CN114983973B - Urapidil sustained-release capsule and preparation method thereof - Google Patents

Urapidil sustained-release capsule and preparation method thereof Download PDF

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CN114983973B
CN114983973B CN202210610443.7A CN202210610443A CN114983973B CN 114983973 B CN114983973 B CN 114983973B CN 202210610443 A CN202210610443 A CN 202210610443A CN 114983973 B CN114983973 B CN 114983973B
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ethyl cellulose
urapidil
release
coating
sustained
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CN114983973A (en
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孙立杰
程彦超
张乐
朱明月
戎艳艳
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Shijiazhuang No 4 Pharmaceutical Co Ltd
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Shijiazhuang No 4 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
    • A61K9/5005—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
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • 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
    • A61P9/12—Antihypertensives
    • 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 belongs to the technical field of pharmacy, and provides a urapidil sustained-release capsule and a preparation method thereof, wherein the problems of double medicine feeding and release are cooperatively solved by limiting different viscosities, dosage and particle size ranges of ethyl cellulose, and the product quality is further ensured while the product yield and the production efficiency are further improved by controlling the technological parameters of a medicine feeding link and a coating link, so that the medicine release is stable, and the content uniformity is good. The invention adopts an aqueous solvent system to develop the urapidil sustained-release capsule, reduces potential safety hazard, reduces environmental protection pressure, realizes continuous production of medicine feeding and coating by using a centrifugal granulator, and is more beneficial to industrial production.

Description

Urapidil sustained-release capsule and preparation method thereof
Technical Field
The invention belongs to the technical field of pharmacy, and in particular relates to a urapidil sustained-release capsule and a preparation method thereof.
Background
Urapidil belongs to an alpha 1 receptor blocker, has dual antihypertensive effects on the periphery and the center, has unique advantages in the aspects of treating severe hypertension, hypertension emergency and controlling perioperative hypertension, can be used for urination difficulty related to benign prostatic hyperplasia and urination difficulty related to neurogenic bladder, and has wide clinical application.
Urapidil was developed by Byk Gulden corporation, was first marketed in germany in 1980 as an injection, and then in 1981 as a sustained-release capsule, marketed in japan in 1989 as a sustained-release capsule under the trade name
Figure BDA0003671820300000011
Approval and sales have been obtained in several tens of countries worldwide.
The half-life period of urapidil is short and is 2.7 hours, and the common preparation needs to be frequently administered, so that a slow release preparation needs to be developed to reduce the administration times and improve the patient compliance, but because urapidil is a weak alkaline indissolvable drug, release is influenced by the pH of a gastrointestinal tract in vivo, the dissolution is large in an acidic environment, the dissolution is small in an alkaline condition, and the characteristic drug is not suitable for being prepared into a slow release preparation, because the change of the pharmacokinetics performance of the drug is large, the release is unstable, the normal blood pressure cannot be always ensured, the occurrence of blood pressure values causing undesirable side effects (such as erectile hypotension) cannot be avoided, and great difficulty exists in preparing a long-acting oral preparation.
The original research company adopts coating materials with different properties to form a pH dependent film, thereby solving the influence of the change of the dissolution of urapidil along with the change of pH and developing the sustained-release capsule. However, the existing technology adopts organic solvents such as ethanol and isopropanol to carry out operations such as drug feeding or coating, the ethanol and the isopropanol belong to explosive solvents, potential safety hazards exist, the organic solvents are easy to remain, and meanwhile, the emission of a large amount of organic solvents also causes a small environmental protection pressure, so that the technology is not beneficial to industrial mass production.
The invention aims to solve the problem of adopting an organic solvent to prepare an adhesive solution or a coating solution in industrial production, and adopts an aqueous solvent system to develop the urapidil sustained-release capsule, but the problem of low drug application rate is found in the actual research and development process, so that the urapidil sustained-release capsule which can ensure the quality of products, improve the production efficiency and be beneficial to industrial production needs to be further researched.
Disclosure of Invention
The invention aims at overcoming the defects of the prior art and provides a urapidil sustained-release capsule and a preparation method thereof. By researching different viscosities, dosage and particle size ranges of the ethyl cellulose, the medicine feeding rate can be improved, and even the double problems of medicine feeding and release are cooperatively solved; the technological parameters of the medicine feeding link and the coating link are controlled, so that the product yield and the production efficiency are further improved, and the product quality is ensured; the mixed powder of ethyl cellulose and hydroxypropyl methylcellulose acetate succinate is selected for coating, so that the drug release is stable, and the content uniformity is good; continuous production of the drug delivery and coating is achieved by using a centrifugal granulator.
In order to achieve the purpose of the invention, the following technical scheme is adopted:
The invention aims to provide a urapidil sustained-release capsule A for improving the drug loading rate, which consists of sustained-release pellets and a capsule shell, wherein the sustained-release pellets comprise a pellet core, a drug loading part and a coating part, the drug loading part comprises ethyl cellulose with the viscosity of 9-14CP and the particle size D90 of 90-130 mu m, the dosage of the ethyl cellulose is 4-6% of the urapidil mass, and the coating part comprises ethyl cellulose with the viscosity of 3-14CP and the particle size D90 of 70-90 mu m.
Still further, another object of the present invention is to provide a sustained release urapidil capsule B with improved drug delivery rate and improved release behavior, which is composed of sustained release pellets and a capsule shell, wherein the sustained release pellets comprise a pellet core, a drug delivery part and a coating part, the drug delivery part comprises ethyl cellulose with a viscosity of 9-11CP and a particle size D90 of 90-110 μm, the amount of the ethyl cellulose is 4-6% of urapidil mass, and the coating part comprises ethyl cellulose with a viscosity of 3-9CP and a particle size D90 of 70-90 μm.
More preferably, the dosage of the above-mentioned urapidil sustained-release capsule B for improving the drug administration rate and improving the release behavior is 5% of the mass of urapidil.
Still further, another object of the present invention is to provide a sustained release urapidil capsule C with improved drug delivery rate and improved release behavior, which is composed of sustained release pellets and a capsule shell, wherein the sustained release pellets comprise a pellet core, a drug delivery part and a coating part, the drug delivery part comprises ethyl cellulose with a viscosity of 9-11CP and a particle size D90 of 110-130 μm, the amount of the ethyl cellulose is 4-6% of urapidil mass, and the coating part comprises ethyl cellulose with a viscosity of 9-14CP and a particle size D90 of 70-90 μm.
Still further, another object of the present invention is to provide a sustained release urapidil capsule D with improved drug delivery rate and improved release behavior, which is composed of sustained release pellets and a capsule shell, wherein the sustained release pellets comprise a pellet core, a drug delivery part and a coating part, the drug delivery part comprises ethyl cellulose with a viscosity of 11-14CP and a particle size D90 of 90-110 μm, the amount of the ethyl cellulose is 4-6% of urapidil mass, and the coating part comprises ethyl cellulose with a viscosity of 9-14CP and a particle size D90 of 70-90 μm.
The urapidil sustained-release capsule is prepared by carrying out drug loading and coating on a pill core, wherein a layered drug loading process is adopted in the drug loading link, and a layered coating process is adopted in the coating link.
Furthermore, the lamination medicine-feeding process adopted in the medicine-feeding link is to spray medicine-feeding layer powder and medicine-feeding layer adhesive on the pill core to obtain the medicine-feeding micropill.
Further, the components of the medicine-feeding layer powder are urapidil, ethyl cellulose and talcum powder.
Further, the adhesive of the medicine applying layer is an aqueous dispersion with 39% -41% of solid content.
Still further, the solid components of the drug-applying layer binder are oleic acid, dibutyl sebacate and polysorbate 80.
Further, the coating process adopted in the coating step is to spray coating material powder and coating plasticizer onto the drug-loading pellets to obtain the sustained-release pellets.
Further, the coating material powder comprises ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder.
Further, the hydroxypropyl methylcellulose acetate succinate in the coating material powder is of the AS-LF type.
Further, the coating plasticizer is an aqueous dispersion with a solid content of 39% -41%.
