Levofloxacin tablet and preparation method thereof

Abstract

This application provides a levofloxacin tablet and its preparation method. The levofloxacin tablet comprises 200-800 parts by weight of levofloxacin, 30-60 parts by weight of microcrystalline cellulose, 5-25 parts by weight of pregelatinized starch, 5-20 parts by weight of inulin, 10-40 parts by weight of disintegrant, 10-40 parts by weight of binder, and 5-20 parts by weight of lubricant. The levofloxacin tablet of this invention has moderate hardness, fast disintegration rate, high dissolution rate, and can be stored stably for a long time. Its preparation method is simple, convenient to operate, and has low production cost, making it suitable for industrial production.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical technology, and in particular to a levofloxacin tablet and its preparation method. Background Technology

[0002] Levofloxacin, CAS No.: 100986-85-4, molecular formula: C18H20FN3O4·1 / 2(H2O), chemical name: (-)-(S)-3-methyl-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid hemihydrate. Its structural formula is as follows: Figure 1 :

[0003] Levofloxacin is the levorotatory isomer of the third-generation quinolone drug ofloxacin. It has strong antibacterial activity, approximately twice that of ofloxacin. It also possesses broad-spectrum antibacterial activity, exhibiting strong antibacterial activity against most Enterobacteriaceae, such as Escherichia coli, Klebsiella spp., Proteus spp., Salmonella spp., Shigella spp., and Gram-negative bacteria like Haemophilus influenzae, Legionella pneumophila, and Neisseria gonorrhoeae. It also has antibacterial activity against Gram-positive bacteria such as Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes, as well as Mycoplasma pneumoniae and Chlamydia pneumoniae. However, its activity against anaerobic bacteria and Enterococci is relatively poor.

[0004] Its mechanism of action involves inhibiting the activity of DNA topoisomerase IV and DNA gyrase (topoisomerase II), which are required for bacterial DNA replication, transcription, repair, and recombination, thereby preventing bacterial DNA synthesis and replication and leading to bacterial death. Levofloxacin was first marketed in Japan in 1994 and has achieved good efficacy in treating respiratory tract infections, genitourinary tract infections, and skin and soft tissue infections. Its efficacy and bacterial clearance rate for treating acute and chronic lower respiratory tract infections reach 80%–100%, with high clearance rates against Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and Streptococcus pneumoniae, but poorer clearance against Pseudomonas aeruginosa. Its efficacy and bacterial clearance rate for complicated and uncomplicated urinary tract infections are also 80%–100%. Its efficacy rate for treating skin and soft tissue infections is 80%–91%, with a clearance rate of nearly 90% against methicillin-sensitive Staphylococcus aureus. Its efficacy rate for treating gynecological, ear, nose, and throat infections is also around 90%.

[0005] Levofloxacin possesses excellent in vitro activity, exhibits fewer toxic side effects and greater safety compared to ofloxacin, and boasts favorable pharmacokinetic properties, thus remaining widely used clinically. Currently, the main formulations are oral and injectable. Injectable administration has a higher incidence of adverse reactions than oral administration, particularly allergic reactions and central nervous system adverse reactions. Therefore, oral tablets remain the preferred dosage form. Patent CN 111110641A discloses a levofloxacin tablet containing levofloxacin, fillers, lubricants, disintegrants, binders, and oleic acid, resulting in a tablet with good product stability and high dissolution rate even after accelerated dissolution testing. However, levofloxacin has low hardness and is easily broken after compression. Adjusting the amount or type of binder or filler may cause slow disintegration and dissolution problems. Therefore, obtaining tablets with moderate hardness, fast disintegration rate, and high dissolution rate is a technical problem that needs to be solved in this field. Summary of the Invention

[0006] The purpose of this invention is to provide a levofloxacin tablet composition that has moderate hardness, fast disintegration rate, high dissolution rate, and can be stored stably for a long time.

[0007] The present invention further provides a method for preparing a levofloxacin tablet composition. This preparation method is simple, easy to operate, and has low production cost, making it suitable for large-scale industrial production.

[0008] To achieve the above objectives, the technical solution provided by this invention is as follows:

[0009] A levofloxacin tablet composition comprising:

[0010] Levofloxacin 200-800 parts by weight;

[0011] 30-60 parts by weight of microcrystalline cellulose;

[0012] 5-25 parts by weight of pregelatinized starch;

[0013] Inulin 5-20 parts by weight;

[0014] Disintegrant 10-40 parts by weight;

[0015] 10-40 parts by weight of adhesive;

[0016] Lubricant 5-20 parts by weight.

