Fine granule and preparation method therefor

Abstract

The present invention relates to the field of pharmaceutical formulations, and in particular to a fine granule and a preparation method therefor. The provided fine granule is a fine granule having core particles, a coating layer and an additional material layer. Hydroxypropyl cellulose and / or hydroxypropyl methylcellulose in a specific proportion are selected as a tackifier, and low-substituted hydroxypropyl cellulose is used as a disintegrating agent, so that the prepared fine granule has good particle compactness, disintegration performance and dissolution performance. An anti-adherent is homogenized during the preparation of the coating layer material, so that the prepared coating layer material has good anti-adhesion effect, and does not adhere in the particle coating process, thereby ensuring the integrity of the particles. A fluidized granulation coating machine is selected for preparation and coating of the core particles, thereby ensuring more uniform particle size distribution of the fine granule.

Description

A fine granule and its preparation method Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and in particular relates to a fine granule and a preparation method thereof. Background Art

[0002] Fine granules, a dosage form developed in the mid-1980s, are widely marketed in Japan. Compared to other solid preparations, fine granules have achieved significant improvements in dissolution, bioavailability, drug stability, and patient adaptability. For example, fine granules with a taste-masking functional coating can mask the bitterness of the API, eliminating the gritty sensation experienced by patients when taking the medication. This improves medication compliance and is particularly beneficial for the elderly and infants.

[0003] However, in the preparation process of fine granules, there are common problems such as granule sticking during the coating process and large particle size distribution. Therefore, there is a need in the art to provide a fine granule with better granule compactness, granule integrity, particle size distribution, disintegration performance and dissolution performance and a preparation method thereof. Summary of the Invention

[0004] The present invention provides a fine granule having a core particle, a coating layer and an added material layer. By selecting hydroxypropyl cellulose and / or hydroxypropyl methylcellulose in a specific ratio as a viscosity enhancer and low-substituted hydroxypropyl cellulose as a disintegrant, the prepared fine granule has good particle compactness, disintegration performance and dissolution performance. By homogenizing the anti-sticking agent in advance during the preparation of the coating layer material, the prepared coating layer material has a good anti-sticking effect, the particles do not stick during the coating process, and the integrity of the particles is ensured. By selecting a fluidized granulation coating machine for the preparation and coating of the core particles, the particle size distribution of the fine granule is ensured to be more uniform.

[0005] In one aspect, the present invention provides a fine granule comprising the following components:

[0006] In some embodiments, the pharmaceutical active ingredient is selected from one of arbidol hydrochloride, cloperidin hydrochloride, azithromycin, cefdinir, loxoprofen sodium and rivaroxaban.

[0007] In some embodiments, the filler is selected from one or more of microcrystalline cellulose, lactose, and mannitol; the coating material is selected from one or more of ethyl cellulose, methacrylic acid copolymer, and aminoalkyl methacrylate copolymer; the plasticizer is selected from one or more of polyethylene glycol, phthalate, and castor oil; the anti-adherent is selected from one or more of talc, silicon dioxide, and magnesium stearate; the suspending agent is selected from xanthan gum and / or RC591; the lubricant is selected from magnesium stearate and / or talc.

[0008] In some embodiments, the fine granules comprise the following components:

[0009] Preferably, the flavoring agent is selected from sucrose and / or mannitol; the opacifier is selected from titanium dioxide and / or calcium carbonate; the flavoring agent is selected from one or more of strawberry flavor, pineapple flavor, and apple flavor; and the sweetener is selected from sucralose and / or aspartame.

[0010] Preferably, the fine granules contain the following components:

[0011] In some embodiments, during the preparation of the coating layer material, the anti-adherent agent is first homogenized, and then the anti-adherent agent solution obtained after homogenization is mixed with the coating material.

[0012] In some embodiments, the preparation and coating of the core particles are performed in a fluidized granulation coater.

