Lomefloxacin hydrochloride ear drop composition as well as product, preparation method and application thereof

Abstract

The invention provides a lomefloxacin hydrochloride ear drop composition as well as a product, a preparation method and application thereof, and relates to the technical field of pharmaceutical preparations. The lomefloxacin hydrochloride ear drop composition disclosed by the invention is prepared from the following raw materials in parts by weight: 3.0 to 6.7 parts of lomefloxacin hydrochloride, 30 to 50 parts of polyethylene glycol 200 to 300 parts, 20 to 40 parts of propylene glycol, 3 to 6 parts of hydroxy propyl cellulose, 1 to 3 parts of polyvinylpyrrolidone, 0.5 to 2 parts of sodium acetate and 0.5 to 2 parts of disodium ethylene diamine tetraacetate. The lomefloxacin hydrochloride ear drop composition is prepared into lomefloxacin hydrochloride ear drops by adopting a step-by-step heating and ultrasonic mixing method. The lomefloxacin hydrochloride ear drop composition disclosed by the invention is high in transdermal absorption speed, and the drug effect of lomefloxacin hydrochloride can be quickly exerted in a short time; the compound still has high stability under a strong light condition, and the medication safety is high.

Description

Technical Field

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

[0002] Otitis media, otitis externa, and myringitis are common diseases in the otolaryngology department, which are often caused by fungal and bacterial infections. They can cause discomfort, swelling or itching in the ear canal, and a feeling of stuffiness. In severe cases, it can cause pain or even pus discharge. Lomefloxacin hydrochloride is a third-generation broad-spectrum quinolone antibiotic. It has high antibacterial activity against Enterobacteriaceae such as Escherichia coli, Shigella, Klebsiella, Proteus, and Enterobacter. Lomefloxacin hydrochloride also has a certain antibacterial effect on Pseudomonas such as Acinetobacter and Pseudomonas aeruginosa, Staphylococcus, Pneumococcus, and hemolytic Streptococcus. Haemophilus influenzae and Neisseria gonorrhoeae are also highly sensitive to lomefloxacin hydrochloride.

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

[0004] In order to increase the solubility and permeability of lomefloxacin hydrochloride, ethanol is usually added to lomefloxacin hydrochloride ear drops to help the drug act on the inflammatory site. Wen Qiuju published an article in the journal "Chinese Modern Drug Application": Research on the Preparation Process of Lomefloxacin Hydrochloride Ear Drops (2015, 9(6): 274-275); the prescription of the lomefloxacin hydrochloride ear drops is: 15.0g lomefloxacin hydrochloride, 1260g glycerol, 1230g ethanol, 5g disodium edetate and purified water quantified to 5000mL, to prepare 1000 tubes (5mL / tube) of ear drops. This technical solution also increases the solubility and permeability of the drug through ethanol, alleviates the irritation of ethanol to the mucosa through glycerol, and prolongs the local retention time of the drug. However, ethanol is somewhat irritating. In addition, the currently available lomefloxacin hydrochloride ear drops have poor light and heat stability and need to be stored away from light, which not only increases storage and transportation costs, but also easily leads to quality problems with the lomefloxacin hydrochloride ear drops.

[0005] The Chinese invention patent with publication number CN109260152A discloses a lomefloxacin hydrochloride ear drop solution, wherein each 1000 mL of the ear drop solution 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 solution provided by the technical solution uses hydrogenated castor oil and polyethylene glycol as cosolvents, uses glycerol as a penetration enhancer, and uses disodium ethylenediaminetetraacetate as a buffer, so that the lomefloxacin hydrochloride ear drop solution can self-aggregate to form a micellar solution, which not only reduces the irritation of the ear drop solution and reduces the patient's discomfort, but also prolongs the retention time in the ear, improves the bioavailability, and achieves a better therapeutic effect.

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

[0007] In view of this, it is necessary to provide an ear drop solution with safe auxiliary material ingredients, stable mutual combination, no ethanol is used and no additional modification is performed on the auxiliary materials, and which can significantly improve the permeability and storage stability of lomefloxacin hydrochloride. Summary of the invention

[0008] The present invention aims at the problems existing in the prior art and provides a lomefloxacin hydrochloride ear drop composition and its product, preparation method and application. In the composition of the present invention, the transdermal absorption of lomefloxacin hydrochloride is improved by rationally using auxiliary material components, and the efficacy of lomefloxacin hydrochloride can be quickly 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 purpose, the technical solution adopted by the present invention is as follows: First, the present invention provides a lomefloxacin hydrochloride ear drop composition, which 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 (HPC), 1-3 parts of polyvinyl pyrrolidone (PVP), 0.5-2 parts of sodium acetate and 0.5-2 parts of disodium ethylenediaminetetraacetate.

