Preparation method of levofloxacin hydrochloride capsule

Abstract

The invention discloses a preparation method of levofloxacin hydrochloride capsules, and relates to the technical field of levofloxacin hydrochloride preparations, and the preparation method specifically comprises the following preparation steps: step 1, adding levofloxacin hydrochloride into distilled water, and uniformly stirring; step 2, dropwise adding acetic acid, stirring until levofloxacin hydrochloride is completely dissolved, and filtering; step 3, adding auxiliary antibiotics and an antioxidant, and uniformly stirring and mixing to prepare a solution A; step 4, pouring the modified chitosan into distilled water, dropwise adding acetic acid until the modified chitosan is naturally peptized, stirring until the modified chitosan is completely dissolved, uniformly shaking, and filtering to obtain a solution B; and step five, mixing the solution A and the solution B, performing high-pressure sterilization for 30-45 minutes, and performing capsule filling through a capsule filling machine to obtain the levofloxacin hydrochloride capsule. According to the preparation method of the levofloxacin hydrochloride capsule, chitosan is subjected to modification treatment, so that the chitosan can wrap levofloxacin hydrochloride, and the action time of a medicine is prolonged.

Description

Technical Field

[0001] The invention relates to the technical field of levofloxacin hydrochloride preparations, in particular to a preparation method of levofloxacin hydrochloride capsules. Background Art

[0002] Chinese patent publication number CN113559080A discloses a method for preparing levofloxacin hydrochloride capsules, which comprises the following steps: (1) uniformly mixing 100 parts by weight of levofloxacin hydrochloride raw material, 128 parts by weight of starch, and 13 parts by weight of hydroxypropyl cellulose to obtain a first premix; (2) adding 5% starch slurry as a binder to the first premix to prepare a soft material, and then granulating; (3) drying the granules prepared in step (2), adding 3 parts by weight of magnesium stearate and 16 parts by weight of sodium carboxymethyl starch thereto, mixing uniformly, and granulating to obtain levofloxacin hydrochloride granules; (4) filling the levofloxacin hydrochloride granules into capsules, and sealing the capsules to obtain levofloxacin hydrochloride capsules; the application adopts a specific prescription, and uses the "internal addition method" and the "external addition method" in combination during the preparation process; the disintegration time of the levofloxacin hydrochloride capsules prepared thereby can be shortened to 9 minutes, which is significantly shorter than other prescriptions. However, the antibacterial properties and sustained-release properties of the levofloxacin hydrochloride capsules prepared by the above-mentioned prior art solutions need to be improved. To this end, the present invention provides a method for preparing levofloxacin hydrochloride capsules to solve the above-mentioned problems. Summary of the Invention

[0003] In view of the deficiencies of the prior art, the present invention provides a method for preparing levofloxacin hydrochloride capsules, which solves the problems mentioned in the above background technology.

[0004] To achieve the above objectives, the present invention is implemented through the following technical solutions: a method for preparing levofloxacin hydrochloride capsules, specifically comprising the following preparation steps: Step 1: Add levofloxacin hydrochloride to distilled water and stir evenly; Step 2: Add acetic acid dropwise, stir until levofloxacin hydrochloride is completely dissolved, and filter; Step 3: Add auxiliary antibiotics and antioxidants, stir and mix, and prepare solution A; Step 4: Pour the modified chitosan into distilled water, add acetic acid dropwise until it is naturally peptized, stir until it is completely dissolved, shake well, and filter to obtain solution B; Step 5: Mix solution A and solution B, sterilize under high pressure for 30-45 minutes, and fill capsules using a capsule filling machine to obtain levofloxacin hydrochloride capsules.

[0005] Preferably, the raw materials are formulated according to the following proportions (not the content in a single capsule): distilled water 600-650 mL, levofloxacin hydrochloride 85-100 g, auxiliary antibiotics 6-10 g, antioxidants 14-20 g, and modified chitosan 35-50 g.

[0006] Preferably, in step 3, the auxiliary antibiotic is selected from any one or more of carbenicillin, piperacillin, mezlocillin or cephalexin.

[0007] Preferably, in step three, the antioxidant is selected from any one or more of potassium sorbate, sodium benzoate, sodium metabisulfite, potassium sorbate, sodium benzoate or sodium metabisulfite.

