Levocetirizine hydrochloride particles and preparation method thereof

Abstract

The invention provides a preparation method of levocetirizine hydrochloride granules, which comprises the following steps: S1, mixing sodium alginate with deionized water, sodium hydroxymethyl starch, hydroxypropyl methylcellulose and maltitol, and performing ultrasonic oscillation and uniform mixing to obtain a mixed solution; s2, uniformly mixing levocetirizine hydrochloride with hydroxypropyl-beta-cyclodextrin, sodium bicarbonate and lactose to obtain a mixed material A; s3, uniformly mixing the mixed solution with the mixed material A to obtain a mixed material B; and S4, carrying out wet granulation, drying and dry granulation on the mixed material B by using an oscillating granulator, mixing with sucralose, and subpackaging to obtain the levocetirizine hydrochloride granules. Through a specific raw material formula and control of preparation process conditions, the particle uniformity of the levocetirizine hydrochloride particle medicine can be improved, the production efficiency can be improved, meanwhile, the stability of the levocetirizine hydrochloride medicine in the storage period can be improved, the product quality is not obviously changed, and the levocetirizine hydrochloride particle medicine has a good application prospect.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to levocetirizine hydrochloride granules and a preparation method thereof. Background Art

[0002] The chemical name of levocetirizine hydrochloride is R-(-)-2-[2-[4-[(4-chlorophenyl)benzyl]-1-piperazinyl]ethoxy]acetic acid, which is a selective histamine H1 receptor antagonist, mainly used to relieve some allergic symptoms caused by allergic diseases of the body, such as urticaria, allergic rhinitis, eczema, dermatitis, pruritus, etc. The dosage forms currently on the market include oral solutions, dispersible tablets, capsules and granules. Dispersible tablets and capsules take effect slowly, are difficult to swallow, and are inconvenient to take; oral liquids are inconvenient to carry and have poor drug stability. Granular drugs are easier to swallow than tablets, capsules and other dosage forms, and are very suitable for specific groups such as the elderly and children. At present, when preparing levocetirizine hydrochloride granular dosage forms, the traditional wet processing technology has poor particle uniformity and poor drug stability during storage, and also affects the solubility of the drug and the efficacy. Summary of the invention

[0003] In view of this, the present invention provides a levocetirizine hydrochloride granule and a preparation method thereof.

[0004] The technical solution of the present invention is achieved in this way:

[0005] A method for preparing levocetirizine hydrochloride granules comprises the following steps:

[0006] S1. After mixing sodium alginate and deionized water, sodium hydroxymethyl starch, hypromellose and maltitol are added and stirred again, and then ultrasonically oscillated to obtain a mixed solution;

[0007] S2, adding levocetirizine hydrochloride, hydroxypropyl-β-cyclodextrin and sodium bicarbonate into a wet granulator, without turning on the cutter, mixing at a stirring speed of 120-150 rpm for 5-8 min, then adding 1 / 2 of the formula amount of lactose, mixing at a stirring speed of 180-200 rpm for 6-8 min, and then adding the remaining 1 / 2 of the formula amount of lactose, mixing at a stirring speed of 250-300 rpm for 10-15 min, to obtain a mixed material A;

[0008] S3, adding the mixed solution into the wet granulator through a spray gun at a stirring speed of 200-300 rpm, and then mixing for 3-5 minutes at a stirring speed of 120-150 rpm and a cutting speed of 2000-2500 rpm to obtain a mixed material B;

[0009] S4. Use a swing granulator to wet granulate the mixed material B, place the wet granulated material in a boiling dryer for drying, dry granulate the dried granules, mix the prepared granule sieve with sucralose, and package them to obtain levocetirizine hydrochloride granules.

[0010] Furthermore, the specific process of S1 is: stirring and mixing sodium alginate and deionized water at a rotation speed of 200-300 rpm for 5-7 minutes, adding sodium hydroxymethyl starch, hydroxypropyl methylcellulose, and maltitol and stirring and mixing at a rotation speed of 400-500 rpm for 10-12 minutes, and then performing ultrasonic oscillation to obtain a mixed solution.

