CN116747206B - Flunarizine hydrochloride capsule and preparation method thereof - Google Patents

Flunarizine hydrochloride capsule and preparation method thereof Download PDF

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Publication number
CN116747206B
CN116747206B CN202310831048.6A CN202310831048A CN116747206B CN 116747206 B CN116747206 B CN 116747206B CN 202310831048 A CN202310831048 A CN 202310831048A CN 116747206 B CN116747206 B CN 116747206B
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flunarizine hydrochloride
film coating
coating agent
layer film
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CN116747206A (en
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殷金喜
曲金栋
罗伟成
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Guangdong PD Pharmaceutical Co ltd
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Guangdong PD Pharmaceutical Co ltd
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    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/501—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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

A flunarizine hydrochloride capsule and its preparation method, the technical field of pharmaceutical preparation, the granule main ingredient in the capsule includes flunarizine hydrochloride 5-10 parts and pregelatinized starch 30-40 parts; the granule is two layers of film coated granule, and the solid capsule is prepared by encapsulating. The invention designs two components of the flunarizine hydrochloride and the pregelatinized starch for granulation, so that the types of the granule components are reduced to the greatest extent, and the property of the flunarizine hydrochloride is not influenced after long-term storage to the greatest extent. The granulating particles are designed to be coated in two layers, and the inner layer coating has the properties of water resistance, moisture resistance and crack resistance, protects the components of the particles from deterioration, and can also protect the particles from powder removal; the outer coating has further moisture and mildew resistance and corrosion resistance, and further protects the particle components from deterioration. Further greatly prolongs the shelf life of the flunarizine hydrochloride, and the dissolution rate of the active ingredients is not greatly reduced when the flunarizine hydrochloride is stored for a long time, thus having good practical value.

Description

Flunarizine hydrochloride capsule and preparation method thereof
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a flunarizine hydrochloride capsule and a preparation method thereof.
Background
The flunarizine hydrochloride is a calcium channel blocker, and can block excessive calcium ions from entering cells through a membrane, prevent excessive calcium load in the cells and relieve vasospasm; is mainly used for treating cerebral arteriosclerosis, cerebral thrombosis, cerebral embolism, cerebral circulation disorder caused by hypertension, cerebral hemorrhage, cerebral circulation disorder caused by arachnoid and mental nerve symptom caused by cerebral circulation disorder; can be used for preventing and treating motion sickness, dizziness, tinnitus, intractable urticaria, bronchiectasis hemoptysis, migraine, epilepsy, etc.
At present, the flunarizine hydrochloride solid medicament has poor stability, the content of active ingredients is reduced, the content of impurities is increased, the dissolution rate of the active ingredients is obviously reduced, and the medication safety and the medication efficacy are affected when the flunarizine hydrochloride solid medicament is stored for a long time. Therefore, the stability of the flunarizine hydrochloride medicine is improved, the storage time is prolonged, and the high-quality medicine effect dissolution rate is ensured, so that the problem which is always needed to be solved is solved.
In the current market, in order to improve the dissolution rate, there are schemes of crushing flunarizine hydrochloride into micro powder, adopting polyethylene glycol for dispersion and then freeze-drying for crushing, and adopting N, N-dimethylformamide for recrystallising the flunarizine hydrochloride. The method can improve the dissolution rate to a certain extent when the preparation or short-term storage is carried out, but the long-term storage effect is still poor, the stability of the flunarizine hydrochloride medicine is improved at present, the storage time is prolonged, and meanwhile, the high-quality dissolution rate is ensured, so that the problem which is always needed to be solved is still solved.
Disclosure of Invention
Aiming at the problems of unstable quality and reduced dissolution rate after long-term storage of the existing flunarizine hydrochloride solid preparation, the invention provides a flunarizine hydrochloride capsule and a preparation method thereof, wherein two components of flunarizine hydrochloride and pregelatinized starch are designed for granulation, so that the types of the particle components are reduced to the greatest extent, and the property of flunarizine hydrochloride is not influenced after long-term storage to the greatest extent. The granulating particles are designed to be coated in two layers, and the inner layer coating has the properties of water resistance, moisture resistance and crack resistance, protects the components of the particles from deterioration, and can also protect the particles from powder removal; the outer coating has further moisture and mildew resistance and corrosion resistance, and further protects the particle components from deterioration. Further greatly prolonging the shelf life of the flunarizine hydrochloride, and preventing the dissolution of the effective components from being greatly reduced during long-term storage. The specific technical scheme is as follows:
the main components of the granule in the capsule comprise 5-10 parts of flunarizine hydrochloride and 30-40 parts of pregelatinized starch; the preparation method is characterized in that the granules are two layers of film coated granules, and the solid capsules are prepared by adopting capsule encapsulation.
In the technical scheme, the flunarizine hydrochloride is newly prepared flunarizine hydrochloride.
The preparation method of the flunarizine hydrochloride capsule is used for preparing the flunarizine hydrochloride capsule, and comprises the following steps:
s1: respectively carrying out jet milling on the flunarizine hydrochloride and the pregelatinized starch raw material to obtain micron-sized or nano-sized powder with the granularity smaller than 2 um; and then uniformly mixing the materials in an airflow mode according to the mass ratio of flunarizine hydrochloride to pregelatinized starch= (5-10) to (30-40) to obtain mixed powder.
S2: mixing the purified water, polyvinylpyrrolidone and absolute ethyl alcohol with the mass ratio of 100:3-15:8-15, and preparing the spray.
S3: granulating the mixed powder and the spray by adopting a fluidized spray granulation method, wherein the parameters are as follows: the spray has a temperature of 20-30 ℃, a spraying speed of 0.2-0.3L/min, an atomization pressure of 0.2-0.4 MPa, and a drying temperature of 50-55 ℃ to obtain granulated particles with a particle diameter of less than 0.5 mm.
S4: coating the granulated particles and the inner layer film coating agent by adopting a fluidized spraying method, wherein the parameters are as follows: the temperature of the inner layer film coating agent is 20-30 ℃, the spraying speed of the inner layer film coating agent is 0.5-0.8L/min, the atomization pressure is 0.2-0.3 MPa, and the drying temperature is 35-40 ℃; and drying to obtain the primary coating granule.
S5: the primary coating granule and the outer layer film coating agent are coated by adopting a fluidization spraying method, and the parameters are as follows: the temperature of the outer layer film coating agent is 35-40 ℃, the spraying speed is 0.3-0.4L/min, the atomization pressure is 0.1-0.3 MPa, and the drying temperature is 45-55 ℃; and drying to obtain a secondary coating granule, and finally, carrying out liquid nitrogen freeze-drying, and encapsulating to obtain the flunarizine hydrochloride capsule.