[0008] Preferably, the preparation method of the modified chitosan is: S1. Pour chitosan into 2%-4% acetic acid solution and react for 20-24 hours; S2. Add polyethylene glycol, stir evenly, then add liquid paraffin and Tween-80 in sequence, and stir and emulsify for 30-45 minutes; S3, add formaldehyde and react for 45-60 minutes; S4. Pour the reaction solution into a mixed solvent, let it stand for 18-20 hours, separate the layers, filter, and wash with petroleum ether, ethanol, and deionized water in sequence; S5. Add epichlorohydrin solution, raise the temperature to 65-75°C, react for 1.5-2.5 hours, filter, and wash with deionized water and ethanol solution in sequence; S6. Pour into dilute hydrochloric acid, react at 65-75°C for 6-8 hours, filter, wash with deionized water and 10% sodium hydroxide solution, and then rinse with deionized water until neutral; S7, placing in a pH regulator until the pH value is 4-7; S8, heating to 35-45°C, reacting for 8-10 hours, and then adjusting the pH value to 5.6-6.2 with sodium hydroxide solution; S9, dropwise add 10% sodium borohydride solution, stir to react for 1.5-2 hours, let stand for 2-2.5 hours, filter, and wash alternately with deionized water and anhydrous ethanol 3-4 times; S10, extracting with ethanol Soxhlet for 42-50 hours, and then drying in a vacuum drying oven to obtain modified chitosan; Preferably, the addition amount of each component is: chitosan 18-25g, acetic acid solution 35-45mL, polyethylene glycol 8-12g, liquid paraffin 6-10g, Tween-80 5.5-9g, formaldehyde 6-8g, mixed solvent 45-60mL, epichlorohydrin solution 12.5-16g, dilute hydrochloric acid 20-35mL, sodium borohydride solution 6-9g.

[0009] Preferably, in S4, the mixed solvent is a mixed solution of 95% anhydrous ethanol and 10% sodium hydroxide solution, and the volume ratio of anhydrous ethanol to sodium hydroxide solution is 0.6:(0.5-0.7).

[0010] Preferably, during the preparation of the modified chitosan, the mass fraction of sodium hydroxide used when adjusting the pH of the solution is 8%-10%.

[0011] Preferably, in S7, the pH regulator is prepared by adding 8.5-12 g of α-ketoglutaric acid to 20-30 mL of 3.5% acetic acid solution and mixing the mixture to obtain the pH regulator.

[0012] Preferably, in S10, the drying temperature is 40-50° C., and the drying time is 55-70 min.

[0013] The present invention provides a method for preparing levofloxacin hydrochloride capsules. Compared with the prior art, the method for preparing levofloxacin hydrochloride capsules has the following advantages: chitosan is modified to enable it to encapsulate levofloxacin hydrochloride, and this encapsulation effect can slowly release the drug, prolong the drug's duration of action, and reduce the number of drug administrations; because chitosan itself has a certain chemical stability, after modification and combination with the drug, the stability of the drug molecules can be enhanced, making the drug less likely to deteriorate during storage and transportation; and the modified chitosan has a certain targeting property in the body, and can deliver the encapsulated levofloxacin hydrochloride to specific parts of the body based on certain signals from the internal environment, allowing the drug to act more accurately on diseased tissues and reducing side effects on normal tissues. At the same time, this targeting effect causes the drug to accumulate more at the infected site, resulting in a higher concentration in the infected area, more effectively killing bacteria, and better exerting antibacterial effects than traditional preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 The present invention provides X-ray diffraction spectra of chitosan and modified chitosan. DETAILED DESCRIPTION