[0011] Furthermore, in step S1, the water content of the mixed solution is 1-15%.

[0012] Furthermore, in step S1, the ultrasonic oscillation treatment process is: oscillation treatment is performed for 8 to 10 minutes under the conditions of an ultrasonic power of 100 to 120 W and an ultrasonic frequency of 20 to 25 kHz.

[0013] Furthermore, in step S4, the dry granulation is performed by passing the dried granules through an upper 16-mesh sieve and a lower 40-mesh sieve.

[0014] Furthermore, in step S4, the mixing speed is 10 to 20 rpm and the mixing time is 10 to 12 min.

[0015] Furthermore, during the drying process, the material temperature is maintained at ≤40°C and the material is dried to a moisture content of ≤1.0%.

[0016] The levocetirizine hydrochloride granules prepared by the preparation method of the invention comprise the following raw materials in parts by weight: 2-5 parts of levocetirizine hydrochloride, 1500-2000 parts of lactose, 50-80 parts of hydroxypropyl-β-cyclodextrin, 12-16 parts of sucralose, 12-18 parts of sodium alginate, 10-14 parts of sodium hydroxymethyl starch, 7-10 parts of hypromellose, 11-15 parts of sodium bicarbonate and 9-13 parts of maltitol.

[0017] Compared with the prior art, the present invention has the following beneficial effects:

[0018] The invention can improve the particle uniformity of the levocetirizine hydrochloride granule medicine and improve the production efficiency through a specific raw material formula and control of the preparation process conditions, and can also improve the stability of the levocetirizine hydrochloride medicine during storage, and the product quality does not change significantly, and has good application prospects.

[0019] In the preparation process of the present invention, levocetirizine hydrochloride is firstly mixed with hydroxypropyl-β-cyclodextrin and sodium bicarbonate, so that the hydroxypropyl-β-cyclodextrin can wrap the levocetirizine hydrochloride, cover the bitter taste of the levocetirizine hydrochloride, and improve the palatability; lactose is added multiple times at a specific stirring speed, so that the lactose and other raw materials can be mixed more fully; in addition, appropriate amounts of sodium alginate, sodium hydroxymethyl starch, hydroxypropyl methylcellulose and maltitol are used for ultrasonic oscillation mixing, so that the mixing uniformity of each raw material in the mixed solution can be improved; at the same time, the stirring parameters of the wet granulator and other materials are controlled, so that the particle size distribution of the material is more uniform, and the particle size distribution of the prepared particles is also more uniform, and the particles are not easy to break, so that the pharmaceutical efficiency is improved, and the dissolution efficiency is not affected, and the storage stability is good. DETAILED DESCRIPTION

[0020] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0021] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0022] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0023] Example 1

[0024] The levocetirizine hydrochloride granules of this embodiment include the following raw materials in parts by weight: 4 parts of levocetirizine hydrochloride, 1500 parts of lactose, 50 parts of hydroxypropyl-β-cyclodextrin, 12 parts of sucralose, 12 parts of sodium alginate, 10 parts of sodium hydroxymethyl starch, 7 parts of hypromellose, 11 parts of sodium bicarbonate, and 9 parts of maltitol;

[0025] The preparation method of levocetirizine hydrochloride granules comprises the following steps:

[0026] S1. Sodium alginate and deionized water were stirred and mixed at a speed of 300 rpm for 5 min, sodium hydroxymethyl starch, hydroxypropyl methylcellulose and maltitol were added and stirred and mixed at a speed of 400 rpm for 12 min, and then oscillated for 10 min under the conditions of ultrasonic power of 100 W and ultrasonic frequency of 22 kHz to obtain a mixed solution with a water content of 5%;

[0027] S2, adding levocetirizine hydrochloride, hydroxypropyl-β-cyclodextrin and sodium bicarbonate into a wet granulator, without turning on the cutter, mixing at a stirring speed of 150 rpm for 8 min, then adding 1 / 2 of the formula amount of lactose and mixing at a stirring speed of 190 rpm for 8 min, and then adding the remaining formula amount of 1 / 2 of lactose and mixing at a stirring speed of 280 rpm for 12 min to obtain a mixed material A;

