CN115068437A - Preparation method of benzbromarone capsule - Google Patents

Preparation method of benzbromarone capsule Download PDF

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Publication number
CN115068437A
CN115068437A CN202210927909.6A CN202210927909A CN115068437A CN 115068437 A CN115068437 A CN 115068437A CN 202210927909 A CN202210927909 A CN 202210927909A CN 115068437 A CN115068437 A CN 115068437A
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benzbromarone
capsule
granulation
preparing
time
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CN115068437B (en
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钱德拉帕卡提克
王旭丽
曹俊章
李吉荣
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Kunshan Rotam Reddy Pharmaceutical Co ltd
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Kunshan Rotam Reddy Pharmaceutical Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
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  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Inorganic Chemistry (AREA)
  • Pain & Pain Management (AREA)
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  • Physical Education & Sports Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention discloses a preparation method of benzbromarone capsules, which comprises the steps of premixing, primary dry-wet granulation, primary granulation, secondary dry granulation, secondary granulation, sieving, final mixing, capsule filling and the like. The invention adopts secondary dry granulation, so that the capsule is more compact, the drug release effect is consistent with that of a tablet, and the dissolution amount can reach the quality same as that of a reference preparation. In addition, the invention adopts dry granulation, saves a plurality of steps of wet granulation, has simple process and saves cost.

