Norfloxacin preparation as well as preparation method and application thereof

Abstract

The invention discloses a norfloxacin preparation as well as a preparation method and application thereof, and belongs to the technical field of medicines. The norfloxacin preparation comprises a skeleton sustained-release tablet and a regulation and control layer wrapping the surface of the skeleton sustained-release tablet, the main drug of the matrix sustained release tablet is crystal form X norfloxacin. According to the norfloxacin preparation, through a mode of combining a skeleton and membrane control, the aim of slowly releasing the drug by combining the skeleton and the membrane control is fulfilled while the drug is enhanced to cope with the influence of environmental water, heat and oxygen, and the dissolution behavior similar to that of an existing reference preparation can be achieved.

Description

Technical Field

[0001] The invention relates to a norfloxacin preparation, in particular to a skeleton sustained-release tablet whose main drug is crystal form X norfloxacin, and also to a preparation method and application thereof, belonging to the technical field of medicines. Background Art

[0002] The original product of norfloxacin oral preparation is norfloxacin tablets (trade name: BACCIDAL, Baccidal) produced by KYORIN Pharmaceutical Co., Ltd., Japan. It was approved for marketing in Japan in 1984 and is a reference preparation included in the Japanese Orange Book and my country's consistency evaluation. Norfloxacin is a fluoroquinolone antibacterial drug with a broad-spectrum antibacterial effect, especially high antibacterial activity against Gram-negative bacteria. It has good antibacterial effects in vitro against the following bacteria: most bacteria of the Enterobacteriaceae family, including Citrobacter, Enterobacter cloacae, Enterobacter aerogenes and other Enterobacteriaceae, Escherichia coli, Klebsiella, Proteus, Salmonella, Shigella, Vibrio, Yersinia, etc. Norfloxacin also has antibacterial effects against a variety of drug-resistant bacteria in vitro. Norfloxacin is a bactericide that acts on the A subunit of bacterial DNA helicase, inhibiting DNA synthesis and replication, leading to bacterial death.

[0003] On the market, the common dosage forms of norfloxacin are tablets, capsules, external preparations, eye drops, suppositories, injections, etc. It is worth mentioning that, as of now, there is only one specification for domestic norfloxacin tablets and norfloxacin capsules. Among them, norfloxacin tablets have 45 domestic drug approvals and no imported drug approvals; norfloxacin capsules have 568 domestic drug approvals and no imported drug approvals. However, norfloxacin has high solubility in water, strong hygroscopicity, and is unstable in light, high temperature and high humidity environments to produce impurities A (1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid) and impurity B (1-ethyl-6-fluoro-7-[(2-aminoethyl)amino]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid). At present, the preparation process of pharmaceutical tablets mainly includes several methods such as wet granulation tableting, dry granulation tableting, powder direct tableting and freeze-drying tableting, but none of them can solve the defect of instability of norfloxacin. Chinese patent CN116889554A provides a preparation process that can improve the stability of norfloxacin tablets, which uses two auxiliary agents, polyvinyl pyrrolidone and trehalose, to mix with norfloxacin in a certain proportion, grind together, dry, and add pharmaceutically acceptable conventional auxiliary materials, and use powder direct tableting method to prepare norfloxacin tablets, which overcomes the defect of norfloxacin being easy to absorb moisture and solves the problem that norfloxacin tablets are easily decomposed by light, heat and moisture to produce related substances. Chinese patent CN115501232A discloses a norfloxacin composition and a preparation method thereof. In practice, norfloxacin is embedded by a film-forming agent polyacrylic acid resin, and then the remaining auxiliary materials are added for total mixing, and finally the powder is directly compressed into tablets or filled into gelatin hollow capsules, thereby avoiding the hygroscopicity problem during storage to a certain extent, but does not solve the problem that norfloxacin is prone to produce impurities under high temperature, high humidity and light conditions.

