CN114983973A - Urapidil sustained-release capsule and preparation method thereof - Google Patents
Urapidil sustained-release capsule and preparation method thereof Download PDFInfo
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- CN114983973A CN114983973A CN202210610443.7A CN202210610443A CN114983973A CN 114983973 A CN114983973 A CN 114983973A CN 202210610443 A CN202210610443 A CN 202210610443A CN 114983973 A CN114983973 A CN 114983973A
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- Prior art keywords
- urapidil
- ethyl cellulose
- sustained
- release
- pellets
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- ICMGLRUYEQNHPF-UHFFFAOYSA-N Uraprene Chemical compound COC1=CC=CC=C1N1CCN(CCCNC=2N(C(=O)N(C)C(=O)C=2)C)CC1 ICMGLRUYEQNHPF-UHFFFAOYSA-N 0.000 title claims abstract description 159
- 229960001130 urapidil Drugs 0.000 title claims abstract description 159
- 238000013268 sustained release Methods 0.000 title claims abstract description 134
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 134
- 239000002775 capsule Substances 0.000 title claims abstract description 84
- 238000002360 preparation method Methods 0.000 title abstract description 27
- 238000000576 coating method Methods 0.000 claims abstract description 127
- 239000011248 coating agent Substances 0.000 claims abstract description 120
- 239000003814 drug Substances 0.000 claims abstract description 98
- 239000001856 Ethyl cellulose Substances 0.000 claims description 169
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 169
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 169
- 229920001249 ethyl cellulose Polymers 0.000 claims description 169
- 239000008188 pellet Substances 0.000 claims description 147
- 239000002245 particle Substances 0.000 claims description 98
- 239000000463 material Substances 0.000 claims description 96
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 63
- 238000011068 loading method Methods 0.000 claims description 51
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 claims description 46
- 238000005303 weighing Methods 0.000 claims description 45
- 239000006187 pill Substances 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 38
- 229930006000 Sucrose Natural products 0.000 claims description 33
- 239000005720 sucrose Substances 0.000 claims description 33
- 238000011049 filling Methods 0.000 claims description 32
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 31
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 30
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 30
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 30
- PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 claims description 30
- 239000005642 Oleic acid Substances 0.000 claims description 30
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 30
- 239000000853 adhesive Substances 0.000 claims description 30
- 230000001070 adhesive effect Effects 0.000 claims description 30
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 30
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 30
- 238000005507 spraying Methods 0.000 claims description 30
- 239000000843 powder Substances 0.000 claims description 29
- 239000006185 dispersion Substances 0.000 claims description 28
- 230000008569 process Effects 0.000 claims description 27
- 230000032683 aging Effects 0.000 claims description 24
- 229940079593 drug Drugs 0.000 claims description 24
- 239000007788 liquid Substances 0.000 claims description 23
- 239000004014 plasticizer Substances 0.000 claims description 22
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 18
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 18
- 229920000053 polysorbate 80 Polymers 0.000 claims description 18
- 229940068968 polysorbate 80 Drugs 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 18
- 238000002156 mixing Methods 0.000 claims description 16
- 238000012377 drug delivery Methods 0.000 claims description 15
- 238000001035 drying Methods 0.000 claims description 12
- 229920000136 polysorbate Polymers 0.000 claims description 12
- 229950008882 polysorbate Drugs 0.000 claims description 12
- 229920002678 cellulose Polymers 0.000 claims description 6
- 239000001913 cellulose Substances 0.000 claims description 6
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 claims 1
- 239000000454 talc Substances 0.000 claims 1
- 235000012222 talc Nutrition 0.000 claims 1
- 229910052623 talc Inorganic materials 0.000 claims 1
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000003125 aqueous solvent Substances 0.000 abstract description 3
- 238000010924 continuous production Methods 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 239000011812 mixed powder Substances 0.000 description 21
- 239000007921 spray Substances 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 238000000889 atomisation Methods 0.000 description 16
- 239000011230 binding agent Substances 0.000 description 11
- 210000001630 jejunum Anatomy 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 210000001198 duodenum Anatomy 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 230000036772 blood pressure Effects 0.000 description 3
- 239000003405 delayed action preparation Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 238000005457 optimization Methods 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 206010013990 dysuria Diseases 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000003475 lamination Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 125000000185 sucrose group Chemical group 0.000 description 2
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010058179 Hypertensive emergency Diseases 0.000 description 1
- 208000001089 Multiple system atrophy Diseases 0.000 description 1
- 208000000693 Neurogenic Urinary Bladder Diseases 0.000 description 1
- 206010029279 Neurogenic bladder Diseases 0.000 description 1
- 206010031127 Orthostatic hypotension Diseases 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 201000005857 malignant hypertension Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
Classifications
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Urology & Nephrology (AREA)
- Inorganic Chemistry (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the technical field of pharmacy, and provides an urapidil sustained-release capsule and a preparation method thereof. The sustained-release urapidil capsule is developed by adopting an aqueous solvent system, so that the potential safety hazard is reduced, the environmental protection pressure is reduced, and the continuous production of medicine application and coating is realized by using a centrifugal granulator, thereby being more beneficial to industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmacy, and particularly relates to urapidil sustained-release capsules and a preparation method thereof.
Background
Urapidil belongs to an alpha 1 receptor blocker, has the functions of lowering blood pressure peripherally and centrally, has unique advantages in the aspects of treating severe hypertension and hypertensive emergency and controlling perioperative hypertension, can be used for dysuria related to benign prostatic hyperplasia and dysuria related to neurogenic bladder, and has wide clinical application.
Urapidil was developed by Byk Gulden corporation and was first approved as an injection in Germany in 1980, and then approved as a sustained-release capsule in 1981 and Japanese in 1989 under the trade name of sustained-release capsule
Approval and sale are now available in several tens of countries around the world.
The urapidil has short half-life period of 2.7 hours, and common preparations need frequent administration, so a sustained release preparation needs to be developed to reduce the administration times and improve the compliance of patients, but because urapidil is a weakly alkaline insoluble medicament, the release of the urapidil in vivo is influenced by the pH value of gastrointestinal tracts, the solubility of the urapidil in an acidic environment is high, the solubility of the urapidil in an alkaline condition is low, the characteristic medicament is not suitable for being prepared into a sustained release preparation, because the pharmacokinetic performance of the medicament is greatly changed, the medicament release is not stable, the normal blood pressure cannot be ensured all the time, the occurrence of the blood pressure value causing undesirable side effects (such as orthostatic 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 be mixed and used to form a pH-dependent film, thereby solving the problem that the solubility of urapidil changes along with the change of pH and developing the sustained-release capsule. However, in the existing process, organic solvents such as ethanol and isopropanol are adopted for medicine application 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 causes no small environmental protection pressure, so that the industrial mass production is not facilitated.
In order to solve the problem of avoiding adopting an organic solvent to prepare a binder solution or a coating solution in industrial production, an aqueous solvent system is used for developing 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 ensures the product quality, improves the production efficiency and is beneficial to industrial production needs to be further researched.