In the S4 of the method, the premix of the inner layer film coating agent comprises, by mass, 30-50 parts of a composite film forming agent, 0.1-2 parts of an adhesive, 0.5-2 parts of a dampproof agent, 0.2-2 parts of an anticracking agent, 2-5 parts of a glidant and 8-12 parts of a plasticizer; the composite film forming agent comprises the following components in percentage by mass of hydroxypropyl methylcellulose, polyvinyl alcohol, copovidone and beta-cyclodextrin= (2-6) to (1-3) to (1-2) to (0.01-0.1); the adhesive is polyvinylpyrrolidone; the moisture-proof agent is diatomite; the anticracking agent is nanocrystalline cellulose NCC; the glidant is talcum powder; the plasticizer is polyethylene glycol 6000, polyethylene glycol 300 or polyethylene glycol 400; the premix is diluted and dissolved by purified water to obtain the inner layer film coating agent, and the mass concentration is 5-15%.
In the S5 of the method, the premix of the outer layer film coating agent comprises, by mass, 20-30 parts of hydroxypropyl methylcellulose, 10-15 parts of polyvinyl alcohol, 10-20 parts of corn starch, 0.1-2 parts of an adhesive, 2-5 parts of a glidant, 8-12 parts of a plasticizer and 0.1-0.3 part of a medicinal preservative; the adhesive is polyvinylpyrrolidone; the glidant is talcum powder; the plasticizer is polyethylene glycol 6000, polyethylene glycol 300 or polyethylene glycol 400; the premix is diluted and dissolved by purified water to obtain the outer layer film coating agent, and the mass concentration is 5-10%.
Compared with the prior art, the flunarizine hydrochloride capsule and the preparation method thereof have the beneficial effects that:
1. the invention designs the flunarizine hydrochloride and the pregelatinized starch as main raw materials for granulation, the types of the material components for granulation are few, other components such as lactose, magnesium stearate and the like are not contained, the property of the flunarizine hydrochloride is not affected after the flunarizine hydrochloride is stored, the rapid deterioration is avoided, and the storage time can be prolonged.
2. The pregelatinized starch is designed to be matched with the viscosity of polyvinylpyrrolidone to carry out granulation, so that the dosage of polyvinylpyrrolidone can be reduced, the granulation parameters and the granularity of the granulation raw materials are designed according to the properties of the raw materials, the granulation effect can be achieved, the dosage of polyvinylpyrrolidone can be reduced, the properties of flunarizine hydrochloride are well kept unaffected, and the storage time is ensured. After granulation, the granules are not as compact as tablets, so that the pregelatinized starch can quickly absorb water and disintegrate when taken, thereby quickly releasing the flunarizine hydrochloride and promoting absorption.
3. The invention designs the granulating particle to coat by adopting the inner layer film coating agent, on one hand, because the surface viscosity of the granulating particle for reducing the dosage of polyvinylpyrrolidone is low and the powder is loose, a special coating step and the components of the coating agent are designed, and the components of the inner layer film coating agent can well consolidate the surface compactibility of the granulating particle and can not generate the surface powder removing phenomenon. Especially, the addition of the copovidone, the beta-cyclodextrin and the nanocrystalline cellulose NCC can improve the toughness of the coating surface, and prevent water and crack; the diatomite is added to have water absorption and good water resistance and moisture resistance; the combination effect of the components can not only protect the granulated particles from powder removal, but also well ensure that the granulated particles are isolated from the outside air, and are dampproof and mildew-proof, so that the shelf life of the flunarizine hydrochloride is greatly prolonged, and the dissolution rate of the active ingredients is not greatly reduced during long-term storage.
4. The invention designs a method for sequentially coating the particles for secondary coating, and the outer coating can further isolate moisture and bacteria, prevent mildew and moisture and prolong the shelf life of the particles. In addition, because the two layers of film coatings are thicker, the release speed of the medicine can be influenced, corn starch is added into the outer layer film coating agent, after the medicine is taken, the corn starch can accelerate the disintegration and dissolution speed of the coating, and the problem that the release speed of the medicine can be delayed due to the two layers of film coatings is effectively solved.
5. The invention designs coating parameters aiming at granule properties and components of the coating agent, can well prepare a thin and compact film coating layer, and has good protection.
6. The invention designs that the inner coating agent is added with beta-cyclodextrin and nanocrystalline cellulose NCC to combine with the outer coating agent to add corn starch, and the combination firmness of the inner coating layer and the outer coating layer can be improved.
7. In order to prevent incomplete coating drying and influence on long-term storage stability, the invention carries out liquid nitrogen freeze-drying after the coating drying, thereby further improving the storage stability of the flunarizine hydrochloride.
In summary, the invention designs two components of the flunarizine hydrochloride and the pregelatinized starch for granulation, so that the types of the granule components are reduced to the greatest extent, and the property of the flunarizine hydrochloride is not influenced after long-term storage to the greatest extent. The granulating particles are designed to be coated in two layers, and the inner layer coating has the properties of water resistance, moisture resistance and crack resistance, protects the components of the particles from deterioration, and can also protect the particles from powder removal; the outer coating has further moisture and mildew resistance and corrosion resistance, and further protects the particle components from deterioration. Further greatly prolonging the shelf life of the flunarizine hydrochloride, and preventing the dissolution of the effective components from being greatly reduced during long-term storage.
Detailed Description
The invention will be further illustrated with reference to specific examples, but the invention is not limited to these examples.
Example 1
The main components of the granule in the capsule comprise 8 parts of flunarizine hydrochloride and 35 parts of pregelatinized starch; the preparation method is characterized in that the granules are two layers of film coated granules, and the solid capsules are prepared by adopting capsule encapsulation.
The preparation method of the flunarizine hydrochloride capsule is used for preparing the flunarizine hydrochloride capsule, and comprises the following steps:
s1: respectively carrying out jet milling on the flunarizine hydrochloride and the pregelatinized starch raw material to obtain powder with the granularity of less than 2 um; and then uniformly mixing the components by airflow according to the mass ratio of the flunarizine hydrochloride to the pregelatinized starch=8:35 to obtain mixed powder.
S2: mixing the above materials according to the mass ratio of purified water to polyvinylpyrrolidone to absolute ethyl alcohol=100:10:10, and making into spray.
S3: granulating the mixed powder and the spray by adopting a fluidized spray granulation method, wherein the parameters are as follows: the spray has a temperature of 25deg.C, a spray speed of 0.3L/min, an atomization pressure of 0.3MPa, and a drying temperature of 50deg.C to obtain granulated particles with particle diameter of below 0.5 mm.
S4: coating the granulated particles and the inner layer film coating agent by adopting a fluidized spraying method, wherein the parameters are as follows: the temperature of the inner layer film coating agent is 25 ℃, the spraying speed of the inner layer film coating agent is 0.6L/min, the atomization pressure is 0.3MPa, and the drying temperature is 40 ℃; and drying to obtain the primary coating granule.