[0013] In another aspect, the present invention provides a method for preparing fine granules, comprising the following steps:

[0014] Step 1: After the active ingredient of the drug is crushed, it is added together with the filler and low-substituted hydroxypropyl cellulose into a fluidized granulation coating machine, and hydroxypropyl cellulose and / or hypromellose are sprayed to prepare the core particles;

[0015] Step 2: Add the anti-adhesive agent to 95% ethanol and homogenize, add the coating material and plasticizer to 95% ethanol and stir, then add the homogenized anti-adhesive agent to the stirred solution, and continue stirring to obtain the coating layer material;

[0016] Step 3: Place the core particles in a fluidized granulation coating machine, start the turntable speed, control the inlet air temperature and fan speed, and coat with the coating layer material;

[0017] Step 4: Mix the coated granules with the external materials and package them.

[0018] Preferably, the preparation method of fine granules comprises the following steps:

[0019] Step 1: After the active pharmaceutical ingredient is crushed, it is added together with the filler and low-substituted hydroxypropyl cellulose into a fluidized granulation coating machine. The turntable speed is set to 100-500 rpm, the inlet air temperature is 40-50°C, the fan speed is 500-850 rpm, and the peristaltic pump speed is 8-30 rpm. Hydroxypropyl cellulose and / or hypromellose are sprayed to prepare the core particles.

[0020] Step 2: Add the anti-adhesive agent to 95% ethanol and homogenize for 10 minutes, add the coating material and plasticizer to 95% ethanol and stir for 10 minutes, then add the homogenized anti-adhesive agent to the stirred solution and continue stirring to obtain the coating layer material;

[0021] Step 3: Place the core particles in a fluidized granulation coater, set the turntable speed to 70-90 rpm, the air inlet temperature to 55-65°C, the fan speed to 500-850 rpm, and the peristaltic pump speed to 5-7.5 rpm, and coat with the coating material;

[0022] Step 4: Mix the coated granules with the external materials and package them.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] 1. The core particles use low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose in combination, which can make the prepared particles have better compactness, while also ensuring rapid disintegration of the particles without affecting the dissolution of the active ingredients of the drug;

[0025] 2. During the preparation of the coating material, the anti-sticking agent is first homogenized and then mixed with the coating material in a solution state, thus avoiding the uneven stirring caused by directly preparing the anti-sticking agent. This ensures that the prepared coating material has a good anti-sticking effect and the particles do not stick during the coating process.

[0026] 3. The fluidized granulation coating machine used has bottom ventilation, sufficient air volume, high heat exchange efficiency, fast coating speed, high coating efficiency, short production cycle, and greatly reduced production costs. Moreover, the unique R angle design can effectively ensure that the centrifugal material forms a turnover cycle. The gap between the chassis and the barrel wall can be infinitely adjusted as long as no rigid friction is formed, completely avoiding the occurrence of material leakage;

[0027] 4. The present invention effectively solves the problem of large particle size distribution and large amount of fine powder in fine granules by controlling parameters such as turntable speed, air inlet temperature, air volume, and spraying speed, thereby obtaining stable and uniform granules.

[0028] 5. The auxiliary materials of the present invention are cheap and readily available, easy to prepare, do not require special equipment, have a short production cycle, low cost, and are also very suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] FIG1 is a microscopic observation picture of the fine granules prepared in Example 1;

[0030] FIG2 is a microscopic observation picture of the fine granules prepared in Example 2;

[0031] FIG3 is a microscopic observation picture of the fine granules prepared in Example 3;

[0032] FIG4 is a microscopic observation picture of the fine granules prepared in Example 5;

[0033] FIG5 is a microscopic observation picture of the fine granules prepared in Example 6;

[0034] FIG6 is a microscopic observation picture of the fine granules prepared in Example 7;

[0035] FIG7 is a particle size distribution diagram of the fine granules prepared in Example 1;

[0036] FIG8 is a particle size distribution diagram of the fine granules prepared in Example 2. DETAILED DESCRIPTION

[0037] The technical solution of the present invention is further described below by way of specific embodiments. It should be understood by those skilled in the art that the embodiments are merely to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0038] As used herein, the terms "comprises," "including," "having," "containing" or any other variations thereof, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises a listed element is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.