Disclosure of Invention
The invention aims to provide urapidil sustained-release capsules and a preparation method thereof aiming at the defects of the prior art. By researching different viscosity, dosage and particle size ranges of the ethyl cellulose, the medicine application rate can be improved, and even the double problems of medicine application and release are solved in a synergistic manner; and by controlling the technological parameters of the medicine feeding link and the coating link, the product quality is ensured while the product yield and the production efficiency are further improved; the mixed powder of ethyl cellulose and hydroxypropyl methylcellulose acetate succinate is selected for coating, so that the stable release of the medicine is further ensured, and the content uniformity is good; the continuous production of the medicine application and the coating is realized by using a centrifugal granulator.
In order to realize the purpose of the invention, the following technical scheme is adopted:
the sustained-release pellet comprises a pellet core, a medicine-applying part and a coating part, wherein the medicine-applying 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 mass of the urapidil, 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 an urapidil sustained release capsule B for increasing the drug delivery rate and improving the release behavior, which comprises 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 the viscosity of 9-11CP and the particle size D90 of 90-110 μm, the dosage of the ethyl cellulose is 4-6% of the mass of urapidil, and the coating part comprises ethyl cellulose with the viscosity of 3-9CP and the particle size D90 of 70-90 μm.
More preferably, the amount of ethyl cellulose in the urapidil sustained-release capsule B for improving the drug-applying rate and the release behavior is 5% of the mass of urapidil.
Still further, another object of the present invention is to provide an urapidil sustained release capsule C for increasing the drug delivery rate and improving the release behavior, which comprises 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 the viscosity of 9-11CP and the particle size of D90 of 110-130 μm, the dosage of the ethyl cellulose is 4-6% of the mass of urapidil, and the coating part comprises ethyl cellulose with the viscosity of 9-14CP and the particle size of D90 of 70-90 μm.
Still further, another object of the present invention is to provide an urapidil sustained-release capsule D for increasing the drug-loading rate and improving the release behavior, which comprises 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 11-14CP and the particle size of D90 of 90-110 μm, the dosage of the ethyl cellulose is 4-6% of the mass of urapidil, and the coating part comprises ethyl cellulose with the viscosity of 9-14CP and the particle size of D90 of 70-90 μm.
According to the urapidil sustained-release capsule, the sustained-release pellets are prepared by loading and coating the pellet cores, wherein the loading link adopts a laminated loading process, and the coating link adopts a laminated coating process.
Furthermore, the laminated medicine-feeding process adopted in the medicine-feeding link is to spray the medicine-feeding layer powder and the medicine-feeding layer adhesive on the pill core to obtain the medicine-feeding pellets.
Further, the components of the upper medicine layer powder are urapidil, ethyl cellulose and talcum powder.
Further, the upper medicine layer adhesive is an aqueous dispersion with the solid content of 39% -41%.
Further, the solid components of the upper drug layer adhesive are oleic acid, dibutyl sebacate and polysorbate 80.
Furthermore, the lamination coating process adopted in the coating link is to spray coating material powder and coating plasticizer on the drug-loaded 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 AS-LF type.
Further, the coating plasticizer is an aqueous dispersion with 39% -41% of solid content.
Further, the solid components of the coating plasticizer are oleic acid, dibutyl sebacate and polysorbate 80.
Further, according to the urapidil sustained-release capsule, the pill core is a sucrose pill core.
Further, the urapidil sustained-release capsule comprises the following components in percentage by mass: 30% urapidil, 1.2% -1.8% ethyl cellulose, 0.4% -0.8% talcum powder, 5.5% -6.5% oleic acid, 1.5% -2.5% dibutyl sebacate and 0.02% polysorbate 80, and the balance is 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 pellet comprises the following components in percentage by mass: 2.2 to 3.2 percent of ethyl cellulose, 5.7 to 6.7 percent of AS-LF type hydroxypropyl methylcellulose acetate succinate, 0.4 percent of talcum powder, 1.1 to 1.3 percent of oleic acid, 0.4 to 0.7 percent of dibutyl sebacate and 0.02 percent of polysorbate 80, and the balance of the medicine-adding pellets, wherein the viscosity of the ethyl cellulose in the coating part is 3 to 9CP, and the particle size D90 is 70 to 90 mu m.
Further, the urapidil sustained-release capsule comprises the following components in percentage by mass: 30% urapidil, 1.2% -1.8% ethyl cellulose, 0.2% -0.8% talcum powder, 5.5% -6.5% oleic acid, 1.5% -2.5% dibutyl sebacate and 0.02% polysorbate 80, and the balance is sucrose pill core, wherein the viscosity of the ethyl cellulose in the medicine feeding part is 9-11CP, and the particle size D90 is 110-; the sustained-release pellet comprises 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 the medicine-applying 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% urapidil, 1.2% -1.8% ethyl cellulose, 0.2% -0.8% talcum powder, 5.0% -5.7% oleic acid, 2.3% -3.2% dibutyl sebacate and 0.02% polysorbate 80, and the balance being 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 pellet comprises 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 the medicine-adding pellets, wherein the viscosity of the ethyl cellulose in the coating part is 9-14CP, and the particle size D90 is 70-90 μm.
Further, the urapidil sustained-release capsule comprises the following components in percentage by mass:
the invention also aims to provide a preparation method of the urapidil sustained-release capsule, which comprises the following steps:
(1) micronizing ethyl cellulose to a first preset particle size to obtain first ethyl cellulose micropowder; weighing a formula amount of sucrose pill core, urapidil, first ethyl cellulose micro powder and talcum powder;
(2) uniformly mixing the first ethyl cellulose micro powder, urapidil and talcum powder according to the prescription amount to obtain upper medicine layer powder;
(3) respectively preparing oleic acid, dibutyl sebacate and polysorbate which are weighed according to the prescription amount into aqueous dispersion with the solid content of 40 percent to obtain an upper medicine layer adhesive and a coating plasticizer;
(4) spraying the powder of the upper medicinal layer and the adhesive of the upper medicinal layer on the pellet core at the same time, and drying to obtain the micro-pellets;
(6) micronizing ethyl cellulose to a second preset particle size to obtain second diethyl cellulose micropowder; weighing the prescription amount of the medicine-feeding micro-pills, the second diethyl cellulose micro-powder, AS-LF type hydroxypropyl methylcellulose acetate succinate and talcum powder;
(7) uniformly mixing the second diethyl cellulose micro powder, AS-LF type hydroxypropyl methyl cellulose 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 onto the pellet to obtain sustained-release pellet;
(9) and aging the sustained-release pellets, and filling to obtain the urapidil sustained-release capsule.
The first preset particle size is that the particle size D90 of the ethyl cellulose of the upper medicine part is 90-110 μm or 110-130 μm; the second predetermined particle size is such that the coating portion ethyl cellulose particle size D90 is 70-90 μm.
