Levofloxacin tablet and preparation method thereof

Abstract

The invention discloses a levofloxacin tablet and a preparation method thereof. The levofloxacin tablet is prepared from the following components in parts by weight: 500 parts of levofloxacin, 10-30 parts of microcrystalline cellulose, 1-5 parts of hydroxypropyl methyl cellulose, 1-5 parts of polacrilin potassium, 1-2 parts of sodium stearyl fumarate, 0.05-0.1 part of iso-tridecanol polyoxyethylene ether and a proper amount of purified water. The preparation process is wet granulation and comprises the following steps: granulation, drying I, size stabilization, drying II, total mixing and tabletting. The levofloxacin tablet disclosed by the invention is simple in prescription, stable in process, easy to operate and stable in product quality, solves the trend that the in-vitro dissolution of the levofloxacin tablet is reduced during the stability period, solves the problem of ethanol residue in the levofloxacin tablet, and improves the curative effect and safety of the medicine.

Description

Technical Field

[0001] The invention belongs to the new technical field of drug manufacturing, and specifically relates to a levofloxacin tablet and a preparation method thereof. Background Art

[0002] Levofloxacin is a fluoroquinolone drug developed by Daiichi Pharmaceutical Co., Ltd. of Japan. It is the left-handed optically active L-isomer of ofloxacin. Its antibacterial activity is twice that of ofloxacin and it is a spectrum antibiotic. Its mechanism of action is to inhibit DNA gyrase activity. It has strong antibacterial activity against both Gram-positive and Gram-negative bacteria. After oral administration, levofloxacin is well absorbed and has high bioavailability. It can quickly and widely penetrate into various tissues and body fluids of the body. It has good antibacterial effects on Escherichia coli, Pseudomonas aeruginosa, Haemophilus influenzae, some methicillin-sensitive Staphylococci, Streptococcus pneumoniae, and hemolytic Streptococci.

[0003] The chemical name of levofloxacin is (S)-(-)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazine)-7-oxo-7H-pyridinium[1,2,3-de]-[1,4]benzoxazine-6-carboxylic acid. Its main existing form is levofloxacin hemihydrate, and its structural formula is as follows:

[0004]

[0005] Levofloxacin is an off-white to light yellow crystalline powder, odorless. This product is slightly soluble in water, very slightly soluble in ethanol, insoluble in ether, easily soluble in glacial acetic acid, and slightly soluble in 0.1 mol / L hydrochloric acid solution. Levofloxacin is rapidly and completely absorbed after oral administration, and the plasma drug concentration usually reaches a peak 1 to 2 hours after oral administration. The absolute bioavailability of levofloxacin 500mg tablets and 750mg tablets is about 99%, indicating that levofloxacin is completely absorbed after oral administration. When healthy volunteers were given a single intravenous dose of 500mg and the infusion time was greater than 60 minutes, the Mean±SD of the peak plasma concentration was 6.2±1.0μg / ml; when the dose was 750mg and the infusion time was greater than 90 minutes, the Mean±SD of the peak plasma concentration was 11.5±4.0μg / ml.

[0006] Chinese patent CN104288112A discloses a levofloxacin hydrochloride tablet, which uses talc and stearic acid added in a specific ratio. The tablet exhibits excellent quality controllability in a large-scale production test of levofloxacin hydrochloride tablets. The prepared levofloxacin hydrochloride tablet has good safety and effectiveness, but fails to solve the problem that the levofloxacin hydrochloride tablet is easy to aggregate during long-term storage, and the solubility tends to decrease.

[0007] Chinese patent CN 111110641A discloses a levofloxacin tablet composition and a preparation method thereof, which adopts a new composition method to make the product stable and completely dissolve. However, ethanol is used as a solvent to prepare an adhesive during the granulation process, which will cause ethanol to be wrapped in the granules and leave a certain degree of residue. Since this product is an antibiotic drug, it is clinically required that it cannot be exposed to ethanol during administration, and its ethanol residue may cause safety problems for patients.

[0008] Therefore, developing a levofloxacin tablet with a simple prescription, stable process, easy operation, stable in vitro dissolution and no ethanol residue is a current technical difficulty. Summary of the invention

[0009] The purpose of the present invention is to provide a levofloxacin tablet with a simple prescription and no ethanol residue, and the drug has good in vitro dissolution stability during the stability period.

[0010] Another object of the present invention is to provide a method for preparing the levofloxacin tablets.