[0004] Therefore, it is necessary to provide more norfloxacin preparations to provide more choices for clinical patients. Summary of the invention

[0005] In view of the deficiencies in the prior art, the present invention aims to provide a norfloxacin preparation, wherein the norfloxacin adopts crystal form X norfloxacin as a main drug, which has the characteristics of low hygroscopicity, good chemical stability, etc., and can avoid the problem that norfloxacin is prone to produce impurities under high temperature, high humidity and light conditions. At the same time, skeleton sustained-release technology and membrane controlled-release technology are adopted to realize surface coating with sustained-release coating, prolong the half-life in vivo, improve drug stability, improve the pharmacokinetic properties of the drug in vivo, reduce the toxic and side effects of the drug, thereby improving its bioavailability, and effectively improving the compliance of children, elderly patients and patients with dysphagia with drug administration.

[0006] The second object of the present invention is to provide a method for preparing a norfloxacin preparation, which is simple, low-cost and meets the requirements of large-scale production.

[0007] The third object of the present invention is to provide a use of a norfloxacin preparation in the preparation of a broad-spectrum antibacterial drug, wherein the prepared norfloxacin preparation has a long half-life in the body and good stability, improves its pharmacokinetic properties in the body, reduces the toxic and side effects of the drug, and thereby improves its bioavailability.

[0008] In order to achieve the above technical purpose, the present invention provides a norfloxacin preparation, which includes a skeleton sustained-release tablet and a regulating layer coated on the surface thereof; the main drug of the skeleton sustained-release tablet is crystal form X norfloxacin.

[0009] The crystalline form of norfloxacin in the norfloxacin preparation of the present invention is crystalline form X, and its chemical structural formula is as follows:

[0010]

[0011] As a preferred embodiment, the X-ray powder diffraction pattern of the crystalline form X norfloxacin has diffraction peaks at the following 2θ angles: 7.83°±0.2°, 9.88°±0.2°, 11.77°±0.2°, 12.03°±0.2°, 12.39°±0.2°, 18.79°±0.2°, 20.10°±0.2°, 22.80°±0.2°, 23.71°±0.2°, 25.17°±0.2°, 25.45°±0.2°, and 26.39°±0.2°.

[0012] The norfloxacin preparation of the present invention adopts a new crystal form of norfloxacin as the main drug, and has the broad-spectrum antibacterial efficacy of norfloxacin. More importantly, it has low hygroscopicity, which can avoid the hygroscopicity problem during storage to a certain extent. It also has good chemical stability, good antioxidant and high temperature resistance, and can avoid the problem of impurities being easily generated under processing conditions such as high temperature, high humidity and light.

[0013] The norfloxacin preparation of the present invention adopts both skeleton sustained-release technology and membrane controlled-release technology to realize sustained-release coating on the surface, prolong the half-life in vivo, improve the drug stability, improve the pharmacokinetic properties of the drug in vivo, reduce the toxic and side effects of the drug, and thus improve its bioavailability, which can effectively improve the compliance of children, elderly patients, and patients with dysphagia with drug administration.

[0014] As a preferred solution, the skeleton sustained-release tablet comprises auxiliary materials including fillers, skeleton sustained-release materials, adhesives, stabilizers and lubricants. The auxiliary materials are bonded and formed to wrap the main drug (crystalline form X norfloxacin) to achieve the purpose of sustained release and protection of the main drug.

[0015] As a preferred embodiment, the filler includes at least one of partially pregelatinized starch, microcrystalline cellulose, lactose, silicified microcrystalline cellulose, pregelatinized starch, corn starch and sucrose.

[0016] As a preferred solution, the skeleton sustained-release material includes at least one of polyethylene, ethyl cellulose, polyacrylic acid resin, hydroxypropyl methylcellulose, butyl stearate, methacrylic acid copolymer, carboxymethyl cellulose, and carbomer.

[0017] As a preferred solution, the binder includes at least one of hypromellose and povidone.

[0018] As a preferred solution, the stabilizer includes at least one of sodium hydroxide, sodium bicarbonate and potassium hydroxide.

[0019] As a preferred solution, the lubricant includes at least one of colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate and talc.

[0020] As a preferred solution, the skeleton sustained-release tablet comprises the following components in parts by weight: 200 parts of crystal form X norfloxacin; 20-100 parts of filler; 10-50 parts of skeleton sustained-release material; 5-35 parts of binder; 1-3 parts of stabilizer; and 1-10 parts of lubricant.