[0017] The levofloxacin tablet composition comprises:

[0018] Levofloxacin 300-600 parts by weight;

[0019] 40-50 parts by weight of microcrystalline cellulose;

[0020] 10-20 parts by weight of pregelatinized starch;

[0021] 5-10 parts by weight of inulin;

[0022] Disintegrant 20-30 parts by weight;

[0023] 20-30 parts by weight of adhesive;

[0024] Lubricant 5-15 parts by weight.

[0025] The levofloxacin tablet composition comprises:

[0026] Levofloxacin 500 parts by weight;

[0027] 45 parts by weight of microcrystalline cellulose;

[0028] 15 parts by weight of pregelatinized starch;

[0029] 8 parts by weight of inulin;

[0030] 25 parts by weight of disintegrant;

[0031] 25 parts by weight of adhesive;

[0032] 10 parts by weight of lubricant.

[0033] In some embodiments of the present invention, the particle size distribution of the levofloxacin is D90≤60μm, D50≤20μm, and D10≤5μm.

[0034] In some embodiments of the present invention, the disintegrant is one or more of sodium carboxymethyl starch, crospovidone, and crospovidone, preferably crospovidone.

[0035] In some embodiments of the present invention, the adhesive is one or more of hydroxypropyl cellulose, glyceryl tristearate, and methyl methacrylate, preferably hydroxypropyl cellulose.

[0036] In some embodiments of the present invention, the lubricant is one or more of micronized silica gel, talc, magnesium stearate, and sodium stearate fumarate, preferably sodium stearate fumarate.

[0037] Furthermore, the present invention also provides a method for preparing a levofloxacin tablet composition, comprising the following steps:

[0038] (1) Take microcrystalline cellulose and pass it through a 40-mesh sieve. Crush levofloxacin and disintegrant using a pulverizing device and then pass them through a 120-mesh sieve. Add levofloxacin, microcrystalline cellulose, inulin, pregelatinized starch and disintegrant to a high-efficiency wet granulator in the specified weight proportions and mix well for later use.

[0039] (2) Add the binder according to the weight parts to purified water to prepare a 10%-20% aqueous solution, add it to the high-efficiency wet granulation machine, and stir and mix it evenly;

[0040] (3) Granulate the mixture obtained in step (2) to obtain wet granules, dry the wet granules, and then sieve them to form semi-dry granules.

[0041] (4) The material obtained in step (3) is dried at a temperature below 60°C, sieved and granulated to obtain a mixture;

[0042] (5) Add the lubricant according to the weight proportions to the mixture obtained in step (4) and compress it into tablets.

[0043] In the above preparation method, the levofloxacin is pulverized by a pulverizing device and then sieved. The particle size distribution of the pulverized levofloxacin is D90≤60μm, D50≤20μm, and D10≤5μm.

[0044] The disintegrant is pulverized using a pulverizing device and then sieved. The particle size distribution of the pulverized disintegrant is D90≤65μm, D50≤30μm, and D10≤10μm.

[0045] In some embodiments of the present invention, the method for preparing the levofloxacin composition may further include a coating step.

[0046] The coating step is as follows: after preparing the film coating premix into an aqueous solution with a mass fraction of 10-15%, the tablets obtained in step (5) are added to the coating pan for coating.

[0047] The film premix can be a common coating premix in the art, such as ordinary coating, gastrointestinal coating, enteric coating, etc.

[0048] Compared with the prior art, the present invention has the following advantages: the tablet composition of the present invention has moderate hardness, fast disintegration rate, high dissolution rate, and can be stored stably for a long time. Its preparation method is simple, easy to operate, and has low production cost, making it suitable for industrial production.

[0049] To make the above-mentioned objectives, features and advantages of this application more apparent and understandable, preferred embodiments are described below in detail with reference to the accompanying drawings. Attached Figure Description

[0050] To more clearly illustrate the technical solutions of the embodiments of this application, the accompanying drawings used in the embodiments of this application will be briefly introduced below. It should be understood that the following drawings only show some embodiments of this application and should not be regarded as a limitation of the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0051] Figure 1 This is the structural formula for levofloxacin.

[0052] Figure 2 This is a chromatogram determined by high performance liquid chromatography. Detailed Implementation

[0053] The technical solutions in the embodiments of this application will now be described with reference to the accompanying drawings.