[0010] Preferably, the lomefloxacin hydrochloride ear drop composition is made of the following raw materials, in parts 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 polyvinyl pyrrolidone, 0.5-2 parts of sodium acetate and 0.5-2 parts of disodium ethylenediaminetetraacetate.

[0011] Preferably, the lomefloxacin hydrochloride ear drop composition is made of the following raw materials, in parts 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 polyvinyl pyrrolidone, 1-1.5 parts of sodium acetate and 0.6-1.4 parts of disodium ethylenediaminetetraacetate.

[0012] Further preferably, the lomefloxacin hydrochloride ear drop composition is made of the following raw materials, in parts 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 polyvinyl pyrrolidone, 1-1.5 parts of sodium acetate and 0.6-1.4 parts of disodium ethylenediaminetetraacetate.

[0013] More preferably, the lomefloxacin hydrochloride ear drop composition is made of the following raw materials, in parts 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 polyvinyl pyrrolidone, 1.3 parts of sodium acetate and 1 part of disodium ethylenediaminetetraacetate.

[0014] Preferably, the polyethylene glycol 200-300 is polyethylene glycol with a molecular weight of 200-300.

[0015] Furthermore, the present invention provides a lomefloxacin hydrochloride ear drop solution, the components of which include a lomefloxacin hydrochloride ear drop solution composition and water.

[0016] 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.

[0017] Further preferably, in the lomefloxacin hydrochloride ear drops, the concentration of the active ingredient lomefloxacin hydrochloride is 3.3-6.0 g / L.

[0018] More preferably, in the lomefloxacin hydrochloride ear drops, the concentration of the active ingredient lomefloxacin hydrochloride is 3.8 g / L.

[0019] Then, the present invention provides a method for preparing the lomefloxacin hydrochloride ear drops, comprising the steps of: (1) Preheat water to 40-50°C, add lomefloxacin hydrochloride, and stir to dissolve; add polyethylene glycol 200-300, sodium acetate, disodium ethylenediaminetetraacetate, and 1 / 4-1 / 2 of the formula amount of propylene glycol in sequence under the condition of keeping warm at 40-50°C, and sonicate to obtain solution A; (2) Solution A is mixed with hydroxypropyl cellulose, polyvinyl pyrrolidone and the remaining amount of propylene glycol, stirred, and ultrasonicated to obtain solution B; (3) Add water to solution B to make up to volume to obtain lomefloxacin hydrochloride ear drops.

[0020] Preferably, in step (1), the water is preheated at a temperature of 45°C.

[0021] Preferably, in step (1), the amount of propylene glycol used is 1 / 3 of the propylene glycol formula amount.

[0022] Preferably, in step (1), there is no particular 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 volume.

[0023] Preferably, in step (2), the mixing temperature is 40-50°C; more preferably 45°C.

[0024] Preferably, in step (1) and step (2), the ultrasonic time is 5-15 min and the ultrasonic frequency is 140-160 Hz.

[0025] Further preferably, in step (1), the ultrasonic time is 10-15 min and the ultrasonic frequency is 160 Hz.

[0026] Further preferably, in step (2), the ultrasonic time is 5-10 min and the ultrasonic frequency is 140 Hz.

[0027] 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.

[0028] Finally, the present invention provides the use of the lomefloxacin hydrochloride ear drop composition in the preparation of a drug for treating otitis media, otitis externa, myringitis, and / or restoring hearing.

[0029] Compared with the prior art, the present invention has the following beneficial effects: 1. After research, the inventor unexpectedly discovered that the simultaneous use of hydroxypropyl cellulose, polyvinyl pyrrolidone and sodium acetate can significantly improve the stability of the drug preparation. The three work synergistically to make the lomefloxacin hydrochloride ear drop composition have excellent light and heat stability.