[0039] "Optionally" or "either" means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event occurs and instances where it does not.

[0040] The indefinite articles "a" and "an" before the elements or components of the present invention do not limit the quantity requirement (i.e. the number of times they appear). Therefore, "a" or "an" should be interpreted as including one or at least one, and elements or components in the singular also include plural forms, unless the quantity clearly refers to only the singular form.

[0041] In the present invention, features defined as "first" or "second" may explicitly or implicitly include one or more of the features, and are used to distinguish and describe features, without regard to order or importance. In the description of the present invention, unless otherwise specified, "plurality" means two or more.

[0042] Example 1 Preparation of Arbidol Hydrochloride Fine Granules

[0043] Table 1 Prescription table of Example 1

[0044] The preparation steps are as follows:

[0045] 1. Preparation of core particles: After the active ingredient of the drug is crushed, it is added together with microcrystalline cellulose and low-substituted hydroxypropyl cellulose into a fluidized granulation coating machine. The turntable speed is set to 100-500 rpm, the inlet air temperature is 45°C (the material temperature is about 20°C), the fan speed is 500-850 rpm, and the peristaltic pump speed is 8-30 rpm. Hydroxypropyl cellulose is sprayed to prepare the core particles.

[0046] 2. Coating material preparation: Add talcum powder to 95% ethanol and disperse it using a homogenizer for 10 minutes. Add aminoalkyl methacrylate copolymer and polyethylene glycol to 95% ethanol and stir for 10 minutes. Then add the homogenized talcum powder to the stirred solution, continue stirring until evenly mixed, and set aside.

[0047] 3. Granule coating: Place the core granules in a fluidized granulation coating machine, set the turntable speed to 80 rpm, the air inlet temperature to 60°C (material temperature 25-35°C), the fan speed to 500-850 rpm, and the peristaltic pump speed to 5-7.5 rpm for coating.

[0048] 4. Mix the coated granules with the added materials and package them.

[0049] Example 2 Preparation of Arbidol Hydrochloride Fine Granules

[0050] Table 2 Example 2 Prescription

[0051] The preparation steps are as follows:

[0052] 1. Preparation of core particles: After the active ingredient of the drug is crushed, it is mixed with microcrystalline cellulose, hydroxypropyl cellulose, and low-substituted hydroxypropyl cellulose in a high-shear mixer granulator. After stirring evenly, purified water is added to wet the soft material, and granulated through a 40-mesh sieve. After drying, the granules are sieved through a 40-mesh sieve, and the fine powder is removed through a 120-mesh sieve. The 40-120 mesh particles are collected.

[0053] 2. Coating material preparation: Add talcum powder to 95% ethanol and disperse it using a homogenizer for 10 minutes. Add aminoalkyl methacrylate copolymer and polyethylene glycol to 95% ethanol and stir for 10 minutes. Then add the homogenized talcum powder to the stirred solution, continue stirring until evenly mixed, and set aside.

[0054] 3. Particle Coating: The collected particles were placed in a multifunctional fluidized bed and sprayed with the coating material using a cut-and-spray process. The process parameters were: blast air volume: 30 m³ / h, inlet air temperature: 45°C, material temperature: 25-30°C, atomization pressure: 2.5 kg / cm², turntable speed: 350 rpm / min, and flow rate: 10 mL / min.

[0055] 4. Mix the coated granules with the added materials and package them.

[0056] Example 3 Preparation of Arbidol Hydrochloride Fine Granules

[0057] Table 3 Prescription table of Example 3

[0058] The preparation steps are as follows:

[0059] 1. Preparation of core particles: After the active ingredient of the drug is crushed, it is added together with microcrystalline cellulose and low-substituted hydroxypropyl cellulose into a fluidized granulation coating machine. The turntable speed is set to 100-500 rpm, the inlet air temperature is 45°C (the material temperature is about 20°C), the fan speed is 500-850 rpm, and the peristaltic pump speed is 8-30 rpm. Hydroxypropyl cellulose is sprayed to prepare the core particles.