[0021] As a preferred solution, the regulating layer includes a porogen, an adhesive and a lubricant. The regulating layer includes a porogen, which forms holes under the action of water, so that osmotic pressure is formed inside and outside the regulating layer, and under the action of the osmotic pressure, the main drug is slowly released.

[0022] As a preferred solution, the regulating layer comprises the following components in parts by weight: 1 to 20 parts of a porogen; 10 to 35 parts of a binder; and 5 to 20 parts of a lubricant.

[0023] As a preferred solution, the adhesive includes at least one of hypromellose and povidone.

[0024] As a preferred solution, the lubricant includes at least one of colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate and talc.

[0025] As a preferred solution, the porogen includes at least one of polyethylene glycol, lactose, glucose and sodium chloride.

[0026] The present invention also provides a method for preparing a norfloxacin preparation, which comprises the following steps:

[0027] 1) mixing and tableting the crystal form X norfloxacin, a filler, a skeleton sustained-release material, a binder, a stabilizer and a lubricant to obtain a skeleton sustained-release tablet;

[0028] 2) coating the skeleton sustained-release tablet with a mixed solution containing a pore-forming agent, a binder and a lubricant to obtain the sustained-release tablet.

[0029] As a preferred solution, the mixing is completed by a hopper mixer, and the mixing parameters are: mixing speed 10-15 rpm, mixing time 3-5 min;

[0030] As a preferred solution, the tableting hardness is controlled within the range of 200 to 250 N. During the tableting process, the mixed raw materials are tableted using an elliptical punch with a long diameter of 17 mm and a tablet weight within the range of 95% to 105% of the theoretical tablet weight.

[0031] As a preferred solution, the coating treatment conditions are: air inlet speed of 45-55°C, tablet bed temperature of 32-38°C, peristaltic pump speed of 3-12rpm, atomization pressure of 0.2-0.4MPa, and coating weight gain of 2%-4%.

[0032] The present invention also provides an application of a norfloxacin preparation for preparing a broad-spectrum antibacterial drug.

[0033] The crystal form X norfloxacin of the present invention is prepared by the following method:

[0034] Step 1: dissolving norfloxacin in an alkaline solution to obtain a norfloxacin salt solution; the alkaline solution comprises at least one of a sodium hydroxide solution and a potassium hydroxide solution;

[0035] Step 2: adjusting the pH of the norfloxacin salt solution to a weakly acidic state with an acid solution for precipitation, filtering, and obtaining a solid; the acid solution is at least one of boric acid, hydrochloric acid, sulfuric acid, tartaric acid, phosphoric acid, and citric acid;

[0036] Step 3: Transfer the solid to an organic solvent, first heat it up and reflux it, then cool it down and age it, filter and dry it, and obtain Form X norfloxacin; the organic solvent includes acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, l -At least one of methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-acetone, pyridine, tetrahydrofuran, toluene, and xylene; the heating and reflux time is 1 to 3 hours, and the cooling process is cooled to 0 to 10°C at a cooling rate of 5 to 10°C / h; the aging time is 10 to 20 hours; the drying condition is that the filter cake is dried in a vacuum drying oven at 60 to 70°C and about 0.05MPa for 8 to 10 hours.

[0037] The crystal form X norfloxacin of the present invention can be prepared by using commercial norfloxacin as a raw material, or can be synthesized by existing methods.

[0038] The crystalline form X norfloxacin of the present invention has crystalline properties and preferably has at least 50% crystallinity, more preferably at least 60% crystallinity, still more preferably at least 70% crystallinity and most preferably at least 80% crystallinity. Crystallinity or crystallinity can be assessed by conventional X-ray diffraction techniques.

[0039] Different crystalline or amorphous forms of the same drug may have significant differences in such important pharmaceutical properties as dissolution rate and bioavailability. Likewise, different crystalline or amorphous forms may have different processing properties, such as hygroscopicity, flowability, etc., which may affect their suitability as active drugs for commercial preparations.

[0040] Crystalline or amorphous forms can be identified by a variety of technical means, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, solution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.