[0030] 2. In the composition of the present invention, ethanol is not used as a solvent, the medication is safe and can improve patient compliance; and propylene glycol, as a penetration enhancer, can not only improve the stability of the composition, but also interact with disodium ethylenediaminetetraacetic acid and small molecule polyethylene glycol to increase the transdermal absorption rate of lomefloxacin hydrochloride, thereby improving the efficacy of the drug and shortening the treatment time. DETAILED DESCRIPTION

[0031] The following non-limiting examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The following content is merely an exemplary description of the scope of the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, which should also fall within the scope of the present invention.

[0032] When the embodiments give numerical ranges, it should be understood that, unless otherwise specified in the present invention, both endpoints of each numerical range and any numerical value between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used in the present invention have the same meanings as those generally understood by those of ordinary skill in the art to which the present invention belongs.

[0033] The present invention is further described below by way of specific examples. Unless otherwise specified, the various chemical reagents used in the examples of the present invention are obtained through conventional commercial channels.

[0034] In the following examples, the lomefloxacin hydrochloride was purchased from Yichang Renfu Pharmaceutical Co., Ltd.; the hydroxypropyl cellulose was purchased from Adamas; and the polyvinyl pyrrolidone was polyvinyl pyrrolidone k30, purchased from BASF New Materials Co., Ltd. Products from different manufacturers had no significant effect on the effect.

