride ear drop composition with the formula: 3.8 g of lomefloxacin hydrochloride, 30 g of polyethylene glycol 200, 20 g of propylene glycol, 3 g of hydroxypropyl cellulose, 1 g of polyvinylpyrrolidone, 0.5 g of sodium acetate, and 0.5 g of disodium ethylenediaminetetraacetate;

[0057] (1) 700 mL of water was preheated to 45 °C, 3.8 g of lomefloxacin hydrochloride was added, and stirred thoroughly to dissolve; under the condition of maintaining the temperature at 45 °C, 30 g of polyethylene glycol 300, 0.5 g of sodium acetate, 0.5 g of disodium ethylenediaminetetraacetate, and 6 g of propylene glycol were added in sequence, and sonicated at 160 Hz for 10 min to obtain solution A;

[0058] (2) At a temperature of 45 °C, solution A was mixed with 3 g of hydroxypropyl cellulose, 1 g of polyvinylpyrrolidone, and 14 g of propylene glycol, stirred evenly, and sonicated at 140 Hz for 10 min to obtain solution B;

[0059] (3) Solution B was made up to 1000 mL with water to obtain lomefloxacin hydrochloride ear drops.

[0060] Example 5

[0061] A lomefloxacin hydrochloride ear drop composition with the formula: 3.8 g of lomefloxacin hydrochloride, 50 g of polyethylene glycol 200, 40 g of propylene glycol, 6 g of hydroxypropyl cellulose, 3 g of polyvinylpyrrolidone, 2 g of sodium acetate, and 2 g of disodium ethylenediaminetetraacetate;

[0062] (1) 600 mL of water was preheated to 45 °C, 3.8 g of lomefloxacin hydrochloride was added, and stirred thoroughly to dissolve; under the condition of maintaining the temperature at 45 °C, 50 g of polyethylene glycol 300, 2 g of sodium acetate, 2 g of disodium ethylenediaminetetraacetate, and 12 g of propylene glycol were added in sequence, and sonicated at 160 Hz for 10 min to obtain solution A;

[0063] (2) At a temperature of 45 °C, solution A was mixed with 6 g of hydroxypropyl cellulose, 3 g of polyvinylpyrrolidone, and 28 g of propylene glycol, stirred evenly, and sonicated at 140 Hz for 10 min to obtain solution B;

[0064] (3) Solution B was made up to 1000 mL with water to obtain lomefloxacin hydrochloride ear drops.

[0065] Example 6

[0066] A composition of lomefloxacin hydrochloride ear drops, the formula being: 3.3 g of lomefloxacin hydrochloride, 35 g of polyethylene glycol 200, 25 g of propylene glycol, 4 g of hydroxypropyl cellulose, 1.5 g of polyvinylpyrrolidone, 1 g of sodium acetate, and 0.6 g of disodium edetate;

[0067] (1) Preheat 700 mL of water to 40 °C, add 3.3 g of lomefloxacin hydrochloride, and stir well to dissolve; under the condition of maintaining the temperature at 40 °C, sequentially add 35 g of polyethylene glycol 200, 1 g of sodium acetate, 0.6 g of disodium edetate, and 12.5 g of propylene glycol, and perform ultrasonic treatment at 140 Hz for 15 min to obtain solution A;

[0068] (2) At a temperature of 40 °C, mix solution A with 4 g of hydroxypropyl cellulose, 1.5 g of polyvinylpyrrolidone, and 12.5 g of propylene glycol, stir evenly, and perform ultrasonic treatment at 160 Hz for 5 min to obtain solution B;

[0069] (3) Dilute solution B with water to a volume of 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0070] Example 7

[0071] A composition of lomefloxacin hydrochloride ear drops, the formula being: 6.0 g of lomefloxacin hydrochloride, 45 g of polyethylene glycol 200, 35 g of propylene glycol, 5 g of hydroxypropyl cellulose, 2.5 g of polyvinylpyrrolidone, 1.5 g of sodium acetate, and 1.4 g of disodium edetate;