[0041] X-ray powder diffraction (XRPD) can detect information such as changes in crystal forms, crystallinity, and crystal structure states, and is a common means of identifying crystal forms. The peak position of the XRPD spectrum depends mainly on the structure of the crystal form, is relatively insensitive to experimental details, and its relative peak height depends on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal form of the present invention is characterized by an XRPD pattern with certain peak positions, which is substantially as shown in the XRPD pattern provided in the accompanying drawings of the present invention. At the same time, the measurement of 2θ of the XRPD spectrum may have experimental errors, and the measurement of 2θ of the XRPD spectrum may be slightly different between different instruments and different samples, so the value of 2θ cannot be regarded as absolute. According to the instrument conditions used in the test of the present invention, there is an error tolerance of ±0.2° for the diffraction peak.

[0042] In the context of the present invention, 2θ values ​​in X-ray powder diffraction patterns are given in degrees (°).

[0043] The term "substantially as shown" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern, or the DSC pattern, or the Raman spectrum pattern, or the infrared spectrum pattern are shown in the pattern.

[0044] When referring to a spectrum and / or data appearing in a graph, a "peak" refers to a feature that can be identified by one skilled in the art and which cannot be attributed to background noise.

[0045] Whenever a number having the value N is disclosed, any number having the value N±0.01, N±0.02, N±0.03, N±0.05, N±0.07, N±0.08, N±0.1, N±0.15, N±0.2, N±1, N±2, N±1.5, N±3, N±4, N±5, N±6, N±7, N±8, N±9, N±10, N±15, N±20 is specifically disclosed, where "±" means plus or minus. Whenever a lower limit, RL, and an upper limit, RU, are disclosed in a numerical range, any value within the disclosed range is specifically disclosed.

[0046] “Relative intensity” refers to the ratio of the intensity of other peaks to the intensity of the first strongest peak among all diffraction peaks in an X-ray powder diffraction pattern (XRPD) when the intensity of the first strongest peak is 100%.

[0047] In the context of the present invention, when or whether the word "about" or "approximately" is used, it means within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, for a person of ordinary skill in the art, the term "about" or "approximately" means within an acceptable standard error range of the mean value.

[0048] The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0049] Compared with the prior art, the technical solution of the present invention has the following beneficial technical effects:

[0050] The norfloxacin preparation provided by the present invention is a film-controlled coating layer wrapped on the surface of a sustained-release skeleton tablet core containing a crystalline form X norfloxacin main drug, the film-controlled coating layer forms a protective effect on the sustained-release skeleton tablet core, delays the collapse speed of the sustained-release skeleton tablet core, and slows down the release speed of the tablet core itself; in the film-controlled coating layer, a porogen forms holes under the action of water, so that osmotic pressure is formed inside and outside the coating layer, and under the action of the osmotic pressure, the main drug is slowly controlled and released; the slow release of the sustained-release skeleton tablet core cooperates with the slow controlled release of the film-controlled coating layer, and the combined synergistic effect effectively forms an effective controlled release of the main drug.

[0051] The norfloxacin preparation provided by the present invention has a sustained-release skeleton tablet core and is coated with a membrane-controlled coating on the surface. The combination of the two can enhance the drug's ability to cope with environmental water, heat and oxygen, while achieving the purpose of slow drug release by combining skeleton-membrane control and achieving a dissolution behavior similar to that of the existing reference preparation.

[0052] The main drug of the norfloxacin preparation provided by the present invention is crystalline form X norfloxacin, which has low hygroscopicity and can avoid the hygroscopicity problem during storage to a certain extent. It also has good chemical stability, good antioxidant and high temperature resistance, and can avoid the problem of easy generation of impurities under processing conditions such as high temperature, high humidity and light.

[0053] The preparation method of the norfloxacin preparation provided by the invention is simple, low in cost and meets the requirements of large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 X-ray powder diffraction pattern of Form X norfloxacin. DETAILED DESCRIPTION

[0055] The technical solution of the present invention is illustrated below by way of example, and the scope of protection requested by the present invention includes but is not limited to the following embodiments.

[0056] Unless otherwise specified, the chemical reagents involved in the following specific embodiments are all conventional commercial analytically pure products.