[0015] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0016] Example 1 A preparation method of levofloxacin hydrochloride capsules specifically comprises the following preparation steps: Step 1: Add 85 g of levofloxacin hydrochloride to 300 mL of distilled water and stir evenly; Step 2: Add acetic acid dropwise, stir until levofloxacin hydrochloride is completely dissolved, and filter; Step 3: Add 6 g of piperacillin and 14 g of potassium sorbate, stir and mix to prepare solution A; Step 4: Pour 35 g of modified chitosan into 300 mL of distilled water, add acetic acid dropwise until it is naturally peptized, stir until it is completely dissolved, shake well, and filter to obtain solution B; The preparation method of modified chitosan is as follows: pour 18g of chitosan into 35mL of acetic acid solution with a mass fraction of 2.5%, and react for 20h; add 8g of polyethylene glycol, stir evenly, and then add 6g of liquid paraffin and 5.5g of Tween-80 in turn, stir and emulsify for 30min; add 6g of formaldehyde and react for 45min; pour the reaction solution into 55mL of a mixed solvent of 95% anhydrous ethanol and 10% sodium hydroxide solution with a volume ratio of 0.6:0.5, let it stand for 18h, layer it, filter it, and wash it with petroleum ether, ethanol and deionized water in turn; add 12.5g of epichlorohydrin solution, heat it to 65℃, react it for 1.5h, filter it, and The mixture was washed with deionized water and ethanol solution for 2 times; poured into 20 mL of dilute hydrochloric acid, reacted at 65 ° C for 6 hours, filtered, washed with deionized water and 10% sodium hydroxide solution by mass, and then washed with deionized water until neutral; placed in a pH regulator until the pH value was 4; heated to 35 ° C, reacted for 8 hours, and then adjusted to 5.6 with 8% sodium hydroxide solution; 6 g of 10% sodium borohydride solution by mass was added dropwise, stirred for 1.5 hours, allowed to stand for 2 hours, filtered, and washed alternately with deionized water and anhydrous ethanol for 3 times; extracted with ethanol Soxhlet for 42 hours, and then dried in a vacuum drying oven at 40 ° C for 55 minutes to obtain modified chitosan; The pH regulator is prepared by adding 8.5 g of α-ketoglutaric acid to 20 mL of 2.5% acetic acid solution and mixing the mixture to obtain the pH regulator. Step 5: Mix solution A and solution B, sterilize under high pressure for 30 minutes, and fill capsules using a capsule filling machine to obtain levofloxacin hydrochloride capsules.

[0017] Example 2 A preparation method of levofloxacin hydrochloride capsules specifically comprises the following preparation steps: Step 1: Add 90 g of levofloxacin hydrochloride to 330 mL of distilled water and stir evenly; Step 2: Add acetic acid dropwise, stir until levofloxacin hydrochloride is completely dissolved, and filter; Step 3: Add 8 g of cephalexin and 17 g of sodium benzoate, stir and mix to prepare solution A; Step 4: Pour 40 g of modified chitosan into 300 mL of distilled water, add acetic acid dropwise until it is naturally peptized, stir until it is completely dissolved, shake well, and filter to obtain solution B; The preparation method of modified chitosan is as follows: pour 22g of chitosan into 40mL of 3% acetic acid solution and react for 22h; add 10g of polyethylene glycol, stir evenly, add 8g of liquid paraffin and 7.5g of Tween-80 in turn, stir and emulsify for 35min; add 7g of formaldehyde and react for 50min; pour the reaction solution into 48mL of a mixed solvent of 95% anhydrous ethanol and 10% sodium hydroxide solution with a volume ratio of 0.6:0.6, let it stand for 19h, layer it, filter it, and wash it with petroleum ether, ethanol and deionized water in turn; add 14g of epichlorohydrin solution, heat it to 70℃, react it for 2h, filter it, and use The chitosan was prepared by washing with deionized water and ethanol solution; pouring into 25 mL of dilute hydrochloric acid, reacting at 70 ° C for 7 hours, filtering, washing with deionized water and 10% sodium hydroxide solution by mass, and then washing with deionized water until neutral; placing in a pH regulator until the pH value is 5; heating to 40 ° C, reacting for 9 hours, and then adjusting the pH value to 6 with 9% sodium hydroxide solution; adding 8 g of 10% sodium borohydride solution by mass, stirring and reacting for 1.8 hours, standing for 2.2 hours, filtering, and washing with deionized water and anhydrous ethanol alternately for 4 times; extracting with ethanol Soxhlet for 46 hours, and then drying in a vacuum drying oven at 45 ° C for 60 minutes to obtain modified chitosan; The pH regulator is prepared by adding 10 g of α-ketoglutaric acid to 25 mL of 3% acetic acid solution and mixing the mixture to obtain the pH regulator. Step 5: Mix solution A and solution B, sterilize under high pressure for 35 minutes, and fill capsules using a capsule filling machine to obtain levofloxacin hydrochloride capsules.