Wherein, the premix of the inner film coating agent comprises 40 parts of composite film forming agent, 1 part of adhesive, 1 part of moisture-proof agent, 1 part of anticracking agent, 3 parts of glidant and 10 parts of plasticizer; the composition mass ratio of the composite film forming agent is hydroxypropyl methylcellulose, polyvinyl alcohol, copovidone and beta-cyclodextrin=4:2:1.5:0.05; the adhesive is polyvinylpyrrolidone; the moisture-proof agent is diatomite; the anticracking agent is nanocrystalline cellulose NCC; the glidant is talcum powder; the plasticizer is polyethylene glycol 6000; the premix is diluted and dissolved by purified water to obtain the inner layer film coating agent with the mass concentration of 10 percent.
S5: the primary coating granule and the outer layer film coating agent are coated by adopting a fluidization spraying method, and the parameters are as follows: the temperature of the outer layer film coating agent is 35 ℃, the spraying speed is 0.4L/min, the atomization pressure is 0.2MPa, and the drying temperature is 50 ℃; and drying to obtain a secondary coating granule, and finally, carrying out liquid nitrogen freeze-drying, and encapsulating to obtain the flunarizine hydrochloride capsule.
Wherein the premix of the outer film coating agent comprises, by mass, 25 parts of hypromellose, 12 parts of polyvinyl alcohol, 15 parts of corn starch, 1 part of an adhesive, 3 parts of a glidant, 10 parts of a plasticizer and 0.18 part of a medicinal preservative; the adhesive is polyvinylpyrrolidone; the glidant is talcum powder; the plasticizer is polyethylene glycol 6000; the premix is diluted and dissolved by purified water to obtain the outer layer film coating agent with the mass concentration of 8 percent.
The flunarizine hydrochloride capsules prepared in this example were directly subjected to dissolution test, and after storage for different periods at 40±2 ℃ and 70±5% humidity, the dissolution test was performed, and the moisture absorption, swelling and mildew conditions of the particle appearance were observed. And under the dissolution test condition, 25mL of 10% diluted hydrochloric acid is added with water to 1000mL of the diluted hydrochloric acid to be used as an in-vitro solvent, the rotating speed is 60r/min, and the dissolution test is carried out at 10min, 20min and 30min respectively. The number of each test sample for dissolution test was 12 capsules, and the test results are shown in table 1.
Example 2
The main components of the granule in the capsule comprise 5 parts of flunarizine hydrochloride and 30 parts of pregelatinized starch; the preparation method is characterized in that the granules are two layers of film coated granules, and the solid capsules are prepared by adopting capsule encapsulation.
The preparation method of the flunarizine hydrochloride capsule is used for preparing the flunarizine hydrochloride capsule, and comprises the following steps:
s1: respectively carrying out jet milling on the flunarizine hydrochloride and the pregelatinized starch raw material to obtain powder with the granularity of less than 2 um; and then uniformly mixing the components by airflow according to the mass ratio of the flunarizine hydrochloride to the pregelatinized starch=5:30 to obtain mixed powder.
S2: mixing the above materials according to the mass ratio of purified water to polyvinylpyrrolidone to absolute ethyl alcohol=100:3:8, and making into spray.
S3: granulating the mixed powder and the spray by adopting a fluidized spray granulation method, wherein the parameters are as follows: the spray has a temperature of 20deg.C, a spray speed of 0.2L/min, an atomization pressure of 0.2MPa, and a drying temperature of 50deg.C to obtain granulated particles with a particle diameter of below 0.5 mm.
S4: coating the granulated particles and the inner layer film coating agent by adopting a fluidized spraying method, wherein the parameters are as follows: the temperature of the inner layer film coating agent is 20 ℃, the spraying speed of the inner layer film coating agent is 0.5L/min, the atomization pressure is 0.2MPa, and the drying temperature is 35 ℃; and drying to obtain the primary coating granule.
Wherein the premix of the inner film coating agent comprises, by mass, 30 parts of a composite film forming agent, 0.1 part of an adhesive, 0.5 part of a moisture-proof agent, 0.2 part of an anticracking agent, 2 parts of a glidant and 8 parts of a plasticizer; the composition mass ratio of the composite film forming agent is hydroxypropyl methylcellulose, polyvinyl alcohol, copovidone and beta-cyclodextrin=2:1:1:0.01; the adhesive is polyvinylpyrrolidone; the moisture-proof agent is diatomite; the anticracking agent is nanocrystalline cellulose NCC; the glidant is talcum powder; the plasticizer is polyethylene glycol 300; the premix is diluted and dissolved by purified water to obtain the inner layer film coating agent with the mass concentration of 5 percent.
S5: the primary coating granule and the outer layer film coating agent are coated by adopting a fluidization spraying method, and the parameters are as follows: the temperature of the outer layer film coating agent is 35 ℃, the spraying speed is 0.3L/min, the atomization pressure is 0.1MPa, and the drying temperature is 45 ℃; and drying to obtain a secondary coating granule, and finally, carrying out liquid nitrogen freeze-drying, and encapsulating to obtain the flunarizine hydrochloride capsule.
Wherein the premix of the outer film coating agent comprises 20 parts by mass of hypromellose, 10 parts by mass of polyvinyl alcohol, 10 parts by mass of corn starch, 0.1 part by mass of adhesive, 2 parts by mass of glidant, 8 parts by mass of plasticizer and 0.26 part by mass of medicinal preservative; the adhesive is polyvinylpyrrolidone; the glidant is talcum powder; the plasticizer is polyethylene glycol 300; the premix is diluted and dissolved by purified water to obtain the outer layer film coating agent with the mass concentration of 5 percent.
The flunarizine hydrochloride capsules prepared in this example were directly subjected to dissolution test, and after storage for different periods at 40±2 ℃ and 70±5% humidity, the dissolution test was performed, and the moisture absorption, swelling and mildew conditions of the particle appearance were observed. And under the dissolution test condition, 25mL of 10% diluted hydrochloric acid is added with water to 1000mL of the diluted hydrochloric acid to be used as an in-vitro solvent, the rotating speed is 60r/min, and the dissolution test is carried out at 10min, 20min and 30min respectively. The number of each test sample for dissolution test was 12 capsules, and the test results are shown in table 1.
Example 3
The main components of the granule in the capsule comprise 10 parts of flunarizine hydrochloride and 40 parts of pregelatinized starch; the preparation method is characterized in that the granules are two layers of film coated granules, and the solid capsules are prepared by adopting capsule encapsulation.
The preparation method of the flunarizine hydrochloride capsule is used for preparing the flunarizine hydrochloride capsule, and comprises the following steps:
s1: respectively carrying out jet milling on the flunarizine hydrochloride and the pregelatinized starch raw material to obtain powder with the granularity of less than 2 um; and then uniformly mixing the components by airflow according to the mass ratio of the flunarizine hydrochloride to the pregelatinized starch=10:40 to obtain mixed powder.
S2: mixing the above materials according to the mass ratio of purified water to polyvinylpyrrolidone to absolute ethyl alcohol=100:15:15, and making into spray.
S3: granulating the mixed powder and the spray by adopting a fluidized spray granulation method, wherein the parameters are as follows: the spray has a temperature of 30deg.C, a spray speed of 0.3L/min, an atomization pressure of 0.4MPa, and a drying temperature of 55deg.C to obtain granulated particles with a particle diameter of below 0.5 mm.