[0060] 2. Preparation of coating layer materials: Add aminoalkyl methacrylate copolymer, polyethylene glycol, and talc into 95% ethanol and homogenize for 10 minutes and stir evenly.

[0061] 3. Granule coating: Place the core granules in a fluidized granulation coating machine, set the turntable speed to 80 rpm, the inlet air temperature to 60°C (material temperature 25-30°C), the fan speed to 500-850 rpm, and the peristaltic pump speed to 5-7.5 rpm for coating.

[0062] 4. Mix the coated granules with the added materials and package them.

[0063] Example 4 Preparation of Arbidol Hydrochloride Fine Granules

[0064] Table 4 Prescription table of Example 4

[0065] The preparation steps are as follows:

[0066] 1. Preparation of core particles: After the active ingredient of the drug is crushed, it is added together with microcrystalline cellulose and low-substituted hydroxypropyl cellulose into a fluidized granulation coating machine. The turntable speed is set to 100-500 rpm, the inlet air temperature is 45°C (the material temperature is about 20°C), the fan speed is 500-850 rpm, and the peristaltic pump speed is 8-30 rpm. Hydroxypropyl cellulose is sprayed to prepare the core particles.

[0067] 2. Preparation of coating layer materials: Add aminoalkyl methacrylate copolymer, polyethylene glycol, and talc into 59% ethanol and homogenize for 10 minutes and stir evenly.

[0068] 3. Granule coating: Place the core granules in a fluidized granulation coating machine, set the turntable speed to 80 rpm, the inlet air temperature to 60°C (material temperature 25-30°C), the fan speed to 500-850 rpm, and the peristaltic pump speed to 5-7.5 rpm for coating.

[0069] 4. Mix the coated granules with the added materials and package them.

[0070] Example 5 Preparation of Arbidol Hydrochloride Fine Granules

[0071] Table 5 Prescription table of Example 5

[0072] The preparation steps are as follows:

[0073] 1. Preparation of core particles: After the active ingredient of the drug is crushed, it is added together with microcrystalline cellulose and low-substituted hydroxypropyl cellulose into a fluidized granulation coating machine. The turntable speed is set to 100-500 rpm, the inlet air temperature is 45°C (the material temperature is about 20°C), the fan speed is 500-850 rpm, the peristaltic pump speed is 8-30 rpm, and purified water is sprayed to prepare the core particles.

[0074] 2. Coating material preparation: Add talcum powder to 95% ethanol and disperse it using a homogenizer for 10 minutes. Add aminoalkyl methacrylate copolymer and polyethylene glycol to 95% ethanol and stir for 10 minutes. Then add the homogenized talcum powder to the stirred solution, continue stirring until evenly mixed, and set aside.

[0075] 3. Granule coating: Place the core granules in a fluidized granulation coating machine, set the turntable speed to 80 rpm, the air inlet temperature to 60°C (material temperature 25-35°C), the fan speed to 500-850 rpm, and the peristaltic pump speed to 5-7.5 rpm for coating.

[0076] 4. Mix the coated granules with the added materials and package them.

[0077] Example 6 Preparation of Azithromycin Fine Granules

[0078] Table 6 Prescription table of Example 6

[0079] The preparation steps are as follows:

[0080] 1. Preparation of core particles: After the active ingredient of the drug is crushed, it is added together with microcrystalline cellulose and low-substituted hydroxypropyl cellulose into a fluidized granulation coating machine. The turntable speed is set to 100-500 rpm, the inlet air temperature is 45°C (the material temperature is about 20°C), the fan speed is 500-850 rpm, and the peristaltic pump speed is 8-30 rpm. Hydroxypropyl cellulose is sprayed to prepare the core particles.