Furthermore, in the step (4), the process parameters of the medicine feeding procedure are as follows: the rotating speed of the turntable of the centrifugal granulator is 200 plus 300r/min, the blanking speed is 15g/min, the liquid spraying speed is 9g/min, and the atomizing pressure is 2.0-2.5 bar.
Furthermore, in the step (4), the process parameters of the medicine feeding process further comprise: the air inlet temperature of the centrifugal granulator is 25 ℃, and the material temperature is 20 ℃.
Furthermore, in the step (8), the process parameters of the coating process are as follows: the rotating speed of the turntable of the centrifugal granulator is 250-300r/min, the blanking speed is 8g/min, the liquid spraying speed is 3.5g/min, and the atomizing pressure is 1.5-2.5 bar.
Furthermore, in the step (8), the coating process further comprises the following process parameters: the air inlet temperature of the centrifugal granulator is 25 ℃, and the material temperature is 20 ℃.
By adopting the technical scheme, the invention has the following beneficial effects:
(1) in the research process of changing an aqueous solvent slow-release enteric-coated system, the viscosity, the dosage and the particle size range of ethyl cellulose are researched, the dual problems of medicine application and release are synergistically solved, three optimal schemes are explored, the release behavior of the slow-release capsule can be ensured to be consistent with that of the original research, the medicine application rate can reach more than 90%, and the optimal schemes are as follows:
A. the mass percentage of the ethyl cellulose of the medicine part accounts for 4-6% of urapidil, the viscosity is 9-11CP, the grain diameter D90 is 90-110 μm, the viscosity of the ethyl cellulose of the coating part is 3-9CP, and the grain diameter D90 is 70-90 μm;
B. the mass percentage of the ethyl cellulose of the upper medicine part accounts for 4-6 percent of urapidil, the viscosity is 9-11CP, the particle diameter D90 is 110-: the viscosity is 9-14CP, the particle diameter D90 is 70-90 μm;
C. the medicine part is ethyl cellulose: the using amount accounts for 4-6 percent of the urapidil by mass percent, the viscosity is 11-14CP, the particle size D90 is 90-110 mu m, and the coating part is ethyl cellulose: the viscosity is 9-14CP, and the particle diameter D90 is 70-90 μm.
(2) The invention finds better optimization conditions by combining with the technological parameter investigation of a centrifugal granulator, further improves the product yield and the production efficiency, ensures the product quality, realizes the medicine application rate of more than 95 percent, has no adhesion among pellets, smooth and flat pellet surface, good content uniformity, the release behavior is closest to the original grinding, has the medicine application time of 600g urapidil within 30min, and improves the efficiency by 2-4 times. The optimization conditions are specifically as follows: the medicine part is ethyl cellulose: the using amount accounts for 5 percent of the mass percent of urapidil, the viscosity is 9-11CP, the grain diameter D90 is 90-110 mu m, the coating part is ethyl cellulose, the viscosity is 3-9CP, the grain diameter D90 is 70-90 mu m, and the technological parameters of the medicine feeding link are as follows: the blanking speed is 15g/min, the guniting speed is 9g/min, the atomization pressure is 2.0-2.5bar, the rotating speed of a turntable is 200-: the blanking speed is 8g/min, the guniting speed is 3.5g/min, the atomization pressure is 1.5-2.5bar, and the rotating speed of the rotary disc is 250-300 r/min.
(3) In the process of slow release coating, the characteristic that urapidil is absorbed in a human body is combined, the invention mixes two powders of ethyl cellulose with specific viscosity and grain size and AS-LF type hydroxypropyl methylcellulose acetate succinate, takes aqueous dispersion of oleic acid, dibutyl sebacate and polysorbate 80 AS a plasticizer, carries out powder lamination coating in a centrifugal granulator, can achieve good enteric slow release effect when the weight of the coating is increased by 10% -15%, and also provides guarantee for the release behavior close to that of the original developer.
(4) The invention does not use organic solvent in the whole process, only uses a small amount of water, greatly reduces the potential safety hazard, improves the production efficiency and is beneficial to industrial production.
(5) The whole process of the invention only uses one equipment of the centrifugal granulator to complete the whole process of drug loading and coating of the pellets, and realizes industrial continuous production.
Detailed Description
The following detailed description of the invention is provided to facilitate an understanding of the invention and to enable any person skilled in the art to make or use the invention without limiting it.
Example 1
An urapidil sustained release capsule comprises the following components in percentage by mass:
the preparation method comprises the following steps:
(1) firstly, ethyl cellulose with the viscosity of 9-11CP is micronized to the particle size D90:90-110 μm, and weighing the sucrose pill core, urapidil, ethyl cellulose and talcum powder according to the prescription amount.
(2) The treated ethyl cellulose is uniformly mixed with urapidil and talcum powder.
(3) Oleic acid, dibutyl sebacate and polysorbate with the prescribed amount are respectively weighed and prepared into water dispersion with the solid content of 40 percent, and the water dispersion is used as a binding agent for medicine application and a plasticizer for coating.
(4) Medicine application: placing the sucrose pellet core in a pot of a centrifugal granulator, placing the raw and auxiliary material mixed powder in a hopper, connecting an adhesive to a spray gun in the pot, starting the centrifugal granulator, setting parameters of 200 plus materials/min of a rotating disc, 15g/min of blanking speed, 9g/min of liquid spraying speed, 25 ℃ of air inlet temperature, 20 ℃ of material temperature and 2.0-2.5bar of atomization pressure.
(5) And (3) drying: setting the parameters of a centrifugal granulator to dry the micro-pills, wherein the rotating speed of a turntable is 300r/min, the air inlet temperature is 80 ℃, and the material temperature is 45 ℃.
(6) Coating material weighing: weighing the prescription amount of the medicine-loading pellets, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder, wherein before weighing, micronizing the ethyl cellulose with the viscosity of 3-9CP to the particle size D90:70-90 μm, and hydroxypropyl methylcellulose acetate succinate AS AS-LF.
(7) And uniformly mixing the treated ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder.
(8) Coating: and (3) filling coating material mixed powder into a hopper of a centrifugal granulator, connecting an adhesive to a spray gun in a pan, setting parameters of the centrifugal granulator to coat the dried medicine-loading pellets, wherein the rotating speed of a turntable is 250-300r/min, the blanking speed is 8g/min, the liquid spraying speed is 3.5g/min, the air inlet temperature is 25 ℃, the material temperature is 20 ℃, and the atomizing pressure is 1.5-2.0bar, so that the sustained-release pellets are obtained.
(9) Aging: setting the parameters of a centrifugal granulator to age the sustained-release pellets, wherein the rotating speed of a turntable is 300r/min, the air inlet temperature is 80 ℃, the material temperature is 45 ℃, and the aging time is 60 min.
(10) Filling: detecting the content of the sustained-release pellets, and filling according to the content to obtain the urapidil sustained-release capsule.