[0035] Example 1 A lomefloxacin hydrochloride ear drop composition, the formula of which is: 3.8g lomefloxacin hydrochloride, 40g polyethylene glycol 200, 30g propylene glycol, 4.5g hydroxypropyl cellulose, 2g polyvinyl pyrrolidone, 1.3g sodium acetate and 1g disodium ethylenediaminetetraacetate; (1) Preheat 700 mL of water to 45°C, add 3.8 g of lomefloxacin hydrochloride, and stir thoroughly to dissolve; 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 under the condition of keeping warm at 45°C, and perform ultrasonic treatment at 160 Hz for 10 min to obtain solution A; (2) At 45°C, solution A was mixed with 4.5 g hydroxypropyl cellulose, 2 g polyvinyl pyrrolidone and 20 g propylene glycol, stirred evenly, and subjected to ultrasonic treatment at 140 Hz for 10 min to obtain solution B. (3) Add water to solution B to make the volume up to 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0036] Example 2 A lomefloxacin hydrochloride ear drop composition, the formula of which is: 3.8g lomefloxacin hydrochloride, 35g polyethylene glycol 200, 25g propylene glycol, 4g hydroxypropyl cellulose, 1.5g polyvinyl pyrrolidone, 1g sodium acetate and 0.6g disodium ethylenediaminetetraacetate; (1) Preheat 700 mL of water to 45°C, add 3.8 g of lomefloxacin hydrochloride, and stir thoroughly to dissolve; 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 under the condition of keeping warm at 45°C, and treat with ultrasound at 160 Hz for 10 min to obtain solution A; (2) At 45°C, solution A was mixed with 4 g hydroxypropyl cellulose, 1.5 g polyvinyl pyrrolidone and 17 g propylene glycol, stirred evenly, and subjected to ultrasonic treatment at 140 Hz for 10 min to obtain solution B. (3) Add water to solution B to make the volume up to 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0037] Example 3 A lomefloxacin hydrochloride ear drop composition, comprising: 3.8 g lomefloxacin hydrochloride, 45 g polyethylene glycol 200, 35 g propylene glycol, 5 g hydroxypropyl cellulose, 2.5 g polyvinyl pyrrolidone, 1.5 g sodium acetate and 1.4 g disodium ethylenediaminetetraacetate; (1) Preheat 600 mL of water to 45°C, add 3.8 g of lomefloxacin hydrochloride, and stir thoroughly to dissolve; 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 at 45°C, and perform ultrasonic treatment at 160 Hz for 10 min to obtain solution A; (2) At 45°C, solution A was mixed with 5 g hydroxypropyl cellulose, 2.5 g polyvinyl pyrrolidone and 21 g propylene glycol, stirred evenly, and subjected to ultrasonic treatment at 140 Hz for 10 min to obtain solution B. (3) Add water to solution B to make the volume up to 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0038] Example 4 A lomefloxacin hydrochloride ear drop composition, comprising: 3.8 g lomefloxacin hydrochloride, 30 g polyethylene glycol 200, 20 g propylene glycol, 3 g hydroxypropyl cellulose, 1 g polyvinyl pyrrolidone, 0.5 g sodium acetate and 0.5 g disodium ethylenediaminetetraacetate; (1) Preheat 700 mL of water to 45°C, add 3.8 g of lomefloxacin hydrochloride, and stir thoroughly to dissolve; add 30 g of polyethylene glycol 300, 0.5 g of sodium acetate, 0.5 g of disodium ethylenediaminetetraacetate, and 6 g of propylene glycol in sequence under the condition of keeping warm at 45°C, and perform ultrasonic treatment at 160 Hz for 10 min to obtain solution A; (2) At 45°C, solution A was mixed with 3 g of hydroxypropyl cellulose, 1 g of polyvinyl pyrrolidone and 14 g of propylene glycol, stirred evenly, and subjected to ultrasonic treatment at 140 Hz for 10 min to obtain solution B. (3) Add water to solution B to make the volume up to 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0039] Example 5 A lomefloxacin hydrochloride ear drop composition, comprising: 3.8 g lomefloxacin hydrochloride, 50 g polyethylene glycol 200, 40 g propylene glycol, 6 g hydroxypropyl cellulose, 3 g polyvinyl pyrrolidone, 2 g sodium acetate and 2 g disodium ethylenediaminetetraacetate; (1) Preheat 600 mL of water to 45°C, add 3.8 g of lomefloxacin hydrochloride, and stir thoroughly to dissolve; add 50 g of polyethylene glycol 300, 2 g of sodium acetate, 2 g of disodium ethylenediaminetetraacetate, and 12 g of propylene glycol in sequence under the condition of keeping warm at 45°C, and treat with ultrasound at 160 Hz for 10 min to obtain solution A; (2) At 45°C, solution A was mixed with 6 g hydroxypropyl cellulose, 3 g polyvinyl pyrrolidone and 28 g propylene glycol, stirred evenly, and subjected to ultrasonic treatment at 140 Hz for 10 min to obtain solution B. (3) Add water to solution B to make the volume up to 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0040] Example 6 A lomefloxacin hydrochloride ear drop composition, the formula of which is: 3.3g lomefloxacin hydrochloride, 35g polyethylene glycol 200, 25g propylene glycol, 4g hydroxypropyl cellulose, 1.5g polyvinyl pyrrolidone, 1g sodium acetate and 0.6g disodium ethylenediaminetetraacetate; (1) Preheat 700 mL of water to 40°C, add 3.3 g of lomefloxacin hydrochloride, and stir thoroughly to dissolve; then add 35 g of polyethylene glycol 200, 1 g of sodium acetate, 0.6 g of disodium ethylenediaminetetraacetate, and 12.5 g of propylene glycol in sequence at 40°C, and perform ultrasonic treatment at 140 Hz for 15 min to obtain solution A; (2) At 40°C, solution A was mixed with 4 g hydroxypropyl cellulose, 1.5 g polyvinyl pyrrolidone and 12.5 g propylene glycol, stirred evenly, and subjected to ultrasonic treatment at 160 Hz for 5 min to obtain solution B. (3) Add water to solution B to make the volume up to 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0041] Example 7 A lomefloxacin hydrochloride ear drop composition, comprising: 6.0 g lomefloxacin hydrochloride, 45 g polyethylene glycol 200, 35 g propylene glycol, 5 g hydroxypropyl cellulose, 2.5 g polyvinyl pyrrolidone, 1.5 g sodium acetate and 1.4 g disodium ethylenediaminetetraacetate; (1) Preheat 600 mL of water to 50°C, add 6.0 g of lomefloxacin hydrochloride, and stir thoroughly to dissolve; add 45 g of polyethylene glycol 200, 1.5 g of sodium acetate, 1.4 g of disodium ethylenediaminetetraacetate, and 9 g of propylene glycol in sequence under the condition of keeping warm at 50°C, and perform ultrasonic treatment at 140 Hz for 15 min to obtain solution A; (2) At 50°C, solution A was mixed with 5 g of hydroxypropyl cellulose, 2.5 g of polyvinyl pyrrolidone and 26 g of propylene glycol, stirred evenly, and subjected to ultrasonic treatment at 140 Hz for 10 min to obtain solution B. (3) Add water to solution B to make the volume up to 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0042] Example 8 A lomefloxacin hydrochloride ear drop composition, the formula of which is: 3.0g lomefloxacin hydrochloride, 30g polyethylene glycol 200, 20g propylene glycol, 3g hydroxypropyl cellulose, 1g polyvinyl pyrrolidone, 0.5g sodium acetate and 0.5g disodium ethylenediaminetetraacetate; (1) Preheat 700 mL of water to 45°C, add 3.0 g of lomefloxacin hydrochloride, and stir thoroughly to dissolve; 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 under the condition of keeping warm at 45°C, and perform ultrasonic treatment at 160 Hz for 10 min to obtain solution A; (2) At 45°C, solution A was mixed with 3 g of hydroxypropyl cellulose, 1 g of polyvinyl pyrrolidone and 14 g of propylene glycol, stirred evenly, and subjected to ultrasonic treatment at 140 Hz for 10 min to obtain solution B. (3) Add water to solution B to make the volume up to 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0043] Example 9 A lomefloxacin hydrochloride ear drop composition, comprising: 6.7 g lomefloxacin hydrochloride, 50 g polyethylene glycol 200, 40 g propylene glycol, 6 g hydroxypropyl cellulose, 3 g polyvinyl pyrrolidone, 2 g sodium acetate and 2 g disodium ethylenediaminetetraacetate; (1) Preheat 600 mL of water to 45°C, add 6.7 g of lomefloxacin hydrochloride, and stir thoroughly to dissolve; 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 under the condition of keeping warm at 45°C, and perform ultrasonic treatment at 160 Hz for 10 min to obtain solution A; (2) At 45°C, solution A was mixed with 6 g hydroxypropyl cellulose, 3 g polyvinyl pyrrolidone and 28 g propylene glycol, stirred evenly, and subjected to ultrasonic treatment at 140 Hz for 10 min to obtain solution B. (3) Add water to solution B to make the volume up to 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0044] Comparative Example 1 Different from Example 1, the lomefloxacin hydrochloride ear drops composition does not contain hydroxypropyl cellulose, and hydroxypropyl cellulose is replaced by polyethylene glycol 200.