S4: coating the granulated particles and the inner layer film coating agent by adopting a fluidized spraying method, wherein the parameters are as follows: the temperature of the inner layer film coating agent is 30 ℃, the spraying speed of the inner layer film coating agent is 0.8L/min, the atomization pressure is 0.3MPa, and the drying temperature is 40 ℃; and drying to obtain the primary coating granule.
Wherein the premix of the inner film coating agent comprises, by mass, 50 parts of a composite film forming agent, 2 parts of an adhesive, 2 parts of a moisture-proof agent, 2 parts of an anti-cracking agent, 5 parts of a glidant and 12 parts of a plasticizer; the composition mass ratio of the composite film forming agent is hydroxypropyl methylcellulose, polyvinyl alcohol, copovidone and beta-cyclodextrin=6:3:2:0.1; the adhesive is polyvinylpyrrolidone; the moisture-proof agent is diatomite; the anticracking agent is nanocrystalline cellulose NCC; the glidant is talcum powder; the plasticizer is polyethylene glycol 400; the premix is diluted and dissolved by purified water to obtain the inner layer film coating agent with the mass concentration of 15 percent.
S5: the primary coating granule and the outer layer film coating agent are coated by adopting a fluidization spraying method, and the parameters are as follows: the temperature of the outer layer film coating agent is 40 ℃, the spraying speed is 0.4L/min, the atomization pressure is 0.3MPa, and the drying temperature is 55 ℃; and drying to obtain a secondary coating granule, and finally, carrying out liquid nitrogen freeze-drying, and encapsulating to obtain the flunarizine hydrochloride capsule.
Wherein the premix of the outer film coating agent comprises, by mass, 30 parts of hypromellose, 15 parts of polyvinyl alcohol, 20 parts of corn starch, 2 parts of an adhesive, 5 parts of a glidant, 12 parts of a plasticizer and 0.2 part of a medicinal preservative; the adhesive is polyvinylpyrrolidone; the glidant is talcum powder; the plasticizer is polyethylene glycol 400; the premix is diluted and dissolved by purified water to obtain the outer layer film coating agent with the mass concentration of 10 percent.
The flunarizine hydrochloride capsules prepared in this example were directly subjected to dissolution test, and after storage for different periods at 40±2 ℃ and 70±5% humidity, the dissolution test was performed, and the moisture absorption, swelling and mildew conditions of the particle appearance were observed. And under the dissolution test condition, 25mL of 10% diluted hydrochloric acid is added with water to 1000mL of the diluted hydrochloric acid to be used as an in-vitro solvent, the rotating speed is 60r/min, and the dissolution test is carried out at 10min, 20min and 30min respectively. The number of each test sample for dissolution test was 12 capsules, and the test results are shown in table 1.
Example 4
The main components of the granule in the capsule comprise 5 parts of flunarizine hydrochloride and 40 parts of pregelatinized starch; the preparation method is characterized in that the granules are two layers of film coated granules, and the solid capsules are prepared by adopting capsule encapsulation.
The preparation method of the flunarizine hydrochloride capsule is used for preparing the flunarizine hydrochloride capsule, and comprises the following steps:
s1: respectively carrying out jet milling on the flunarizine hydrochloride and the pregelatinized starch raw material to obtain powder with the granularity of less than 2 um; and then uniformly mixing the components by airflow according to the mass ratio of the flunarizine hydrochloride to the pregelatinized starch=5:40 to obtain mixed powder.
S2: mixing the above materials according to the mass ratio of purified water to polyvinylpyrrolidone to absolute ethyl alcohol=100:3:15, and making into spray.
S3: granulating the mixed powder and the spray by adopting a fluidized spray granulation method, wherein the parameters are as follows: the spray has a temperature of 20deg.C, a spray speed of 0.3L/min, an atomization pressure of 0.2MPa, and a drying temperature of 55deg.C to obtain granulated particles with a particle diameter of below 0.5 mm.
S4: coating the granulated particles and the inner layer film coating agent by adopting a fluidized spraying method, wherein the parameters are as follows: the temperature of the inner layer film coating agent is 20 ℃, the spraying speed of the inner layer film coating agent is 0.8L/min, the atomization pressure is 0.2MPa, and the drying temperature is 40 ℃; and drying to obtain the primary coating granule.
Wherein the premix of the inner film coating agent comprises, by mass, 30 parts of a composite film forming agent, 2 parts of an adhesive, 0.5 part of a moisture-proof agent, 2 parts of an anticracking agent, 2 parts of a glidant and 12 parts of a plasticizer; the composition mass ratio of the composite film forming agent is hydroxypropyl methylcellulose, polyvinyl alcohol, copovidone and beta-cyclodextrin=2:3:1:0.1; the adhesive is polyvinylpyrrolidone; the moisture-proof agent is diatomite; the anticracking agent is nanocrystalline cellulose NCC; the glidant is talcum powder; the plasticizer is polyethylene glycol 6000; the premix is diluted and dissolved by purified water to obtain the inner layer film coating agent with the mass concentration of 5 percent.
S5: the primary coating granule and the outer layer film coating agent are coated by adopting a fluidization spraying method, and the parameters are as follows: the temperature of the outer layer film coating agent is 40 ℃, the spraying speed is 0.3L/min, the atomization pressure is 0.3MPa, and the drying temperature is 45 ℃; and drying to obtain a secondary coating granule, and finally, carrying out liquid nitrogen freeze-drying, and encapsulating to obtain the flunarizine hydrochloride capsule.
Wherein the premix of the outer film coating agent comprises, by mass, 30 parts of hypromellose, 10 parts of polyvinyl alcohol, 20 parts of corn starch, 0.1 part of an adhesive, 5 parts of a glidant, 8 parts of a plasticizer and 0.1 part of a medicinal preservative; the adhesive is polyvinylpyrrolidone; the glidant is talcum powder; the plasticizer is polyethylene glycol 6000; the premix is diluted and dissolved by purified water to obtain the outer layer film coating agent with the mass concentration of 10 percent.
The flunarizine hydrochloride capsules prepared in this example were directly subjected to dissolution test, and after storage for different periods at 40±2 ℃ and 70±5% humidity, the dissolution test was performed, and the moisture absorption, swelling and mildew conditions of the particle appearance were observed. And under the dissolution test condition, 25mL of 10% diluted hydrochloric acid is added with water to 1000mL of the diluted hydrochloric acid to be used as an in-vitro solvent, the rotating speed is 60r/min, and the dissolution test is carried out at 10min, 20min and 30min respectively. The number of each test sample for dissolution test was 12 capsules, and the test results are shown in table 1.
Example 5
The main components of the granule in the capsule comprise 10 parts of flunarizine hydrochloride and 30 parts of pregelatinized starch; the preparation method is characterized in that the granules are two layers of film coated granules, and the solid capsules are prepared by adopting capsule encapsulation.