Example 2
An urapidil sustained release capsule comprises the following components in percentage by mass:
the preparation method comprises the following steps:
(1) firstly, ethyl cellulose with the viscosity of 9-11CP is micronized to the particle size D90: and (3) weighing sucrose pill cores, urapidil, ethyl cellulose and talcum powder according to the prescription amount, wherein the size of the sucrose pill cores is 90-110 microns.
(2) The treated ethyl cellulose is uniformly mixed with urapidil and talcum powder.
(3) Oleic acid, dibutyl sebacate and polysorbate with the prescribed amount are respectively weighed and prepared into water dispersion with the solid content of 40 percent, and the water dispersion is used as a binding agent for medicine application and a plasticizer for coating.
(4) Medicine application: placing the sucrose pellet core in a pot of a centrifugal granulator, placing the raw and auxiliary material mixed powder in a hopper, connecting an adhesive to a spray gun in the pot, starting the centrifugal granulator, setting parameters of a rotating disc, the rotating speed of 250 plus materials/min, the blanking speed of 15g/min, the liquid spraying speed of 9g/min, the air inlet temperature of 25 ℃, the material temperature of 20 ℃ and the atomization pressure of 2.0-2.5 bar.
(5) And (3) drying: setting the parameters of a centrifugal granulator to dry the micro-pills, wherein the rotating speed of a turntable is 300r/min, the air inlet temperature is 80 ℃, and the material temperature is 45 ℃.
(6) Coating material weighing: weighing the prescription amount of the medicine-loading pellets, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder, wherein before weighing, micronizing the ethyl cellulose with the viscosity of 3-9CP to the particle size D90:70-90 μm, and hydroxypropyl methylcellulose acetate succinate AS AS-LF.
(7) And uniformly mixing the treated ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder.
(8) Coating: and (3) filling coating material mixed powder into a hopper of a centrifugal granulator, connecting an adhesive to a spray gun in a pan, setting parameters of the centrifugal granulator to coat the dried medicine-loading pellets, wherein the rotating speed of a turntable is 250-300r/min, the blanking speed is 8g/min, the liquid spraying speed is 3.5g/min, the air inlet temperature is 25 ℃, the material temperature is 20 ℃, and the atomizing pressure is 2.0-2.5bar, so that the sustained-release pellets are obtained.
(9) Aging: setting the parameters of a centrifugal granulator to age the sustained-release pellets, wherein the rotating speed of a turntable is 300r/min, the air inlet temperature is 80 ℃, the material temperature is 45 ℃, and the aging time is 60 min.
(10) Filling: detecting the content of the sustained-release pellets, and filling according to the content to obtain the urapidil sustained-release capsule.
Example 3
An urapidil sustained release capsule comprises the following components in percentage by mass:
the preparation method comprises the following steps:
(1) firstly, ethyl cellulose with the viscosity of 9-11CP is micronized to the particle size D90:90-110 μm, and weighing the sucrose pill core, urapidil, ethyl cellulose and talcum powder according to the prescription amount.
(2) And uniformly mixing the treated ethyl cellulose with urapidil and talcum powder.
(3) Oleic acid, dibutyl sebacate and polysorbate with the prescribed amount are respectively weighed and prepared into water dispersion with the solid content of 40 percent, and the water dispersion is used as a binding agent for medicine application and a plasticizer for coating.
(4) Medicine application: placing the sucrose pellet core in a pot of a centrifugal granulator, placing the raw and auxiliary material mixed powder in a hopper, connecting an adhesive to a spray gun in the pot, starting the centrifugal granulator, setting parameters of a rotating disc, the rotating speed of 250 plus materials/min, the blanking speed of 15g/min, the liquid spraying speed of 9g/min, the air inlet temperature of 25 ℃, the material temperature of 20 ℃ and the atomization pressure of 2.0-2.5 bar.
(5) And (3) drying: setting the parameters of a centrifugal granulator to dry the micro-pills, wherein the rotating speed of a turntable is 300r/min, the air inlet temperature is 80 ℃, and the material temperature is 45 ℃.
(6) Coating material weighing: weighing the prescription amount of the medicine-loading pellets, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder, wherein before weighing, micronizing the ethyl cellulose with the viscosity of 3-9CP to the particle size D90:70-90 μm, and hydroxypropyl methylcellulose acetate succinate AS AS-LF.
(7) And uniformly mixing the treated ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder.
(8) Coating: and (3) filling coating material mixed powder into a hopper of a centrifugal granulator, connecting an adhesive to a spray gun in a pan, setting parameters of the centrifugal granulator to coat the dried medicine-loading pellets, wherein the rotating speed of a turntable is 250-300r/min, the blanking speed is 8g/min, the liquid spraying speed is 3.5g/min, the air inlet temperature is 25 ℃, the material temperature is 20 ℃, and the atomizing pressure is 2.0-2.5bar, so that the sustained-release pellets are obtained.
(9) Aging: setting the parameters of a centrifugal granulator to age the sustained-release pellets, wherein the rotating speed of a turntable is 300r/min, the air inlet temperature is 80 ℃, the material temperature is 45 ℃, and the aging time is 60 min.
(10) Filling: detecting the content of the sustained-release pellets, and filling according to the content to obtain the urapidil sustained-release capsule.
Example 4
An urapidil sustained release capsule comprises the following components in percentage by mass:
the preparation method comprises the following steps:
(1) firstly, ethyl cellulose with the viscosity of 9-11CP is micronized to the particle size D90:90-110 μm, and weighing the sucrose pill core, urapidil, ethyl cellulose and talcum powder according to the prescription amount.
(2) The treated ethyl cellulose is uniformly mixed with urapidil and talcum powder.
(3) Oleic acid, dibutyl sebacate and polysorbate with the prescribed amount are respectively weighed and prepared into water dispersion with the solid content of 40 percent, and the water dispersion is used as a binding agent for medicine application and a plasticizer for coating.
(4) Medicine application: placing the sucrose pellet core in a pot of a centrifugal granulator, placing the raw and auxiliary material mixed powder in a hopper, connecting an adhesive to a spray gun in the pot, starting the centrifugal granulator, setting parameters of 200 plus materials/min of a rotating disc, 15g/min of blanking speed, 9g/min of liquid spraying speed, 25 ℃ of air inlet temperature, 20 ℃ of material temperature and 2.0-2.5bar of atomization pressure.
(5) And (3) drying: setting the parameters of a centrifugal granulator to dry the medicine-loading pellets, wherein the rotating speed of a turntable is 300r/min, the air inlet temperature is 80 ℃, and the material temperature is 45 ℃.
(6) Coating material weighing: weighing the prescription amount of the medicine-loading pellets, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder, wherein before weighing, micronizing the ethyl cellulose with the viscosity of 3-9CP to the particle size D90:70-90 μm, and hydroxypropyl methylcellulose acetate succinate AS AS-LF.
(7) And uniformly mixing the treated ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder.