[0045] A lomefloxacin hydrochloride ear drop composition, the formula of which is: 3.8g lomefloxacin hydrochloride, 44.5g polyethylene glycol 200, 30g propylene glycol, 2g polyvinyl pyrrolidone, 1.3g sodium acetate and 1g disodium ethylenediaminetetraacetate; (1) Preheat 700 mL of water to 45°C, add 3.8 g of lomefloxacin hydrochloride, and stir thoroughly to dissolve; 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 in sequence at 45°C, and perform ultrasonic treatment at 160 Hz for 10 min to obtain solution A; (2) At 45°C, solution A was mixed with 2 g of polyvinyl pyrrolidone and 20 g of propylene glycol, stirred evenly, and subjected to ultrasonic treatment at 140 Hz for 10 min to obtain solution B. (3) Add water to solution B to make the volume up to 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0046] Comparative Example 2 Different from Example 1, the lomefloxacin hydrochloride ear drops composition does not contain components of polyvinyl pyrrolidone and sodium acetate, and polyvinyl pyrrolidone and sodium acetate are replaced by polyethylene glycol 200.

[0047] A lomefloxacin hydrochloride ear drop composition, the formula of which is: 3.8 g lomefloxacin hydrochloride, 43.3 g polyethylene glycol 200, 30 g propylene glycol, 4.5 g hydroxypropyl cellulose and 1 g disodium edetate; (1) Preheat 700 mL of water to 45°C, add 3.8 g of lomefloxacin hydrochloride, and stir thoroughly to dissolve; add 43.3 g of polyethylene glycol 200, 1 g of disodium ethylenediaminetetraacetate, and 10 g of propylene glycol in sequence under the condition of keeping warm at 45°C, and perform ultrasonic treatment at 160 Hz for 10 min to obtain solution A; (2) At 45°C, solution A was mixed with 4.5 g of hydroxypropyl cellulose and 20 g of propylene glycol, stirred evenly, and subjected to ultrasonic treatment at 140 Hz for 10 min to obtain solution B. (3) Add water to solution B to make the volume up to 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0048] Comparative Example 3 Different from Example 1, the mass ratios of hydroxypropyl cellulose, polyvinyl pyrrolidone and sodium acetate in the lomefloxacin hydrochloride ear drops composition are different.

