CN115089550B - Preparation method of mosapride citrate particles - Google Patents

Preparation method of mosapride citrate particles Download PDF

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Publication number
CN115089550B
CN115089550B CN202210933466.1A CN202210933466A CN115089550B CN 115089550 B CN115089550 B CN 115089550B CN 202210933466 A CN202210933466 A CN 202210933466A CN 115089550 B CN115089550 B CN 115089550B
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mosapride citrate
mixing
granulating
finishing
slurry
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CN115089550A (en
Inventor
黄小明
周亚健
陈洁
徐颖
骆翠
王丽云
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Zhejiang Yatai Pharmaceutical Co ltd
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Zhejiang Yatai 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • 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
    • 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
    • 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
    • A61K9/1682—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • 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

Abstract

The invention relates to the field of medicine production, in particular to a preparation method of mosapride citrate particles. The invention relates to a preparation method of mosapride citrate particles, which comprises the following steps: (1) raw and auxiliary materials are pretreated; (2) solvent configuration: adding purified water into ethanol, stirring, adding mosapride citrate with prescribed amount into part of ethanol solution, and turning on stirrer; (3) Granulating, namely adding mannitol and hydroxypropyl cellulose with a prescription amount into a wet mixing granulator, starting stirring and mixing, adding slurry for granulating, finishing adding within 2 minutes, rinsing a slurry barrel with the rest ethanol water solution, performing total granulation for 4 minutes from slurry pouring, cutting and granulating for 1 minute, and discharging; (4) wet finishing: sieving with 20 mesh sieve, and wet finishing; (5) drying; (6) dry granulation: swing and pass through a 30-mesh sieve; (7) total mixing: adding magnesium stearate and silicon dioxide for total mixing; and (8) filling.