Still further, the solid components of the coating plasticizer are oleic acid, dibutyl sebacate and polysorbate 80.
Further, the urapidil sustained-release capsule is characterized in that the pill core is a sucrose pill core.
Further, the urapidil sustained-release capsule comprises the following components in percentage by mass: 30% of urapidil, 1.2% -1.8% of ethyl cellulose, 0.4% -0.8% of talcum powder, 5.5% -6.5% of oleic acid, 1.5% -2.5% of dibutyl sebacate and 0.02% of polysorbate 80, and the balance of sucrose pill cores, wherein the viscosity of the ethyl cellulose in the medicine-feeding part is 9-11CP, and the particle size D90 is 90-110 mu m; the sustained-release pellets comprise the following components in percentage by mass: 2.2% -3.2% of ethyl cellulose, 5.7% -6.7% of AS-LF type hydroxypropyl methylcellulose acetate succinate, 0.4% of talcum powder, 1.1% -1.3% of oleic acid, 0.4% -0.7% of dibutyl sebacate and 0.02% of polysorbate 80, and the balance of drug-loading pellets, wherein the viscosity of the ethyl cellulose in the coating part is 3-9CP, and the particle size D90 is 70-90 mu m.
Further, the urapidil sustained-release capsule comprises the following components in percentage by mass: 30% of urapidil, 1.2% -1.8% of ethyl cellulose, 0.2% -0.8% of talcum powder, 5.5% -6.5% of oleic acid, 1.5% -2.5% of dibutyl sebacate and 0.02% of polysorbate 80, and the balance of sucrose pill cores, wherein the viscosity of the ethyl cellulose in the medicine-feeding part is 9-11CP, and the particle size D90 is 110-130 mu m; the sustained-release pellets comprise the following components in percentage by mass: 2.7% -2.8% of ethyl cellulose, 6.0% -6.2% of AS-LF type hydroxypropyl methylcellulose acetate succinate, 0.4% of talcum powder, 0.9% -1.5% of oleic acid, 0.3% -0.9% of dibutyl sebacate and 0.02% of polysorbate 80, and the balance of drug-loading pellets, wherein the viscosity of the ethyl cellulose in the coating part is 9-14CP, and the particle size D90 is 70-90 mu m.
Further, the urapidil sustained-release capsule comprises the following components in percentage by mass: 30% of urapidil, 1.2% -1.8% of ethyl cellulose, 0.2% -0.8% of talcum powder, 5.0% -5.7% of oleic acid, 2.3% -3.2% of dibutyl sebacate and 0.02% of polysorbate 80, and the balance of sucrose pill cores, wherein the viscosity of the ethyl cellulose in the medicine-feeding part is 11-14CP, and the particle size D90 is 90-110 mu m; the sustained-release pellets comprise the following components in percentage by mass: 2.4% -3.0% of ethyl cellulose, 5.7% -6.2% of AS-LF type hydroxypropyl methylcellulose acetate succinate, 0.6% -0.7% of talcum powder, 1.1% -1.2% of oleic acid, 0.5% -0.7% of dibutyl sebacate and 0.02% of polysorbate 80, and the balance of drug-loading pellets, wherein the viscosity of the ethyl cellulose in the coating part is 9-14CP, and the particle size D90 is 70-90 mu m.
Further, the urapidil sustained-release capsule comprises the following components in percentage by mass:
Figure BDA0003671820300000041
another object of the present invention is to provide a method for preparing the above-mentioned urapidil sustained-release capsule, comprising the following steps:
(1) Micronizing the ethyl cellulose to a first preset particle size to obtain first ethyl cellulose micropowder; weighing sucrose pill core, urapidil, first ethyl cellulose micropowder and talcum powder according to the prescription amount;
(2) Uniformly mixing the first ethyl cellulose micropowder, urapidil and talcum powder in a prescription amount to obtain upper medicine layer powder;
(3) Respectively preparing the oleic acid, the dibutyl sebacate and the polysorbate with the prescription amount into water dispersion with the solid content of 40 percent to obtain a medicine coating adhesive and a coating plasticizer;
(4) Spraying the powder of the medicine applying layer and the adhesive of the medicine applying layer on the pill core simultaneously, and drying to obtain medicine applying micropills;
(6) Micronizing the ethyl cellulose to a second preset particle size to obtain second ethyl cellulose micropowder; weighing prescription amount of the drug-loading micropill, second ethyl cellulose micropowder, AS-LF type hydroxypropyl methylcellulose acetate succinate and talcum powder;
(7) Uniformly mixing the second ethyl cellulose micropowder, AS-LF hydroxypropyl methylcellulose acetate succinate and talcum powder according to the prescription amount to obtain coating material powder;
(8) Spraying the coating material powder and the coating plasticizer on the drug-loading pellets simultaneously to obtain slow-release pellets;
(9) Aging the sustained-release pellets, and filling to obtain the urapidil sustained-release capsules.
The first preset particle size is that the particle size D90 of ethyl cellulose of the medicine feeding part is 90-110 mu m or 110-130 mu m; the second preset particle size is that the particle size D90 of the ethyl cellulose of the coating part is 70-90 mu m.
Further, in the step (4), the technological parameters of the drug feeding procedure are as follows: the rotating speed of the rotary table of the centrifugal granulator is 200-300r/min, the blanking speed is 15g/min, the spraying speed is 9g/min, and the atomization pressure is 2.0-2.5bar.
Further, in the step (4), the technological parameters of the medicine feeding procedure include: the inlet air temperature of the centrifugal granulator is 25 ℃ and the material temperature is 20 ℃.
Further, in the step (8), the process parameters of the coating process are as follows: the rotating speed of the rotary table of the centrifugal granulator is 250-300r/min, the blanking speed is 8g/min, the spraying speed is 3.5g/min, and the atomization pressure is 1.5-2.5bar.
Further, in the step (8), the process parameters of the coating process include: the inlet air temperature of the centrifugal granulator is 25 ℃ and the material temperature is 20 ℃.
By adopting the technical scheme, the beneficial effects of the invention are as follows:
(1) In the research process of changing an aqueous solvent slow-release enteric system, the viscosity, the dosage and the particle size range of the ethyl cellulose are researched, so that the double problems of medicine feeding and release are cooperatively solved, three preferred schemes are explored, the release behavior of the slow-release capsule can be ensured to be consistent with that of the original research, and meanwhile, the medicine feeding rate reaches more than 90%, and the preferred scheme is as follows:
A. the dosage of the ethyl cellulose of the upper part accounts for 4-6 percent of the weight of urapidil, the viscosity is 9-11CP, the grain diameter D90 is 90-110 mu m, and the viscosity of the ethyl cellulose of the coating part is 3-9CP, the grain diameter D90 is 70-90 mu m;
B. The dosage of the ethyl cellulose of the medicine feeding part accounts for 4-6 percent of the weight of urapidil, the viscosity is 9-11CP, the particle size D90 is 110-130 mu m, and the ethyl cellulose of the medicine feeding part is coated: viscosity is 9-14CP, particle diameter D90 is 70-90 μm;
C. drug loading part ethylcellulose: the dosage of the composition accounts for 4-6% of the weight of urapidil, the viscosity of the composition is 11-14CP, the particle size D90 is 90-110 mu m, and the composition is coated with part of ethyl cellulose: the viscosity is 9-14CP, and the particle diameter D90 is 70-90 μm.
(2) According to the invention, better optimization conditions are found by combining the technological parameter investigation of the centrifugal granulator, the product yield and the production efficiency are further improved, the product quality is guaranteed, the drug loading rate is up to more than 95%, the pellets are free from adhesion, the pellet surfaces are smooth and flat, the content uniformity is good, the release behavior is closest to that of the original grinding, the drug loading time of 600g urapidil is within 30min, and the efficiency is improved by 2-4 times. The optimization conditions are specifically as follows: drug loading part ethylcellulose: the dosage of the composition accounts for 5 percent of the weight of urapidil, the viscosity is 9-11CP, the grain diameter D90 is 90-110 mu m, the coating part of the ethyl cellulose comprises the technological parameters of the medicine feeding link, wherein the viscosity is 3-9CP, the grain diameter D90 is 70-90 mu m: the blanking speed is 15g/min, the spraying speed is 9g/min, the atomization pressure is 2.0-2.5bar, the rotating speed of the rotating disc is 200-300r/min, and the technological parameters of the coating link are as follows: the blanking speed is 8g/min, the spraying speed is 3.5g/min, the atomization pressure is 1.5-2.5bar, and the rotating speed of the turntable is 250-300r/min.