[0018] Example 3 A preparation method of levofloxacin hydrochloride capsules specifically comprises the following preparation steps: Step 1: Add 100 g of levofloxacin hydrochloride to 350 mL of distilled water and stir evenly; Step 2: Add acetic acid dropwise, stir until levofloxacin hydrochloride is completely dissolved, and filter; Step 3: Add 10 g of mezlocillin and 20 g of sodium metabisulfite and potassium sorbate, stir and mix to prepare solution A; Step 4: Pour 50 g of modified chitosan into 300 mL of distilled water, add acetic acid dropwise until it is naturally peptized, stir until it is completely dissolved, shake well, and filter to obtain solution B; The preparation method of modified chitosan is as follows: pour 25g of chitosan into 45mL of 3.5% acetic acid solution and react for 24h; add 12g of polyethylene glycol, stir evenly, then add 10g of liquid paraffin and 9g of Tween-80 in turn, stir and emulsify for 45min; add 8g of formaldehyde and react for 60min; pour the reaction solution into 52mL of a mixed solvent of 95% anhydrous ethanol and 10% sodium hydroxide solution with a volume ratio of 0.6:0.7, let it stand for 20h, layer it, filter it, and wash it with petroleum ether, ethanol and deionized water in turn; add 16g of epichlorohydrin solution, heat it to 75℃, react it for 2.5h, filter it, and wash it with The chitosan was prepared by washing with deionized water and ethanol solution; pouring into 35 mL of dilute hydrochloric acid, reacting at 75 ° C for 8 hours, filtering, washing with deionized water and 10% sodium hydroxide solution, and then washing with deionized water until neutral; placing in a pH regulator until the pH value is 7; heating to 45 ° C, reacting for 10 hours, and then adjusting the pH value to 6.2 with 10% sodium hydroxide solution; adding 9 g of 10% sodium borohydride solution by weight, stirring and reacting for 2 hours, standing for 2.5 hours, filtering, and washing with deionized water and anhydrous ethanol alternately for 4 times; extracting with ethanol Soxhlet for 50 hours, and then drying in a vacuum drying oven at 50 ° C for 70 minutes to obtain modified chitosan; The pH regulator is prepared by adding 12 g of α-ketoglutaric acid to 30 mL of 3.5% acetic acid solution and mixing the mixture to obtain the pH regulator. Step 5: Mix solution A and solution B, sterilize under high pressure for 45 minutes, and fill capsules using a capsule filling machine to obtain levofloxacin hydrochloride capsules.

[0019] Comparative Example 1 Compared with Example 1, the difference is that the modified chitosan in Example 1 is replaced by chitosan; the rest remains unchanged.

[0020] like Figure 1As shown in the figure, chitosan has two crystallization peaks at 2θ of 11.6° and 20.2°; the diffraction peak of modified chitosan near 11.6° almost completely disappears, and the diffraction peak near 20.2° is significantly weakened, indicating that the chitosan modification is successful.

[0021] Antibacterial Activity Test: Preparation of bacterial culture fluid: 10 g of peptone, 5 g of yeast powder, and 10 g of sodium chloride were dissolved in 0.9 L of water. After complete dissolution, the pH was adjusted to 7.0 using 1 N sodium hydroxide. The levofloxacin hydrochloride capsules prepared above were used to conduct in vitro antibacterial tests to determine the minimum inhibitory concentration (MIC) of the drug against Escherichia coli and Staphylococcus aureus. The results are shown in Table 1.

[0022] Release performance test: water was used as the release medium, and the sampling points were: 0.5h, 2h, 6h, and 12h. About 5mL of the solution was taken from the above sampling points, filtered with a 0.45μm filter membrane, and an equal amount of solvent at the same temperature was added at the same time; Determination method: Take the above filtrate as the test solution, and take another 10uL sample, and perform high performance liquid chromatography (Appendix VD of Part II of the 2010 edition of the Chinese Pharmacopoeia), using octadecylsilane bonded silica gel as the filler, 0.02mol / L diammonium hydrogen phosphate buffer as the mobile phase, the flow rate is 1.0mL / min, and the detection wavelength is 230nm; accurately measure the above solutions and inject them into the high performance liquid chromatograph respectively, record the chromatogram, and calculate the release amount of each particle and the cumulative release amount by the peak area according to the external standard method; the results are shown in Table 2.

[0023] Meanwhile, the contents not described in detail in this specification belong to the prior art known to those skilled in the art.

[0024] It should be noted that, in this document, relational terms such as first and second, etc., are used only to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the terms "comprises," "comprising," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that includes a list of elements includes not only those elements but also other elements not explicitly listed, or elements inherent to such process, method, article, or apparatus.