[0028] S3, at a stirring speed of 300 rpm, without turning on the cutter, the mixed solution was added to the wet granulator through a spray gun, the mixed solution was added for 3 minutes, and then mixed for 4 minutes at a stirring speed of 150 rpm and a cutter speed of 2300 rpm to obtain a mixed material B;

[0029] S4. Use a swing granulator to wet granulate the mixed material B, place the wet granulated material in a boiling dryer to dry, keep the material temperature ≤40°C during the drying process, dry until the material moisture is ≤1.0%, and pass the dried granules through an upper 16-mesh and a lower 40-mesh sieve for dry granulation. Mix the prepared granule sieve with sucralose at a speed of 20 rpm for 10 minutes, and package it to obtain levocetirizine hydrochloride granules.

[0030] Example 2

[0031] The levocetirizine hydrochloride granules of this embodiment include the following raw materials in parts by weight: 4.8 parts of levocetirizine hydrochloride, 1800 parts of lactose, 60 parts of hydroxypropyl-β-cyclodextrin, 15 parts of sucralose, 17 parts of sodium alginate, 14 parts of sodium hydroxymethyl starch, 9 parts of hypromellose, 13 parts of sodium bicarbonate, and 12 parts of maltitol;

[0032] The preparation method of levocetirizine hydrochloride granules comprises the following steps:

[0033] S1. Sodium alginate and deionized water were stirred and mixed at a speed of 200 rpm for 7 min, sodium hydroxymethyl starch, hydroxypropyl methylcellulose and maltitol were added and stirred and mixed at a speed of 500 rpm for 11 min, and then oscillated for 9 min under the conditions of ultrasonic power of 120 W and ultrasonic frequency of 20 kHz to obtain a mixed solution with a water content of 15%;

[0034] S2, adding levocetirizine hydrochloride, hydroxypropyl-β-cyclodextrin and sodium bicarbonate into a wet granulator, without turning on the cutter, mixing at a stirring speed of 120 rpm for 5 min, then adding 1 / 2 of the formula amount of lactose and mixing at a stirring speed of 180 rpm for 7 min, and then adding the remaining formula amount of 1 / 2 of the lactose and mixing at a stirring speed of 300 rpm for 15 min to obtain a mixed material A;

[0035] S3, at a stirring speed of 260 rpm, without turning on the cutter, the mixed solution was added to the wet granulator through a spray gun, the mixed solution was added for 2 minutes, and then mixed for 3 minutes under the conditions of a stirring speed of 120 rpm and a cutter speed of 2500 rpm to obtain a mixed material B;

[0036] S4. Use a swing granulator to wet granulate the mixed material B, place the wet granulated material in a boiling dryer to dry, keep the material temperature ≤40°C during the drying process, dry the material until the moisture content is ≤1.0%, and sieve the dried granules through an upper 16-mesh and a lower 40-mesh sieve for dry granulation. Mix the prepared granule sieve with sucralose at a speed of 18 rpm for 12 minutes, and package it to obtain levocetirizine hydrochloride granules.

[0037] Example 3

[0038] The levocetirizine hydrochloride granules of this embodiment include the following raw materials in parts by weight: 4.4 parts of levocetirizine hydrochloride, 1600 parts of lactose, 80 parts of hydroxypropyl-β-cyclodextrin, 16 parts of sucralose, 16 parts of sodium alginate, 12 parts of sodium hydroxymethyl starch, 10 parts of hypromellose, 14 parts of sodium bicarbonate, and 10 parts of maltitol;

[0039] The preparation method of levocetirizine hydrochloride granules comprises the following steps:

[0040] S1. Sodium alginate and deionized water were stirred and mixed at a speed of 250 rpm for 6 min, sodium hydroxymethyl starch, hydroxypropyl methylcellulose and maltitol were added and stirred and mixed at a speed of 450 rpm for 10 min, and then oscillated for 8 min under the conditions of an ultrasonic power of 120 W and an ultrasonic frequency of 25 kHz to obtain a mixed solution with a water content of 10%;