[0057] Example 1

[0058] Preparation of Form X Norfloxacin:

[0059]

[0060] 1. Add compound 1 (50.00 g, 1 eq), acetic anhydride (137.16 g, 8 eq) and boric acid (15.58 g, 1.5 eq) into a three-necked flask, heat to 100°C, and stir for 2 h.

[0061] 2. The reaction system was cooled to 25°C, water (100 ml) was added, and the temperature was further cooled to 0-10°C. The mixture was stirred for 1 h, filtered, and the filter cake was dried to obtain 63.18 g of compound 2 with a yield of 99.63%.

[0062] 3. Add compound 2 (60.00 g, 1 eq), piperazine (18.20 g, 1.4 eq) and dimethyl sulfoxide (120 ml) into a three-necked flask, raise the temperature to 90°C, and stir for 2 h to obtain a reaction solution containing compound 3.

[0063] 4. The reaction solution containing compound 3 was cooled to 40°C, 10% sodium hydroxide aqueous solution (241.50 g, 4 eq) and activated carbon (3 g, 5%) were added, and the mixture was stirred for 1 h.

[0064] 5. Add water (100 ml) to the system, cool to 0°C, filter, add acetic acid to the filtrate to adjust the pH to 6.7, filter, transfer the filter cake to anhydrous ethanol (300 ml), heat and reflux with stirring for 1 hour, cool to 5°C at a cooling rate of 8°C / h, stop stirring, keep warm for 15 hours, filter, and dry the filter cake in a vacuum drying oven at 65°C, about 0.05MPa for 9 hours.

[0065] 6. The material was collected to obtain Form X norfloxacin with a yield of 41.58 g and a yield of 86.27%.

[0066] Performance test of crystal form X norfloxacin:

[0067] The thermal stability of Form X norfloxacin was tested under high temperature conditions of 100°C with air circulation. The purity of the finished product was 99.83% in the initial test. After being stored in a forced air drying oven, i.e., under high temperature conditions of 100°C with air circulation for 72 hours, the purity still remained at 99.77%. However, after being stored in a forced air drying oven, i.e., under high temperature conditions of 100°C with air circulation for 72 hours, the purity of conventional commercialized norfloxacin increased significantly and the purity decreased to 99.04%.

[0068] The weight change of Form X norfloxacin was observed after storage at room temperature and humidity RH65% for 24 hours:

[0069] Table 1 Hygroscopicity test (RH 65%)

[0070]

[0071] From the hygroscopicity data, the hygroscopicity of Form X norfloxacin is relatively low.

[0072] Table 2 pH = 6.8 dissolution data

[0073]

[0074] The results showed that in a pH = 6.8 medium (pH = 6.8 medium refers to sodium phosphate buffer solution, the specific preparation method is as follows: take 6.9g of sodium dihydrogen phosphate, 0.9g of sodium hydroxide, 5g of sodium dodecyl sulfate, add 800ml of water, ultrasonicate for 30 minutes, adjust the pH value to 6.8 with 2mol / L sodium hydroxide solution, dilute to 1000mL with water, shake well, ultrasonicate, and set aside), the dissolution curves of the X crystal form drug substance and are similar to those of the reference preparation.

[0075] Example 2

[0076] The tablet prescription is as follows Table 3:

[0077] category Excipients Weight Main drug Norfloxacin in Form X 200 copies Fillers Corn starch 50 servings Skeleton sustained release material Carboxymethyl cellulose 50 servings Matrix sustained release tablet binder Hydroxypropyl methylcellulose 35 servings Stabilizer Sodium hydroxide 3 servings Lubricant for matrix sustained-release tablets talcum powder 10 servings Porogen lactose 20 servings Film control layer adhesive Povidone 15 servings Film control layer lubricant talcum powder 10 servings

[0078] The preparation steps are as follows:

[0079] (1) Premixing: Add the main drug and filler, skeleton sustained-release material, skeleton sustained-release tablet binder, stabilizer, and skeleton sustained-release tablet lubricant into a hopper mixer, set the mixing speed to 15 rpm, and the mixing time to 3 min.

[0080] (2) Tablet pressing: Tablets were pressed using an elliptical punch with a long diameter of 17 mm and a tablet weight in the range of 95% to 105% of the theoretical tablet weight. The hardness was controlled in the range of 200 to 250 N during the tablet pressing process.