The preparation method of the flunarizine hydrochloride capsule is used for preparing the flunarizine hydrochloride capsule, and comprises the following steps:
s1: respectively carrying out jet milling on the flunarizine hydrochloride and the pregelatinized starch raw material to obtain powder with the granularity of less than 2 um; and then uniformly mixing the components by airflow according to the mass ratio of the flunarizine hydrochloride to the pregelatinized starch=10:30 to obtain mixed powder.
S2: mixing the above materials according to the mass ratio of purified water to polyvinylpyrrolidone to absolute ethyl alcohol=100:15:8, and making into spray.
S3: granulating the mixed powder and the spray by adopting a fluidized spray granulation method, wherein the parameters are as follows: the spray has a temperature of 30deg.C, a spraying speed of 0.2L/min, an atomization pressure of 0.4MPa, and a drying temperature of 50deg.C to obtain granulated particles with a particle diameter of below 0.5 mm.
S4: coating the granulated particles and the inner layer film coating agent by adopting a fluidized spraying method, wherein the parameters are as follows: the temperature of the inner layer film coating agent is 30 ℃, the spraying speed of the inner layer film coating agent is 0.5L/min, the atomization pressure is 0.3MPa, and the drying temperature is 35 ℃; and drying to obtain the primary coating granule.
Wherein the premix of the inner film coating agent comprises, by mass, 50 parts of a composite film forming agent, 0.1 part of an adhesive, 2 parts of a moisture-proof agent, 0.2 parts of an anticracking agent, 5 parts of a glidant and 8 parts of a plasticizer; the composition mass ratio of the composite film forming agent is hydroxypropyl methylcellulose, polyvinyl alcohol, copovidone and beta-cyclodextrin=6:1:2:0.01; the adhesive is polyvinylpyrrolidone; the moisture-proof agent is diatomite; the anticracking agent is nanocrystalline cellulose NCC; the glidant is talcum powder; the plasticizer is polyethylene glycol 300; the premix is diluted and dissolved by purified water to obtain the inner layer film coating agent with the mass concentration of 15 percent.
S5: the primary coating granule and the outer layer film coating agent are coated by adopting a fluidization spraying method, and the parameters are as follows: the temperature of the outer layer film coating agent is 35 ℃, the spraying speed is 0.4L/min, the atomization pressure is 0.1MPa, and the drying temperature is 55 ℃; and drying to obtain a secondary coating granule, and finally, carrying out liquid nitrogen freeze-drying, and encapsulating to obtain the flunarizine hydrochloride capsule.
Wherein the premix of the outer film coating agent comprises 20 parts by mass of hypromellose, 15 parts by mass of polyvinyl alcohol, 10 parts by mass of corn starch, 2 parts by mass of adhesive, 2 parts by mass of glidant, 12 parts by mass of plasticizer and 0.3 part by mass of medicinal preservative; the adhesive is polyvinylpyrrolidone; the glidant is talcum powder; the plasticizer is polyethylene glycol 300; the premix is diluted and dissolved by purified water to obtain the outer layer film coating agent with the mass concentration of 5 percent.
The flunarizine hydrochloride capsules prepared in this example were directly subjected to dissolution test, and after storage for different periods at 40±2 ℃ and 70±5% humidity, the dissolution test was performed, and the moisture absorption, swelling and mildew conditions of the particle appearance were observed. And under the dissolution test condition, 25mL of 10% diluted hydrochloric acid is added with water to 1000mL of the diluted hydrochloric acid to be used as an in-vitro solvent, the rotating speed is 60r/min, and the dissolution test is carried out at 10min, 20min and 30min respectively. The number of each test sample for dissolution test was 12 capsules, and the test results are shown in table 1.
Example 6
The main components of the granule in the capsule comprise 5.5 parts of flunarizine hydrochloride and 32 parts of pregelatinized starch; the preparation method is characterized in that the granules are two layers of film coated granules, and the solid capsules are prepared by adopting capsule encapsulation.
The preparation method of the flunarizine hydrochloride capsule is used for preparing the flunarizine hydrochloride capsule, and comprises the following steps:
s1: respectively carrying out jet milling on the flunarizine hydrochloride and the pregelatinized starch raw material to obtain powder with the granularity of less than 2 um; and then uniformly mixing the components by airflow according to the mass ratio of the flunarizine hydrochloride to the pregelatinized starch=5.5:32 to obtain mixed powder.
S2: mixing the above materials according to the mass ratio of purified water to polyvinylpyrrolidone to absolute ethyl alcohol=100:5:15, and making into spray.
S3: granulating the mixed powder and the spray by adopting a fluidized spray granulation method, wherein the parameters are as follows: the spray has a temperature of 28deg.C, a spray speed of 0.25L/min, an atomization pressure of 0.35MPa, and a drying temperature of 52 deg.C to obtain granulated particles with a particle diameter of below 0.5 mm.
S4: coating the granulated particles and the inner layer film coating agent by adopting a fluidized spraying method, wherein the parameters are as follows: the temperature of the inner layer film coating agent is 24 ℃, the spraying speed of the inner layer film coating agent is 0.7L/min, the atomization pressure is 0.3MPa, and the drying temperature is 36 ℃; and drying to obtain the primary coating granule.
Wherein the premix of the inner film coating agent comprises, by mass, 35 parts of a composite film forming agent, 0.5 part of an adhesive, 0.8 part of a moisture-proof agent, 0.6 part of an anticracking agent, 2.5 parts of a glidant and 10 parts of a plasticizer; the composition mass ratio of the composite film forming agent is hydroxypropyl methylcellulose, polyvinyl alcohol, copovidone and beta-cyclodextrin=3:3:1:0.06; the adhesive is polyvinylpyrrolidone; the moisture-proof agent is diatomite; the anticracking agent is nanocrystalline cellulose NCC; the glidant is talcum powder; the plasticizer is polyethylene glycol 6000; the premix is diluted and dissolved by purified water to obtain the inner layer film coating agent with the mass concentration of 6 percent.
S5: the primary coating granule and the outer layer film coating agent are coated by adopting a fluidization spraying method, and the parameters are as follows: the temperature of the outer layer film coating agent is 36 ℃, the spraying speed is 0.35L/min, the atomization pressure is 0.15MPa, and the drying temperature is 48 ℃; and drying to obtain a secondary coating granule, and finally, carrying out liquid nitrogen freeze-drying, and encapsulating to obtain the flunarizine hydrochloride capsule.
Wherein the premix of the outer film coating agent comprises 24 parts by mass of hypromellose, 12 parts by mass of polyvinyl alcohol, 18 parts by mass of corn starch, 0.5 part by mass of an adhesive, 2.5 parts by mass of a glidant, 9 parts by mass of a plasticizer and 0.15 part by mass of a medicinal preservative; the adhesive is polyvinylpyrrolidone; the glidant is talcum powder; the plasticizer is polyethylene glycol 6000; the premix is diluted and dissolved by purified water to obtain the outer layer film coating agent with the mass concentration of 8 percent.