(3) In the slow-release coating process, the characteristic that urapidil is absorbed in a human body is combined, the invention mixes ethyl cellulose with specific viscosity and particle size and hydroxypropyl methylcellulose acetate succinate with AS-LF type, takes aqueous dispersion of oleic acid, dibutyl sebacate and polysorbate 80 AS plasticizer, carries out powder lamination coating in a centrifugal granulator, can achieve good enteric slow-release effect when the coating weight is increased by 10% -15%, and also provides guarantee for the release behavior close to that of the original developing agent.
(4) The whole process of the invention does not use organic solvent, only uses a small amount of water, greatly reduces potential safety hazard, improves production efficiency and is beneficial to industrial production.
(5) The whole process of the invention only uses one device of the centrifugal granulator to finish the whole process of the drug feeding and coating of the pellets, thereby realizing industrial continuous production.
Detailed Description
The following detailed description of the invention is provided to facilitate an understanding of the invention and is not intended to limit the scope of the invention to those skilled in the art to make or use the invention.
Example 1
A urapidil sustained-release capsule comprises the following components in percentage by mass:
Figure BDA0003671820300000061
Figure BDA0003671820300000071
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The preparation method comprises the following steps:
(1) Micronizing ethyl cellulose with the viscosity of 9-11CP to the particle size D90: weighing sucrose pill core, urapidil, ethyl cellulose and pulvis Talci with the dosage of 90 μm-110 μm.
(2) The treated ethyl cellulose is uniformly mixed with urapidil and talcum powder.
(3) The oleic acid, the dibutyl sebacate and the polysorbate which are weighed according to the prescription amounts are respectively prepared into water dispersion with the solid content of 40 percent and used as a medicine-feeding adhesive and a plasticizer in coating.
(4) And (3) feeding: putting the sucrose pellets into a pot of a centrifugal granulator, putting raw and auxiliary material mixed powder into a hopper, connecting an adhesive to a spray gun in the pot, starting the centrifugal granulator, setting the rotating speed of a parameter rotary table to be 200-250r/min, the blanking speed to be 15g/min, the spraying speed to be 9g/min, the air inlet temperature to be 25 ℃, the material temperature to be 20 ℃ and the atomization pressure to be 2.0-2.5bar.
(5) And (3) drying: and setting parameters of a centrifugal granulator to dry the drug-loaded pellets, wherein the rotating speed of a rotating disc is 300r/min, the air inlet temperature is 80 ℃, and the material temperature is 45 ℃.
(6) And (5) weighing coating materials: weighing prescribed amounts of the drug administration pellets, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder, wherein the ethyl cellulose with the viscosity of 3-9CP is micronized to the particle size D90 before weighing: 70-90 μm, and the model of hydroxypropyl methylcellulose acetate succinate is AS-LF.
(7) The treated ethyl cellulose is uniformly mixed with hydroxypropyl methylcellulose acetate succinate and talcum powder.
(8) Coating: coating material mixed powder is filled in a hopper of a centrifugal granulator, an adhesive is connected to a spray gun in a pot, parameters of the centrifugal granulator are set to coat the dried drug-loaded pellets, the rotating speed of a rotating disc is 250-300r/min, the blanking speed is 8g/min, the spraying speed is 3.5g/min, the air inlet temperature is 25 ℃, the material temperature is 20 ℃, and the atomization pressure is 1.5-2.0bar, so that the sustained-release pellets are obtained.
(9) Aging: and (3) setting parameters of a centrifugal granulator to age the slow-release pellets, wherein the rotating speed of a rotating disc is 300r/min, the air inlet temperature is 80 ℃, the material temperature is 45 ℃, and the aging time is 60min.
(10) And (3) filling: detecting the content of the sustained-release pellets, and filling according to the content to obtain the urapidil sustained-release capsules.
Example 2
A urapidil sustained-release capsule comprises the following components in percentage by mass:
Figure BDA0003671820300000081
the preparation method comprises the following steps:
(1) Micronizing ethyl cellulose with the viscosity of 9-11CP to the particle size D90: weighing sucrose pill core, urapidil, ethyl cellulose and pulvis Talci with the dosage of 90 μm-110 μm.
(2) The treated ethyl cellulose is uniformly mixed with urapidil and talcum powder.
(3) The oleic acid, the dibutyl sebacate and the polysorbate which are weighed according to the prescription amounts are respectively prepared into water dispersion with the solid content of 40 percent and used as a medicine-feeding adhesive and a plasticizer in coating.
(4) And (3) feeding: putting the sucrose pellets into a pot of a centrifugal granulator, putting raw and auxiliary material mixed powder into a hopper, connecting an adhesive to a spray gun in the pot, starting the centrifugal granulator, setting the rotating speed of a parameter rotary table to be 250-300r/min, the blanking speed to be 15g/min, the spraying speed to be 9g/min, the air inlet temperature to be 25 ℃, the material temperature to be 20 ℃ and the atomization pressure to be 2.0-2.5bar.
(5) And (3) drying: and setting parameters of a centrifugal granulator to dry the drug-loaded pellets, wherein the rotating speed of a rotating disc is 300r/min, the air inlet temperature is 80 ℃, and the material temperature is 45 ℃.
(6) And (5) weighing coating materials: weighing prescribed amounts of the drug administration pellets, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder, wherein the ethyl cellulose with the viscosity of 3-9CP is micronized to the particle size D90 before weighing: 70-90 μm, and the model of hydroxypropyl methylcellulose acetate succinate is AS-LF.
(7) The treated ethyl cellulose is uniformly mixed with hydroxypropyl methylcellulose acetate succinate and talcum powder.
(8) Coating: coating material mixed powder is filled in a hopper of a centrifugal granulator, an adhesive is connected to a spray gun in a pot, parameters of the centrifugal granulator are set to coat the dried drug-loaded pellets, the rotating speed of a rotating disc is 250-300r/min, the blanking speed is 8g/min, the spraying speed is 3.5g/min, the air inlet temperature is 25 ℃, the material temperature is 20 ℃, and the atomization pressure is 2.0-2.5bar, so that the sustained-release pellets are obtained.
(9) Aging: and (3) setting parameters of a centrifugal granulator to age the slow-release pellets, wherein the rotating speed of a rotating disc is 300r/min, the air inlet temperature is 80 ℃, the material temperature is 45 ℃, and the aging time is 60min.
(10) And (3) filling: detecting the content of the sustained-release pellets, and filling according to the content to obtain the urapidil sustained-release capsules.
Example 3
A urapidil sustained-release capsule comprises the following components in percentage by mass:
Figure BDA0003671820300000091
Figure BDA0003671820300000101
the preparation method comprises the following steps:
(1) Micronizing ethyl cellulose with the viscosity of 9-11CP to the particle size D90: weighing sucrose pill core, urapidil, ethyl cellulose and pulvis Talci with the dosage of 90 μm-110 μm.
(2) The treated ethyl cellulose is uniformly mixed with urapidil and talcum powder.
(3) The oleic acid, the dibutyl sebacate and the polysorbate which are weighed according to the prescription amounts are respectively prepared into water dispersion with the solid content of 40 percent and used as a medicine-feeding adhesive and a plasticizer in coating.
(4) And (3) feeding: putting the sucrose pellets into a pot of a centrifugal granulator, putting raw and auxiliary material mixed powder into a hopper, connecting an adhesive to a spray gun in the pot, starting the centrifugal granulator, setting the rotating speed of a parameter rotary table to be 250-300r/min, the blanking speed to be 15g/min, the spraying speed to be 9g/min, the air inlet temperature to be 25 ℃, the material temperature to be 20 ℃ and the atomization pressure to be 2.0-2.5bar.