[0054] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0055] Unless otherwise defined herein, the scientific and technical terms used in conjunction with this invention shall have the meanings commonly understood by one of ordinary skill in the art. The meaning and scope of terms shall be clear; however, in any case of potential ambiguity, the definitions provided herein shall prevail over any dictionary or external definitions. In this application, unless otherwise stated, the use of the term "comprising" and other forms is non-limiting.

[0056] In some embodiments of the present invention, the “levofloxacin” is levofloxacin hemihydrate, and its weight parts are calculated as levofloxacin.

[0057] In some embodiments of the present invention, the "pregelatinized starch" is modified starch, which refers to starch obtained by partially or completely breaking down starch granules using chemical or mechanical methods. A common preparation method is the heating method, and commercially available pregelatinized starch can be obtained through market purchases.

[0058] In some embodiments of the present invention, the levofloxacin tablets prepared by this method can be coated in a manner well known to those skilled in the art to further prepare them into coated tablets.

[0059] The coating material can be a common coating premix in the art, such as gastric-soluble coating, enteric-soluble coating, etc., and the coating premix can be obtained by purchasing from the market.

[0060] Test methods

[0061] [Hardness Measurement] The hardness was measured using a YD-2 hardness tester (Tianjin Optical Instrument Factory).

[0062] [Dissolution Test] Take 6 tablets of the drug and perform the dissolution and release test according to the method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method 1). Use 900 ml of hydrochloric acid solution (9→1000) as the dissolution medium. The rotation speed is 100 rpm. After 30 minutes, take an appropriate amount of solution, filter it, accurately measure an appropriate amount of the filtrate, and quantitatively dilute it with the dissolution medium. Measure the absorbance at a wavelength of 294 nm using ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0401). Calculate the amount dissolved per tablet using the external standard method. Plot a dissolution curve table according to the amount dissolved at each point.

[0063] [Disintegration Time Determination] Take 6 tablets of the drug and place them in the disintegration apparatus. Add 900ml of purified water at 37℃, start the disintegration apparatus and check the disintegration time. The actual disintegration time is shown in Table 1.

[0064] [Determination of Related Substances] Accurately weigh an appropriate amount of the fine powder of this product, dissolve it in 0.1 mol / L hydrochloric acid solution, and quantitatively dilute it to prepare a solution containing approximately 1.0 mg of levofloxacin (calculated as C18H20FN3O4) per ml. Filter the solution and use the filtrate as the test solution. Accurately measure an appropriate amount and quantitatively dilute it with 0.1 mol / L hydrochloric acid solution to prepare a solution containing approximately 2 μg per ml as the control solution. Accurately measure an appropriate amount of the control solution and quantitatively dilute it with 0.1 mol / L hydrochloric acid solution to prepare a solution containing approximately 0.2 μg per ml as the sensitivity solution. Determine the chromatogram according to the high performance liquid chromatography method (Chinese Pharmacopoeia 2015 Edition, Part IV, General Chapter 0512), using 294 nm as the detection wavelength, and record the chromatogram. Figure 2 As shown.

[0065] System suitability spectrum: Impurity B, impurity C, impurity D, impurity H, impurity E, levofloxacin, ciprofloxacin and impurity F eluted in sequence.

[0066] The present invention will be further illustrated below with specific embodiments. However, it should be understood that these embodiments are merely for the purpose of more detailed illustration and should not be construed as limiting the present invention in any way.

[0067] The main reagents and instruments used in the embodiments of this invention are as follows:

[0068] Table 1. Reagent and Instrument Information

[0069]

[0070] Example 1: Filler Screening Experiment

[0071] (1) Take microcrystalline cellulose and pass it through a 40-mesh sieve. Use a pulverizing device to pulverize levofloxacin and cross-linked polyvinylpyrrolidone and then pass it through a 120-mesh sieve. Adjust the particle size distribution of levofloxacin after pulverization to D90≤60μm, D50≤20μm, and D10≤5μm. Add 500 parts of levofloxacin, 68 parts of different combinations of excipients, and 25 parts of cross-linked polyvinylpyrrolidone to a high-efficiency wet granulator and mix them evenly for later use.

[0072] (2) Add 25 parts of hydroxypropyl cellulose to purified water to prepare a 10% aqueous solution, add it to a high-efficiency wet granulation machine, and stir and mix well.

[0073] (3) Granulate the mixture obtained in step (2) to obtain wet granules, dry the wet granules for 1.5 hours, and then sieve them to form semi-dry granules.