(8) Coating: and (3) filling coating material mixed powder into a hopper of a centrifugal granulator, connecting an adhesive to a spray gun in a pan, setting parameters of the centrifugal granulator to coat the dried medicine-loading pellets, wherein the rotating speed of a turntable is 250-300r/min, the blanking speed is 8g/min, the liquid spraying speed is 3.5g/min, the air inlet temperature is 25 ℃, the material temperature is 20 ℃, and the atomizing pressure is 1.5-2.0bar, so that the sustained-release pellets are obtained.
(9) Aging: and setting parameters of a centrifugal granulator to age the sustained-release pellets, wherein the rotating speed of a turntable is 300r/min, the air inlet temperature is 80 ℃, the material temperature is 45 ℃, and the aging time is 60 min.
(10) Filling: detecting the content of the sustained-release pellets, and filling according to the content to obtain the urapidil sustained-release capsule.
Example 5
An urapidil sustained release capsule comprises the following components in percentage by mass:
the preparation method comprises the following steps:
(1) firstly, ethyl cellulose with the viscosity of 9-11CP is micronized to the particle size D90: 110-130 μm, and weighing sucrose pill core, urapidil, ethyl cellulose and talcum powder according to the prescription amount.
(2) And uniformly mixing the treated ethyl cellulose with urapidil and talcum powder.
(3) Oleic acid, dibutyl sebacate and polysorbate with the prescribed amount are respectively weighed and prepared into water dispersion with the solid content of 40 percent, and the water dispersion is used as a binding agent for medicine application and a plasticizer for coating.
(4) Medicine application: placing the sucrose pellet core in a pot of a centrifugal granulator, placing the raw and auxiliary material mixed powder in a hopper, connecting an adhesive to a spray gun in the pot, starting the centrifugal granulator, setting parameters of a rotating disc, the rotating speed of 250 plus materials/min, the blanking speed of 15g/min, the liquid spraying speed of 9g/min, the air inlet temperature of 25 ℃, the material temperature of 20 ℃ and the atomization pressure of 2.0-2.5 bar.
(5) And (3) drying: setting the parameters of a centrifugal granulator to dry the micro-pills, wherein the rotating speed of a turntable is 300r/min, the air inlet temperature is 80 ℃, and the material temperature is 45 ℃.
(6) Coating material weighing: weighing the prescription amount of the medicine-loading pellets, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder, wherein before weighing, micronizing the ethyl cellulose with the viscosity of 9-14CP to the particle size D90:70-90 μm, and hydroxypropyl methylcellulose acetate succinate AS AS-LF.
(7) And uniformly mixing the treated ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder.
(8) Coating: and (3) filling coating material mixed powder into a hopper of a centrifugal granulator, connecting an adhesive to a spray gun in a pan, setting parameters of the centrifugal granulator to coat the dried medicine-loading pellets, wherein the rotating speed of a turntable is 250-300r/min, the blanking speed is 8g/min, the liquid spraying speed is 3.5g/min, the air inlet temperature is 25 ℃, the material temperature is 20 ℃, and the atomizing pressure is 2.0-2.5bar, so that the sustained-release pellets are obtained.
(9) Aging: setting the parameters of a centrifugal granulator to age the sustained-release pellets, wherein the rotating speed of a turntable is 300r/min, the air inlet temperature is 80 ℃, the material temperature is 45 ℃, and the aging time is 60 min.
(10) Filling: detecting the content of the sustained-release pellets, and filling according to the content to obtain the urapidil sustained-release capsule.
Example 6
An urapidil sustained release capsule comprises the following components in percentage by mass:
the preparation method comprises the following steps:
(1) firstly, ethyl cellulose with the viscosity of 9-11CP is micronized to the particle size D90: 110-130 μm, and weighing sucrose pill core, urapidil, ethyl cellulose and talcum powder according to the prescription amount.
(2) The treated ethyl cellulose is uniformly mixed with urapidil and talcum powder.
(3) Oleic acid, dibutyl sebacate and polysorbate with the prescribed amount are respectively weighed and prepared into water dispersion with the solid content of 40 percent, and the water dispersion is used as a binding agent for medicine application and a plasticizer for coating.
(4) Medicine application: placing the sucrose pellet core in a pot of a centrifugal granulator, placing the raw and auxiliary material mixed powder in a hopper, connecting an adhesive to a spray gun in the pot, starting the centrifugal granulator, setting parameters of 200 plus materials/min of a rotating disc, 15g/min of blanking speed, 9g/min of liquid spraying speed, 25 ℃ of air inlet temperature, 20 ℃ of material temperature and 2.0-2.5bar of atomization pressure.
(5) And (3) drying: setting the parameters of a centrifugal granulator to dry the micro-pills, wherein the rotating speed of a turntable is 300r/min, the air inlet temperature is 80 ℃, and the material temperature is 45 ℃.
(6) Coating material weighing: weighing the prescription amount of the medicine-loading pellets, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder, wherein before weighing, micronizing the ethyl cellulose with the viscosity of 9-14CP to the particle size D90:70-90 μm, and hydroxypropyl methylcellulose acetate succinate AS AS-LF.
(7) And uniformly mixing the treated ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder.
(8) Coating: and (3) filling coating material mixed powder into a hopper of a centrifugal granulator, connecting an adhesive to a spray gun in a pan, setting parameters of the centrifugal granulator to coat the dried medicine-loading pellets, wherein the rotating speed of a turntable is 250-300r/min, the blanking speed is 8g/min, the liquid spraying speed is 3.5g/min, the air inlet temperature is 25 ℃, the material temperature is 20 ℃, and the atomizing pressure is 2.0-2.5bar, so that the sustained-release pellets are obtained.
(9) Aging: and setting parameters of a centrifugal granulator to age the sustained-release pellets, wherein the rotating speed of a turntable is 300r/min, the air inlet temperature is 80 ℃, the material temperature is 45 ℃, and the aging time is 60 min.
(10) Filling: detecting the content of the sustained-release pellets, and filling according to the content to obtain the urapidil sustained-release capsule.
Example 7
An urapidil sustained release capsule comprises the following components in percentage by mass:
the preparation method comprises the following steps:
(1) firstly micronizing ethyl cellulose with viscosity of 9-11CP to particle size D90: 110-130 μm, and weighing the sucrose pill core, urapidil, ethyl cellulose and talcum powder according to the prescription amount.
(2) The treated ethyl cellulose is uniformly mixed with urapidil and talcum powder.
(3) Oleic acid, dibutyl sebacate and polysorbate with the prescription amount are respectively weighed and prepared into water dispersion with the solid content of 40 percent, and the water dispersion is used as a binding agent for medicine application and a plasticizer in coating.
(4) Medicine application: placing the sucrose pellet core in a pot of a centrifugal granulator, placing the raw and auxiliary material mixed powder in a hopper, connecting an adhesive to a spray gun in the pot, starting the centrifugal granulator, setting parameters of 200 plus materials/min of a rotating disc, 15g/min of blanking speed, 9g/min of liquid spraying speed, 25 ℃ of air inlet temperature, 20 ℃ of material temperature and 2.0-2.5bar of atomization pressure.