[0072] (1) Preheat 600 mL of water to 50 °C, add 6.0 g of lomefloxacin hydrochloride, and stir well to dissolve; under the condition of maintaining the temperature at 50 °C, sequentially add 45 g of polyethylene glycol 200, 1.5 g of sodium acetate, 1.4 g of disodium edetate, and 9 g of propylene glycol, and perform ultrasonic treatment at 140 Hz for 15 min to obtain solution A;

[0073] (2) At a temperature of 50 °C, mix solution A with 5 g of hydroxypropyl cellulose, 2.5 g of polyvinylpyrrolidone, and 26 g of propylene glycol, stir evenly, and perform ultrasonic treatment at 140 Hz for 10 min to obtain solution B;

[0074] (3) Dilute solution B with water to a volume of 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0075] Example 8

[0076] A composition of lomefloxacin hydrochloride ear drops, the formula being: 3.0 g of lomefloxacin hydrochloride, 30 g of polyethylene glycol 200, 20 g of propylene glycol, 3 g of hydroxypropyl cellulose, 1 g of polyvinylpyrrolidone, 0.5 g of sodium acetate, and 0.5 g of disodium edetate;

[0077] (1) Preheat 700 mL of water to 45 °C, add 3.0 g of lomefloxacin hydrochloride, and stir well to dissolve; under the condition of keeping warm at 45 °C, add 30 g of polyethylene glycol 00, 0.5 g of sodium acetate, 0.5 g of disodium ethylenediaminetetraacetate, and 6 g of propylene glycol in sequence, and perform ultrasonic treatment at 160 Hz for 10 min to obtain solution A;

[0078] (2) At 45 °C, mix solution A with 3 g of hydroxypropyl cellulose, 1 g of polyvinylpyrrolidone, and 14 g of propylene glycol, stir evenly, and perform ultrasonic treatment at 140 Hz for 10 min to obtain solution B;

[0079] (3) Dilute solution B with water to a volume of 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0080] Example 9

[0081] A lomefloxacin hydrochloride ear drop composition, the formula is: 6.7 g of lomefloxacin hydrochloride, 50 g of polyethylene glycol 200, 40 g of propylene glycol, 6 g of hydroxypropyl cellulose, 3 g of polyvinylpyrrolidone, 2 g of sodium acetate, and 2 g of disodium ethylenediaminetetraacetate;

[0082] (1) Preheat 600 mL of water to 45 °C, add 6.7 g of lomefloxacin hydrochloride, and stir well to dissolve; under the condition of keeping warm at 45 °C, add 50 g of polyethylene glycol 200, 2 g of sodium acetate, 2 g of disodium ethylenediaminetetraacetate, and 12 g of propylene glycol in sequence, and perform ultrasonic treatment at 160 Hz for 10 min to obtain solution A;

[0083] (2) At 45 °C, mix solution A with 6 g of hydroxypropyl cellulose, 3 g of polyvinylpyrrolidone, and 28 g of propylene glycol, stir evenly, and perform ultrasonic treatment at 140 Hz for 10 min to obtain solution B;

[0084] (3) Dilute solution B with water to a volume of 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0085] Comparative Example 1

[0086] Different from Example 1, the lomefloxacin hydrochloride ear drop composition does not contain the component hydroxypropyl cellulose, and hydroxypropyl cellulose is replaced by polyethylene glycol 200.