[0049] A lomefloxacin hydrochloride ear drop composition, comprising: 3.8 g lomefloxacin hydrochloride, 40 g polyethylene glycol 200, 30 g propylene glycol, 1 g hydroxypropyl cellulose, 4 g polyvinyl pyrrolidone, 2.8 g sodium acetate and 1 g disodium ethylenediaminetetraacetate; (1) Preheat 700 mL of water to 45°C, add 3.8 g of lomefloxacin hydrochloride, and stir thoroughly to dissolve; add 40 g of polyethylene glycol 200, 2.8 g of sodium acetate, 1 g of disodium ethylenediaminetetraacetate, and 10 g of propylene glycol in sequence under the condition of keeping warm at 45°C, and perform ultrasonic treatment at 160 Hz for 10 min to obtain solution A; (2) At 45°C, solution A was mixed with 1 g of hydroxypropyl cellulose, 4 g of polyvinyl pyrrolidone and 20 g of propylene glycol, stirred evenly, and subjected to ultrasonic treatment at 140 Hz for 10 min to obtain solution B. (3) Add water to solution B to make the volume up to 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0050] Comparative Example 4 The difference from Example 1 is that the polyethylene glycol 200 in the lomefloxacin hydrochloride ear drops composition is replaced by polyethylene glycol 600.

[0051] A lomefloxacin hydrochloride ear drop composition, comprising: 3.8 g lomefloxacin hydrochloride, 40 g polyethylene glycol 600, 30 g propylene glycol, 4.5 g hydroxypropyl cellulose, 2 g polyvinyl pyrrolidone, 1.3 g sodium acetate and 1 g disodium ethylenediaminetetraacetate; (1) Preheat 700 mL of water to 45°C, add 3.8 g of lomefloxacin hydrochloride, and stir thoroughly to dissolve; add 40 g of polyethylene glycol 600, 1.3 g of sodium acetate, 1 g of disodium ethylenediaminetetraacetate, and 10 g of propylene glycol in sequence under the condition of keeping warm at 45°C, and treat with ultrasound at 160 Hz for 10 min to obtain solution A; (2) At 45°C, solution A was mixed with 4.5 g hydroxypropyl cellulose, 2 g polyvinyl pyrrolidone and 20 g propylene glycol, stirred evenly, and subjected to ultrasonic treatment at 140 Hz for 10 min to obtain solution B. (3) Add water to solution B to make the volume up to 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0052] Comparative Example 5 The difference from Example 1 is that the propylene glycol in the lomefloxacin hydrochloride ear drops composition is replaced by glycerol.

[0053] A lomefloxacin hydrochloride ear drop composition, the formula of which is: 3.8g lomefloxacin hydrochloride, 40g polyethylene glycol 200, 30g glycerol, 4.5g hydroxypropyl cellulose, 2g polyvinyl pyrrolidone, 1.3g sodium acetate and 1g disodium ethylenediaminetetraacetate; (1) Preheat 700 mL of water to 45°C, add 3.8 g of lomefloxacin hydrochloride, and stir thoroughly to dissolve; add 40 g of polyethylene glycol 200, 1.3 g of sodium acetate, 1 g of disodium ethylenediaminetetraacetate, and 10 g of glycerol in sequence under the condition of keeping warm at 45°C, and perform ultrasonic treatment at 160 Hz for 10 min to obtain solution A; (2) At 45°C, solution A was mixed with 4.5 g hydroxypropyl cellulose, 2 g polyvinyl pyrrolidone and 20 g glycerol, stirred evenly, and subjected to ultrasonic treatment at 140 Hz for 10 min to obtain solution B. (3) Add water to solution B to make the volume up to 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0054] Comparative Example 6 The difference from Example 1 is that the preparation method of lomefloxacin hydrochloride ear drops is different, specifically, all of the propylene glycol is added in step (2): (1) Preheat 700 mL of water to 45°C, add 3.8 g of lomefloxacin hydrochloride, and stir thoroughly to dissolve; add 40 g of polyethylene glycol 200, 1.3 g of sodium acetate, and 1 g of disodium ethylenediaminetetraacetate in sequence under the condition of keeping warm at 45°C, and perform ultrasonic treatment at 160 Hz for 10 min to obtain solution A; (2) At 45°C, solution A was mixed with 4.5 g hydroxypropyl cellulose, 2 g polyvinyl pyrrolidone and 30 g propylene glycol, stirred evenly, and subjected to ultrasonic treatment at 140 Hz for 10 min to obtain solution B. (3) Add water to solution B to make the volume up to 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0055] Comparative Example 7 Different from Example 1, in the preparation method of lomefloxacin hydrochloride ear drops, ultrasonic treatment was not performed: (1) Preheat 700 mL of water to 45°C, add 3.8 g of lomefloxacin hydrochloride, and stir thoroughly to dissolve; 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 under the condition of keeping warm at 45°C, and stir to mix evenly to obtain solution A; (2) At 45°C, solution A was mixed with 4.5 g hydroxypropyl cellulose, 2 g polyvinyl pyrrolidone and 20 g propylene glycol and stirred evenly to obtain solution B. (3) Add water to solution B to make the volume up to 1000 mL to obtain lomefloxacin hydrochloride ear drops.