(5) And (3) drying: setting the parameters of a centrifugal granulator to dry the micro-pills, wherein the rotating speed of a turntable is 300r/min, the air inlet temperature is 80 ℃, and the material temperature is 45 ℃.
(6) Coating material weighing: weighing the prescription amount of the medicine-loading pellets, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder, wherein before weighing, micronizing the ethyl cellulose with the viscosity of 9-14CP to the particle size D90:70-90 μm, and hydroxypropyl methylcellulose acetate succinate AS AS-LF.
(7) And uniformly mixing the treated ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder.
(8) Coating: and (3) filling coating material mixed powder into a hopper of a centrifugal granulator, connecting an adhesive to a spray gun in a pan, setting parameters of the centrifugal granulator to coat the dried medicine-loading pellets, wherein the rotating speed of a turntable is 250-300r/min, the blanking speed is 8g/min, the liquid spraying speed is 3.5g/min, the air inlet temperature is 25 ℃, the material temperature is 20 ℃, and the atomizing pressure is 1.5-2.0bar, so that the sustained-release pellets are obtained.
(9) Aging: setting the parameters of a centrifugal granulator to age the sustained-release pellets, wherein the rotating speed of a turntable is 300r/min, the air inlet temperature is 80 ℃, the material temperature is 45 ℃, and the aging time is 60 min.
(10) Filling: detecting the content of the sustained-release pellets, and filling according to the content to obtain the urapidil sustained-release capsule.
Example 8
An urapidil sustained release capsule comprises the following components in percentage by mass:
the preparation method comprises the following steps:
(1) firstly, ethyl cellulose with the viscosity of 11-14CP is micronized to the particle size D90: and (3) weighing sucrose pill cores, urapidil, ethyl cellulose and talcum powder according to the prescription amount, wherein the size of the sucrose pill cores is 90-110 microns.
(2) The treated ethyl cellulose is uniformly mixed with urapidil and talcum powder.
(3) Oleic acid, dibutyl sebacate and polysorbate with the prescription amount are respectively weighed and prepared into water dispersion with the solid content of 40 percent, and the water dispersion is used as a binding agent for medicine application and a plasticizer in coating.
(4) Medicine application: placing the sucrose pellet core in a pot of a centrifugal granulator, placing the raw and auxiliary material mixed powder in a hopper, connecting an adhesive to a spray gun in the pot, starting the centrifugal granulator, and setting parameters of a turntable, the rotating speed of 250-300r/min, the blanking speed of 15g/min, the liquid spraying speed of 9g/min, the air inlet temperature of 25 ℃, the material temperature of 20 ℃ and the atomization pressure of 2.0-2.5 bar.
(5) And (3) drying: setting the parameters of a centrifugal granulator to dry the medicine-loading pellets, wherein the rotating speed of a turntable is 300r/min, the air inlet temperature is 80 ℃, and the material temperature is 45 ℃.
(6) Coating material weighing: weighing the prescription amount of the medicine-loading pellets, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder, wherein before weighing, micronizing the ethyl cellulose with the viscosity of 9-14CP to the particle size D90:70-90 μm, and hydroxypropyl methylcellulose acetate succinate AS AS-LF.
(7) And uniformly mixing the treated ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder.
(8) Coating: and filling coating material mixed powder into a hopper of a centrifugal granulator, connecting an adhesive to a spray gun in a pan, setting parameters of the centrifugal granulator to coat the dried medicine-feeding pellets, and setting the rotating speed of a turntable at 250-300r/min, the blanking speed at 8g/min, the liquid spraying speed at 3.5g/min, the air inlet temperature at 25 ℃, the material temperature at 20 ℃ and the atomizing pressure at 2.0-2.5bar to obtain the sustained-release pellets.
(9) Aging: setting the parameters of a centrifugal granulator to age the sustained-release pellets, wherein the rotating speed of a turntable is 300r/min, the air inlet temperature is 80 ℃, the material temperature is 45 ℃, and the aging time is 60 min.
(10) Filling: detecting the content of the sustained-release pellets, and filling according to the content to obtain the urapidil sustained-release capsule.
Example 9
An urapidil sustained release capsule comprises the following components in percentage by mass:
the preparation method comprises the following steps:
(1) firstly micronizing ethyl cellulose with the viscosity of 11-14CP to the particle size D90: and (3) weighing sucrose pill cores, urapidil, ethyl cellulose and talcum powder according to the prescription amount, wherein the size of the sucrose pill cores is 90-110 microns.
(2) The treated ethyl cellulose is uniformly mixed with urapidil and talcum powder.
(3) Oleic acid, dibutyl sebacate and polysorbate with the prescribed amount are respectively weighed and prepared into water dispersion with the solid content of 40 percent, and the water dispersion is used as a binding agent for medicine application and a plasticizer for coating.
(4) Medicine application: placing the sucrose pellet core in a pot of a centrifugal granulator, placing the raw and auxiliary material mixed powder in a hopper, connecting an adhesive to a spray gun in the pot, starting the centrifugal granulator, setting parameters of a rotating disc, the rotating speed of 250 plus materials/min, the blanking speed of 15g/min, the liquid spraying speed of 9g/min, the air inlet temperature of 25 ℃, the material temperature of 20 ℃ and the atomization pressure of 2.0-2.5 bar.
(5) And (3) drying: setting the parameters of a centrifugal granulator to dry the medicine-loading pellets, wherein the rotating speed of a turntable is 300r/min, the air inlet temperature is 80 ℃, and the material temperature is 45 ℃.
(6) Coating material weighing: weighing the prescription amount of the medicine-loading pellets, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder, wherein before weighing, micronizing the ethyl cellulose with the viscosity of 9-14CP to the particle size D90:70-90 μm, and hydroxypropyl methylcellulose acetate succinate AS AS-LF.
(7) And uniformly mixing the treated ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder.
(8) Coating: and filling coating material mixed powder into a hopper of a centrifugal granulator, connecting an adhesive to a spray gun in a pan, setting parameters of the centrifugal granulator to coat the dried medicine-feeding pellets, and setting the rotating speed of a turntable at 250-300r/min, the blanking speed at 8g/min, the liquid spraying speed at 3.5g/min, the air inlet temperature at 25 ℃, the material temperature at 20 ℃ and the atomizing pressure at 2.0-2.5bar to obtain the sustained-release pellets.
(9) Aging: setting the parameters of a centrifugal granulator to age the sustained-release pellets, wherein the rotating speed of a turntable is 300r/min, the air inlet temperature is 80 ℃, the material temperature is 45 ℃, and the aging time is 60 min.
(10) Filling: detecting the content of the sustained-release pellets, and filling according to the content to obtain the urapidil sustained-release capsule.
Example 10
An urapidil sustained release capsule comprises the following components in percentage by mass:
the preparation method comprises the following steps:
(1) firstly, ethyl cellulose with the viscosity of 11-14CP is micronized to the particle size D90: and (3) weighing sucrose pill cores, urapidil, ethyl cellulose and talcum powder according to the prescription amount, wherein the size of the sucrose pill cores is 90-110 microns.