Description

Preparation method of mosapride citrate particles
Technical Field
The invention relates to the field of medicine production, in particular to a preparation method of mosapride citrate particles.
Background
Mosapride citrate is a prokinetic drug, is an agonist of selective 5-hydroxytryptamine 4 receptor, can promote the release of acetylcholine so as to promote gastrointestinal tract movement, can improve functional dyspepsia symptoms, such as abdominal distension and constipation of patients, and has good effect when taken. Has good therapeutic effect on gastroparesis caused by gastroesophageal reflux disease, diabetes, etc., nausea, early satiety, and upper abdominal distention and pain caused by dyspepsia.
The existing mosapride citrate medicament is generally tablets, for example, the patents CN104188927A, CN107684548A and the like are tablets, and the tablets are inconvenient for swallowing by special people such as children.
The prior art CN104940148A discloses a mosapride citrate granule and a preparation method thereof, however, the application must use polyethylene glycol, and melting mosapride citrate and polyethylene glycol is required. The crystal form of the raw materials can be changed after the raw materials are melted. Different crystal forms of the raw materials have different chemical and physical characteristics and influence the stability, solubility and bioavailability of the preparation.
Disclosure of Invention
The invention hopefully provides a preparation method of mosapride citrate particles, which comprises the following specific scheme:
a preparation method of mosapride citrate particles comprises the following steps:
(1) Pretreatment of raw materials and auxiliary materials: mosapride citrate is crushed until D90 is smaller than 5um, mannitol and hydroxypropyl cellulose are respectively sieved by a sieve with 40 meshes, and magnesium stearate and superfine silica powder are respectively sieved by a sieve with 20 meshes;
(2) Solvent configuration: adding purified water into ethanol, stirring, adding mosapride citrate with prescribed amount into part of ethanol solution, and turning on stirrer;
(3) Granulating, namely adding mannitol and hydroxypropyl cellulose with a prescription amount into a wet mixing granulator, starting stirring and mixing, adding slurry for granulating, finishing adding within 2 minutes (including 2 minutes), rinsing a slurry barrel with the rest ethanol water solution, performing total granulation for 4 minutes from slurry pouring, cutting and granulating for 1 minute, and discharging;
(4) Wet finishing: sieving with 20 mesh sieve, and wet finishing;
(5) Drying;
(6) And (3) dry finishing: swing and pass through a 30-mesh sieve;
(7) Total mixing: adding magnesium stearate and silicon dioxide for total mixing;
(8) And (5) filling.
The mass ratio of the mosapride citrate to the mannitol to the hydroxypropyl cellulose to the silicon dioxide to the magnesium stearate is 4:371.8:20:2:2.
The mass fraction of the ethanol solution in the step (2) is 60-65%.
The mass ratio of the ethanol solution used in the steps (2) and (3) is 5-5.1:1.5.
The air inlet temperature in the step (5) is 50 ℃, the drying time is more than or equal to 3min, and the drying weight loss is less than or equal to 1.0%.
The filling steps are as follows: before filling, opening the air inlet compression pipe, checking the air pressure to be 0.4-0.8 MPa, the front longitudinal temperature to be 110-140 ℃, the rear longitudinal temperature to be 110-140 ℃, the front transverse temperature to be 110-140 ℃, the rear transverse temperature to be 110-140 ℃ and the host speed: 100-300 bags/min, wherein the sampling frequency is 30 min/time in the packaging process, 10 bags are respectively packaged, the average packaging amount is controlled to be +/-2.0%, and the packaging difference is controlled to be +/-7.0%.
Mannitol in the invention: mannitol can be used in direct compression and wet granulation processes. The mannitol-containing granule has the advantage of easy drying, and is suitable for heat sensitive medicine. Mannitol has sweetness and good taste due to its negative heat of solution, and is generally used as an excipient for chewable tablets and granules. Silica: the product is white amorphous powder with fine odor-free hygroscopicity, and is mainly used as disintegrating agent, anti-adhesion agent and glidant in pharmaceutical preparation. The product can greatly improve granule fluidity, increase bulk density, increase hardness of the prepared tablet, shorten disintegration time, and increase drug dissolution rate; the product can also be used as internal desiccant to improve stability of hygroscopic drug. Magnesium stearate: has lubricating, anti-adhesion, and glidant effects. Used as lubricants, glidants or anti-tackifiers in tablets, capsules. Magnesium stearate and silica mainly improve the flowability of the granules in the formulation.
And the raw and auxiliary materials of the invention are pretreated: the freeze-drying treatment process of the mosapride citrate inclusion compound raw materials in the mosapride citrate dispersible tablets in the prior art is time-consuming and labor-consuming, and has complex process for workshops and needs to be operated cooperatively across workshops. The mosapride citrate granule raw material only needs to be crushed to control the grain diameter D90 to be less than 5 mu m, and when the raw material is in the interval, the dissolution is quick. When the particle size of the raw material increases beyond this range, dissolution decreases. Preparing slurry: the content of the API (mosapride citrate) of the mosapride citrate granule is about 1% in the prescription, and the API has high risk of uneven mixing in the dry mixing stage, so that the API is added into the adhesive in the prescription design stage to ensure the mixing uniformity of materials. Total mixing and dry finishing: the prior art of the mosapride citrate dispersible tablet adopts the steps of firstly mixing and then drying and granulating, which is opposite to the process of the mosapride citrate granules. The way of total mixing and granulating of the dispersible tablets has extrusion and slight mixing effect on the granulating machine of the granules and the additional auxiliary materials, which can have a certain influence on dissolution.
Detailed Description
Example 1
(1) Pretreatment of raw materials and auxiliary materials: the API is crushed until the D90 is smaller than 5um (specifically 2.2 um), mannitol and hydroxypropyl cellulose are respectively sieved by a sieve of 40 meshes, and magnesium stearate and superfine silica powder are respectively sieved by a sieve of 20 meshes.
(2) Solvent configuration: taking 4.12kg of ethanol, adding purified water to 6.52kg, stirring uniformly, taking 5.02kg of ethanol solution from the mixture, adding the prescription dose of mosapride citrate, starting a stirrer at 3500-4500rpm, stirring for 60min, and keeping 1.5kg of ethanol water solution for later use.
(3) Granulating the prescribed amount of mannitol and hydroxypropyl cellulose are added into a wet mixing granulator, stirring is started for 70rpm mixing for 10 minutes, the slurry is added for granulating, the slurry is added for 2 minutes, a slurry barrel is moistened with the rest 1.50kg of ethanol water solution, the total process is total granulating for 4 minutes, cutting is started for granulating for 1 minute at 900rpm, and discharging is carried out.
(4) Wet finishing: the soft material is sieved by a 20-mesh sieve for wet granulation.
(5) And (3) drying: setting the air inlet temperature to 50 ℃, drying for more than or equal to 3min, drying weight loss less than or equal to 1.0%, and discharging.
(6) And (3) dry finishing: swing through 30 mesh sieve.
(7) Total mixing: adding magnesium stearate and silicon dioxide, mixing for 5min, and mixing at a speed of: 40Hz, and discharging. Sampling and detecting intermediate particles.
The effect is as follows: the fluidity of the particles becomes good, the filling and discharging of the particles are smooth, and the filling quantity difference is stable. Because mannitol auxiliary materials are over multipolar and easy to absorb moisture, the stability of the medicament with hygroscopicity can be greatly improved by adding magnesium stearate and micro-powder silica gel
(8) And (3) filling: according to the particle detection content, calculating the instruction loading quantity, carrying out formal packaging, opening a compressed air inlet pipe before filling, checking the air pressure to be 0.4-0.8 MPa, the front longitudinal temperature to be 110-140 ℃, the rear longitudinal temperature to be 110-140 ℃, the front transverse temperature to be 110-140 ℃, the rear transverse temperature to be 110-140 ℃ and the host speed by an operator: 100-300 bags/min, wherein the sampling frequency is 30 min/time in the packaging process, 10 bags are respectively packaged, the average packaging amount is controlled to be +/-2.0%, and the packaging difference is controlled to be +/-7.0%.
Examples 2 to 3 (the following examples are the same as example 1 except that the contents in the tables are different, for explaining the effect of magnesium stearate and silica in combination)
Examples 4-5 (the following examples are otherwise identical to example 1, except for the differences in the table, for studying the effect of different aqueous ethanol concentrations in step (2)
Examples 6 to 8 (the following examples are the same as example 1 except that the contents in the tables are different, and the effect of the particle size of the raw material in step (2) is examined)
Examples 9 to 10 (the following examples are all the same as example 1 except that the contents in the table are different, and the effect of the addition time of the slurry in step (3) was investigated)
The above embodiments are only for illustrating the inventive concept of the present invention and not for limiting the protection of the claims of the present invention, and all the insubstantial modifications of the present invention using the concept shall fall within the protection scope of the present invention.