[0056] Test 1 Light stability The control preparation (marketed lomefloxacin hydrochloride ear drops, specification: 15 mg / 5 ml, batch number: 230401, manufacturer Heilongjiang Tianlong Pharmaceutical Co., Ltd.) and the lomefloxacin hydrochloride ear drops of the embodiments of the present invention and the comparative example were placed under light (total illumination not less than 1.2×10 6 lux·hr, near ultraviolet energy not less than 200w·hr / m 2 ) for 15 days to examine the changes in lomefloxacin hydrochloride content and total impurity content. The results are shown in Table 1. When the total impurity content is ≤1.0%, it meets the requirements.

[0057] Evaluated according to the 2020 edition of the "Chinese Pharmacopoeia", detection method: high performance liquid chromatography, wavelength: 287nm, chromatographic column: C18, 4.6mm×250mm, 5μm, mobile phase is 10mmol / L ammonium formate aqueous solution: acetonitrile = 85:15.

[0058] Table 1

[0059] As can be seen from Table 1, after the lomefloxacin hydrochloride ear drops of the control preparation and comparative examples 1 to 5 were placed under light conditions for 15 days, the total impurity content did not meet the requirements, and lomefloxacin hydrochloride was decomposed under light conditions, and the lomefloxacin hydrochloride content decreased significantly.

[0060] After the lomefloxacin hydrochloride ear drops of Examples 1 to 9 of the present invention were placed under light for 15 days, the lomefloxacin hydrochloride content changed slightly and the total impurity content met the requirements.

[0061] The above results show that after the components of Comparative Examples 1, 2, 4 and 5 were changed, the total impurity content of the lomefloxacin hydrochloride ear drops did not meet the requirements after being placed under light for 15 days, and the active ingredient of lomefloxacin hydrochloride decreased significantly.

[0062] Comparative Example 3: After changing the mass ratio of hydroxypropyl cellulose, polyvinyl pyrrolidone and sodium acetate, the total impurity content of lomefloxacin hydrochloride ear drops placed under light for 15 days did not meet the requirements, and the active ingredient of lomefloxacin hydrochloride was easily degraded, thereby significantly decreasing.

[0063] After the preparation method of lomefloxacin hydrochloride ear drops was changed in Comparative Examples 6 and 7, the stability of lomefloxacin hydrochloride ear drops decreased and the impurity content increased significantly.

[0064] Test 2 Transdermal absorption rate Otitis media, external otitis, myringitis, etc. can all cause damage to the sensorineural nerves, which in turn cause neurological tinnitus and hearing loss. The present invention uses a blood flow change experiment to study the transdermal absorption rate.

[0065] Thirty rabbits were randomly divided into 6 groups, 5 rabbits in each group, namely: (1) Normal control group, no combination or saline was used; (2) Model control group: endotoxin (LPS) was injected into the ear base of normal rabbits to damage the inner ear auditory cells and slow blood flow, thus obtaining a model rabbit with microcirculatory disorders. No drugs or saline were administered. (3) Control group: 3 drops of lomefloxacin hydrochloride ear drops (specification: 15 mg / 5 ml, batch number: 230401, manufacturer: Heilongjiang Tianlong Pharmaceutical Co., Ltd.) were dripped into the ear canal of the model rabbits, once every 12 hours; (4) Experimental group: 3 drops of lomefloxacin hydrochloride ear drops of Example 1, Comparative Example 4 and Comparative Example 5 were respectively dripped into the ear canal of model rabbits, once every 12 hours; they were Example 1 group, Comparative Example 4 group and Comparative Example 5 group.

[0066] Laser Doppler blood flow meter was used to measure the blood perfusion volume (PU) of the inner ear microcirculation of rabbits before administration, 0.5h after administration, and 120h after administration. The results are shown in Table 2.