[0074] (4) Dry the material obtained in step (3) at 50°C for 1 hour, sieve and granulate to obtain a mixture;

[0075] (5) Add 10 parts of sodium stearate fumarate to the mixture obtained in step (4) and compress into tablets.

[0076] The different tablets obtained above were tested for hardness, dissolution rate and disintegration time. The components of different tablets and the test results are shown in Table 2.

[0077] Table 2. Different tablet components and test results

[0078]

[0079] In summary, the results above show that tablets made with the filler combination (combination 1) of this invention are easy to compress, have moderate hardness, disintegrate quickly, and have the best dissolution.

[0080] Example 2: Tablet Composition Ratio Screening Experiment

[0081] (1) Take microcrystalline cellulose and pass it through a 40-mesh sieve. Then, pulverize levofloxacin and crospovidone using a pulverizing device and pass them through a 120-mesh sieve. Adjust the particle size distribution of levofloxacin after pulverization to D90≤60μm, D50≤20μm, and D10≤5μm. Add a certain weight of levofloxacin, pregelatinized starch, microcrystalline cellulose, inulin, and crospovidone to a high-efficiency wet granulator in sequence and mix them evenly for later use.

[0082] (2) Add a certain amount of hydroxypropyl cellulose to purified water to prepare a 10% aqueous solution, add it to a high-efficiency wet granulation machine, and stir and mix it evenly.

[0083] (3) Granulate the mixture obtained in step (2) to obtain wet granules, dry the wet granules for 1.5 hours, and then sieve them to form semi-dry granules.

[0084] (4) Dry the material obtained in step (3) at 50°C for 1 hour, sieve and granulate to obtain a mixture;

[0085] (5) Add a certain amount of sodium stearate fumarate to the mixture obtained in step (4) and compress it into tablets.

[0086] The different tablets obtained above were tested for hardness, dissolution rate, and disintegration time. The component ratios of different tablets and the test results are shown in Table 3.

[0087] Table 3. Different tablet ratios and test results

[0088]

[0089] In summary, the results show that when the content of levofloxacin is 200-800 parts by weight, microcrystalline cellulose is 30-60 parts by weight, pregelatinized starch is 5-25 parts by weight, inulin is 5-20 parts by weight, disintegrant is 10-40 parts by weight, binder is 10-40 parts by weight, and lubricant is 5-20 parts by weight, the tablets prepared by this invention have a hardness > 5 kg·f, a disintegration time ≤ 10 min, and a dissolution rate of over 90%. Specifically, when the content of levofloxacin is 300-600 parts by weight, microcrystalline cellulose is 40-50 parts by weight, pregelatinized starch is 10-20 parts by weight, and inulin is 5-10 parts by weight, the tablets prepared by this invention have a hardness > 5 kg·f, a disintegration time ≤ 10 min, and a dissolution rate of over 90%. When the weight ratios of disintegrant, binder, and lubricant are 20-30 parts by weight, the resulting tablets have a hardness of ≥8 and ≤10 kgf, moderate hardness, disintegration time of less than 8 minutes, rapid disintegration rate, and dissolution rate of over 95%, meeting production requirements. Among these, the best results are achieved when the weight ratios of levofloxacin (500 parts by weight), microcrystalline cellulose (45 parts by weight), pregelatinized starch (15 parts by weight), inulin (8 parts by weight), disintegrant (25 parts by weight), binder (25 parts by weight), and lubricant (10 parts by weight) are: moderate hardness, rapid disintegration rate, and high dissolution rate.

[0090] Example 3: Comparison of Levofloxacin Particle Sizes

[0091] Levofloxacin raw material was pulverized using a pulverizing device to prepare raw materials with different particle size distributions. Then, according to the optimal ratio and preparation method of combination 6 in Example 2, different tablets were prepared, and their dissolution was tested. The test results of different particle sizes and dissolution are shown in Table 4.

[0092] Table 4. Results of particle size distribution and dissolution rate testing of levofloxacin tablets.

[0093]

[0094] In summary, the results show that when the particle size distribution of levofloxacin is controlled within the range of D90≤60μm, D50≤20μm, and D10≤5μm, the dissolution rate of the formulation product is ≥98%, resulting in the best effect.

[0095] Example 4: Comparison of different granulation methods

[0096] A set of sample tablets were prepared according to the proportion of combination 6 in Example 2, the preparation method and the optimal particle size in Example 3. Then, the semi-dry granulation process in step (3) was changed to the conventional granulation process (i.e. granulation, direct drying and sizing) to prepare a set of sample tablets. The performance of the two sets of processes is compared as shown in Table 5.