(5) And (3) drying: and setting parameters of a centrifugal granulator to dry the drug-loaded pellets, wherein the rotating speed of a rotating disc is 300r/min, the air inlet temperature is 80 ℃, and the material temperature is 45 ℃.
(6) And (5) weighing coating materials: weighing prescribed amounts of the drug administration pellets, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder, wherein the ethyl cellulose with the viscosity of 3-9CP is micronized to the particle size D90 before weighing: 70-90 μm, and the model of hydroxypropyl methylcellulose acetate succinate is AS-LF.
(7) The treated ethyl cellulose is uniformly mixed with hydroxypropyl methylcellulose acetate succinate and talcum powder.
(8) Coating: coating material mixed powder is filled in a hopper of a centrifugal granulator, an adhesive is connected to a spray gun in a pot, parameters of the centrifugal granulator are set to coat the dried drug-loaded pellets, the rotating speed of a rotating disc is 250-300r/min, the blanking speed is 8g/min, the spraying speed is 3.5g/min, the air inlet temperature is 25 ℃, the material temperature is 20 ℃, and the atomization pressure is 2.0-2.5bar, so that the sustained-release pellets are obtained.
(9) Aging: and (3) setting parameters of a centrifugal granulator to age the slow-release pellets, wherein the rotating speed of a rotating disc is 300r/min, the air inlet temperature is 80 ℃, the material temperature is 45 ℃, and the aging time is 60min.
(10) And (3) filling: detecting the content of the sustained-release pellets, and filling according to the content to obtain the urapidil sustained-release capsules.
Example 4
A urapidil sustained-release capsule comprises the following components in percentage by mass:
Figure BDA0003671820300000102
Figure BDA0003671820300000111
the preparation method comprises the following steps:
(1) Micronizing ethyl cellulose with the viscosity of 9-11CP to the particle size D90: weighing sucrose pill core, urapidil, ethyl cellulose and pulvis Talci with the dosage of 90 μm-110 μm.
(2) The treated ethyl cellulose is uniformly mixed with urapidil and talcum powder.
(3) The oleic acid, the dibutyl sebacate and the polysorbate which are weighed according to the prescription amounts are respectively prepared into water dispersion with the solid content of 40 percent and used as a medicine-feeding adhesive and a plasticizer in coating.
(4) And (3) feeding: putting the sucrose pellets into a pot of a centrifugal granulator, putting raw and auxiliary material mixed powder into a hopper, connecting an adhesive to a spray gun in the pot, starting the centrifugal granulator, setting the rotating speed of a parameter rotary table to be 200-250r/min, the blanking speed to be 15g/min, the spraying speed to be 9g/min, the air inlet temperature to be 25 ℃, the material temperature to be 20 ℃ and the atomization pressure to be 2.0-2.5bar.
(5) And (3) drying: and setting parameters of a centrifugal granulator to dry the drug-loaded pellets, wherein the rotating speed of a rotating disc is 300r/min, the air inlet temperature is 80 ℃, and the material temperature is 45 ℃.
(6) And (5) weighing coating materials: weighing prescribed amounts of the drug administration pellets, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder, wherein the ethyl cellulose with the viscosity of 3-9CP is micronized to the particle size D90 before weighing: 70-90 μm, and the model of hydroxypropyl methylcellulose acetate succinate is AS-LF.
(7) The treated ethyl cellulose is uniformly mixed with hydroxypropyl methylcellulose acetate succinate and talcum powder.
(8) Coating: coating material mixed powder is filled in a hopper of a centrifugal granulator, an adhesive is connected to a spray gun in a pot, parameters of the centrifugal granulator are set to coat the dried drug-loaded pellets, the rotating speed of a rotating disc is 250-300r/min, the blanking speed is 8g/min, the spraying speed is 3.5g/min, the air inlet temperature is 25 ℃, the material temperature is 20 ℃, and the atomization pressure is 1.5-2.0bar, so that the sustained-release pellets are obtained.
(9) Aging: and (3) setting parameters of a centrifugal granulator to age the slow-release pellets, wherein the rotating speed of a rotating disc is 300r/min, the air inlet temperature is 80 ℃, the material temperature is 45 ℃, and the aging time is 60min.
(10) And (3) filling: detecting the content of the sustained-release pellets, and filling according to the content to obtain the urapidil sustained-release capsules.
Example 5
A urapidil sustained-release capsule comprises the following components in percentage by mass:
Figure BDA0003671820300000121
the preparation method comprises the following steps:
(1) Micronizing ethyl cellulose with the viscosity of 9-11CP to the particle size D90: weighing sucrose pill core, urapidil, ethyl cellulose and pulvis Talci with the dosage of 110 μm-130 μm.
(2) The treated ethyl cellulose is uniformly mixed with urapidil and talcum powder.
(3) The oleic acid, the dibutyl sebacate and the polysorbate which are weighed according to the prescription amounts are respectively prepared into water dispersion with the solid content of 40 percent and used as a medicine-feeding adhesive and a plasticizer in coating.
(4) And (3) feeding: putting the sucrose pellets into a pot of a centrifugal granulator, putting raw and auxiliary material mixed powder into a hopper, connecting an adhesive to a spray gun in the pot, starting the centrifugal granulator, setting the rotating speed of a parameter rotary table to be 250-300r/min, the blanking speed to be 15g/min, the spraying speed to be 9g/min, the air inlet temperature to be 25 ℃, the material temperature to be 20 ℃ and the atomization pressure to be 2.0-2.5bar.
(5) And (3) drying: and setting parameters of a centrifugal granulator to dry the drug-loaded pellets, wherein the rotating speed of a rotating disc is 300r/min, the air inlet temperature is 80 ℃, and the material temperature is 45 ℃.
(6) And (5) weighing coating materials: weighing prescribed amounts of the drug administration pellets, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder, wherein the ethyl cellulose with the viscosity of 9-14CP is micronized to the particle size D90 before weighing: 70-90 μm, and the model of hydroxypropyl methylcellulose acetate succinate is AS-LF.
(7) The treated ethyl cellulose is uniformly mixed with hydroxypropyl methylcellulose acetate succinate and talcum powder.
(8) Coating: coating material mixed powder is filled in a hopper of a centrifugal granulator, an adhesive is connected to a spray gun in a pot, parameters of the centrifugal granulator are set to coat the dried drug-loaded pellets, the rotating speed of a rotating disc is 250-300r/min, the blanking speed is 8g/min, the spraying speed is 3.5g/min, the air inlet temperature is 25 ℃, the material temperature is 20 ℃, and the atomization pressure is 2.0-2.5bar, so that the sustained-release pellets are obtained.
(9) Aging: and (3) setting parameters of a centrifugal granulator to age the slow-release pellets, wherein the rotating speed of a rotating disc is 300r/min, the air inlet temperature is 80 ℃, the material temperature is 45 ℃, and the aging time is 60min.
(10) And (3) filling: detecting the content of the sustained-release pellets, and filling according to the content to obtain the urapidil sustained-release capsules.
Example 6
A urapidil sustained-release capsule comprises the following components in percentage by mass:
Figure BDA0003671820300000131
Figure BDA0003671820300000141
the preparation method comprises the following steps:
(1) Micronizing ethyl cellulose with the viscosity of 9-11CP to the particle size D90: weighing sucrose pill core, urapidil, ethyl cellulose and pulvis Talci with the dosage of 110 μm-130 μm.
(2) The treated ethyl cellulose is uniformly mixed with urapidil and talcum powder.
(3) The oleic acid, the dibutyl sebacate and the polysorbate which are weighed according to the prescription amounts are respectively prepared into water dispersion with the solid content of 40 percent and used as a medicine-feeding adhesive and a plasticizer in coating.