[0011] A levofloxacin tablet comprises the following components by weight: 500 parts of levofloxacin, 10-30 parts of microcrystalline cellulose, 1-5 parts of hydroxypropyl methylcellulose, 1-5 parts of polyclinic potassium, 1-2 parts of sodium stearyl fumarate, 0.05-0.1 parts of isomeric tridecanol polyoxyethylene ether and an appropriate amount of purified water.

[0012] The levofloxacin is levofloxacin hemihydrate.

[0013] The weight ratio of hydroxypropyl methylcellulose to polyclinic potassium in the components is 1:1 to 1:1.2.

[0014] The amount of isomeric tridecanol polyoxyethylene ether in the components is 0.05 to 0.1 parts.

[0015] The method for preparing a levofloxacin tablet comprises:

[0016] (1) placing the prescribed amount of levofloxacin, microcrystalline cellulose, hydroxypropyl methylcellulose, and polyclidinium potassium in a wet granulator, starting stirring, and fully mixing to form a premixed powder;

[0017] (2) adding a prescribed amount of isomeric tridecanol polyoxyethylene ether to an appropriate amount of purified water to form a solution;

[0018] (3) while stirring and cutting, spraying the solution of step (2) onto the premixed powder prepared in step (1) to obtain wet granules;

[0019] (4) placing the wet granules in a fluidized bed for drying I;

[0020] (5) granulating the granules after drying I;

[0021] (6) Drying the granulated particles II;

[0022] (7) mixing the prescribed amount of sodium stearyl fumarate with the granules;

[0023] (8) The granules are compressed into tablets to obtain levofloxacin tablets.

[0024] The method for preparing levofloxacin tablets is characterized in that: in the drying step (4), the moisture content of the particles in the drying step I is controlled to be 8-15%.

[0025] The method for preparing levofloxacin tablets is characterized in that: in the step (6), the moisture content of the dried II particles is controlled to be ≤3%.

[0026] The method for preparing levofloxacin tablets is characterized in that: in the step (8), the tableting hardness is controlled to be 60N to 150N.

[0027] The method for preparing levofloxacin tablets is characterized in that it further comprises coating the levofloxacin tablets obtained in step (8) with a coating agent to obtain coated tablets.

[0028] Compared with the prior art, the present invention has the following advantages and positive effects:

[0029] (1) The present invention optimizes the types and dosage ratios of auxiliary materials, and realizes that a product with complete dissolution and stable quality can be prepared by using a simple prescription composition and purified water as a wetting agent, thereby reducing production costs and eliminating the risk of ethanol residue in the product. (2) The present invention can effectively remove the moisture added in the preparation process of levofloxacin tablets by adding a granulation process between the two drying processes, thereby solving the problem of reduced in vitro dissolution of levofloxacin tablets during storage. In addition, the process is stable and easy to operate, and can be used for industrial-scale production. DETAILED DESCRIPTION

[0030] The present invention is further explained or illustrated by the following examples, but the examples provided should not be construed as limiting the scope of protection of the present invention.

[0031] The experimental methods used in the embodiments of the present invention are all based on the quality standards of levofloxacin tablets in the 2020 edition of the Chinese Pharmacopoeia, and are all conventional methods.

[0032] Example 1 Levofloxacin tablets and preparation method thereof

[0033] 500 parts of levofloxacin, 30 parts of microcrystalline cellulose, 3 parts of hydroxypropyl methylcellulose, 3 parts of polyclinic potassium, 2 parts of sodium stearyl fumarate, 0.05 parts of isomeric tridecyl alcohol polyoxyethylene ether and an appropriate amount of purified water.

[0034] Preparation method: Levofloxacin, microcrystalline cellulose, hydroxypropyl methylcellulose and polyclidinium potassium are placed in a wet granulator, mixed, and then the prepared isomeric tridecanol polyoxyethylene ether solution is sprayed into the material while stirring and cutting are turned on to obtain wet granules, which are placed in a fluidized bed for drying I to control the moisture content of the granules to 8%, the granules are sized, and dried II to control the moisture content of the granules to ≤3%, sodium stearyl fumarate is mixed with the granules, tabletted to obtain levofloxacin tablets, and coated to obtain coated tablets.

[0035] Example 2 Levofloxacin tablets and preparation method thereof

[0036] A levofloxacin tablet comprises the following components by weight: 500 parts of levofloxacin, 30 parts of microcrystalline cellulose, 3 parts of hydroxypropyl methylcellulose, 3.6 parts of polyclinic potassium, 2 parts of sodium stearyl fumarate, 0.05 parts of isomeric tridecanol polyoxyethylene ether and an appropriate amount of purified water.