The flunarizine hydrochloride capsules prepared in this example were directly subjected to dissolution test, and after storage for different periods at 40±2 ℃ and 70±5% humidity, the dissolution test was performed, and the moisture absorption, swelling and mildew conditions of the particle appearance were observed. And under the dissolution test condition, 25mL of 10% diluted hydrochloric acid is added with water to 1000mL of the diluted hydrochloric acid to be used as an in-vitro solvent, the rotating speed is 60r/min, and the dissolution test is carried out at 10min, 20min and 30min respectively. The number of each test sample for dissolution test was 12 capsules, and the test results are shown in table 1.
Example 7
The main components of the granule in the capsule comprise 6 parts of flunarizine hydrochloride and 34 parts of pregelatinized starch; the preparation method is characterized in that the granules are two layers of film coated granules, and the solid capsules are prepared by adopting capsule encapsulation.
The preparation method of the flunarizine hydrochloride capsule is used for preparing the flunarizine hydrochloride capsule, and comprises the following steps:
s1: respectively carrying out jet milling on the flunarizine hydrochloride and the pregelatinized starch raw material to obtain powder with the granularity of less than 2 um; and then uniformly mixing the components by airflow according to the mass ratio of the flunarizine hydrochloride to the pregelatinized starch=6:34 to obtain mixed powder.
S2: mixing the above materials according to the mass ratio of purified water to polyvinylpyrrolidone to absolute ethyl alcohol=100:6:8, and making into spray.
S3: granulating the mixed powder and the spray by adopting a fluidized spray granulation method, wherein the parameters are as follows: the spray has a temperature of 25deg.C, a spray speed of 0.2L/min, an atomization pressure of 0.25MPa, and a drying temperature of 53 deg.C to obtain granulated particles with particle diameter of below 0.5 mm.
S4: coating the granulated particles and the inner layer film coating agent by adopting a fluidized spraying method, wherein the parameters are as follows: the temperature of the inner layer film coating agent is 22 ℃, the spraying speed of the inner layer film coating agent is 0.6L/min, the atomization pressure is 0.25MPa, and the drying temperature is 40 ℃; and drying to obtain the primary coating granule.
Wherein the premix of the inner film coating agent comprises 38 parts of composite film forming agent, 2 parts of adhesive, 1.5 parts of moisture-proof agent, 1.5 parts of anticracking agent, 4 parts of glidant and 11 parts of plasticizer; the composition mass ratio of the composite film forming agent is hydroxypropyl methylcellulose, polyvinyl alcohol, copovidone and beta-cyclodextrin=5.5:2.5:2:0.08; the adhesive is polyvinylpyrrolidone; the moisture-proof agent is diatomite; the anticracking agent is nanocrystalline cellulose NCC; the glidant is talcum powder; the plasticizer is polyethylene glycol 6000; the premix is diluted and dissolved by purified water to obtain the inner layer film coating agent with the mass concentration of 6 percent.
S5: the primary coating granule and the outer layer film coating agent are coated by adopting a fluidization spraying method, and the parameters are as follows: the temperature of the outer layer film coating agent is 36 ℃, the spraying speed is 0.3L/min, the atomization pressure is 0.25MPa, and the drying temperature is 52 ℃; and drying to obtain a secondary coating granule, and finally, carrying out liquid nitrogen freeze-drying, and encapsulating to obtain the flunarizine hydrochloride capsule.
Wherein the premix of the outer film coating agent comprises 26 parts by mass of hypromellose, 14 parts by mass of polyvinyl alcohol, 12 parts by mass of corn starch, 1.2 parts by mass of an adhesive, 4.5 parts by mass of a glidant, 11 parts by mass of a plasticizer and 0.2 part by mass of a medicinal preservative; the adhesive is polyvinylpyrrolidone; the glidant is talcum powder; the plasticizer is polyethylene glycol 6000; the premix is diluted and dissolved by purified water to obtain the outer layer film coating agent with the mass concentration of 8 percent.
The flunarizine hydrochloride capsules prepared in this example were directly subjected to dissolution test, and after storage for different periods at 40±2 ℃ and 70±5% humidity, the dissolution test was performed, and the moisture absorption, swelling and mildew conditions of the particle appearance were observed. And under the dissolution test condition, 25mL of 10% diluted hydrochloric acid is added with water to 1000mL of the diluted hydrochloric acid to be used as an in-vitro solvent, the rotating speed is 60r/min, and the dissolution test is carried out at 10min, 20min and 30min respectively. The number of each test sample for dissolution test was 12 capsules, and the test results are shown in table 1.
Example 8
The main components of the granule in the capsule comprise 8.5 parts of flunarizine hydrochloride and 35 parts of pregelatinized starch; the preparation method is characterized in that the granules are two layers of film coated granules, and the solid capsules are prepared by adopting capsule encapsulation.
The preparation method of the flunarizine hydrochloride capsule is used for preparing the flunarizine hydrochloride capsule, and comprises the following steps:
s1: respectively carrying out jet milling on the flunarizine hydrochloride and the pregelatinized starch raw material to obtain powder with the granularity of less than 2 um; and then uniformly mixing the components in an airflow manner according to the mass ratio of the flunarizine hydrochloride to the pregelatinized starch=9:33, so as to obtain mixed powder.
S2: mixing the above materials according to the mass ratio of purified water to polyvinylpyrrolidone to absolute ethyl alcohol=100:4:10, and making into spray.
S3: granulating the mixed powder and the spray by adopting a fluidized spray granulation method, wherein the parameters are as follows: the spray has a temperature of 22 ℃, a spray speed of 0.3L/min, an atomization pressure of 0.25MPa and a drying temperature of 53 ℃ to obtain granulation particles with a particle size of less than 0.5 mm.
S4: coating the granulated particles and the inner layer film coating agent by adopting a fluidized spraying method, wherein the parameters are as follows: the temperature of the inner layer film coating agent is 25 ℃, the spraying speed of the inner layer film coating agent is 0.7L/min, the atomization pressure is 0.3MPa, and the drying temperature is 38 ℃; and drying to obtain the primary coating granule.
Wherein the premix of the inner film coating agent comprises, by mass, 42 parts of a composite film forming agent, 1.6 parts of an adhesive, 1.5 parts of a moisture-proof agent, 0.8 part of an anticracking agent, 4.5 parts of a glidant and 10 parts of a plasticizer; the composition mass ratio of the composite film forming agent is hydroxypropyl methylcellulose, polyvinyl alcohol, copovidone and beta-cyclodextrin=5:3:1.5:0.06; the adhesive is polyvinylpyrrolidone; the moisture-proof agent is diatomite; the anticracking agent is nanocrystalline cellulose NCC; the glidant is talcum powder; the plasticizer is polyethylene glycol 300; the premix is diluted and dissolved by purified water to obtain the inner layer film coating agent with the mass concentration of 10 percent.