[0081] (3) Coating: Dissolve the membrane control layer adhesive, pore-forming agent, and membrane control layer lubricant in an ethanol aqueous solution (anhydrous ethanol: water = 80:20 w / w) to prepare a sustained-release coating solution; use the sustained-release coating solution to coat the plain tablets prepared in step (2) to prepare tablets. The specific conditions for the coating treatment are: air inlet speed of 45°C, tablet bed temperature of 32°C, peristaltic pump speed of 12 rpm, atomization pressure of 0.2 MPa, and coating weight gain of 2%.

[0082] Example 3

[0083] The tablet prescription is as follows Table 4:

[0084]

[0085]

[0086] The preparation steps are as follows:

[0087] (1) Premixing: Add the main drug and filler, skeleton sustained-release material, skeleton sustained-release tablet binder, stabilizer, and skeleton sustained-release tablet lubricant into a hopper mixer, set the mixing speed to 15 rpm, and the mixing time to 3 min.

[0088] (2) Tablet pressing: Tablets were pressed using an elliptical punch with a long diameter of 17 mm and a tablet weight in the range of 95% to 105% of the theoretical tablet weight. The hardness was controlled in the range of 200 to 250 N during the tablet pressing process.

[0089] (3) Coating: Dissolve the membrane control layer adhesive, pore-forming agent, and membrane control layer lubricant in an ethanol aqueous solution (anhydrous ethanol: water = 80:20 w / w) to prepare a sustained-release coating solution; use the sustained-release coating solution to coat the plain tablets prepared in step (2) to prepare tablets. The specific conditions for the coating treatment are: air inlet speed of 45°C, tablet bed temperature of 32°C, peristaltic pump speed of 12 rpm, atomization pressure of 0.2 MPa, and coating weight gain of 2%.

[0090] Example 4

[0091] The tablet prescription is as follows Table 5:

[0092]

[0093]

[0094] The preparation steps are as follows:

[0095] (1) Premixing: Add the main drug and filler, skeleton sustained-release material, skeleton sustained-release tablet binder, stabilizer, and skeleton sustained-release tablet lubricant into a hopper mixer, set the mixing speed to 15 rpm, and the mixing time to 3 min.

[0096] (2) Tablet pressing: Tablets were pressed using an elliptical punch with a long diameter of 17 mm and a tablet weight in the range of 95% to 105% of the theoretical tablet weight. The hardness was controlled in the range of 200 to 250 N during the tablet pressing process.

[0097] (3) Coating: Dissolve the membrane control layer adhesive, pore-forming agent, and membrane control layer lubricant in an ethanol aqueous solution (anhydrous ethanol: water = 80:20 w / w) to prepare a sustained-release coating solution; use the sustained-release coating solution to coat the plain tablets prepared in step (2) to prepare tablets. The specific conditions for the coating treatment are: air inlet speed of 45°C, tablet bed temperature of 32°C, peristaltic pump speed of 12 rpm, atomization pressure of 0.2 MPa, and coating weight gain of 2%.

[0098] Comparative Example 1

[0099] Tablets prepared in Example 1 of Chinese Patent CN102940612A.

[0100] Test Case

[0101] The differential scanning calorimetry (DSC) analysis method used in the present invention is: differential scanning calorimetry is performed using a TA Q2000 module with a thermal analysis controller. Data is collected and analyzed using TA Instruments Thermal Solutions software. About 1 to 5 mg of sample is accurately weighed into an aluminum crucible with a lid, and a linear heating device of 10°C / min is used to analyze the sample from room temperature to about 250°C. During use, the DSC chamber is purged with dry nitrogen.

[0102] The X-ray powder diffraction (XRPD) analysis was performed using Cu-Kα radiation and the following characteristic peaks were found: Figure 1 As shown:

[0103] Table 6

[0104]

[0105]

[0106] Note: Only data with strength above 25% are recorded.

[0107] Stability test

[0108] The norfloxacin preparations prepared in Example 2 of the present invention and Comparative Example 1 were subjected to accelerated stability tests according to the testing standards of Part 4 of the Chinese Pharmacopoeia 2015 Edition.