(4) And (3) feeding: putting the sucrose pellets into a pot of a centrifugal granulator, putting raw and auxiliary material mixed powder into a hopper, connecting an adhesive to a spray gun in the pot, starting the centrifugal granulator, setting the rotating speed of a parameter rotary table to be 200-250r/min, the blanking speed to be 15g/min, the spraying speed to be 9g/min, the air inlet temperature to be 25 ℃, the material temperature to be 20 ℃ and the atomization pressure to be 2.0-2.5bar.
(5) And (3) drying: and setting parameters of a centrifugal granulator to dry the drug-loaded pellets, wherein the rotating speed of a rotating disc is 300r/min, the air inlet temperature is 80 ℃, and the material temperature is 45 ℃.
(6) And (5) weighing coating materials: weighing prescribed amounts of the drug administration pellets, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder, wherein the ethyl cellulose with the viscosity of 9-14CP is micronized to the particle size D90 before weighing: 70-90 μm, and the model of hydroxypropyl methylcellulose acetate succinate is AS-LF.
(7) The treated ethyl cellulose is uniformly mixed with hydroxypropyl methylcellulose acetate succinate and talcum powder.
(8) Coating: coating material mixed powder is filled in a hopper of a centrifugal granulator, an adhesive is connected to a spray gun in a pot, parameters of the centrifugal granulator are set to coat the dried drug-loaded pellets, the rotating speed of a rotating disc is 250-300r/min, the blanking speed is 8g/min, the spraying speed is 3.5g/min, the air inlet temperature is 25 ℃, the material temperature is 20 ℃, and the atomization pressure is 2.0-2.5bar, so that the sustained-release pellets are obtained.
(9) Aging: and (3) setting parameters of a centrifugal granulator to age the slow-release pellets, wherein the rotating speed of a rotating disc is 300r/min, the air inlet temperature is 80 ℃, the material temperature is 45 ℃, and the aging time is 60min.
(10) And (3) filling: detecting the content of the sustained-release pellets, and filling according to the content to obtain the urapidil sustained-release capsules.
Example 7
A urapidil sustained-release capsule comprises the following components in percentage by mass:
Figure BDA0003671820300000151
the preparation method comprises the following steps:
(1) Micronizing ethyl cellulose with the viscosity of 9-11CP to the particle size D90: weighing sucrose pill core, urapidil, ethyl cellulose and pulvis Talci with the dosage of 110 μm-130 μm.
(2) The treated ethyl cellulose is uniformly mixed with urapidil and talcum powder.
(3) The oleic acid, the dibutyl sebacate and the polysorbate which are weighed according to the prescription amounts are respectively prepared into water dispersion with the solid content of 40 percent and used as a medicine-feeding adhesive and a plasticizer in coating.
(4) And (3) feeding: putting the sucrose pellets into a pot of a centrifugal granulator, putting raw and auxiliary material mixed powder into a hopper, connecting an adhesive to a spray gun in the pot, starting the centrifugal granulator, setting the rotating speed of a parameter rotary table to be 200-250r/min, the blanking speed to be 15g/min, the spraying speed to be 9g/min, the air inlet temperature to be 25 ℃, the material temperature to be 20 ℃ and the atomization pressure to be 2.0-2.5bar.
(5) And (3) drying: and setting parameters of a centrifugal granulator to dry the drug-loaded pellets, wherein the rotating speed of a rotating disc is 300r/min, the air inlet temperature is 80 ℃, and the material temperature is 45 ℃.
(6) And (5) weighing coating materials: weighing prescribed amounts of the drug administration pellets, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder, wherein the ethyl cellulose with the viscosity of 9-14CP is micronized to the particle size D90 before weighing: 70-90 μm, and the model of hydroxypropyl methylcellulose acetate succinate is AS-LF.
(7) The treated ethyl cellulose is uniformly mixed with hydroxypropyl methylcellulose acetate succinate and talcum powder.
(8) Coating: coating material mixed powder is filled in a hopper of a centrifugal granulator, an adhesive is connected to a spray gun in a pot, parameters of the centrifugal granulator are set to coat the dried drug-loaded pellets, the rotating speed of a rotating disc is 250-300r/min, the blanking speed is 8g/min, the spraying speed is 3.5g/min, the air inlet temperature is 25 ℃, the material temperature is 20 ℃, and the atomization pressure is 1.5-2.0bar, so that the sustained-release pellets are obtained.
(9) Aging: and (3) setting parameters of a centrifugal granulator to age the slow-release pellets, wherein the rotating speed of a rotating disc is 300r/min, the air inlet temperature is 80 ℃, the material temperature is 45 ℃, and the aging time is 60min.
(10) And (3) filling: detecting the content of the sustained-release pellets, and filling according to the content to obtain the urapidil sustained-release capsules.
Example 8
A urapidil sustained-release capsule comprises the following components in percentage by mass:
Figure BDA0003671820300000161
/>
Figure BDA0003671820300000171
the preparation method comprises the following steps:
(1) Micronizing ethyl cellulose with viscosity of 11-14CP to particle size D90: weighing sucrose pill core, urapidil, ethyl cellulose and pulvis Talci with the dosage of 90 μm-110 μm.
(2) The treated ethyl cellulose is uniformly mixed with urapidil and talcum powder.
(3) The oleic acid, the dibutyl sebacate and the polysorbate which are weighed according to the prescription amounts are respectively prepared into water dispersion with the solid content of 40 percent and used as a medicine-feeding adhesive and a plasticizer in coating.
(4) And (3) feeding: putting the sucrose pellets into a pot of a centrifugal granulator, putting raw and auxiliary material mixed powder into a hopper, connecting an adhesive to a spray gun in the pot, starting the centrifugal granulator, setting the rotating speed of a parameter rotary table to be 250-300r/min, the blanking speed to be 15g/min, the spraying speed to be 9g/min, the air inlet temperature to be 25 ℃, the material temperature to be 20 ℃ and the atomization pressure to be 2.0-2.5bar.
(5) And (3) drying: and setting parameters of a centrifugal granulator to dry the drug-loaded pellets, wherein the rotating speed of a rotating disc is 300r/min, the air inlet temperature is 80 ℃, and the material temperature is 45 ℃.
(6) And (5) weighing coating materials: weighing prescribed amounts of the drug administration pellets, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder, wherein the ethyl cellulose with the viscosity of 9-14CP is micronized to the particle size D90 before weighing: 70-90 μm, and the model of hydroxypropyl methylcellulose acetate succinate is AS-LF.
(7) The treated ethyl cellulose is uniformly mixed with hydroxypropyl methylcellulose acetate succinate and talcum powder.
(8) Coating: coating material mixed powder is filled in a hopper of a centrifugal granulator, an adhesive is connected to a spray gun in a pot, parameters of the centrifugal granulator are set to coat the dried drug-loaded pellets, the rotating speed of a rotating disc is 250-300r/min, the blanking speed is 8g/min, the spraying speed is 3.5g/min, the air inlet temperature is 25 ℃, the material temperature is 20 ℃, and the atomization pressure is 2.0-2.5bar, so that the sustained-release pellets are obtained.
(9) Aging: and (3) setting parameters of a centrifugal granulator to age the slow-release pellets, wherein the rotating speed of a rotating disc is 300r/min, the air inlet temperature is 80 ℃, the material temperature is 45 ℃, and the aging time is 60min.
(10) And (3) filling: detecting the content of the sustained-release pellets, and filling according to the content to obtain the urapidil sustained-release capsules.
Example 9
A urapidil sustained-release capsule comprises the following components in percentage by mass:
Figure BDA0003671820300000172
/>
Figure BDA0003671820300000181
the preparation method comprises the following steps:
(1) Micronizing ethyl cellulose with viscosity of 11-14CP to particle size D90: weighing sucrose pill core, urapidil, ethyl cellulose and pulvis Talci with the dosage of 90 μm-110 μm.
(2) The treated ethyl cellulose is uniformly mixed with urapidil and talcum powder.
(3) The oleic acid, the dibutyl sebacate and the polysorbate which are weighed according to the prescription amounts are respectively prepared into water dispersion with the solid content of 40 percent and used as a medicine-feeding adhesive and a plasticizer in coating.
