Nadifloxacin emulsifiable paste and preparation method thereof

Abstract

The invention relates to a nadifloxacin emulsifiable paste and a preparation method thereof, the nadifloxacin emulsifiable paste comprises an active component nadifloxacin and pharmaceutic adjuvants, and is a water-in-oil or oil-in-water external emulsifiable paste preparation. The chemical and physical stability of the product is remarkably improved by adopting a buffer type alkaline hydrotropy system formed by sodium hydroxide and diethanol amine in a synergistic manner, an edetate disodium metal chelating agent and a specifically-formed composite oil phase matrix and combining a vacuum emulsification and double homogenization process; and the preparation process parameters are clear, the industrial amplification can be realized, and the technical problems of poor stability, large quality fluctuation, limited curative effect and the like of the existing nadifloxacin external preparation are solved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a kind of nadifloxacin cream and a preparation method thereof, which is especially suitable for treating common acne and other skin infections caused by gram-positive bacteria (such as propionibacterium acnes and staphylococcus aureus). BACKGROUND

[0002] Nadifloxacin is a quinolone broad-spectrum antibacterial drug developed by Otsuka Pharmaceutical Co., Ltd. in Japan. It was launched in Japan in 1993 in the form of ointment for the treatment of acne. It has strong antibacterial activity against propionibacterium acnes, staphylococcus aureus, staphylococcus epidermidis and some pseudomonas aeruginosa, and shows a low incidence of drug resistance in early studies.

[0003] However, the existing nadifloxacin external preparation (such as ointment or gel) still has the following problems in actual application: Poor physical stability: the cream is prone to delamination, water separation or oil separation, affecting drug uniformity and patient compliance; Insufficient chemical stability: nadifloxacin is prone to degradation under light, high temperature or alkaline environment, resulting in an increase in related substances and a decrease in effective content; Poor transdermal performance: the traditional matrix has limited solubility and release capacity for nadifloxacin, making it difficult to maintain an effective concentration at the infection site; Uncontrollable production process: lack of standardized emulsification and homogenization process, large batch-to-batch quality fluctuation.

[0004] Although some literature has reported the prescription of nadifloxacin ointment (such as containing petrolatum and cetyl alcohol), the above stability and process reproducibility problems have not been solved. Therefore, it is urgent to develop a nadifloxacin cream with high chemical stability, good physical uniformity, excellent skin compatibility and industrial scalability. SUMMARY

[0005] The present application aims to provide a nadifloxacin cream with high stability, high homogeneity and low irritation.

[0006] Another object of the present application is to provide a preparation method that is industrialized, reproducible, quality controllable.

[0007] In order to achieve the above-mentioned application purposes, the present application adopts the following technical solutions: A nadifloxacin ointment, comprising an active ingredient nadifloxacin and a pharmaceutically acceptable excipient, is a water-in-oil or oil-in-water external cream preparation.

[0008] The nadifloxacin cream comprises the following components: Nadifloxacin, content 0.5% to 2.0% (w / w) of the total weight of the cream; A basic co-solvent system comprising sodium hydroxide and diethanolamine is used to facilitate the dissolution of norfloxacin and to maintain the pH of the cream system at 7.0-10.0; A metal chelator selected from disodium edetate or a pharmaceutically acceptable salt thereof is present in an amount of 0.1%-2.0% (w / w) of the total weight of the cream; An oil phase base comprising petrolatum, liquid paraffin, C16-C18 higher fatty alcohol, and a non-ionic emulsifier polyoxyethylene (20) cetyl ether or an equivalent thereof; A humectant selected from glycerin, propylene glycol, or a combination thereof; The balance is purified water; The content of norfloxacin is not less than 90.0% of the labeled amount, and the total amount of related substances is not more than 1.0% after the cream is placed at 25±2℃ and a relative humidity of 60%±5% for 36 months.

[0009] Further, the content of norfloxacin is 1.0% (w / w).

[0010] Further, the C16-C18 higher fatty alcohol is a combination of cetyl alcohol and stearyl alcohol, each present in an amount of 2%-6% (w / w) of the total weight of the cream.

[0011] Further, the non-ionic emulsifier is polyoxyethylene (20) cetyl ether, present in an amount of 1%-5% (w / w) of the total weight of the cream.

[0012] Further, the humectant is glycerin, present in an amount of 5%-15% (w / w) of the total weight of the cream.