[0087] A lomefloxacin hydrochloride ear drop composition, the formula is: 3.8 g of lomefloxacin hydrochloride, 44.5 g of polyethylene glycol 200, 30 g of propylene glycol, 2 g of polyvinylpyrrolidone, 1.3 g of sodium acetate, and 1 g of disodium ethylenediaminetetraacetate;

[0088] (1) Preheat 700 mL of water to 45 °C, add 3.8 g of lomefloxacin hydrochloride, and stir well until dissolved; successively add 44.5 g of polyethylene glycol 200, 1.3 g of sodium acetate, 1 g of disodium ethylenediaminetetraacetate, and 10 g of propylene glycol under the condition of maintaining the temperature at 45 °C, and perform ultrasonic treatment at 160 Hz for 10 min to obtain Solution A;

[0089] (2) At a temperature of 45 °C, mix Solution A with 2 g of polyvinylpyrrolidone and 20 g of propylene glycol, stir evenly, and perform ultrasonic treatment at 140 Hz for 10 min to obtain Solution B;

[0090] (3) Dilute Solution B with water to a volume of 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0091] Comparative Example 2

[0092] Different from Example 1, the lomefloxacin hydrochloride ear drop composition does not contain the components of polyvinylpyrrolidone and sodium acetate, and polyvinylpyrrolidone and sodium acetate are replaced with polyethylene glycol 200.

[0093] A lomefloxacin hydrochloride ear drop composition, with the formula: 3.8 g of lomefloxacin hydrochloride, 43.3 g of polyethylene glycol 200, 30 g of propylene glycol, 4.5 g of hydroxypropyl cellulose, and 1 g of disodium ethylenediaminetetraacetate;

[0094] (1) Preheat 700 mL of water to 45 °C, add 3.8 g of lomefloxacin hydrochloride, and stir well until dissolved; successively add 43.3 g of polyethylene glycol 200, 1 g of disodium ethylenediaminetetraacetate, and 10 g of propylene glycol under the condition of maintaining the temperature at 45 °C, and perform ultrasonic treatment at 160 Hz for 10 min to obtain Solution A;

[0095] (2) At a temperature of 45 °C, mix Solution A with 4.5 g of hydroxypropyl cellulose and 20 g of propylene glycol, stir evenly, and perform ultrasonic treatment at 140 Hz for 10 min to obtain Solution B;

[0096] (3) Dilute Solution B with water to a volume of 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0097] Comparative Example 3

[0098] Different from Example 1, the mass ratio of hydroxypropyl cellulose, polyvinylpyrrolidone, and sodium acetate in the lomefloxacin hydrochloride ear drop composition is different.

[0099] A lomefloxacin hydrochloride ear drop composition, with the formula: 3.8 g of lomefloxacin hydrochloride, 40 g of polyethylene glycol 200, 30 g of propylene glycol, 1 g of hydroxypropyl cellulose, 4 g of polyvinylpyrrolidone, 2.8 g of sodium acetate, and 1 g of disodium ethylenediaminetetraacetate;

[0100] (1) Preheat 700 mL of water to 45 °C, add 3.8 g of lomefloxacin hydrochloride, and stir well to dissolve; sequentially add 40 g of polyethylene glycol 200, 2.8 g of sodium acetate, 1 g of disodium ethylenediaminetetraacetate, and 10 g of propylene glycol under the condition of maintaining the temperature at 45 °C, and perform ultrasonic treatment at 160 Hz for 10 min to obtain solution A;

[0101] (2) At a temperature of 45 °C, mix solution A with 1 g of hydroxypropyl cellulose, 4 g of polyvinylpyrrolidone, and 20 g of propylene glycol, stir evenly, and perform ultrasonic treatment at 140 Hz for 10 min to obtain solution B;

[0102] (3) Dilute solution B with water to a volume of 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0103] Comparative Example 4

[0104] Differing from Example 1, the polyethylene glycol 200 in the lomefloxacin hydrochloride ear drop composition is replaced with polyethylene glycol 600.