[0037] Preparation method: Same as Example 1

[0038] Example 3 Levofloxacin tablets and preparation method thereof

[0039] A levofloxacin tablet, the weight of each component includes: 500 parts of levofloxacin, 10 parts of microcrystalline cellulose, 1 part of hydroxypropyl methylcellulose, 1 part of polyclinic potassium, 1 part of sodium stearyl fumarate, 0.1 part of isomeric tridecanol polyoxyethylene ether And purified water.

[0040] Preparation method: Except for drying I, the moisture content of the particles was controlled to 15%, and the rest was the same as in Example 1.

[0041] Example 4 Levofloxacin tablets and preparation method thereof

[0042] A levofloxacin tablet, the weight of each component includes: 500 parts of levofloxacin, 30 parts of microcrystalline cellulose, 4.5 parts of hydroxypropyl methylcellulose, 5 parts of polyclinic potassium, 2 parts of sodium stearyl fumarate, and 0.1 parts of isomeric tridecanol polyoxyethylene ether And purified water.

[0043] Preparation method: Except for drying I, the moisture content of the particles was controlled to 15%, and the rest was the same as in Example 1.

[0044] Example 5 Levofloxacin tablets and preparation method thereof

[0045] A levofloxacin tablet, the weight of each component includes: 500 parts of levofloxacin, 30 parts of microcrystalline cellulose, 3 parts of hydroxypropyl methylcellulose, 3 parts of polyclinic potassium, 2 parts of sodium stearyl fumarate, and 0.1 parts of isomeric tridecanol polyoxyethylene ether And purified water.

[0046] Preparation method: Same as Example 1.

[0047] Comparative Example 1

[0048] A levofloxacin tablet, the weight of each component includes: 500 parts of levofloxacin, 30 parts of microcrystalline cellulose, 3 parts of hydroxypropyl methylcellulose, 4 parts of polyclinic potassium, 2 parts of sodium stearyl fumarate, and 0.05 parts of isomeric tridecanol polyoxyethylene ether And purified water.

[0049] Preparation method: Same as Example 1

[0050] Comparative Example 2

[0051] A levofloxacin tablet, the weight of each component includes: 500 parts of levofloxacin, 30 parts of microcrystalline cellulose, 3 parts of hydroxypropyl methylcellulose, 3.6 parts of polyclinic potassium, 2 parts of sodium stearyl fumarate, 0.05 parts of isomeric tridecanol polyoxyethylene ether and an appropriate amount of purified water

[0052] Preparation method: The whole granulation process is removed, and the moisture content of drying II is controlled to be ≥ 3%, and the rest is the same as in Example 1.

[0053] Comparative Example 3

[0054] A levofloxacin tablet, the weight of each component includes: 500 parts of levofloxacin, 30 parts of microcrystalline cellulose, 3 parts of hydroxypropyl methylcellulose, 3.6 parts of polyclinic potassium, 2 parts of sodium stearyl fumarate, 0.12 parts of isomeric tridecanol polyoxyethylene ether and an appropriate amount of purified water

[0055] Preparation method: Same as Example 1.

[0056] Comparative Example 4

[0057] A levofloxacin tablet, the weight of each component includes: 500 parts of levofloxacin, 30 parts of microcrystalline cellulose, 3.1 parts of hydroxypropyl methylcellulose, 3 parts of polyclinic potassium, 2 parts of sodium stearyl fumarate, 0.1 part of isomeric tridecanol polyoxyethylene ether and an appropriate amount of purified water

[0058] Preparation method: Same as Example 1.

[0059] Comparative Example 5

[0060] A levofloxacin tablet, the weight of each component includes: 500 parts of levofloxacin, 30 parts of microcrystalline cellulose, 3.1 parts of hydroxypropyl methylcellulose, 3 parts of polyclinic potassium, 2 parts of sodium stearyl fumarate, 0.04 parts of isomeric tridecanol polyoxyethylene ether and an appropriate amount of purified water

[0061] Preparation method: Same as Example 1.

[0062] Test Example 1

[0063] The levofloxacin tablets prepared in the embodiment and the comparative example were taken for accelerated (40°C, RH 75±5%) stability retention samples, and the properties, related substances, solubility and content were tested according to the quality standard of levofloxacin tablets in the 2020 edition of the "Chinese Pharmacopoeia". The results are shown in Table 1.