Claims (1)

1. A method for preparing mosapride citrate particles, which is characterized by comprising the following steps:
(1) Pretreatment of raw materials and auxiliary materials: mosapride citrate is crushed until D90 is smaller than 5um, mannitol and hydroxypropyl cellulose are respectively sieved by a sieve with 40 meshes, and magnesium stearate and superfine silica powder are respectively sieved by a sieve with 20 meshes;
(2) Solvent configuration: adding purified water into ethanol, stirring, adding mosapride citrate with prescribed amount into part of ethanol solution, and turning on stirrer;
(3) Granulating, namely adding mannitol and hydroxypropyl cellulose with a prescription amount into a wet mixing granulator, starting stirring and mixing, adding slurry for granulating, finishing adding within 2 minutes, rinsing a slurry barrel with the rest ethanol water solution, performing total granulation for 4 minutes from slurry pouring, cutting and granulating for 1 minute, and discharging;
(4) Wet finishing: sieving with 20 mesh sieve, and wet finishing;
(5) Drying;
(6) And (3) dry finishing: swing and pass through a 30-mesh sieve;
(7) Total mixing: adding magnesium stearate and silicon dioxide for total mixing;
(8) Filling;
the mass ratio of the mosapride citrate to the mannitol to the hydroxypropyl cellulose to the silicon dioxide to the magnesium stearate is 4:371.8:20:2:2; the mass fraction of the ethanol solution in the step (2) is 60-65%; the mass ratio of the ethanol solution used in the steps (2) and (3) is 5-5.1:1.5; the air inlet temperature in the step (5) is 50 ℃, the drying time is more than or equal to 3min, and the drying weight loss is less than or equal to 1.0%; the filling steps are as follows: before filling, opening the air inlet compression pipe, checking the air pressure to be 0.4-0.8 MPa, the front longitudinal temperature to be 110-140 ℃, the rear longitudinal temperature to be 110-140 ℃, the front transverse temperature to be 110-140 ℃, the rear transverse temperature to be 110-140 ℃ and the host speed: 100-300 bags/min, wherein the sampling frequency is 30 min/time in the packaging process, 10 bags are respectively packaged, the average packaging amount is controlled to be +/-2.0%, and the packaging difference is controlled to be +/-7.0%.
CN202210933466.1A 2022-08-04 2022-08-04 Preparation method of mosapride citrate particles Active CN115089550B (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20150075959A (en) * 2013-12-26 2015-07-06 한국유나이티드제약 주식회사 Capsule containing mini-tablets comprising mosapride citrate for sustained-releasing formulation improving gastrointestinal disease and preparing the method thereof
CN104940148A (en) * 2015-07-11 2015-09-30 鲁南制药集团股份有限公司 Mosapride citrate granules and preparation method thereof
CN106913879A (en) * 2015-12-28 2017-07-04 山东新时代药业有限公司 A kind of Mosapride Citrate Tablets agent and preparation method thereof
CN108324697A (en) * 2017-01-19 2018-07-27 科贝源(北京)生物医药科技有限公司 A kind of capsule and preparation method thereof containing mosapride citrate

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4740740B2 (en) * 2003-12-09 2011-08-03 大日本住友製薬株式会社 Drug-containing particles and solid preparation containing the particles

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20150075959A (en) * 2013-12-26 2015-07-06 한국유나이티드제약 주식회사 Capsule containing mini-tablets comprising mosapride citrate for sustained-releasing formulation improving gastrointestinal disease and preparing the method thereof
CN104940148A (en) * 2015-07-11 2015-09-30 鲁南制药集团股份有限公司 Mosapride citrate granules and preparation method thereof
CN106913879A (en) * 2015-12-28 2017-07-04 山东新时代药业有限公司 A kind of Mosapride Citrate Tablets agent and preparation method thereof
CN108324697A (en) * 2017-01-19 2018-07-27 科贝源(北京)生物医药科技有限公司 A kind of capsule and preparation method thereof containing mosapride citrate

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