[0105] A lomefloxacin hydrochloride ear drop composition, with the formula: 3.8 g of lomefloxacin hydrochloride, 40 g of polyethylene glycol 600, 30 g of propylene glycol, 4.5 g of hydroxypropyl cellulose, 2 g of polyvinylpyrrolidone, 1.3 g of sodium acetate, and 1 g of disodium ethylenediaminetetraacetate;

[0106] (1) Preheat 700 mL of water to 45 °C, add 3.8 g of lomefloxacin hydrochloride, and stir well to dissolve; sequentially add 40 g of polyethylene glycol 600, 1.3 g of sodium acetate, 1 g of disodium ethylenediaminetetraacetate, and 10 g of propylene glycol under the condition of maintaining the temperature at 45 °C, and perform ultrasonic treatment at 160 Hz for 10 min to obtain solution A;

[0107] (2) At a temperature of 45 °C, mix solution A with 4.5 g of hydroxypropyl cellulose, 2 g of polyvinylpyrrolidone, and 20 g of propylene glycol, stir evenly, and perform ultrasonic treatment at 140 Hz for 10 min to obtain solution B;

[0108] (3) Dilute solution B with water to a volume of 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0109] Comparative Example 5

[0110] Differing from Example 1, the propylene glycol in the lomefloxacin hydrochloride ear drop composition is replaced with glycerol.

[0111] A lomefloxacin hydrochloride ear drop composition, with the formula: 3.8 g of lomefloxacin hydrochloride, 40 g of polyethylene glycol 200, 30 g of glycerol, 4.5 g of hydroxypropyl cellulose, 2 g of polyvinylpyrrolidone, 1.3 g of sodium acetate, and 1 g of disodium ethylenediaminetetraacetate;

[0112] (1) Preheat 700 mL of water to 45 °C, add 3.8 g of lomefloxacin hydrochloride, and stir well until dissolved; under the condition of maintaining the temperature at 45 °C, sequentially add 40 g of polyethylene glycol 200, 1.3 g of sodium acetate, 1 g of disodium ethylenediaminetetraacetate, and 10 g of glycerol, and perform ultrasonic treatment at 160 Hz for 10 min to obtain solution A;

[0113] (2) At a temperature of 45 °C, mix solution A with 4.5 g of hydroxypropyl cellulose, 2 g of polyvinylpyrrolidone, and 20 g of glycerol, stir evenly, and perform ultrasonic treatment at 140 Hz for 10 min to obtain solution B;

[0114] (3) Dilute solution B with water to a volume of 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0115] Comparative Example 6

[0116] Different from Example 1, the preparation method of lomefloxacin hydrochloride ear drops is different. Specifically, all propylene glycol is added in step (2):

[0117] (1) Preheat 700 mL of water to 45 °C, add 3.8 g of lomefloxacin hydrochloride, and stir well until dissolved; under the condition of maintaining the temperature at 45 °C, sequentially add 40 g of polyethylene glycol 200, 1.3 g of sodium acetate, and 1 g of disodium ethylenediaminetetraacetate, and perform ultrasonic treatment at 160 Hz for 10 min to obtain solution A;

[0118] (2) At a temperature of 45 °C, mix solution A with 4.5 g of hydroxypropyl cellulose, 2 g of polyvinylpyrrolidone, and 30 g of propylene glycol, stir evenly, and perform ultrasonic treatment at 140 Hz for 10 min to obtain solution B;

[0119] (3) Dilute solution B with water to a volume of 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0120] Comparative Example 7

[0121] Different from Example 1, in the preparation method of lomefloxacin hydrochloride ear drops, ultrasonic treatment is not performed:

[0122] (1) Preheat 700 mL of water to 45 °C, add 3.8 g of lomefloxacin hydrochloride, and stir well until dissolved; under the condition of maintaining the temperature at 45 °C, sequentially add 40 g of polyethylene glycol 200, 1.3 g of sodium acetate, 1 g of disodium ethylenediaminetetraacetate, and 10 g of propylene glycol, and stir and mix evenly to obtain solution A;

[0123] (2) At a temperature of 45 °C, mix solution A with 4.5 g of hydroxypropyl cellulose, 2 g of polyvinylpyrrolidone, and 20 g of propylene glycol, stir evenly to obtain solution B;

[0124] (3) Dilute solution B with water to a volume of 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0125] Test 1 Light Stability

[0126] The control preparation (marketed lomefloxacin hydrochloride ear drops, specification: 15mg / 5ml, batch number: 230401, manufacturer Heilongjiang Tianlong Pharmaceutical Co., Ltd.) and the lomefloxacin hydrochloride ear drops of the examples and comparative examples of the present invention were placed under light (total illuminance not less than 1.2×10 6 lux·hr, near-ultraviolet energy not less than 200w•hr / m 2 ) for 15 days, and the changes in the content of lomefloxacin hydrochloride and the total impurity content were examined. The results are shown in Table 1. When the total impurity content ≤ 1.0%, it indicates compliance.