(4) And (3) feeding: putting the sucrose pellets into a pot of a centrifugal granulator, putting raw and auxiliary material mixed powder into a hopper, connecting an adhesive to a spray gun in the pot, starting the centrifugal granulator, setting the rotating speed of a parameter rotary table to be 250-300r/min, the blanking speed to be 15g/min, the spraying speed to be 9g/min, the air inlet temperature to be 25 ℃, the material temperature to be 20 ℃ and the atomization pressure to be 2.0-2.5bar.
(5) And (3) drying: and setting parameters of a centrifugal granulator to dry the drug-loaded pellets, wherein the rotating speed of a rotating disc is 300r/min, the air inlet temperature is 80 ℃, and the material temperature is 45 ℃.
(6) And (5) weighing coating materials: weighing prescribed amounts of the drug administration pellets, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder, wherein the ethyl cellulose with the viscosity of 9-14CP is micronized to the particle size D90 before weighing: 70-90 μm, and the model of hydroxypropyl methylcellulose acetate succinate is AS-LF.
(7) The treated ethyl cellulose is uniformly mixed with hydroxypropyl methylcellulose acetate succinate and talcum powder.
(8) Coating: coating material mixed powder is filled in a hopper of a centrifugal granulator, an adhesive is connected to a spray gun in a pot, parameters of the centrifugal granulator are set to coat the dried drug-loaded pellets, the rotating speed of a rotating disc is 250-300r/min, the blanking speed is 8g/min, the spraying speed is 3.5g/min, the air inlet temperature is 25 ℃, the material temperature is 20 ℃, and the atomization pressure is 2.0-2.5bar, so that the sustained-release pellets are obtained.
(9) Aging: and (3) setting parameters of a centrifugal granulator to age the slow-release pellets, wherein the rotating speed of a rotating disc is 300r/min, the air inlet temperature is 80 ℃, the material temperature is 45 ℃, and the aging time is 60min.
(10) And (3) filling: detecting the content of the sustained-release pellets, and filling according to the content to obtain the urapidil sustained-release capsules.
Example 10
A urapidil sustained-release capsule comprises the following components in percentage by mass:
Figure BDA0003671820300000191
the preparation method comprises the following steps:
(1) Micronizing ethyl cellulose with viscosity of 11-14CP to particle size D90: weighing sucrose pill core, urapidil, ethyl cellulose and pulvis Talci with the dosage of 90 μm-110 μm.
(2) The treated ethyl cellulose is uniformly mixed with urapidil and talcum powder.
(3) The oleic acid, the dibutyl sebacate and the polysorbate which are weighed according to the prescription amounts are respectively prepared into water dispersion with the solid content of 40 percent and used as a medicine-feeding adhesive and a plasticizer in coating.
(4) And (3) feeding: putting the sucrose pellets into a pot of a centrifugal granulator, putting raw and auxiliary material mixed powder into a hopper, connecting an adhesive to a spray gun in the pot, starting the centrifugal granulator, setting the rotating speed of a parameter rotary table to be 200-250r/min, the blanking speed to be 15g/min, the spraying speed to be 9g/min, the air inlet temperature to be 25 ℃, the material temperature to be 20 ℃ and the atomization pressure to be 2.0-2.5bar.
(5) And (3) drying: and setting parameters of a centrifugal granulator to dry the drug-loaded pellets, wherein the rotating speed of a rotating disc is 300r/min, the air inlet temperature is 80 ℃, and the material temperature is 45 ℃.
(6) And (5) weighing coating materials: weighing prescribed amounts of the drug administration pellets, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder, wherein the ethyl cellulose with the viscosity of 9-14CP is micronized to the particle size D90 before weighing: 70-90 μm, and the model of hydroxypropyl methylcellulose acetate succinate is AS-LF.
(7) The treated ethyl cellulose is uniformly mixed with hydroxypropyl methylcellulose acetate succinate and talcum powder.
(8) Coating: coating material mixed powder is filled in a hopper of a centrifugal granulator, an adhesive is connected to a spray gun in a pot, parameters of the centrifugal granulator are set to coat the dried drug-loaded pellets, the rotating speed of a rotating disc is 250-300r/min, the blanking speed is 8g/min, the spraying speed is 3.5g/min, the air inlet temperature is 25 ℃, the material temperature is 20 ℃, and the atomization pressure is 1.5-2.0bar, so that the sustained-release pellets are obtained.
(9) Aging: and (3) setting parameters of a centrifugal granulator to age the slow-release pellets, wherein the rotating speed of a rotating disc is 300r/min, the air inlet temperature is 80 ℃, the material temperature is 45 ℃, and the aging time is 60min.
(10) And (3) filling: detecting the content of the sustained-release pellets, and filling according to the content to obtain the urapidil sustained-release capsules.
Test example 1: influence of viscosity, particle size and dosage of ethyl cellulose on drug administration process of urapidil sustained-release capsule
Samples of urapidil drug delivery pellets of ethylcellulose of different viscosities, particle sizes and amounts in the drug delivery links in table 1 were prepared according to the preparation method of example 1. The pill characteristics of the prepared different urapidil drug administration pellets are observed, the drug administration rate is calculated, the influence of the viscosity, the particle size and the dosage of the ethyl cellulose in the process of the urapidil drug administration is examined, and the experimental results are shown in table 1.
The medicine loading rate calculating method comprises the following steps: drug loading (%) =gladil drug loading pellet content of gladil drug loading pellet/gladil dose of 100%
TABLE 1 influence of the viscosity, particle size and amount of ethylcellulose on the loading of Ulapdil onto the pellets
Figure BDA0003671820300000201
Figure BDA0003671820300000211
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Conclusion:
as can be seen from the test results of the above table, when the viscosity of the ethylcellulose is 9-11CP, the particle size D90: the sample prepared by the method with the dosage of 90-110 mu m accounting for 5 percent of the mass percent of the urapidil bulk drug has the drug loading rate of more than 95 percent on the basis of ensuring the round and smooth property of the drug loading pellets, and is the most preferable condition.
The amount of ethylcellulose used leads to a degree of adhesion between the pellets, at a viscosity of 9-11CP, particle size D90: when the dosage is 90-110 mu m, the ethyl cellulose accounting for 4-6% of the mass percent of the urapidil bulk drug can ensure the drug loading rate to be more than 90%; the ethyl cellulose accounting for 4 to 5 percent of the weight of the urapidil bulk drug ensures the drug loading rate, and the pellets are round and smooth, have no burrs and have no adhesion; when the dosage is 3%, the dosage is lower than 90%, the dosage of the ethyl cellulose is too low, the dosage is not good, and when the dosage is 7%, the dosage is 95.2%, but the serious adhesion between the micropills occurs, so that the later-stage coating operation can not be performed normally, and the dosage of the ethyl cellulose is too high and too low, preferably 4% -6%.
In the aspect of viscosity of ethyl cellulose, when the viscosity is too low, for example, the viscosity is 6-9CP, the drug application rate is not 85%, and when the viscosity is too high, for example, the viscosity is 11-14CP, the drug application rate of partial samples can reach more than 90%, but the surface of the pellets has obvious burrs and has adhesion phenomenon, and the subsequent coating uniformity can be influenced.
In the aspect of the particle size of the ethylcellulose, when the particle size is too small, the material is easy to be blown away by air inlet in the pressure cooker, so that the medicine feeding rate is low, for example, the viscosity is 9-11CP, and the particle size D90 is as follows: 70-90 μm and viscosity 11-14CP, particle size D90: the medicine feeding rate is about 80% under the condition of 70-90 mu m; when the particle size is too large, burrs are formed on the surface of the pellets, and coating uniformity is poor.