[0067] Table 2

[0068] The data in each column of Table 2 show that each group is compared with the model control group. △ P≤0.05, △△ P≤0.01, there is a significant difference; the data in each column of Table 2, each group is compared with the group in Example 1, # P≤0.05, ## P≤0.01, there is a significant difference.

[0069] It can be seen from the data in Table 2 that the microcirculatory blood perfusion of the inner ear of rabbits treated with the lomefloxacin hydrochloride ear drops of the embodiment of the present invention was greatly improved at 0.5h after administration, and recovered by 65.70% compared with the normal control group. The microcirculatory blood perfusion 2h after administration recovered by 91.67% compared with the normal control group. The microcirculatory blood perfusion 120h after administration returned to the normal level.

[0070] While the blood perfusion of the inner ear microcirculation of rabbits using lomefloxacin hydrochloride ear drops of comparative examples 4 and 5 was slightly increased at 0.5h after administration, the drug effect was slow, and the transdermal absorption rate was lower than that of the embodiment; the blood perfusion of the inner ear microcirculation was not restored to the normal level 120h after administration. The blood perfusion of the inner ear microcirculation of rabbits using the control preparation was not improved 0.5h after administration, the drug effect was slow, and the transdermal absorption rate was lower than that of the embodiment; the blood perfusion of the inner ear microcirculation was restored to the normal level 120h after administration.

[0071] Therefore, the lomefloxacin hydrochloride ear drops of specific components provided by the present invention, polyethylene glycol 200-300 and propylene glycol and other components 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 lesions, quickly exert the efficacy, and improve the compliance of patients.

[0072] 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 scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A lomefloxacin hydrochloride ear drop composition, characterized in that: The 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 polyvinyl pyrrolidone, 0.5-2 parts of sodium acetate and 0.5-2 parts of disodium ethylenediaminetetraacetate.

2. The lomefloxacin hydrochloride ear drop composition according to claim 1, characterized in that The invention is prepared from the following raw materials in parts 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 polyvinyl pyrrolidone, 0.5-2 parts of sodium acetate and 0.5-2 parts of disodium ethylenediaminetetraacetate.

3. The lomefloxacin hydrochloride ear drop composition according to claim 1, characterized in that The invention is prepared from the following raw materials in parts 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 polyvinyl pyrrolidone, 1-1.5 parts of sodium acetate and 0.6-1.4 parts of disodium ethylenediaminetetraacetate.

4. The lomefloxacin hydrochloride ear drop composition according to claim 2 or claim 3, characterized in that The invention is prepared from the following raw materials in parts 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 polyvinyl pyrrolidone, 1-1.5 parts of sodium acetate and 0.6-1.4 parts of disodium ethylenediaminetetraacetate.

5. The lomefloxacin hydrochloride ear drop composition according to claim 4, characterized in that The invention is prepared from the following raw materials in parts 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 polyvinyl pyrrolidone, 1.3 parts of sodium acetate and 1 part of disodium ethylenediaminetetraacetate.

6. A lomefloxacin hydrochloride ear drops, characterized in that: The components include the lomefloxacin hydrochloride ear drop composition according to any one of claims 1 to 5 and water.

7. The method for preparing the lomefloxacin hydrochloride ear drops according to claim 6, characterized in that: Includes steps: (1) Preheat water to 40-50°C, add lomefloxacin hydrochloride, and stir to dissolve; add polyethylene glycol 200-300, sodium acetate, disodium ethylenediaminetetraacetate, and 1 / 4-1 / 2 of the formula amount of propylene glycol in sequence under the condition of keeping warm at 40-50°C, and sonicate to obtain solution A; (2) Solution A is mixed with hydroxypropyl cellulose, polyvinyl pyrrolidone and the remaining amount of propylene glycol, stirred, and ultrasonicated to obtain solution B; (3) Add water to solution B to make up to volume to obtain lomefloxacin hydrochloride ear drops.

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

9. The preparation method according to claim 7, characterized in that: In step (2), the mixing temperature is 40-50°C; In step (1) and step (2), the ultrasonic time is 5-15 minutes, and the ultrasonic frequency is 140-160 Hz.

10. Use of the lomefloxacin hydrochloride ear drops composition according to any one of claims 1 to 5, the lomefloxacin hydrochloride ear drops according to claim 6, or the lomefloxacin hydrochloride ear drops prepared by the preparation method according to any one of claims 7 to 9 in preparing drugs for treating otitis media, otitis externa, myringitis, and / or restoring hearing.

Images