[0041] S2, adding levocetirizine hydrochloride, hydroxypropyl-β-cyclodextrin and sodium bicarbonate into a wet granulator, without turning on the cutter, mixing at a stirring speed of 130 rpm for 7 min, then adding 1 / 2 of the formula amount of lactose and mixing at a stirring speed of 200 rpm for 6 min, and then adding the remaining formula amount of 1 / 2 of lactose and mixing at a stirring speed of 250 rpm for 13 min to obtain a mixed material A;

[0042] S3, at a stirring speed of 240 rpm, without turning on the cutter, the mixed solution was added to the wet granulator through a spray gun, the mixed solution was added for 4 minutes, and then mixed for 5 minutes at a stirring speed of 130 rpm and a cutter speed of 2000 rpm to obtain a mixed material B;

[0043] S4. Use a swing granulator to wet granulate the mixed material B, place the wet granulated material in a boiling dryer to dry, keep the material temperature ≤40°C during the drying process, dry to the material moisture ≤1.0%, pass the dried granules through an upper 16-mesh and a lower 40-mesh sieve for dry granulation, mix the prepared granule sieve with sucralose at a speed of 10 rpm for 11 minutes, and package to obtain levocetirizine hydrochloride granules.

[0044] Comparative Example 1

[0045] Compared with Example 3, the process of step S1 is changed in this comparative example, and the rest remains the same as Example 1.

[0046] The preparation method of the levocetirizine hydrochloride granules of this comparative example comprises the following steps:

[0047] S1. Add sodium alginate, sodium hydroxymethyl starch, hypromellose and maltitol into deionized water at a speed of 100 rpm while stirring to prepare a mixed solution with a water content of 10%;

[0048] S2, adding levocetirizine hydrochloride, hydroxypropyl-β-cyclodextrin and sodium bicarbonate into a wet granulator, without turning on the cutter, mixing at a stirring speed of 130 rpm for 7 min, then adding 1 / 2 of the formula amount of lactose and mixing at a stirring speed of 200 rpm for 6 min, and then adding the remaining formula amount of 1 / 2 of lactose and mixing at a stirring speed of 250 rpm for 13 min to obtain a mixed material A;

[0049] S3, at a stirring speed of 240 rpm, without turning on the cutter, the mixed solution was added to the wet granulator through a spray gun, the mixed solution was added for 4 minutes, and then mixed for 5 minutes at a stirring speed of 130 rpm and a cutter speed of 2000 rpm to obtain a mixed material B;

[0050] S4. Use a swing granulator to wet granulate the mixed material B, place the wet granulated material in a boiling dryer to dry, keep the material temperature ≤40°C during the drying process, dry to the material moisture ≤1.0%, pass the dried granules through an upper 16-mesh and a lower 40-mesh sieve for dry granulation, mix the prepared granule sieve with sucralose at a speed of 10 rpm for 11 minutes, and package to obtain levocetirizine hydrochloride granules.

[0051] Comparative Example 2

[0052] Compared with Example 3, the process of step S2 is changed in this comparative example, and the rest remains the same as Example 1.

[0053] The preparation method of levocetirizine hydrochloride granules comprises the following steps:

[0054] S1. Sodium alginate and deionized water were stirred and mixed at a speed of 250 rpm for 6 min, sodium hydroxymethyl starch, hydroxypropyl methylcellulose and maltitol were added and stirred and mixed at a speed of 450 rpm for 10 min, and then oscillated for 8 min under the conditions of an ultrasonic power of 120 W and an ultrasonic frequency of 25 kHz to obtain a mixed solution with a water content of 10%;

[0055] S2, adding levocetirizine hydrochloride, hydroxypropyl-β-cyclodextrin, sodium bicarbonate and lactose into a wet granulator and stirring at a speed of 120 rpm for 26 minutes to obtain a mixed material A;

[0056] S3, at a stirring speed of 240 rpm, without turning on the cutter, the mixed solution was added to the wet granulator through a spray gun, the mixed solution was added for 4 minutes, and then mixed for 5 minutes at a stirring speed of 130 rpm and a cutter speed of 2000 rpm to obtain a mixed material B;

[0057] S4. Use a swing granulator to wet granulate the mixed material B, place the wet granulated material in a boiling dryer to dry, keep the material temperature ≤40°C during the drying process, dry to the material moisture ≤1.0%, pass the dried granules through an upper 16-mesh and a lower 40-mesh sieve for dry granulation, mix the prepared granule sieve with sucralose at a speed of 10 rpm for 11 minutes, and package to obtain levocetirizine hydrochloride granules.