Description

Preparation method of benzbromarone capsule
Technical Field
The invention relates to the technical field of medicines, and in particular relates to a preparation method of a benzbromarone capsule.
Background
Benzbromarone, also known as bromobenzoyl benzofuran, is a strong uric acid-removing benzofuran derivative and has the effect of removing uric acid. The benzbromarone can effectively inhibit reabsorption of uric acid by renal tubules, promote excretion of uric acid and has double functions of reducing blood uric acid concentration.
Benzbromarone is white or almost white crystalline powder, is insoluble in water and slightly soluble in ethanol, is generally prepared by a traditional method of crushing benzbromarone raw materials and then granulating and tabletting, and has the defects that the benzbromarone raw materials are crushed, and after the particle size is reduced, static electricity is easily generated, so that lumps are easily formed due to the electrostatic action in subsequent granulation, the dissolution effect is poor, and the product quality is influenced.
Disclosure of Invention
The invention aims to provide a preparation method of benzbromarone capsules aiming at the prior technical problems, the capsules are filled by a secondary dry granulation process, and the dissolution curve is consistent with that of a reference preparation.
In order to achieve the purpose, the invention adopts the technical scheme that: a preparation method of benzbromarone capsules comprises the following steps:
1) premixing
Sieving benzbromarone and corn starch together, adding the sieved benzbromarone and corn starch into a hopper mixer, and mixing;
2) dry granulation
2.1) first Dry granulation
Carrying out first dry granulation on the premixed material by using a dry granulator;
2.2) first size stabilization
Granulating the materials after the first granulation by a crushing and granulating machine, and sieving;
2.3) second Dry granulation
Performing secondary dry granulation on the granulated material;
2.4) second size stabilization
The materials after the second granulation are firstly granulated for the first time through a crushing and granulating machine, and are sieved by a screen mesh and then granulated for the second time;
calculating the yield of the particles, and converting the dosage of the added auxiliary materials according to the yield;
3) sieving
Sieving lactose and low-substituted hydroxypropyl cellulose respectively, and sieving pulvis Talci and magnesium stearate respectively;
4) final mix
Mixing before lubrication: adding the granules obtained in 2.4) into a mixer, and mixing;
lubrication: adding the converted talcum powder and magnesium stearate into a mixer, and mixing;
5) capsule filling
The capsule mold is used for filling.
Wherein in the step 1), the benzbromarone and the corn starch are screened by a 20-mesh screen; the mixing time after sieving was 30min at 10 rpm.
Wherein, in the step 2.2), the first time of granule finishing is carried out, and 250Q is selected by a screen.
In the step 2.4), after the first time of granule finishing, the material is firstly screened by a 250Q screen, the material passing through 250Q is then screened by a 040G screen, and then the second time of granule finishing is carried out.
In the step 3), the lactose and the low-substituted hydroxypropyl cellulose are respectively sieved by a 40-mesh sieve, and the talcum powder and the magnesium stearate are respectively sieved by a 60-mesh sieve.
Wherein in the step 4), the mixing time of the mixing before lubrication is 45min, and the rotating speed is 10 rpm;
the mixing time for the lubrication was 6min, the rotational speed 8 rpm.
Wherein, in the step 5), the capsule is filled by using a No. 3 capsule mould.
Wherein each benzbromarone capsule contains 50mg of benzbromarone, 10-50mg of corn starch, 20-90mg of lactose, 1-10mg of low-substituted hydroxypropyl cellulose, 0.5-5mg of talcum powder and 0.5-5mg of magnesium stearate.
Wherein each benzbromarone capsule contains 50mg of benzbromarone, 25mg of corn starch, 80mg of lactose, 5mg of low-substituted hydroxypropyl cellulose, 1mg of talcum powder and 1mg of magnesium stearate.
Most of the benzbromarone on the market is tablets, and the slow drug release can be realized by granulation or coating, but the tablets have the problems of poor dissolution rate and low bioavailability. The benzbromarone preparation is rarely used as a capsule because once the capsule is broken, the contained medicinal powder leaks out and acts immediately, and the capsule is broken within 2 to 3 minutes generally. The invention adopts secondary dry granulation, so that the capsule is more compact, the drug release effect is consistent with that of a tablet, and the dissolution amount can reach the quality same as that of a reference preparation. In addition, the conventional capsules are all prepared by a wet method, namely, dry granules are prepared by the wet method and then packaged into the capsules, water is firstly added in the wet method granulation process and then drying is carried out, the process is multiple, time and labor are wasted, and the cost is increased.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Furthermore, it should be understood that various changes or modifications can be made by those skilled in the art after reading the disclosure of the present invention, and such equivalents also fall within the scope of the invention.
Example 1:
table 1 shows the amounts of the raw materials used to prepare the benzbromarone capsules.
TABLE 1
Figure BDA0003780449990000041
1. Premixing
Sieving benzbromarone and corn starch together with a 20-mesh sieve, adding the sieved benzbromarone and corn starch into a hopper mixer, and mixing for 30min at the rotation speed of 10 rpm;
2. dry granulation
2.1. First dry granulation
Carrying out first dry granulation on the premixed material by using a dry granulator, wherein the granulation parameters are as follows:
dry granulation parameters Range
Feeder speed 60～80rpm
Nip of rollers 0.5～1.5mm
Rotational speed of the press rolls 5～20rpm
Pressure of the press roll 60～100Bar
2.2. First size stabilization
Granulating the granulated material by a crushing and granulating machine, and selecting 250Q by a screen;
2.3. second dry granulation
And (3) carrying out secondary dry granulation on the granulated material, wherein the granulation parameters are as follows:
dry granulation parameters Range
Feeder speed 40～80rpm
Nip of rollers 0.5～4.5mm
Rotational speed of the press roll 5～20rpm
Pressure of press roll 60～100Bar
2.4. Second size stabilization
The materials after the secondary granulation are subjected to primary granulation through a crushing granulator, the materials are sieved by a 250Q screen, and the materials after the 250Q screen are subjected to secondary granulation through a 040G screen;
calculating the yield of the particles, and converting the dosage of the added auxiliary materials according to the yield;
3. sieving
Sieving lactose and low-substituted hydroxypropyl cellulose with 40 mesh sieve, respectively sieving pulvis Talci and magnesium stearate with 60 mesh sieve;
4. final mix
Mixing before lubrication: adding the granules, the reduced lactose and the low-substituted hydroxypropyl cellulose into a mixer, mixing for 45min at the rotation speed of 10 rpm;
lubrication: adding the converted talcum powder and magnesium stearate into a mixer, mixing for 6min, and rotating at 8 rpm;
5. capsule filling
Fill using # 3 capsule mold.
The theoretical loading of each grain is as follows: 162mg
theoretical net weight of 20 granules filled 3.24g
Disintegration time limit Within 30min
Example 2: dissolution Performance test
The results of the dissolution curve comparison of the benzbromarone capsule preparation prepared by the invention, the reference preparation and the comparative preparation (wet granulation process capsule) are shown in table 2. The average dissolution amounts of 12 tablets in a phosphate buffer solution (containing 0.25% sodium lauryl sulfate) at pH7.5 in the wet granulation process capsules (specification: 50mg, lot numbers: 200422, 200723, and 200906) of the benzbromarone capsule imitation preparations (specification: 50mg, lot numbers: BEC211103, BEC211104, and BEC211105) and the reference preparation (trade name: URINORM, specification: 50mg, lot number: NIC081, form: tablets) of the present invention were compared. As can be seen from table 2, the dissolution profiles (5 min, 10 min, 15 min, 20 min and 30 min) of the capsule samples prepared by the two-shot dry granulation of the present invention are similar to the tablets of the reference formulation. The in vitro dissolution behavior of each batch of the capsule preparation prepared by the invention is consistent with that of the tablet of the reference preparation, and the quality of the capsule preparation is the same as that of the original ground product.
The invention adopts secondary dry granulation, so that the capsule is more compact, the drug release effect is consistent with that of a tablet, and the dissolution amount can reach the quality same as that of a reference preparation. In addition, the invention adopts dry granulation, saves a plurality of steps of wet granulation, has simple process and saves cost.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention, including any reference to the above-mentioned embodiments. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Figure BDA0003780449990000081