[0013] Each 1000 units contains the following components: Norfloxacin 100.0g, Sodium hydroxide 11.2g, Diethanolamine 36.0g, Glycerin 1000.0g, Disodium edetate 10.0g, White petrolatum 1000.0g, Liquid paraffin 900.0g, Stearyl alcohol 400.0g, Cetyl alcohol 400.0g, Polyoxyethylene (20) cetyl ether 300.0g, Purified water to make up the total weight of 10000g.

[0014] The application also discloses a preparation method of norfloxacin cream, comprising the following steps: (1) Oil phase preparation: melt white vaseline, liquid paraffin, octadecanol, cetyl alcohol, polyoxyethylene (20) cetyl ether at 80±2℃, stir at 900 rpm for 30 min; (2) Water phase preparation: dissolve norfloxacin, sodium hydroxide and glycerol in purified water, stir and dissolve at 80±2℃, then add disodium edetate and diethanolamine, stir at the same temperature for 30 min; (3) Vacuum emulsification: slowly add the water phase to the oil phase through a 120-mesh sieve under a vacuum of-0.05 MPa, stir at 65 rpm, 80±2℃ for 30 min; (4) Double homogenization: homogenize at 2050 rpm for 10 min during and before the end of the emulsification process; (5) Cooling, filling and sealing.

[0015] Further, the cream is filled in a specification of 10 g per piece, and the filling amount of a single piece is not less than 93% of the indicated amount.

[0016] The present application provides a high-stability norfloxacin cream and a preparation method thereof. By using a buffer-type alkaline cosolvent system composed of sodium hydroxide and diethanolamine, disodium edetate metal chelating agent, and a specific composition of a composite oil phase matrix, and combining vacuum emulsification and double homogenization process, the chemical and physical stability of the product is significantly improved: after long-term storage at 25℃ / 60% RH for 36 months, the norfloxacin content remains more than 90% of the indicated amount, the total amount of related substances is not more than 1.0%, and there is no delamination, precipitation or particle size exceeding the standard. At the same time, the cream is proved to have good safety through skin irritation and sensitization tests, and multi-center clinical studies show that it has a significant effect on inflammatory acne. The preparation process parameters are clear and can be industrialized, solving the technical problems of poor stability, large quality fluctuations and limited efficacy of existing norfloxacin external preparations, and having outstanding substantial features and significant progress. DETAILED DESCRIPTION

[0017] The present application will be further described by examples, but the protection scope of the present application is not limited by the examples. Example 1

[0018] According to 1000 g of cream, the following components are weighed: norfloxacin 10.0 g (1.0% w / w), sodium hydroxide 1.12 g, diethanolamine 3.6 g, glycerol 100.0 g, disodium edetate 1.0 g, white vaseline 100.0 g, liquid paraffin 90.0 g, octadecanol 40.0 g, cetyl alcohol 40.0 g, polyoxyethylene (20) cetyl ether 30.0 g, and purified water to a total of 1000 g.

[0019] The preparation method is as follows: (1) Oil phase preparation: White petrolatum, liquid paraffin, octadecanol, cetyl alcohol and polyoxyethylene (20) cetyl ether were added into oil phase pot, heated in 80±2°C water bath, stirred at 900 rpm for 30 min, to obtain clear oil phase; (2) Water phase preparation: Norfloxacin, sodium hydroxide and glycerol were dissolved in part of purified water, stirred at 80±2°C until completely dissolved; then disodium edetate and diethanolamine were added, stirred at the same temperature for 30 min, to obtain clear water phase; (3) Vacuum emulsification: Under the vacuum of-0.05 MPa, the water phase was slowly added into the oil phase through 120 mesh sieve, stirred at 65 rpm and 80±2°C for 30 min; (4) Double homogenization: During and before the end of emulsification, homogenization was carried out at 2050 rpm for 10 min, respectively; (5) Cooling to room temperature, filling (10 g / branch).

[0020] The obtained cream was white and uniform O / W type cream, with PH value of 8.5 and no particle larger than 180 μm. After 36 months of long-term stability test (25±2°C, 60%±5%RH), the content of norfloxacin was 96.0%, and the related substance was 0.33%, which met the requirements of quality standards. Example 2

[0021] According to per 1000 g cream, the following components were weighed: norfloxacin 5.0 g (0.5% w / w), sodium hydroxide 0.8 g, diethanolamine 2.5 g, glycerol 80.0 g, disodium edetate 0.5 g, white petrolatum 110.0 g, liquid paraffin 85.0 g, cetyl alcohol 30.0 g, octadecanol 30.0 g, polyoxyethylene (20) cetyl ether 25.0 g, and purified water was added to a total of 1000 g.