[0058] Comparative Example 3

[0059] Compared with Example 3, the process of step S3 is changed in this comparative example, and the rest remains the same as Example 1.

[0060] The preparation method of levocetirizine hydrochloride granules comprises the following steps:

[0061] S1. Sodium alginate and deionized water were stirred and mixed at a speed of 250 rpm for 6 min, sodium hydroxymethyl starch, hydroxypropyl methylcellulose and maltitol were added and stirred and mixed at a speed of 450 rpm for 10 min, and then oscillated for 8 min under the conditions of an ultrasonic power of 120 W and an ultrasonic frequency of 25 kHz to obtain a mixed solution with a water content of 10%;

[0062] S2, adding levocetirizine hydrochloride, hydroxypropyl-β-cyclodextrin and sodium bicarbonate into a wet granulator, without turning on the cutter, mixing at a stirring speed of 130 rpm for 7 min, then adding 1 / 2 of the formula amount of lactose and mixing at a stirring speed of 200 rpm for 6 min, and then adding the remaining formula amount of 1 / 2 of lactose and mixing at a stirring speed of 250 rpm for 13 min to obtain a mixed material A;

[0063] S3, adding the mixed solution into the wet granulator through a spray gun under the conditions of a stirring speed of 250 rpm and a cutting speed of 800 rpm, the mixed solution adding time is 12 min, and stirring is continued for 2 min after adding the mixed solution to obtain a mixed material B;

[0064] S4. Use a swing granulator to wet granulate the mixed material B, place the wet granulated material in a boiling dryer to dry, keep the material temperature ≤40°C during the drying process, dry to the material moisture ≤1.0%, pass the dried granules through an upper 16-mesh and a lower 40-mesh sieve for dry granulation, mix the prepared granule sieve with sucralose at a speed of 10 rpm for 11 minutes, and package to obtain levocetirizine hydrochloride granules.

[0065] According to the method of the above-mentioned Examples 1-3 and Comparative Examples 1-3, levocetirizine acid granules were prepared and tested. The test conditions were: 25°C ± 2°C, 60% RH ± 5% RH, and the test time was 0, 3, and 6 months. The test conditions and results are as follows.

[0066] (1) Content of levocetirizine hydrochloride and total impurities: refer to the method in "Hong Jiangyou, Hong Zhihui, Ling Rijin, et al. Determination of the content of levocetirizine hydrochloride granules by HPLC [J]. Chinese Modern Drug Application, 2012, 6(13): 2. DOI: 10.3969 / j.issn.1673-9523.2012.13.003." and the "Guidelines for Stability Testing of Active Pharmaceutical Ingredients and Preparations of Part IV of the Chinese Pharmacopoeia 2020" for determination; chromatographic conditions: Apollo C column (250x4.6mm, 5mm); mobile phase: methanol-sodium dihydrogen phosphate solution (take NaH2PO4·2H2O3, 12g, add water to 1000ml to dissolve to obtain sodium dihydrogen phosphate solution, the volume ratio of methanol to sodium dihydrogen phosphate solution is 70:30; flow rate 1ml / min; detection wavelength is 230nm; injection volume is 20μL.

[0067] (2) Particle size distribution: Determine according to the Chinese Pharmacopoeia 2020 Edition Part IV 0982 Particle Size and Particle Size Distribution Method.

[0068] (3) Loss on drying: Determine according to the method of loss on drying in Part IV of the Chinese Pharmacopoeia 2020.

[0069] (4) Dissolution: Determine according to the method of dissolution and release rate determination in Part IV of the Chinese Pharmacopoeia 2020.