(2) The treated ethyl cellulose is uniformly mixed with urapidil and talcum powder.
(3) Oleic acid, dibutyl sebacate and polysorbate with the prescribed amount are respectively weighed and prepared into water dispersion with the solid content of 40 percent, and the water dispersion is used as a binding agent for medicine application and a plasticizer for coating.
(4) Medicine application: placing the sucrose pellet core in a pot of a centrifugal granulator, placing the raw and auxiliary material mixed powder in a hopper, connecting an adhesive to a spray gun in the pot, starting the centrifugal granulator, setting parameters of 200 plus materials/min of a rotating disc, 15g/min of blanking speed, 9g/min of liquid spraying speed, 25 ℃ of air inlet temperature, 20 ℃ of material temperature and 2.0-2.5bar of atomization pressure.
(5) And (3) drying: setting the parameters of a centrifugal granulator to dry the micro-pills, wherein the rotating speed of a turntable is 300r/min, the air inlet temperature is 80 ℃, and the material temperature is 45 ℃.
(6) Coating material weighing: weighing the prescription amount of the medicine-loading pellets, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder, wherein before weighing, micronizing the ethyl cellulose with the viscosity of 9-14CP to the particle size D90:70-90 μm, and hydroxypropyl methylcellulose acetate succinate AS AS-LF.
(7) And uniformly mixing the treated ethyl cellulose, hydroxypropyl methylcellulose acetate succinate and talcum powder.
(8) Coating: and (3) filling coating material mixed powder into a hopper of a centrifugal granulator, connecting an adhesive to a spray gun in a pan, setting parameters of the centrifugal granulator to coat the dried medicine-loading pellets, wherein the rotating speed of a turntable is 250-300r/min, the blanking speed is 8g/min, the liquid spraying speed is 3.5g/min, the air inlet temperature is 25 ℃, the material temperature is 20 ℃, and the atomizing pressure is 1.5-2.0bar, so that the sustained-release pellets are obtained.
(9) Aging: and setting parameters of a centrifugal granulator to age the sustained-release pellets, wherein the rotating speed of a turntable is 300r/min, the air inlet temperature is 80 ℃, the material temperature is 45 ℃, and the aging time is 60 min.
(10) Filling: detecting the content of the sustained-release pellets, and filling according to the content to obtain the urapidil sustained-release capsule.
Test example 1: influence of viscosity, particle size and dosage of ethyl cellulose on drug delivery process of urapidil sustained-release capsules
Samples of urapidil dosed pellets of ethylcellulose with varying viscosity, particle size and dosage in the dosing segments of table 1 were prepared according to the preparation method of example 1. The properties of the prepared different urapidil drug-loading pellets are observed, the drug-loading rate is calculated, the influence of the viscosity, the particle size and the dosage of the ethyl cellulose in the drug-loading process of the urapidil is examined, and the experimental results are shown in table 1.
The method for calculating the drug delivery rate comprises the following steps: the percent loading rate (%) of urapidil loading pellet content/100% of urapidil loading pellet amount
TABLE 1 influence of the viscosity, particle size and dosage of ethylcellulose on the administration of urapidil to the micropellets
And (4) conclusion:
as can be seen from the test results in the above table, when the viscosity of the ethyl cellulose is 9-11CP, the particle size D90: the sample prepared when the dosage of 90-110 mu m accounts for 5% of the mass percentage of the urapidil bulk drug is the most preferable condition, and the drug-loading rate reaches more than 95% on the basis of ensuring the round and smooth properties of the drug-loading pellet.
The amount of ethylcellulose results in the degree of adhesion between pellets, when the viscosity is 9-11CP, particle size D90: when the particle size is 90-110 mu m, the dosage of ethyl cellulose accounting for 4-6% of the mass percentage of the urapidil raw material medicine can ensure that the medicine-feeding rate is more than 90%; the dosage of the ethyl cellulose accounting for 4-5% of the mass percentage of the urapidil raw material medicine ensures the medicine-feeding rate, and meanwhile, the pellets are round and smooth, have no burrs and are not adhered; when the dosage is 3%, the dosage is lower than 90%, the dosage is too low, the dosage is not good, and when the dosage is 7%, the dosage is 95.2%, but the pellets are seriously adhered, so that the normal coating operation cannot be performed in the later period, and therefore, the dosage of the ethyl cellulose is too high or too low, preferably 4% -6%.
In the aspect of the viscosity of the ethyl cellulose, when the viscosity is too low, such as the viscosity is 6-9CP, the medicine application rate is not up to 85%, and when the viscosity is too high, such as the viscosity is 11-14CP, the medicine application rate of a part of samples can reach more than 90%, but the surfaces of the micro-pills have obvious burrs and adhesion phenomena, and the subsequent coating uniformity can be influenced.
In the aspect of the particle size of the ethyl cellulose, when the particle size is too small, the materials are easily blown away by air entering the pressure cooker, so that the medicine application rate is low, for example, the viscosity is 9-11CP, and the particle size is D90:70-90 μm and a viscosity of 11-14CP, particle size D90: the medicine application rate is about 80% under the condition of 70-90 mu m; when the particle size is too large, burrs may be formed on the pellet surface, resulting in poor coating uniformity.
Finally, the medicine-feeding micro-pills with the medicine-feeding rate of more than 90% in the medicine-feeding link are preferably selected, and the next coating investigation is carried out, wherein the preferable conditions comprise that ethyl cellulose is selected as follows: a. viscosity 9-11CP, particle size D90:90-110 μm; b. viscosity 9-11CP, particle size D90: 110-; c. viscosity 11-14CP, particle size D90:90-110 μm; d. viscosity 11-14CP, particle size D90: 110-130 mu m of the pellet for medicine application. And the release curve and the uniformity of the urapidil sustained-release capsule prepared after the coating link are combined for optimization, and a scheme capable of solving the problems of the drug application rate and the release behavior at the same time is screened out.
Test example 2: influence of viscosity and particle size of ethyl cellulose on release behavior of urapidil sustained-release capsule
The sustained-release urapidil capsule samples coated with ethyl cellulose with different viscosities and different particle sizes in the coating part in table 2 were prepared according to the preparation method of example 1 by using the above-mentioned pellet for administration prepared under the four conditions a, b, c and d. The release degrees of different urapidil sustained-release capsules prepared are detected, the release uniformity is calculated, the influence of the viscosity and the particle size of ethyl cellulose on the urapidil sustained-release capsules is examined, and the result is shown in table 2.
According to the method for detecting the dissolution curve library of the Japanese preparation, different mediums are adopted to detect the release curve: experimental apparatus II (paddle method), rotation speed of 50r/min, pH1.2 and pH5.5 medium, medium volume 900 ml.
Method for measuring release uniformity: for each sample, 12 cups of release curve were measured in pH5.5 medium, the degree of release at 6 hours was calculated, and the RSD value was calculated for 12 cups.