[0109] Specifically: the preparation particles were placed under ①40±2℃, RH=75%±5% and ②high humidity (RH90%±5%) conditions for a period of time, and samples were taken at 0 and 6 months respectively. The stability key indicators were inspected and the test results are shown in Table 5 below.

[0110] Table 7 Accelerated stability test results

[0111]

[0112] The stability test data show that the stability of the product of Example 2 prepared by the present invention is significantly improved compared with that of Comparative Example 1.

[0113] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention is described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A norfloxacin preparation, characterized in that: It comprises a skeleton sustained-release tablet and a regulating layer coated on the surface thereof; the main drug of the skeleton sustained-release tablet is crystal form X norfloxacin.

2. A norfloxacin preparation according to claim 1, characterized in that: The X-ray powder diffraction pattern of the crystalline form X norfloxacin has diffraction peaks at the following 2θ angles: 7.83°±0.2°, 9.88°±0.2°, 11.77°±0.2°, 12.03°±0.2°, 12.39°±0.2°, 18.79°±0.2°, 20.10°±0.2°, 22.80°±0.2°, 23.71°±0.2°, 25.17°±0.2°, 25.45°±0.2°, and 26.39°±0.2°.

3. A norfloxacin preparation according to claim 1 or 2, characterized in that: The skeleton sustained-release tablet comprises auxiliary materials including a filler, a skeleton sustained-release material, a binder, a stabilizer and a lubricant.

4. A norfloxacin preparation according to claim 3, characterized in that: The filler comprises at least one of partially pregelatinized starch, microcrystalline cellulose, lactose, silicified microcrystalline cellulose, pregelatinized starch, corn starch, and sucrose; The skeleton sustained-release material comprises at least one of polyethylene, ethyl cellulose, polyacrylic acid resin, hydroxypropyl methylcellulose, butyl stearate, methacrylic acid copolymer, carboxymethyl cellulose and carbomer; The binder includes at least one of hypromellose and povidone; The stabilizer includes at least one of sodium hydroxide, sodium bicarbonate, and potassium hydroxide; The lubricant includes at least one of colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate and talc.

5. A norfloxacin preparation according to claim 1, characterized in that: The skeleton sustained-release tablet comprises the following components in parts by weight: 200 parts of crystal form X norfloxacin; 20-100 parts of filler; 10-50 parts of skeleton sustained-release material; 5-35 parts of adhesive; 1-3 parts of stabilizer; and 1-10 parts of lubricant.

6. A norfloxacin preparation according to claim 1, 2, 4 or 5, characterized in that: The regulating layer comprises a porogen, a binder and a lubricant.

7. A norfloxacin preparation according to claim 6, characterized in that: The regulating layer comprises the following components by weight: 1 to 20 parts of a porogen; 10 to 35 parts of a binder; and 5 to 20 parts of a lubricant. The binder includes at least one of hydroxypropyl methylcellulose and povidone. The lubricant includes at least one of colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate and talc; the pore-forming agent includes at least one of polyethylene glycol, lactose, glucose and sodium chloride.

8. The method for preparing a norfloxacin preparation according to any one of claims 1 to 7, characterized in that: The following steps are involved: 1) mixing and tableting the crystal form X norfloxacin, a filler, a skeleton sustained-release material, a binder, a stabilizer and a lubricant to obtain a skeleton sustained-release tablet; 2) coating the skeleton sustained-release tablet with a mixed solution containing a pore-forming agent, a binder and a lubricant to obtain the sustained-release tablet.

9. The method for preparing a norfloxacin preparation according to claim 8, characterized in that: The mixing is completed by a hopper mixer, and the mixing parameters are: mixing speed 10-15 rpm, mixing time 3-5 min; The tabletting is controlled to have a hardness range of 200 to 250N; The coating treatment conditions are: air inlet speed of 45-55°C, tablet bed temperature of 32-38°C, peristaltic pump speed of 3-12rpm, atomization pressure of 0.2-0.4MPa, and coating weight gain of 2%-4%.

10. The use of a norfloxacin preparation according to any one of claims 1 to 7, characterized in that: Used to prepare broad-spectrum antibacterial drugs.

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