[0127] Evaluation was carried out according to the Chinese Pharmacopoeia 2020 Edition. Detection method: High performance liquid chromatography, wavelength: 287nm, chromatographic column: C18, 4.6mm×250mm, 5μm, mobile phase: 10mmol / L ammonium formate aqueous solution: acetonitrile = 85:15.

[0128] Table 1

[0129]

[0130] It can be seen from Table 1 that after the lomefloxacin hydrochloride ear drops of the control preparation, Comparative Example 1 - Comparative Example 5 were placed under light for 15 days, the total impurity content did not meet the requirements, and lomefloxacin hydrochloride decomposed under light, and the content of lomefloxacin hydrochloride decreased significantly.

[0131] After the lomefloxacin hydrochloride ear drops of Examples 1 - 9 of the present invention were placed under light for 15 days, the change degree of the content of lomefloxacin hydrochloride was small, and the total impurity content met the requirements.

[0132] The above results show that after changing the components in Comparative Example 1, Comparative Example 2, Comparative Example 4 and Comparative Example 5, after the lomefloxacin hydrochloride ear drops were placed under light for 15 days, the total impurity content did not meet the requirements, and the active ingredient of lomefloxacin hydrochloride decreased significantly.

[0133] After changing the mass ratio of hydroxypropyl cellulose, polyvinylpyrrolidone and sodium acetate in Comparative Example 3, the total impurity content of the lomefloxacin hydrochloride ear drops after being placed under light for 15 days did not meet the requirements, and the active ingredient of lomefloxacin hydrochloride was prone to degradation, thus decreasing significantly.

[0134] After changing the preparation method of the lomefloxacin hydrochloride ear drops in Comparative Example 6 and Comparative Example 7, the stability of the lomefloxacin hydrochloride ear drops decreased, and the impurity content increased significantly.

[0135] Test 2 Transdermal Absorption Rate

[0136] Otitis media, otitis externa, tympanitis, etc. can all cause damage to the sensory nerves, thereby causing tinnitus nervosa and resulting in hearing impairment. The present invention uses a blood flow change experiment to study the transdermal absorption rate.

[0137] Thirty rabbits were randomly divided into 6 groups, with 5 rabbits in each group, namely:

[0138] (1) Normal control group, without using any composition or physiological saline;

[0139] (2) Model control group, injecting lipopolysaccharide (LPS) at the ear root of normal rabbits to damage the inner ear auditory cells and slow down the blood flow, obtaining model rabbits with microcirculation disorders, without administering any drugs or physiological saline;

[0140] (3) Control preparation group, dropping 3 drops of lomefloxacin hydrochloride ear drops (specification: 15mg / 5ml, batch number: 230401, manufacturer Heilongjiang Tianlong Pharmaceutical Co., Ltd.) into the ear canals of model rabbits, dropping once every 12h;

[0141] (4) Experimental group, dropping 3 drops of the lomefloxacin hydrochloride ear drops of Example 1, Comparative Example 4 and Comparative Example 5 into the ear canals of model rabbits respectively, dropping once every 12h; they are the Example 1 group, the Comparative Example 4 group and the Comparative Example 5 group respectively.

[0142] The microcirculation blood perfusion volume (PU) of the inner ear of rabbits was measured with a laser Doppler blood flowmeter before administration, 0.5h after administration, and 120h after administration respectively. The results are shown in Table 2.