Claims (9)

1. The preparation method of the benzbromarone capsule is characterized by comprising the following steps:
1) premixing
Sieving benzbromarone and corn starch together, adding the sieved benzbromarone and corn starch into a hopper mixer, and mixing;
2) dry granulation
2.1) first Dry granulation
Carrying out first dry granulation on the premixed material by using a dry granulator;
2.2) first size stabilization
Granulating the materials after the first granulation by a crushing and granulating machine, and sieving;
2.3) second Dry granulation
Performing dry granulation on the granulated material for the second time;
2.4) second size stabilization
The materials after the second granulation are firstly granulated for the first time through a crushing and granulating machine, and then granulated for the second time after being screened by a screen mesh;
calculating the yield of the particles, and converting the dosage of the added auxiliary materials according to the yield;
3) sieving
Sieving lactose and low-substituted hydroxypropyl cellulose respectively, and sieving pulvis Talci and magnesium stearate respectively;
4) final mix
Mixing before lubrication: adding the granules obtained in 2.4) into a mixer, and mixing;
lubrication: adding the converted talcum powder and magnesium stearate into a mixer, and mixing;
5) capsule filling
The capsule mold is used for filling.
2. The method for preparing benzbromarone capsules according to claim 1, wherein in step 1), benzbromarone and corn starch are sieved by a 20-mesh sieve; mixing time after sieving is 30min, and the rotating speed is 10 rpm.
3. The method for preparing benzbromarone capsules according to claim 1, wherein in step 2.2), 250Q is selected by a screen after the first time of granule finishing.
4. The method for preparing benzbromarone capsules as claimed in claim 1, wherein in step 2.4), after the first time of size stabilization, the material is sieved by a 250Q sieve, and the material after 250Q is sieved by a 040G sieve, and then the second time of size stabilization is carried out.
5. The method for preparing benzbromarone capsules according to claim 1, wherein in step 3), the lactose and the low-substituted hydroxypropyl cellulose are respectively sieved by a 40-mesh sieve, and the talcum powder and the magnesium stearate are respectively sieved by a 60-mesh sieve.
6. The method for preparing benzbromarone capsules according to claim 1, wherein in the step 4), the mixing time of the mixing before lubrication is 45min, and the rotating speed is 10 rpm;
the mixing time for the lubrication was 6min, the rotational speed 8 rpm.
7. The method for preparing benzbromarone capsules according to claim 1, wherein in the step 5), capsule filling is performed by using a # 3 capsule mold.
8. The method for preparing benzbromarone capsules according to claim 1, wherein each benzbromarone capsule contains 50mg of benzbromarone, 10-50mg of corn starch, 20-90mg of lactose, 1-10mg of low-substituted hydroxypropylcellulose, 0.5-5mg of talcum powder and 0.5-5mg of magnesium stearate.
9. The method for preparing benzbromarone capsules according to claim 1, wherein each benzbromarone capsule contains 50mg of benzbromarone, 25mg of corn starch, 80mg of lactose, 5mg of low-substituted hydroxypropyl cellulose, 1mg of talcum powder and 1mg of magnesium stearate.
CN202210927909.6A 2022-08-03 2022-08-03 Preparation method of benzbromarone capsules Active CN115068437B (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102429881A (en) * 2011-12-01 2012-05-02 常州康普药业有限公司 Method for preparing benzbromarone tablets
US20210283110A1 (en) * 2018-10-15 2021-09-16 Universität Regensburg Compound for use in the treatment of a disease characterized by dysregulated mucus production and/or secretion
CN113425718A (en) * 2021-05-13 2021-09-24 浙江歌文达生物医药科技有限公司 Compound preparation for treating hyperuricemia and gout

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102429881A (en) * 2011-12-01 2012-05-02 常州康普药业有限公司 Method for preparing benzbromarone tablets
US20210283110A1 (en) * 2018-10-15 2021-09-16 Universität Regensburg Compound for use in the treatment of a disease characterized by dysregulated mucus production and/or secretion
CN113425718A (en) * 2021-05-13 2021-09-24 浙江歌文达生物医药科技有限公司 Compound preparation for treating hyperuricemia and gout

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