S5: the primary coating granule and the outer layer film coating agent are coated by adopting a fluidization spraying method, and the parameters are as follows: the temperature of the outer layer film coating agent is 38 ℃, the spraying speed is 0.35L/min, the atomization pressure is 0.25MPa, and the drying temperature is 53 ℃; and drying to obtain a secondary coating granule, and finally, carrying out liquid nitrogen freeze-drying, and encapsulating to obtain the flunarizine hydrochloride capsule.
Wherein the premix of the outer film coating agent comprises 26 parts by mass of hypromellose, 13 parts by mass of polyvinyl alcohol, 17 parts by mass of corn starch, 1.2 parts by mass of an adhesive, 4.5 parts by mass of a glidant, 10 parts by mass of a plasticizer and 0.1 part by mass of a medicinal preservative; the adhesive is polyvinylpyrrolidone; the glidant is talcum powder; the plasticizer is polyethylene glycol 300; the premix is diluted and dissolved by purified water to obtain the outer layer film coating agent with the mass concentration of 8 percent.
The flunarizine hydrochloride capsules prepared in this example were directly subjected to dissolution test, and after storage for different periods at 40±2 ℃ and 70±5% humidity, the dissolution test was performed, and the moisture absorption, swelling and mildew conditions of the particle appearance were observed. And under the dissolution test condition, 25mL of 10% diluted hydrochloric acid is added with water to 1000mL of the diluted hydrochloric acid to be used as an in-vitro solvent, the rotating speed is 60r/min, and the dissolution test is carried out at 10min, 20min and 30min respectively. The number of each test sample for dissolution test was 12 capsules, and the test results are shown in table 1.
Example 9
The main components of the granule in the capsule comprise 8 parts of flunarizine hydrochloride and 32 parts of pregelatinized starch; the preparation method is characterized in that the granules are two layers of film coated granules, and the solid capsules are prepared by adopting capsule encapsulation.
The preparation method of the flunarizine hydrochloride capsule is used for preparing the flunarizine hydrochloride capsule, and comprises the following steps:
s1: respectively carrying out jet milling on the flunarizine hydrochloride and the pregelatinized starch raw material to obtain powder with the granularity of less than 2 um; and then uniformly mixing the components by airflow according to the mass ratio of the flunarizine hydrochloride to the pregelatinized starch=8:32 to obtain mixed powder.
S2: mixing the above materials according to the mass ratio of purified water to polyvinylpyrrolidone to absolute ethyl alcohol=100:5.5:8.5, and making into spray.
S3: granulating the mixed powder and the spray by adopting a fluidized spray granulation method, wherein the parameters are as follows: the spray has a temperature of 26 ℃, a spray speed of 0.25L/min, an atomization pressure of 0.3MPa and a drying temperature of 54 ℃ to obtain granulation particles with a particle size of less than 0.5 mm.
S4: coating the granulated particles and the inner layer film coating agent by adopting a fluidized spraying method, wherein the parameters are as follows: the temperature of the inner layer film coating agent is 22 ℃, the spraying speed of the inner layer film coating agent is 0.7L/min, the atomization pressure is 0.3MPa, and the drying temperature is 40 ℃; and drying to obtain the primary coating granule.
Wherein the premix of the inner film coating agent comprises 45 parts by mass of composite film forming agent, 1.8 parts by mass of adhesive, 1.6 parts by mass of moisture-proof agent, 1.2 parts by mass of anticracking agent, 3 parts by mass of glidant and 9 parts by mass of plasticizer; the composition mass ratio of the composite film forming agent is hydroxypropyl methylcellulose, polyvinyl alcohol, copovidone and beta-cyclodextrin=4.5:2.5:1.5:0.08; the adhesive is polyvinylpyrrolidone; the moisture-proof agent is diatomite; the anticracking agent is nanocrystalline cellulose NCC; the glidant is talcum powder; the plasticizer is polyethylene glycol 400; the premix is diluted and dissolved by purified water to obtain the inner layer film coating agent with the mass concentration of 6.5 percent.
S5: the primary coating granule and the outer layer film coating agent are coated by adopting a fluidization spraying method, and the parameters are as follows: the temperature of the outer layer film coating agent is 34 ℃, the spraying speed is 0.4L/min, the atomization pressure is 0.12MPa, and the drying temperature is 51 ℃; and drying to obtain a secondary coating granule, and finally, carrying out liquid nitrogen freeze-drying, and encapsulating to obtain the flunarizine hydrochloride capsule.
Wherein the premix of the outer film coating agent comprises, by mass, 25 parts of hypromellose, 10 parts of polyvinyl alcohol, 12 parts of corn starch, 0.8 part of an adhesive, 3.5 parts of a glidant, 8 parts of a plasticizer and 0.25 part of a medicinal preservative; the adhesive is polyvinylpyrrolidone; the glidant is talcum powder; the plasticizer is polyethylene glycol 400; the premix is diluted and dissolved by purified water to obtain the outer layer film coating agent with the mass concentration of 6.5 percent.
The flunarizine hydrochloride capsules prepared in this example were directly subjected to dissolution test, and after storage for different periods at 40±2 ℃ and 70±5% humidity, the dissolution test was performed, and the moisture absorption, swelling and mildew conditions of the particle appearance were observed. And under the dissolution test condition, 25mL of 10% diluted hydrochloric acid is added with water to 1000mL of the diluted hydrochloric acid to be used as an in-vitro solvent, the rotating speed is 60r/min, and the dissolution test is carried out at 10min, 20min and 30min respectively. The number of each test sample for dissolution test was 12 capsules, and the test results are shown in table 1.
Example 10
The main components of the granule in the capsule comprise 8 parts of flunarizine hydrochloride and 40 parts of pregelatinized starch; the preparation method is characterized in that the granules are two layers of film coated granules, and the solid capsules are prepared by adopting capsule encapsulation.
The preparation method of the flunarizine hydrochloride capsule is used for preparing the flunarizine hydrochloride capsule, and comprises the following steps:
s1: respectively carrying out jet milling on the flunarizine hydrochloride and the pregelatinized starch raw material to obtain powder with the granularity of less than 2 um; and then uniformly mixing the components by airflow according to the mass ratio of the flunarizine hydrochloride to the pregelatinized starch=8:40 to obtain mixed powder.
S2: mixing the above materials according to the mass ratio of purified water to polyvinylpyrrolidone to absolute ethyl alcohol=100:4:8, and making into spray.
S3: granulating the mixed powder and the spray by adopting a fluidized spray granulation method, wherein the parameters are as follows: the spray has a temperature of 20deg.C, a spray speed of 0.2L/min, an atomization pressure of 0.2MPa, and a drying temperature of 50deg.C to obtain granulated particles with a particle diameter of below 0.5 mm.
S4: coating the granulated particles and the inner layer film coating agent by adopting a fluidized spraying method, wherein the parameters are as follows: the temperature of the inner layer film coating agent is 20 ℃, the spraying speed of the inner layer film coating agent is 0.5L/min, the atomization pressure is 0.2MPa, and the drying temperature is 40 ℃; and drying to obtain the primary coating granule.