Finally, the drug-loading pellets with the drug loading rate of more than 90% in the drug loading link are selected, and the next coating investigation is carried out, wherein the drug-loading pellets comprise ethyl cellulose with the following preferable conditions: a. viscosity 9-11CP, particle size D90:90-110 mu m; b. viscosity 9-11CP, particle size D90:110-130 μm; c. viscosity 11-14CP, particle size D90:90-110 mu m; d. viscosity 11-14CP, particle size D90: the prepared pill is 110-130 μm. And the release curve and uniformity of the prepared urapidil slow-release capsule after the coating link are combined to optimize, and a scheme capable of simultaneously solving the drug loading rate and the release behavior is screened out.
Test example 2: influence of viscosity and particle size of ethylcellulose on release behavior of urapidil sustained-release capsules
Samples of urapidil sustained-release capsules of ethylcellulose with different viscosities and different particle sizes of the coating parts in table 2 were prepared according to the preparation method of example 1 by using the drug-loading pellets prepared under the four conditions of a, b, c, d. The release degree of the prepared different urapidil slow-release capsules is detected, and the release uniformity is calculated to examine the influence of the viscosity and the particle size of the ethyl cellulose on the urapidil slow-release capsules, and the results are shown in Table 2.
According to the method for detecting the dissolution curve library of the preparation on the market in Japan, different mediums are adopted to detect the release curve: experimental apparatus II (paddle method), medium with rotation speed of 50r/min, pH of 1.2 and pH of 5.5, and medium volume of 900ml.
The release uniformity measuring method comprises the following steps: release profile in ph5.5 medium was measured for 12 cups per sample, release at 6 hours was calculated, and RSD values for 12 cups were calculated.
TABLE 2 Effect of different viscosity particle size ethylcellulose on Release behavior of Ulapril sustained release capsules
Figure BDA0003671820300000221
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Figure BDA0003671820300000231
Figure BDA0003671820300000241
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Conclusion:
as can be seen from the test results of the table, the prepared urapidil sustained-release capsules are prepared by adopting the ethyl cellulose coated pellets with the viscosity of 9-11CP and the particle size D90:90-110 mu m and adopting the ethyl cellulose coated pellets with the viscosity of 3-9CP and the particle size D90:70-90 mu m, and have the release curves in the medium with the pH value of 1.2 and the medium with the pH value of 5.5 which are closest to those of the original preparation and have good uniformity. Due to the adoption of the powder coating process, when the particle size of the coated part of the ethylcellulose is overlarge, for example, the particle size D90 is 90-110 mu m, the surface of the micropill is rough, the micropill is not easy to age in the aging process, tiny gaps appear, and the slow release effect cannot be achieved.
The viscosity of the ethyl cellulose is 9-11CP, and the particle size D90: the coated micropill prepared by 110-130 μm has the coating parameters of ethyl cellulose viscosity 9-14CP and particle diameter D90:70-90 μm, and the coated micropill has burr phenomenon, but the ethyl cellulose with higher viscosity is selected for regulating release during coating, thus the sample release curve is good and the uniformity is good.
Ethyl cellulose viscosity is 11-14CP, particle size D90: the drug-loading pellets prepared by 90-110 mu m, and the urapidil sustained-release capsules prepared by coating parameters of ethyl cellulose with the viscosity of 9-14CP and the particle size of D90:70-90 mu m are selected, and the drug-loading pellets have the burr phenomenon, but the ethyl cellulose with higher viscosity is selected as a framework material during drug loading, so that the drug-loading pellets can be released in an adjustable way, and the sample release curve is good and the uniformity is good.
Ethyl cellulose viscosity 9-11CP, particle size D90: the drug-loading pellets prepared by 90-110 mu m are prepared by selecting the urapidil sustained-release capsules prepared by coating parameters such as ethyl cellulose viscosity 9-14CP and particle size D90:70-90 mu m, and compared with the urapidil sustained-release capsules prepared by selecting the ethyl cellulose with coating parameters such as viscosity 3-9CP and particle size D90:70-90 mu m, the release is slower due to the increased viscosity of the coated ethyl cellulose.
Ethyl cellulose viscosity is 11-14CP, particle size D90: the coated pellets prepared at 110-130 μm had poor dissolution uniformity after coating at various viscosities and particle sizes as shown in Table 2.
Under other conditions, when the particle size of the ethyl cellulose of the coating part is too large, the surface of the micropill is rough, the micropill is not easy to age in the aging process, tiny gaps appear, or the coating cannot be completely wrapped due to adhesion of the drug-loading micropill, and the slow-release effect cannot be achieved.
The preferable scheme for taking the medicine feeding rate and the release behavior into consideration is that A. The medicine feeding part of ethyl cellulose accounts for 4-6 percent of the weight of urapidil, the viscosity is 9-11CP, the particle size is 90-110 mu m, and the coating part of ethyl cellulose accounts for 3-9CP, and the particle size is 70-90 mu m; B. the dosage of the ethyl cellulose of the medicine feeding part accounts for 4-6 percent of the weight of urapidil, the viscosity is 9-11CP, the particle size is 110-130 mu m, and the ethyl cellulose of the medicine feeding part is coated: viscosity of 9-14CP and particle size of 70-90 μm; C. drug loading part ethylcellulose: the dosage is 4-6% of urapidil mass percent, the viscosity is 11-14CP, the grain diameter is 90-110 mu m, and the coating part is ethyl cellulose: the viscosity is 9-14CP, and the particle size is 70-90 μm. The best scheme is that the dosage of the ethyl cellulose of the medicine feeding part accounts for 5 percent of the weight of urapidil, the viscosity is 9-11CP, the grain diameter is 90-110 mu m, and the viscosity of the ethyl cellulose of the coating part accounts for 3-9CP, and the grain diameter is 70-90 mu m.
Combined with the characteristic of the absorption of urapidil in human body, the absorption rate of urapidil in human body is in the stomach: 3.05+/-4.83%; duodenum: 86.05±2.13%; jejunum: 90.82 + -1.80%. Therefore, the absorption rate of urapidil in the duodenum and jejunum is the largest, so that the release of urapidil in the stomach is less in the experimental process, otherwise, a large amount of medicine is not absorbed in the stomach and directly enters the intestinal tract to generate the burst release phenomenon, and the urapidil needs to be fully and stably released in the duodenum and jejunum. Intragastric pH in humans: 1-3; duodenal pH:4-6; jejunum pH6-7. Representative pH1.2 medium and 5.5 medium were chosen for assay comparison in the experiments.
The coating step is to mix enteric coating material AS-LF type hydroxypropyl methylcellulose acetate succinate with ethyl cellulose powder with specific viscosity and particle size, and to take aqueous dispersion of oleic acid, dibutyl sebacate and polysorbate 80 AS plasticizer for slow-release coating in a centrifugal granulator. The hydroxypropyl methylcellulose acetate succinate serving as an enteric material is dissolved and released in a medium with the pH value of more than 5.5, so that the full release of the hydroxypropyl methylcellulose acetate succinate in the duodenum and jejunum of a human body is ensured; the ethyl cellulose is added as an insoluble slow-release material, so that the urapidil is ensured not to be suddenly released and is stably released; meanwhile, the preparation of the urapidil sustained-release capsule by a non-organic solvent system is also realized.
Test example 3: influence of technological parameters of medicine feeding link and coating link on urapidil sustained-release capsule
Samples of urapidil drug delivery pellets and sustained release capsules were prepared according to the preparation method of example 1 under different process parameters of the drug delivery link and the coating link in tables 3 and 4. According to the method for detecting the content of urapidil in the second part of the Chinese pharmacopoeia 2020 edition, the content of urapidil drug administration pellets prepared under different conditions is measured, the content uniformity and the drug administration rate are calculated, and the influence of the drug administration process parameters on the process of urapidil drug administration is examined.
The calculation method of the medicine feeding rate is the same as that of the medicine feeding rate.
The content uniformity RSD calculation method comprises the following steps: taking 3 parts of urapidil drug-loading pellet samples at different positions in the upper part, the middle part and the lower part of a pot of a centrifugal granulator, taking 1 part of samples from a discharge hole, weighing 10 parts of samples, respectively weighing a proper amount of the 10 parts of urapidil drug-loading pellet samples, respectively preparing solutions of 0.1mg/ml, respectively detecting the content of the solutions, respectively calculating an SD value and an average value, and further calculating an RSD value.