[0143] Table 2

[0144]

[0145] For each column of data in Table 2, compared with the model control group, △ P≤0.05, △△ P≤0.01, there are significant differences; for each column of data in Table 2, compared with the Example 1 group, # P≤0.05, ## P≤0.01, there are significant differences.

[0146] It can be seen from the data in Table 2 that the microcirculation blood perfusion volume of the inner ear of rabbits dropped with the lomefloxacin hydrochloride ear drops of the example of the present invention was greatly increased at 0.5h after administration, restored 65.70% compared with the normal control group, the microcirculation blood perfusion volume at 2h after administration was restored 91.67% compared with the normal control group, and the microcirculation blood perfusion volume at 120h after administration was restored to the normal level.

[0147] For the rabbits instilled with the ofloxacin ear drops of Comparative Example 4 and Comparative Example 5, although the microcirculation blood perfusion volume of the inner ear increased slightly 0.5 h after administration, the drug effect exerted slowly and the transdermal absorption rate was lower than that of the Examples; the microcirculation blood perfusion volume did not return to the normal level even 120 h after administration. For the rabbits instilled with the control preparation, the promotion effect of the microcirculation blood perfusion volume of the inner ear was poor 0.5 h after administration, the drug effect exerted slowly and the transdermal absorption rate was lower than that of the Examples; the microcirculation blood perfusion volume did not return to the normal level until 120 h after administration.

[0148] Therefore, for the ofloxacin ear drops with specific components provided by the present invention, components such as polyethylene glycol 200 - 300 and propylene glycol interact with each other. While improving the stability, it can also increase the transdermal absorption rate of the active ingredient, which is beneficial for the active ingredient to be directly absorbed by cells, so as to fully act on the focus, rapidly exert the drug effect and improve the compliance of patients.

[0149] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the protection scope of the present invention. Any simple modification or equivalent replacement made by those of ordinary skill in the art to the technical solution of the present invention shall not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A lomefloxacin hydrochloride ear drop, characterized in that, It is made from the following raw materials by weight: 3.0 - 6.7 parts of lomefloxacin hydrochloride, 30 - 50 parts of polyethylene glycol 200 - 300, 20 - 40 parts of propylene glycol, 3 - 6 parts of hydroxypropyl cellulose, 1 - 3 parts of polyvinylpyrrolidone, 0.5 - 2 parts of sodium acetate, 0.5 - 2 parts of disodium ethylenediaminetetraacetate and water; The water is made up to a volume such that the concentration of the active ingredient lomefloxacin hydrochloride in the lomefloxacin hydrochloride ear drops is 3.0 - 6.7 g / L; The preparation method of the lomefloxacin hydrochloride ear drops comprises the steps of: (1) Preheat the water to 40 - 50 °C, add lomefloxacin hydrochloride, and stir to dissolve; Under the condition of keeping warm at 40 - 50 °C, successively add polyethylene glycol 200 - 300, sodium acetate, disodium ethylenediaminetetraacetate and 1 / 4 - 1 / 2 of the formulation amount of propylene glycol, and perform ultrasonic treatment to obtain solution A; (2) Mix solution A with hydroxypropyl cellulose, polyvinylpyrrolidone and the remaining formulation amount of propylene glycol, stir, and perform ultrasonic treatment to obtain solution B; (3) Make up the volume of solution B with water to obtain the lomefloxacin hydrochloride ear drops.

2. The lomefloxacin hydrochloride ear drops according to claim 1, characterized in that, It is made from the following raw materials by weight: 3.8 parts of lomefloxacin hydrochloride, 30 - 50 parts of polyethylene glycol 200 - 300, 20 - 40 parts of propylene glycol, 3 - 6 parts of hydroxypropyl cellulose, 1 - 3 parts of polyvinylpyrrolidone, 0.5 - 2 parts of sodium acetate, 0.5 - 2 parts of disodium ethylenediaminetetraacetate and water; The water is made up to a volume such that the concentration of the active ingredient lomefloxacin hydrochloride in the lomefloxacin hydrochloride ear drops is 3.0 - 6.7 g / L.