Wherein the premix of the inner film coating agent comprises, by mass, 50 parts of a composite film forming agent, 2 parts of an adhesive, 0.5 part of a moisture-proof agent, 0.2 part of an anticracking agent, 5 parts of a glidant and 12 parts of a plasticizer; the composition mass ratio of the composite film forming agent is hydroxypropyl methylcellulose, polyvinyl alcohol, copovidone and beta-cyclodextrin=6:3:2:0.05; the adhesive is polyvinylpyrrolidone; the moisture-proof agent is diatomite; the anticracking agent is nanocrystalline cellulose NCC; the glidant is talcum powder; the plasticizer is polyethylene glycol 6000; the premix is diluted and dissolved by purified water to obtain the inner layer film coating agent, and the mass concentration is 7%.
S5: the primary coating granule and the outer layer film coating agent are coated by adopting a fluidization spraying method, and the parameters are as follows: the temperature of the outer layer film coating agent is 40 ℃, the spraying speed is 0.4L/min, the atomization pressure is 0.3MPa, and the drying temperature is 55 ℃; and drying to obtain a secondary coating granule, and finally, carrying out liquid nitrogen freeze-drying, and encapsulating to obtain the flunarizine hydrochloride capsule.
Wherein the premix of the outer film coating agent comprises 20 parts by mass of hypromellose, 10 parts by mass of polyvinyl alcohol, 10 parts by mass of corn starch, 0.1 part by mass of adhesive, 2 parts by mass of glidant, 8 parts by mass of plasticizer and 0.2 parts by mass of medicinal preservative; the adhesive is polyvinylpyrrolidone; the glidant is talcum powder; the plasticizer is polyethylene glycol 6000; the premix is diluted and dissolved by purified water to obtain the outer layer film coating agent with the mass concentration of 8 percent.
The flunarizine hydrochloride capsules prepared in this example were directly subjected to dissolution test, and after storage for different periods at 40±2 ℃ and 70±5% humidity, the dissolution test was performed, and the moisture absorption, swelling and mildew conditions of the particle appearance were observed. And under the dissolution test condition, 25mL of 10% diluted hydrochloric acid is added with water to 1000mL of the diluted hydrochloric acid to be used as an in-vitro solvent, the rotating speed is 60r/min, and the dissolution test is carried out at 10min, 20min and 30min respectively. The number of each test sample for dissolution test was 12 capsules, and the test results are shown in table 1.
TABLE 1 detection results
The detection results show that the dissolution rate of each stage is high, the external spalling is less, the internal mildew is avoided, the quality guarantee period of the active ingredients is long, and the dissolution rate of the active ingredients is not greatly reduced when the active ingredients are stored in a severe environment for a long time.

Claims (2)

1. The main components of the granule in the capsule comprise 5-10 parts of flunarizine hydrochloride and 30-40 parts of pregelatinized starch; the preparation method is characterized in that the granules are two layers of film coated granules, and solid capsules are prepared by encapsulation;
the preparation method of the flunarizine hydrochloride capsule comprises the following steps:
s1: respectively carrying out jet milling on the flunarizine hydrochloride and the pregelatinized starch raw material to obtain micron-sized or nano-sized powder with the granularity smaller than 2 um; then uniformly mixing the components according to the mass ratio of the flunarizine hydrochloride to the pregelatinized starch=5-10:30-40, and obtaining mixed powder;
s2: uniformly mixing purified water, polyvinylpyrrolidone and absolute ethyl alcohol with the mass ratio of 100:3-15:8-15 to prepare a spray;
s3: granulating the mixed powder and the spray by adopting a fluidized spray granulation method to obtain granulated particles with the particle size of less than 0.5 mm;
S4: coating the granulated particles and the inner layer film coating agent by adopting a fluidized spraying method, and drying to obtain primary coated particles;
the premix of the inner film coating agent comprises, by mass, 30-50 parts of a composite film forming agent, 0.1-2 parts of an adhesive, 0.5-2 parts of a moisture-proof agent, 0.2-2 parts of an anticracking agent, 2-5 parts of a glidant and 8-12 parts of a plasticizer; the composite film forming agent comprises the following components in percentage by mass;
the adhesive is polyvinylpyrrolidone; the moisture-proof agent is diatomite; the anticracking agent is nanocrystalline cellulose NCC; the glidant is talcum powder; the plasticizer is polyethylene glycol 6000, polyethylene glycol 300 or polyethylene glycol 400;
the premix is diluted and dissolved by purified water to obtain an inner layer film coating agent, and the mass concentration is 5-15%;
the parameters of the coating are as follows: the temperature of the inner layer film coating agent is 20-30 ℃, the spraying speed of the inner layer film coating agent is 0.5-0.8L/min, the atomization pressure is 0.2-0.3 MPa, and the drying temperature is 35-40 ℃;
s5: coating the primary coating granules and the outer layer film coating agent by adopting a fluidized spraying method, drying to obtain secondary coating granules, freeze-drying by liquid nitrogen, and encapsulating by adopting a capsule to obtain the flunarizine hydrochloride capsule;
The premix of the outer layer film coating agent comprises, by mass, 20-30 parts of hydroxypropyl methylcellulose, 10-15 parts of polyvinyl alcohol, 10-20 parts of corn starch, 0.1-2 parts of an adhesive, 2-5 parts of a glidant, 8-12 parts of a plasticizer and 0.1-0.3 part of a medicinal preservative;
the adhesive is polyvinylpyrrolidone; the glidant is talcum powder; the plasticizer is polyethylene glycol 6000, polyethylene glycol 300 or polyethylene glycol 400;
the premix is diluted and dissolved by purified water to obtain an outer layer film coating agent with the mass concentration of 5-10%;
the parameters of the coating are as follows: the temperature of the outer layer film coating agent is 35-40 ℃, the spraying speed is 0.3-0.4L/min, the atomization pressure is 0.1-0.3 MPa, and the drying temperature is 45-55 ℃.
2. The flunarizine hydrochloride capsule of claim 1, wherein in S3, the parameters of granulation are: the spray has a spray temperature of 20-30 ℃, a spray speed of 0.2-0.3L/min, an atomization pressure of 0.2-0.4 MPa and a drying temperature of 50-55 ℃.
CN202310831048.6A 2023-07-06 2023-07-06 Flunarizine hydrochloride capsule and preparation method thereof Active CN116747206B (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103462915A (en) * 2013-09-09 2013-12-25 南京正亮医药科技有限公司 Flunarizine hydrochloride tablet and preparation method thereof
CN115645376A (en) * 2022-10-26 2023-01-31 山东德州神牛药业有限公司 Tilmicosin efficient double-layer coated pellet and preparation method thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103462915A (en) * 2013-09-09 2013-12-25 南京正亮医药科技有限公司 Flunarizine hydrochloride tablet and preparation method thereof
CN115645376A (en) * 2022-10-26 2023-01-31 山东德州神牛药业有限公司 Tilmicosin efficient double-layer coated pellet and preparation method thereof

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