[0081] 2. Coating material preparation: Add talcum powder to 95% ethanol and disperse it using a homogenizer for 10 minutes. Add aminoalkyl methacrylate copolymer and polyethylene glycol to 95% ethanol and stir for 10 minutes. Then add the homogenized talcum powder to the stirred solution, continue stirring until evenly mixed, and set aside.

[0082] 3. Granule coating: Place the core granules in a fluidized granulation coating machine, set the turntable speed to 80 rpm, the air inlet temperature to 60°C (material temperature 25-35°C), the fan speed to 500-850 rpm, and the peristaltic pump speed to 5-7.5 rpm for coating.

[0083] 4. Mix the coated granules with the added materials and package them.

[0084] Example 7 Preparation of Arbidol Hydrochloride Fine Granules

[0085] Table 7 Prescription table of Example 7

[0086] The preparation steps are as follows:

[0087] 1. Preparation of core particles: After the active ingredient of the drug is crushed, it is added together with microcrystalline cellulose and low-substituted hydroxypropyl cellulose into a fluidized granulation coating machine. The turntable speed is set to 100-500 rpm, the inlet air temperature is 45°C (the material temperature is about 20°C), the fan speed is 500-850 rpm, and the peristaltic pump speed is 8-30 rpm. Hydroxypropyl cellulose is sprayed to prepare the core particles.

[0088] 2. Coating material preparation: Add talcum powder to 95% ethanol and disperse it using a homogenizer for 10 minutes. Add aminoalkyl methacrylate copolymer and polyethylene glycol to 95% ethanol and stir for 10 minutes. Then add the homogenized talcum powder to the stirred solution, continue stirring until evenly mixed, and set aside.

[0089] 3. Granule coating: Place the core granules in a fluidized granulation coating machine, set the turntable speed to 80 rpm, the air inlet temperature to 60°C (material temperature 25-35°C), the fan speed to 500-850 rpm, and the peristaltic pump speed to 5-7.5 rpm for coating.

[0090] 4. Mix the coated granules with the added materials and package them.

[0091] Example 8 Quality Evaluation

[0092] Microscopic observation method: Take the particles prepared in each example and observe them under a polarizing microscope.

[0093] Particle size distribution detection method: Use a laser particle size analyzer with a dispersion pressure of 75 kPa, a sample injection rate of 50%, and a measurement time of 10 s to detect the particles prepared in each example.

[0094] According to the microscopic observation images of Example 1, Example 5, Example 6 and Example 2, the fine granules prepared by the fluidized granulator have better roundness and more uniform particle distribution than those prepared by the high shear mixing granulator and the fluidized bed coating.

[0095] According to the microscopic observation images of Examples 1 and 3, the particles exhibited better anti-sticking properties when the talc was homogenized before being added to the coating material in a solution state. The particles did not stick together, and the prepared particles were more uniform.

[0096] According to Example 1 and Example 5, it can be seen that the granulation effect is poor when only low-substituted hydroxypropyl cellulose is added to the formulation without adding hydroxypropyl cellulose, and the microscopic observation shows that there is a lot of fine powder.

[0097] According to the particle size distribution diagrams of Example 1 and Example 2, it can be seen that the fine granules prepared by using the fluidized granulator have more uniform particle distribution.

[0098] Example 9 Dissolution Test

[0099] According to the second method of the general rules of the fourth part of the Chinese Pharmacopoeia 2020 edition, pH 6.8 phosphate buffer solution plus 0.05% SDS 900ml is used as the dissolution medium, the rotation speed is 50 revolutions per minute, and the operation is carried out in accordance with the law. 10mL of dissolution solution is taken after 5min, 10min, 15min, 30min, 60min, 90min, and 120min respectively, and the dissolution medium of the same temperature and volume is immediately replenished. Take the test solution and the reference solution, and measure the absorbance at a wavelength of 315nm according to the UV-visible spectrophotometry (0401 of the general rules of the fourth part of the Chinese Pharmacopoeia 2020 edition), and calculate the dissolution amount of each tablet at different times.