[0022] Prepared according to the same process of Example 1. The obtained cream was white and uniform cream, with PH value of 8.2 and particle size meeting the requirements. After 36 months of long-term stability test, the content was 92.3%, and the related substance was 0.87%, indicating that it still had good stability at the lower limit of the concentration claimed. Example 3

[0023] According to per 1000 g cream, the following components were weighed: norfloxacin 15.0 g (1.5% w / w), sodium hydroxide 1.5 g, diethanolamine 5.0 g, glycerol 120.0 g, disodium edetate 1.5 g, yellow petrolatum (pharmaceutical grade) 95.0 g, liquid paraffin 95.0 g, cetyl alcohol 45.0 g, octadecanol 45.0 g, polyoxyethylene (21) stearyl alcohol ether (Brij721 equivalent emulsifier) 32.0 g, and purified water was added to a total of 1000 g.

[0024] Prepared by the process of Example 1 (emulsification temperature adjusted to 81 °C to accommodate the melting point of yellow petrolatum). The resulting cream was a white, fine cream with a pH of 8.8 and no delamination. The 36-month long-term stability study showed a content of 94.7% and a related substance of 0.76%, demonstrating that the use of petrolatum equivalents and C 16 - C 18 The technical effects described in the present application can still be achieved with variations in the combination of alcohols and equivalent non-ionic emulsifiers.

[0025] Comparative Example 1: Formulation (based on 10 g of norfloxacin): sodium hydroxide: 0.9 g, diethanolamine: 3.0 g, disodium edetate: 0.7 g, and the remaining components and processes are the same as in Example 1. The resulting cream was slightly turbid, with an initial pH of 7.8 and incomplete drug dissolution. The 36-month long-term stability study showed a decrease in content to 89.5% and an increase in related substance to 1.15% (>1.0% limit).

[0026] Comparative Example 2: Formulation (based on 10 g of norfloxacin): sodium hydroxide: 1.35 g, diethanolamine: 4.2 g, disodium edetate: 1.3 g, and the remaining components and processes are the same as in Example 1. The resulting cream had an initial pH of 9.6, with a significantly increased viscosity, making it difficult to fill. The 36-month long-term stability study showed that white microcrystals were precipitated on the surface of the cream, with a small amount of particles >180 μm detected by particle size detection. The related substance was 1.08% and the content was 92.1%.

[0027] Comparative Example 3: Formulation (based on 10 g of norfloxacin): sodium hydroxide: 1.5 g, diethanolamine: 2.5 g, disodium edetate: 0.5 g, and the remaining components and processes are the same as in Example 1. The resulting cream was yellowish, with an initial pH of 10.8. The 36-month long-term stability study showed significant yellowing, with a related substance of 1.9% and a content of 85.3%.

[0028] Stability Test: The cream samples obtained in Examples 1-3 and Comparative Examples 1-3 were subjected to a 36-month long-term stability study: I. Purpose of the Test The purpose of the test was to investigate the chemical and physical stability of norfloxacin cream under the proposed storage conditions (light shielding, sealed, stored in a cool place) over a long period of time, in order to provide a basis for determining the shelf life.

[0029] II. Test Conditions (in accordance with ICH Q1A and Chinese Pharmacopoeia) Item Parameter Temperature 25±2℃ Relative humidity 60% ± 5% RH Light Protected from light (packaged in aluminum-plastic composite tube, stored in the dark) Placement Stored upright, avoiding shaking Packaging Consistent with commercial packaging (10 g per unit, aluminum-plastic composite soft tube, sealed) III. Test Results Sample Nafloxacin content Related substances Appearance / physical properties Whether it meets the quality standards Example 1 96.0% 0.33% White and uniform, no delamination Compliant Example 2 92.3%* 0.87% Uniform Compliant Example 3 94.7% 0.76% White and fine Compliant Comparative Example 1 89.5% 1.32% Slightly delaminated Not compliant Comparative Example 2 92.1% 1.08% Crystallization, high viscosity Not compliant Comparative Example 3 85.3% 2.1% Significant yellowing Not compliant IV. Results analysis Only examples 1-3 can continuously meet the quality standards of "content ≥ 90.0%, related substances ≤ 1.0%", while all the comparative examples fail within 12-36 months, proving that the technical solutions of the present application have criticality and irreplaceability; the comparative data of examples and comparative examples fully prove that the present application constructs a "dissolution-buffering-chelation" trinity stabilization system through the synergistic effect of sodium hydroxide, diethanolamine and edetate disodium in a specific proportion range.