[0025] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing levofloxacin hydrochloride capsules, characterized in that: Specifically comprising the following preparation steps: Step 1: Add levofloxacin hydrochloride to distilled water and stir evenly; Step 2: Add acetic acid dropwise, stir until levofloxacin hydrochloride is completely dissolved, and filter; Step 3: Add auxiliary antibiotics and antioxidants, stir and mix, and prepare solution A; Step 4: Pour the modified chitosan into distilled water, add acetic acid dropwise until it is naturally peptized, stir until it is completely dissolved, shake well, and filter to obtain solution B; Step 5: Mix solution A and solution B, sterilize under high pressure for 30-45 minutes, and fill capsules using a capsule filling machine to obtain levofloxacin hydrochloride capsules.

2. The method for preparing levofloxacin hydrochloride capsules according to claim 1, wherein: The raw materials are mixed according to the following components: 600-650 mL of distilled water, 85-100 g of levofloxacin hydrochloride, 6-10 g of auxiliary antibiotics, 14-20 g of antioxidants, and 35-50 g of modified chitosan.

3. The method for preparing levofloxacin hydrochloride capsules according to claim 1, wherein: In the step 3, the auxiliary antibiotic is selected from any one or more of carbenicillin, piperacillin, mezlocillin or cephalexin.

4. The method for preparing levofloxacin hydrochloride capsules according to claim 1, wherein: In the step 3, the antioxidant is selected from any one or more of potassium sorbate, sodium benzoate, sodium metabisulfite, potassium sorbate, sodium benzoate or sodium metabisulfite.

5. The method for preparing levofloxacin hydrochloride capsules according to claim 1, wherein: The preparation method of the modified chitosan is: S1. Pour chitosan into 2%-4% acetic acid solution and react for 20-24 hours; S2. Add polyethylene glycol, stir evenly, then add liquid paraffin and Tween-80 in sequence, and stir and emulsify for 30-45 minutes; S3, add formaldehyde and react for 45-60 minutes; S4. Pour the reaction solution into a mixed solvent, let it stand for 18-20 hours, separate the layers, filter, and wash with petroleum ether, ethanol, and deionized water in sequence; S5. Add epichlorohydrin solution, raise the temperature to 65-75°C, react for 1.5-2.5 hours, filter, and wash with deionized water and ethanol solution in sequence; S6. Pour into dilute hydrochloric acid, react at 65-75°C for 6-8 hours, filter, wash with deionized water and 10% sodium hydroxide solution, and then rinse with deionized water until neutral; S7, placing in a pH regulator until the pH value is 4-7; S8, heating to 35-45°C, reacting for 8-10 hours, and then adjusting the pH value to 5.6-6.2 with sodium hydroxide solution; S9, dropwise add 10% sodium borohydride solution, stir to react for 1.5-2 hours, let stand for 2-2.5 hours, filter, and wash alternately with deionized water and anhydrous ethanol 3-4 times; S10, extracting with ethanol Soxhlet for 42-50 hours, and then drying in a vacuum drying oven to obtain modified chitosan.

6. The method for preparing levofloxacin hydrochloride capsules according to claim 5, wherein: in, The addition amount of each component is: chitosan 18-25g, acetic acid solution 35-45mL, polyethylene glycol 8-12g, liquid paraffin 6-10g, Tween-80 5.5-9g, formaldehyde 6-8g, mixed solvent 45-60mL, epichlorohydrin solution 12.5-16g, dilute hydrochloric acid 20-35mL, and sodium borohydride solution 6-9g.

7. The method for preparing levofloxacin hydrochloride capsules according to claim 5, wherein: In the S4, the mixed solvent is a mixed solution of 95% anhydrous ethanol and 10% sodium hydroxide solution, and the volume ratio of anhydrous ethanol to sodium hydroxide solution is 0.6:(0.5-0.7).

8. The method for preparing levofloxacin hydrochloride capsules according to claim 5, wherein: During the preparation of the modified chitosan, the mass fraction of sodium hydroxide used when adjusting the pH of the solution is 8%-10%.

9. The method for preparing levofloxacin hydrochloride capsules according to claim 5, wherein: In S7, the pH regulator is prepared by adding 8.5-12 g of α-ketoglutaric acid to 20-30 mL of 3.5% acetic acid solution and mixing the mixture to obtain the pH regulator.

10. The method for preparing levofloxacin hydrochloride capsules according to claim 5, wherein: In the step S10 , the drying temperature is 40-50° C., and the drying time is 55-70 minutes.

Images