[0100] Table 9 Dissolution results data of Example 1 and Example 4

[0101] From the dissolution result data in Table 9, it can be seen that in Example 1, hydroxypropyl cellulose and / or hydroxypropyl methylcellulose in a specific ratio are used as a viscosity enhancer, and low-substituted hydroxypropyl cellulose is used as a disintegrant, so that the prepared fine granules have better dissolution performance; adding hydroxypropyl cellulose to the prescription without using low-substituted hydroxypropyl cellulose will slow down the disintegration rate.

Claims

1. A fine granule agent, characterized in that, Comprising the following components:

2. The fine granule according to claim 1, characterized in that, The drug active ingredient is selected from one of arbidol hydrochloride, cloperastine hydrochloride, azithromycin, cefdinir, loxoprofen sodium, and rivaroxaban.

3. The fine granule according to any one of claims 1-2, characterized in that, The filler is selected from one or more of microcrystalline cellulose, lactose, and mannitol; the coating material is selected from one or more of ethyl cellulose, methacrylic acid copolymer, and methacrylic acid aminoalkyl ester copolymer; the plasticizer is selected from one or more of polyethylene glycol, phthalate, and castor oil; the anti-adhesive agent is selected from one or more of talc, silica, and magnesium stearate; the suspending agent is selected from xanthan gum and / or RC591; the lubricant is selected from magnesium stearate and / or talc.

4. The fine granule according to any one of claims 1-3, characterized in that It comprises the following components:

5. The fine granule according to claim 4, wherein, Comprising the following components:

6. The fine granule according to any one of claims 1-5, characterized in that, During the preparation process of the coating layer material, the anti-adhesive agent was first homogenized, and then the anti-adhesive agent solution obtained after homogenization was mixed with the coating material.

7. The fine granule according to any one of claims 1-6, characterized in that, The preparation and coating of the core particles are carried out in a fluidized granulation and coating machine.

8. A method for preparing the fine granule according to any one of claims 1-7, characterized in that, It includes the following steps: Step 1: After crushing the drug active ingredient, add it together with the filler and low-substituted hydroxypropyl cellulose into a fluidized granulation and coating machine, and spray hydroxypropyl cellulose and / or hydroxypropyl methyl cellulose to prepare core particles. Step 2: Homogenize the anti-adhesive agent in 95% ethanol, stir the coating material and plasticizer in 95% ethanol, then add the homogenized anti-adhesive agent into the stirred solution, and continue to stir evenly to obtain the coating layer material. Step 3: Place the core particles in a fluidized granulation and coating machine, start the rotary table speed, control the inlet air temperature and the fan speed, and use the coating layer material for coating. Step 4: Mix the coated particles with the additional materials and divide them into packages.

9. The preparation method of the fine granule according to claim 8, characterized in that It includes the following steps: Step 1: After crushing the drug active ingredient, add it together with the filler and low-substituted hydroxypropyl cellulose into a fluidized granulation and coating machine, set the rotary table speed at 100 - 500 rpm, the inlet air temperature at 40 - 50 °C, the fan speed at 500 - 850 rpm, and the peristaltic pump speed at 8 - 30 rpm, and spray hydroxypropyl cellulose and / or hydroxypropyl methyl cellulose to prepare core particles. Step 2: Homogenize the anti-adhesive agent in 95% ethanol for 10 min, stir the coating material and plasticizer in 95% ethanol for 10 min, then add the homogenized anti-adhesive agent into the stirred solution, and continue to stir evenly to obtain the coating layer material. Step 3: Place the core particles in a fluidized granulation and coating machine, set the rotary table speed at 70 - 90 rpm, the inlet air temperature at 55 - 65 °C, the fan speed at 500 - 850 rpm, set the peristaltic pump speed at 5 - 7.5 rpm, and use the coating layer material for coating. Step 4: Mix the coated particles with the additional materials and divide them into packages.

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