[0070] Table 1 Performance test of levocetirizine hydrochloride granules

[0071]

[0072] The above results show that the levocetirizine hydrochloride particles prepared by the suitable preparation process of Examples 1-3 of the present invention have excellent performance, uniform particle size, can maintain the stability of levocetirizine hydrochloride during storage, have low impurity content, and reduce the loss on drying, and can also maintain good solubility. Compared with Example 3, Comparative Example 1 changes the preparation process of the mixed solution, Comparative Example 2 changes the process steps and parameters of mixing levocetirizine hydrochloride with hydroxypropyl-β-cyclodextrin, lactose, and sodium bicarbonate, and Comparative Example 3 changes the process and parameters of the mixed material processing, which all affect the performance of the levocetirizine hydrochloride particles, causing the particle uniformity distribution performance to decrease, while affecting its stability and solubility.

[0073] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing levocetirizine hydrochloride granules, characterized in that: The following steps are involved: S1. After mixing sodium alginate and deionized water, sodium hydroxymethyl starch, hypromellose and maltitol are added and stirred again, and then ultrasonically oscillated to obtain a mixed solution; S2, adding levocetirizine hydrochloride, hydroxypropyl-β-cyclodextrin and sodium bicarbonate into a wet granulator, without turning on the cutter, mixing at a stirring speed of 120-150 rpm for 5-8 min, then adding 1 / 2 of the formula amount of lactose, mixing at a stirring speed of 180-200 rpm for 6-8 min, and then adding the remaining 1 / 2 of the formula amount of lactose, mixing at a stirring speed of 250-300 rpm for 10-15 min, to obtain a mixed material A; S3, adding the mixed solution into the wet granulator through a spray gun at a stirring speed of 200-300 rpm, and then mixing for 3-5 minutes at a stirring speed of 120-150 rpm and a cutting speed of 2000-2500 rpm to obtain a mixed material B; S4. Use a swing granulator to wet granulate the mixed material B, place the wet granulated material in a boiling dryer for drying, dry granulate the dried granules, mix the prepared granule sieve with sucralose, and package them to obtain levocetirizine hydrochloride granules.

2. The method for preparing levocetirizine hydrochloride granules according to claim 1, characterized in that: The specific process of S1 is: sodium alginate and deionized water are stirred and mixed at a rotation speed of 200-300 rpm for 5-7 minutes, sodium hydroxymethyl starch, hydroxypropyl methylcellulose and maltitol are added and stirred and mixed at a rotation speed of 400-500 rpm for 10-12 minutes, and then ultrasonic oscillation is performed to obtain a mixed solution.

3. The method for preparing levocetirizine hydrochloride granules according to claim 1, characterized in that: In step S1, the water content of the mixed solution is 1-15%.

4. The method for preparing levocetirizine hydrochloride granules according to claim 1, characterized in that: In step S1, the ultrasonic oscillation treatment process is: oscillation treatment is performed for 8 to 10 minutes under the conditions of an ultrasonic power of 100 to 120 W and an ultrasonic frequency of 20 to 25 kHz.

5. The method for preparing levocetirizine hydrochloride granules according to claim 1, characterized in that: In step S4, the dry granulation is to dry granulate the dried granules through an upper 16-mesh sieve and a lower 40-mesh sieve.

6. The method for preparing levocetirizine hydrochloride granules according to claim 1, characterized in that: In step S4, the mixing speed is 10-20 rpm and the mixing time is 10-12 min.

7. The method for preparing levocetirizine hydrochloride granules according to claim 1, characterized in that: During the drying process, the material temperature is maintained at ≤40°C and the material is dried to a moisture content of ≤1.0%.

8. Levocetirizine hydrochloride granules prepared by the preparation method according to any one of claims 1 to 7, characterized in that: The invention comprises the following raw materials in parts by weight: 2-5 parts of levocetirizine hydrochloride, 1500-2000 parts of lactose, 50-80 parts of hydroxypropyl-β-cyclodextrin, 12-16 parts of sucralose, 12-18 parts of sodium alginate, 10-14 parts of sodium hydroxymethyl starch, 7-10 parts of hypromellose, 11-15 parts of sodium bicarbonate and 9-13 parts of maltitol.

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