3. The lomefloxacin hydrochloride ear drops according to claim 1, characterized in that It is made from the following raw materials by weight: 3.3 - 6.0 parts of lomefloxacin hydrochloride, 35 - 45 parts of polyethylene glycol 200 - 300, 25 - 35 parts of propylene glycol, 4 - 5 parts of hydroxypropyl cellulose, 1.5 - 2.5 parts of polyvinylpyrrolidone, 1 - 1.5 parts of sodium acetate, 0.6 - 1.4 parts of disodium ethylenediaminetetraacetate and water; The water is made up to a volume such that the concentration of the active ingredient lomefloxacin hydrochloride in the lomefloxacin hydrochloride ear drops is 3.0 - 6.7 g / L.

4. The lomefloxacin hydrochloride ear drops according to claim 2 or claim 3, characterized in that, It is made from the following raw materials by weight: 3.8 parts of lomefloxacin hydrochloride, 35 - 45 parts of polyethylene glycol 200 - 300, 25 - 35 parts of propylene glycol, 4 - 5 parts of hydroxypropyl cellulose, 1.5 - 2.5 parts of polyvinylpyrrolidone, 1 - 1.5 parts of sodium acetate, 0.6 - 1.4 parts of disodium ethylenediaminetetraacetate and water; The water is made up to a volume such that the concentration of the active ingredient lomefloxacin hydrochloride in the lomefloxacin hydrochloride ear drops is 3.0 - 6.7 g / L.

5. The lomefloxacin hydrochloride ear drops according to claim 4, characterized in that, It is made from the following raw materials by weight: 3.8 parts of lomefloxacin hydrochloride, 40 parts of polyethylene glycol 200 - 300, 30 parts of propylene glycol, 4.5 parts of hydroxypropyl cellulose, 2 parts of polyvinylpyrrolidone, 1.3 parts of sodium acetate, 1 part of disodium ethylenediaminetetraacetate and water The water is made up to a volume such that the concentration of the active ingredient lomefloxacin hydrochloride in the lomefloxacin hydrochloride ear drops is 3.0 - 6.7 g / L.

6. The preparation method of the lomefloxacin hydrochloride ear drops according to any one of claims 1-5, characterized in that, It comprises the steps of: (1) Preheat the water to 40 - 50 °C, add lomefloxacin hydrochloride, and stir to dissolve; Under the condition of keeping warm at 40 - 50 °C, successively add polyethylene glycol 200 - 300, sodium acetate, disodium ethylenediaminetetraacetate and 1 / 4 - 1 / 2 of the formulation amount of propylene glycol, and perform ultrasonic treatment to obtain solution A; (2) Solution A is mixed with hydroxypropyl cellulose, polyvinylpyrrolidone and the remaining formulation amount of propylene glycol, stirred and sonicated to obtain Solution B; (3) Solution B is made up to volume with water to obtain lomefloxacin hydrochloride ear drops; the water is made up to volume so that the concentration of the active ingredient lomefloxacin hydrochloride in the lomefloxacin hydrochloride ear drops is 3.0 - 6.7 g / L.

7. The preparation method according to claim 6, characterized in that, In step (1), the temperature of the preheated water is 45°C; in step (1), the amount of propylene glycol used is 1 / 3 of the formulation amount of propylene glycol.

8. The preparation method according to claim 6, characterized in that, In step (2), the temperature of the mixing is 40 - 50°C; In steps (1) and (2), the sonication time is 5 - 15 min and the sonication frequency is 140 - 160 Hz.

9. Use of the lomefloxacin hydrochloride ear drops according to any one of claims 1 - 5 or the lomefloxacin hydrochloride ear drops prepared by the preparation method according to any one of claims 6 - 8 in the preparation of a drug having the effect of treating otitis media, otitis externa, tympanitis, and / or a drug for restoring hearing impaired due to the above - mentioned inflammation.

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