[0097] Table 5 Comparison of different granulation processes for levofloxacin tablets

[0098]

[0099]

[0100] In summary, the results show that when levofloxacin tablets are granulated using conventional processes (i.e., granulation, direct drying, and sizing), the intermediate particles have poor flowability and compressibility, and the weight variation of the tablets is difficult to control. The semi-dry granulation process is the most effective.

[0101] Example 5

[0102] Tablets prepared using the proportions of combination 6 in Example 2 and the semi-dry granulation method in Example 4 were subjected to an accelerated testing period of 6 months to simulate the worst storage conditions for levofloxacin tablets after they were marketed. Related substances and dissolution rates were measured, and the results are shown in Table 6. The accelerated testing conditions were: temperature 40℃±2℃ / humidity 75% RH±5% RH.

[0103] Table 6. Results of accelerated dissolution and related substance detection of levofloxacin tablets.

[0104]

[0105] Through the above experiments, the inventors were surprised to find that the levofloxacin tablets obtained by the pharmaceutical composition and preparation process described in this invention can maintain high stability in a high temperature and high humidity environment of 40℃±2℃ / 75%RH±5%RH (simulating the worst storage conditions for levofloxacin tablets after they are marketed), with almost no change in drug dissolution, minimal drug degradation, and low impurity content.

[0106] The above description is merely an embodiment of this application and is not intended to limit the scope of protection of this application. Various modifications and variations can be made to this application by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the scope of protection of this application.

Claims

1. A levofloxacin tablet composition characterized in that, The composition comprises the following components: Levofloxacin 200-800 parts by weight; Microcrystalline cellulose 30-60 parts by weight; Pre-gelatinized starch 5-25 parts by weight; Chicory powder 5-20 parts by weight; Disintegrant 10-40 parts by weight; Binder 10-40 parts by weight; Lubricant 5-20 parts by weight; The disintegrant is cross-linked povidone, the binder is hydroxypropyl cellulose, and the lubricant is sodium stearyl fumarate.

2. The levofloxacin tablet composition according to claim 1, characterized by, The levofloxacin tablet composition comprises the following components: Levofloxacin 300-600 parts by weight; Microcrystalline cellulose 40-50 parts by weight; Pre-gelatinized starch 10-20 parts by weight; Chicory powder 5-10 parts by weight; Disintegrant 20-30 parts by weight; Binder 20-30 parts by weight; Lubricant 5-15 parts by weight; The disintegrant is cross-linked povidone, the binder is hydroxypropyl cellulose, and the lubricant is sodium stearyl fumarate.

3. The levofloxacin tablet composition according to claim 2, characterized by, The levofloxacin tablet composition comprises the following components: Levofloxacin 500 parts by weight; Microcrystalline cellulose 45 parts by weight; Pre-gelatinized starch 15 parts by weight; Chicory powder 8 parts by weight; Disintegrant 25 parts by weight; Binder 25 parts by weight; Lubricant 10 parts by weight; The disintegrant is cross-linked povidone, the binder is hydroxypropyl cellulose, and the lubricant is sodium stearyl fumarate.

4. The levofloxacin tablet composition according to any one of claims 1 to 3, wherein The particle size distribution of the levofloxacin is D90≤60μm, D50≤20μm, and D10≤5μm.

5. A process for the preparation of the levofloxacin tablet composition according to any one of claims 1 to 4, characterized in that, The method comprises the following steps: (1) Sieve the microcrystalline cellulose through a 40-mesh sieve, and pulverize the levofloxacin and disintegrant using a pulverizing device and then sieve them through a 120-mesh sieve; add the levofloxacin, microcrystalline cellulose, chicory powder, pre-gelatinized starch, and disintegrant in sequence according to the weight parts, and mix them uniformly in a high-efficiency wet granulator for standby; (2) Add the binder according to the weight parts into purified water to prepare a 10%-20% aqueous solution, and then add the aqueous solution into the aforementioned high-efficiency wet granulator, and mix them uniformly under stirring; (3) Granulate the mixture obtained in step (2) to obtain wet granules, dry the wet granules, and sieve the semi-dry whole granules; (4) Dry the material obtained in step (3) at a temperature below 60℃, sieve the whole granules, and obtain a mixture; (5) Add the lubricant according to the weight parts into the mixture obtained in step (4), and press the mixture into tablets.

6. The preparation method according to claim 5, characterized in that, The particle size distribution of the pulverized disintegrant is D90≤65μm, D50≤30μm, and D10≤10μm.

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