SD value calculation:
Figure BDA0003671820300000261
RSD calculation; rsd=sd/average 100%.
In addition, the release degree of the prepared different urapidil slow-release capsules is detected, and the influence of the coating process parameters on the release degree of the urapidil slow-release capsules is examined.
Detecting the release curve of the urapidil sustained-release capsule according to the detection method of a dissolution curve library of the preparation in Japan, wherein the detection method of the release curve comprises the following steps: experimental device II (Paddle method), medium with rotation speed of 50r/min and pH of 6.8 and medium volume of 900ml.
TABLE 3 influence of drug delivery parameters on Unlafadil drug delivery pellets
Figure BDA0003671820300000262
Conclusion:
as can be seen from the test results of the table, in the medicine feeding link, the blanking rate is 15g/min, the spraying rate is 9g/min, the atomization pressure is 2.0-2.5bar, when the rotating speed of the turntable is 200-300r/min, the pill core is not adhered in the medicine feeding process, the medicine feeding rate is over 95.7%, the content uniformity is good, the medicine feeding time of 600g urapidil is within 30min, the medicine feeding is rapid and efficient, and the process parameter is the preferable condition of the medicine feeding link. The atomizing pressure is too small, so that fog drops are too large, the pill core is adhered, the atomizing pressure is too large, powder is blown away by air pressure, and the medicine feeding rate is low. The test improves the drug feeding efficiency and the drug feeding yield by optimizing the technological parameters of the drug feeding link.
Preparing the drug-loading pellets according to the preferable technological parameters of the drug-loading link, and further researching the technological parameters of the coating link.
TABLE 4 influence of coating parameters on Unlafadil sustained release capsules
Figure BDA0003671820300000263
Figure BDA0003671820300000271
Conclusion:
test example 2 has studied the release conditions of pH1.2 and pH5.5, and has been found that a slow release formulation suitable for gastrointestinal absorption was obtained, test example 3 further investigated the release behavior of the other main absorption site, the absorption rate of urapidil in the jejunum in humans was 90.82 ±1.80%, the pH of the jejunum was 6-7, and a medium pH6.8 was selected for the investigation of the release profile to ensure a sufficient and smooth release of the drug in the jejunum. By examining coating parameters, the blanking rate is 8g/min, the spraying rate is 3.5g/min, the atomization pressure is between 1.5 and 2.5bar, the coating is carried out when the rotating speed of the rotary table is 250 to 300r/min, the release curve of the coated urapidil slow-release capsule in a pH6.8 medium is similar to that of the original preparation, the characteristic of the absorption of urapidil in a human body is met, and the release effect of the urapidil slow-release capsule is further accurately controlled.
Test example 4: quality study of urapidil sustained-release capsules
The samples of the urapidil sustained-release capsules prepared in examples 1 to 10 of the present invention were subjected to quality study, content uniformity, drug loading rate and in vitro release (pH 6.8 medium) were examined, the examination method was the same as in test example 3, and the F2 factor value was calculated based on the release data, the specific calculation method was referred to the dissolution curve guidelines published by the national drug administration, and the results of the study are shown in Table 5.
TABLE 5 quality study of the Urapidil sustained release capsules prepared in examples 1-10
Figure BDA0003671820300000272
Figure BDA0003671820300000281
Conclusion:
the drug loading rates of the examples 1-10 are above 90%, and the F2 value is greater than 50, which shows that the release curve is similar to that of the original developer, and the greater the F2 value is, the higher the degree of similarity of the release curve is, so that the examples 1-10 have the dual effects of drug loading rate and release behavior. The effects of examples 1-4 are best, the drug loading rate is more than 95%, the pellets are round and smooth, the F2 value is more than 75, the release behavior is closer to that of the original preparation, the content uniformity is better, and the RSD is less than 1.5.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, or alternatives falling within the spirit and principles of the invention.

Claims (2)

1. The urapidil sustained-release capsule consists of sustained-release pellets and a capsule shell, wherein the sustained-release pellets comprise a pellet core, a medicine feeding part and a coating part, and are characterized by comprising the following components in percentage by mass: 2.2% -3.2% of ethyl cellulose, 5.7% -6.7% of AS-LF type hydroxypropyl methylcellulose acetate succinate, 0.3% -0.4% of talcum powder, 1.1% -1.3% of oleic acid, 0.4% -0.7% of dibutyl sebacate and 0.02% of polysorbate 80, and the balance of drug-loading pellets, wherein the viscosity of the ethyl cellulose is 3-9CP, and the particle size D90 is 70-90 mu m; the drug-loading micropill comprises the following components in percentage by mass: 30% of urapidil, 1.2% -1.8% of ethyl cellulose, 0.4% -0.8% of talcum powder, 5.5% -6.5% of oleic acid, 1.5% -2.5% of dibutyl sebacate and 0.02% of polysorbate 80, and the balance of sucrose pellet cores, wherein the viscosity of the ethyl cellulose is 9-11CP, the particle size D90 is 90-110 mu m, and the dosage is 4-6% of urapidil mass;
The sustained-release pellet is prepared by feeding and coating a pellet core, and specifically comprises the following steps: spraying the powder of the medicine applying layer and the adhesive of the medicine applying layer on the pill core simultaneously to obtain medicine applying micropills; spraying the coating material powder and the coating plasticizer on the drug-loading pellets simultaneously to obtain slow-release pellets;
the medicine applying layer powder comprises urapidil, ethyl cellulose and talcum powder; the adhesive of the upper drug layer is an aqueous dispersion of oleic acid, dibutyl sebacate and polysorbate 80, and the solid content of the adhesive of the upper drug layer is 39% -41%; the coating material powder comprises ethyl cellulose, AS-LF type hydroxypropyl methylcellulose acetate succinate and talcum powder; the coating plasticizer is an aqueous dispersion of oleic acid, dibutyl sebacate and polysorbate 80, and the solid content of the coating plasticizer is 39-41%.
2. The method for preparing the urapidil sustained-release capsule according to claim 1, characterized in that: the method comprises the following steps:
(1) Micronizing ethyl cellulose until D90 is 90-110 μm to obtain first ethyl cellulose micropowder; weighing sucrose pill core, urapidil, first ethyl cellulose micropowder and talcum powder according to the prescription amount;
(2) Uniformly mixing the first ethyl cellulose micropowder, urapidil and talcum powder in a prescription amount to obtain upper medicine layer powder;
(3) Respectively preparing the oleic acid, the dibutyl sebacate and the polysorbate with the prescription amount into water dispersion with the solid content of 40 percent to obtain a medicine coating adhesive and a coating plasticizer;
(4) Spraying the powder of the medicine applying layer and the adhesive of the medicine applying layer on the pill core simultaneously, and drying to obtain medicine applying micropills;
(6) Micronizing the ethyl cellulose until D90 is 70-90 mu m to obtain second ethyl cellulose micropowder; weighing prescription amount of the drug-loading micropill, second ethyl cellulose micropowder, AS-LF type hydroxypropyl methylcellulose acetate succinate and talcum powder;
(7) Uniformly mixing the second ethyl cellulose micropowder, AS-LF hydroxypropyl methylcellulose acetate succinate and talcum powder according to the prescription amount to obtain coating material powder;
(8) Spraying the coating material powder and the coating plasticizer on the drug-loading pellets simultaneously to obtain slow-release pellets;
(9) Aging the sustained-release pellets, and filling to obtain the urapidil sustained-release capsules;
in the step (4), the technological parameters of the medicine feeding procedure are as follows: the rotating speed of a rotary table of the centrifugal granulator is 200-300r/min, the blanking speed is 15-16g/min, the spraying speed is 8.5-9.5g/min, and the atomization pressure is 2.0-2.5bar;
in the step (8), the technological parameters of the coating procedure are as follows: the rotating speed of a rotary table of the centrifugal granulator is 250-300r/min, the blanking speed is 7-9g/min, the spraying speed is 3-4g/min, and the atomization pressure is 1.5-2.5bar.
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