[0030] The above examples are only used to illustrate the technical solutions of the present application, not to limit them, although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that they can still modify the technical solutions recorded in the foregoing examples, or make equivalent replacement for part or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the examples of the present application.

Claims

1. A nafloxacin ointment, characterized in that, It includes the active ingredient naflufloxacin and pharmaceutical excipients, and is an oil-in-water or water-in-oil type topical cream formulation.

2. The naflufloxacin cream according to claim 1, characterized in that, It contains the following components: Naflufloxacin, in a concentration of 0.5% to 2.0% (w / w) of the total weight of the cream. An alkaline solubilizing system, comprising sodium hydroxide and diethanolamine, is used to promote the dissolution of naflufloxacin and maintain the pH of the cream system at 7.0–10.

0. The amount of sodium hydroxide is 10%–12% and the amount of diethanolamine is 32%–40% based on the weight of naflufloxacin. Metal chelating agents, selected from disodium edetate or its pharmaceutically acceptable salts, are used at a dosage of 8% to 12% based on the weight of naflufloxacin; The oil phase matrix contains petrolatum-like substances, liquid paraffin, and C. 16 –C 18 Higher fatty alcohols, and nonionic emulsifiers such as polyoxyethylene (20) cetyl ether or equivalents thereof; Moisturizer, selected from glycerin, propylene glycol, or combinations thereof; The remainder is purified water; Wherein, after the cream is placed at 25±2℃ and 60%±5% relative humidity for 36 months, the content of naflufloxacin is not less than 90.0% of the labeled amount, and the total amount of related substances does not exceed 1.0%.

3. The naflufloxacin cream according to claim 2, characterized in that, Based on the weight of naflufloxacin, the amount of sodium hydroxide is 11.2%, the amount of diethanolamine is 36.0%, and the amount of disodium edetate is 10.0%.

4. The naflufloxacin cream according to claim 2, characterized in that, The content of naflufloxacin is 1.0% (w / w).

5. The naflufloxacin cream according to claim 2, characterized in that, The C 16 –C 18 Higher fatty alcohols are a combination of hexadecyl alcohol and octadecyl alcohol, each accounting for 2% to 6% (w / w) of the total weight of the cream.

6. The naflufloxacin cream according to claim 2, characterized in that, The nonionic emulsifier is polyoxyethylene (20) cetyl ether, and its content is 1% to 5% (w / w) of the total weight of the cream.

7. The naflufloxacin cream according to claim 2, characterized in that, The moisturizer is glycerin, and its content is 5% to 15% (w / w) of the total weight of the cream.

8. The naflufloxacin cream according to claim 2, characterized in that, Each 10,000g of cream contains the following ingredients: Naflufloxacin 100.0g, 11.2g of sodium hydroxide, Diethanolamine 36.0g, 1000.0g of glycerin Disodium edetate 10.0g, 1000.0g of white petroleum jelly 900.0g of liquid paraffin Octadecyl alcohol 400.0g, Cetyl alcohol 400.0g, Polyoxyethylene (20) cetyl ether 300.0g, Add purified water to the total weight of 10,000g.

9. The method for preparing naflufloxacin cream according to any one of claims 1-8, characterized in that, Includes the following steps: (1) Preparation of oil phase: White petrolatum, liquid paraffin, octadecanol, hexadecyl alcohol, and polyoxyethylene (20) cetyl ether were melted at 80±2℃ and stirred at 900rpm for 30min. (2) Aqueous phase preparation: Dissolve naflufloxacin, sodium hydroxide and glycerol in purified water, stir at 80±2℃ to dissolve, add disodium edetate and diethanolamine, and stir at the same temperature for 30 min; (3) Vacuum emulsification: Under a vacuum of −0.05MPa, the aqueous phase is slowly added to the oil phase through a 120-mesh sieve and stirred at 65rpm and 80±2℃ for 30min. (4) Double homogenization: Homogenize at 2050 rpm for 10 min during emulsification and before the end of the process; (5) Cooling, filling and sealing.

10. The method for preparing naflufloxacin cream according to claim 9, characterized in that, The cream is packaged in 10g tubes, with each tube containing no less than 93% of the labeled amount.