[0064] Table 1 Accelerated conditions levofloxacin tablets test results

[0065] in conclusion: (1) The weight ratio of hydroxypropyl methylcellulose to polyclinic potassium in the formulation of levofloxacin tablets was not 1:1 to 1:1.2, and the dissolution rate of the prepared levofloxacin tablets failed to meet the qualified standards; (2) The content of isomeric tridecanol polyoxyethylene ether added to the levofloxacin tablets was not within the range of 0.05% to 0.1%, and the dissolution rate of the prepared levofloxacin tablets could not meet the qualified standard; (3) In the preparation process of levofloxacin tablets according to this prescription, if the granulation process is removed between drying I and drying II, or if the moisture content in drying II cannot be strictly controlled to be ≤3%, the related substances of the product will increase to a certain extent under accelerated conditions, the dissolution rate will not meet the requirements, and there will be a certain tendency for the dissolution to slow down during the sample retention process. In summary, the levofloxacin tablets of the present invention need to be prepared according to the prescribed dosage and preparation process to obtain a product whose dissolution and other quality indicators meet the requirements.

[0066] Test Example 2

[0067] The stability samples of Example 1 were retained for 24 months under long-term and intermediate conditions, and all met the standards. The results are shown in Table 2.

[0068] The test results of samples under long-term conditions (25°C, RH60±5%) and intermediate conditions (30°C, RH65±5%) are shown in the following table:

[0069] Conclusion: According to the prescription ratio and preparation process parameters of the present invention, the key quality attributes of the obtained product can meet the requirements, and the quality will not change during the stability retention sample (long-term conditions, intermediate conditions), and the product quality can be guaranteed.

[0070] The above contents are further detailed descriptions of the present invention in combination with specific implementation methods, and it cannot be determined that the specific implementation of the present invention is limited to these descriptions. For ordinary technicians in the technical field to which the present invention belongs, several simple deductions or substitutions can be made without departing from the concept of the present invention.

Claims

1. A levofloxacin tablet, characterized in that: The invention comprises the following ingredients in parts by weight: 500 parts of levofloxacin, 10-30 parts of microcrystalline cellulose, 1-5 parts of hydroxypropyl methylcellulose, 1-5 parts of polyclinic potassium, 1-2 parts of sodium stearyl fumarate, 0.05-0.1 parts of isomeric tridecanol polyoxyethylene ether and an appropriate amount of purified water.

2. The levofloxacin tablet according to claim 1, characterized in that: Levofloxacin is a hemihydrate.

3. The levofloxacin tablet according to claim 1, characterized in that: The weight ratio of hydroxypropyl methylcellulose to polyclinic potassium is 1:1 to 1:1.

2.

4. The levofloxacin tablet according to claim 1, characterized in that: The dosage of isomeric tridecanol polyoxyethylene ether is 0.05 to 0.1 parts.

5. The method for preparing the levofloxacin tablets according to claim 1, characterized in that The following steps are involved: (1) placing the prescribed amount of levofloxacin, microcrystalline cellulose, hydroxypropyl methylcellulose, and polyclidinium potassium in a wet granulator, starting stirring, and fully mixing to form a premixed powder; (2) adding a prescribed amount of isomeric tridecanol polyoxyethylene ether to an appropriate amount of purified water to form a solution; (3) while stirring and cutting, spraying the solution of step (2) onto the premixed powder prepared in step (1) to obtain wet granules; (4) placing the wet granules in a fluidized bed for drying I; (5) granulating the granules after drying I; (6) Drying the granulated particles II; (7) mixing the prescribed amount of sodium stearyl fumarate with the granules; (8) The granules are compressed into tablets to obtain levofloxacin tablets.

6. The method for preparing levofloxacin tablets according to claim 5, characterized in that: In the step (4), the moisture content of the particles in the drying step I is controlled to be 8-15%.

7. The method for preparing levofloxacin tablets according to claim 5, characterized in that: In the step (6), the moisture content of the dried II particles is controlled to be ≤3%.

8. The method for preparing levofloxacin tablets according to claim 5, characterized in that: In the step (8), the tableting hardness is controlled to be 60N to 150N.

9. The method for preparing levofloxacin tablets according to claim 5, characterized in that: The method also includes coating the levofloxacin tablets obtained in step (8) with a coating agent to obtain coated tablets.

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