TABLE 2 influence of ethyl cellulose with different viscosity and particle size on release behavior of urapidil sustained-release capsules
And (4) conclusion:
the results of the above tests show that the sustained-release urapidil capsules prepared by coating ethyl cellulose with the viscosity of 3-9CP and the particle size of D90:70-90 μm by ethyl cellulose pellets with the viscosity of 9-11CP and the particle size of D90:90-110 μm have the release curves closest to those of the original preparation in the medium with the pH value of 1.2 and the pH value of 5.5, and have good uniformity. Because of the powder coating process, when the particle size of the ethyl cellulose of the coating part is too large, such as the particle size D90:90-110 μm, the surface of the pellet is rough, the pellet is not easy to age in the aging process, and tiny gaps appear, so that the slow release effect cannot be achieved.
The viscosity of the ethyl cellulose is 9-11CP, the particle size D90: 110-130 mu m prepared drug-loading pellets, the urapidil sustained-release capsule prepared by selecting the coating parameters of 9-14CP of ethyl cellulose viscosity and 70-90 mu m of particle size D90, although the drug-loading pellets have burr phenomenon, the drug-loading pellets can be regulated to release by selecting the ethyl cellulose with higher viscosity during coating, and the sample release curve and the uniformity are good.
The viscosity of the ethyl cellulose is 11-14CP, the particle size D90: the urapidil sustained-release capsule is prepared by 90-110 mu m of micro-pills, and selecting coating parameters of 9-14CP of ethyl cellulose viscosity and 70-90 mu m of particle size D90, although the micro-pills have burr phenomenon, the high-viscosity ethyl cellulose is selected as a framework material during medicine application, the release can be regulated, the sample release curve is good, and the uniformity is good.
Ethyl cellulose viscosity 9-11CP, particle size D90: the sustained-release urapidil capsules prepared by 90-110 mu m and the particle size D90:70-90 mu m are selected from the pellets prepared by 90-110 mu m, and compared with the sustained-release urapidil capsules prepared by selecting the ethyl cellulose with the coating parameter viscosity of 3-9CP and the particle size D90:70-90 mu m, the sustained-release urapidil capsules prepared by the coating parameter viscosity of 3-9CP and the particle size D90:70-90 mu m have the advantage that the release is slow due to the increase of the coating ethyl cellulose viscosity.
The viscosity of the ethyl cellulose is 11-14CP, the particle size D90: the 110-130 μm coated pellets had poor dissolution uniformity under various viscosity and particle size conditions 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 pellet is rough, the pellet is not easy to age in the aging process, tiny gaps appear, or the coating of the traditional Chinese medicine pellet cannot be completely coated due to adhesion, and the slow release effect cannot be achieved.
Therefore, the preferable scheme taking the medicine-applying rate and the releasing behavior into consideration is that A. the medicine-applying part of ethyl cellulose accounts for 4-6 percent of the urapidil by mass percent, the viscosity is 9-11CP, and the particle size is 90-110 mu m, and the coating part of ethyl cellulose has the viscosity of 3-9CP and the particle size is 70-90 mu m; B. the dosage of the ethyl cellulose of the medicine part accounts for 4-6 percent of the urapidil by mass percent, the viscosity is 9-11CP, the particle size is 110-: the viscosity is 9-14CP, and the particle size is 70-90 μm; C. the medicine part is ethyl cellulose: the using amount accounts for 4-6 percent of the urapidil by mass percent, the viscosity is 11-14CP, the particle size is 90-110 mu m, and the coating part is ethyl cellulose: the viscosity is 9-14CP, and the particle diameter is 70-90 μm. The best scheme is that the dosage of the ethyl cellulose of the medicine part accounts for 5 percent of the mass percent 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 is 3-9CP, and the grain diameter is 70-90 mu m.
Combining the characteristic that urapidil is absorbed in a human body, the absorption rate of urapidil in the human body is as follows: 3.05 plus or minus 4.83 percent; duodenum: 86.05 +/-2.13%; jejunum: 90.82 + -1.80%. Therefore, the urapidil has the largest absorption rate in duodenum and jejunum, so that in the experimental process, the urapidil is ensured to be released less in the stomach, otherwise, a large amount of medicaments are not absorbed in the stomach and directly enter the intestinal tract to generate a burst release phenomenon, and the urapidil needs to be fully and stably released in the duodenum and the jejunum. Intragastric pH in humans: 1-3; duodenal pH: 4-6; jejunum pH 6-7. Representative ph1.2 media and 5.5 media were selected for detection comparisons in the experiments.
In the coating step, hydroxypropyl methylcellulose acetate succinate of an enteric coating material AS-LF type is selected to be mixed with ethyl cellulose powder with specific viscosity and particle size, aqueous dispersions of oleic acid, dibutyl sebacate and polysorbate 80 are used AS plasticizers, and slow release coating is carried out in a centrifugal granulator. The purpose is that the hydroxypropyl methylcellulose acetate succinate is used as enteric material to be dissolved and released in a medium with pH more than 5.5, so that the full release in duodenum and jejunum of a human body is ensured; the ethyl cellulose is added as an insoluble sustained-release material, so that the urapidil is not released suddenly and is released stably; simultaneously realizes the preparation of the urapidil sustained-release capsule by a non-organic solvent system.
Test example 3: influence of technological parameters of medicine feeding link and coating link on urapidil sustained-release capsules
Samples of urapidil drug-loaded pellets and sustained-release capsules were prepared according to the preparation method of example 1 under different process parameters in the drug-loading link and the coating link in tables 3 and 4. According to a detection method of the urapidil content in the second part of China pharmacopoeia 2020 edition, the content of the urapidil drug-loading pellets prepared under different conditions is measured, the content uniformity and the drug-loading rate are calculated, and the influence of drug-loading process parameters on the urapidil drug-loading process is examined.
The method for calculating the drug delivery rate is the same as the above.
Content uniformity RSD calculation method: taking 3 portions of urapidil drug-loading pellet samples at different positions of the upper part, the middle part and the lower part of a pot of a centrifugal granulator respectively, taking 1 portion of sample at a discharge port, respectively weighing proper amounts from 10 portions of urapidil drug-loading pellet samples respectively, respectively preparing into 0.1mg/ml solution, respectively detecting the content of the solution, calculating an SD value and an average value, and further calculating an RSD value.
And (3) calculating the SD value:
calculating RSD; RSD-SD/mean 100%.
In addition, the release degree of different prepared urapidil sustained-release capsules is detected, and the influence of the coating process parameters on the release degree of the urapidil sustained-release capsules is examined.
The release curve of the urapidil sustained release capsule is detected according to a Japanese preparation dissolution curve library detection method, and the release curve detection method comprises the following steps: experiment device II (paddle method), rotating speed of 50r/min, pH6.8 medium, medium volume 900 ml.
TABLE 3 influence of the process parameters of the drug delivery process on the delivery pellets of urapidil
And (4) conclusion:
as can be seen from the test results in the above table, in the medicine feeding link, the blanking rate is 15g/min, the guniting rate is 9g/min, the atomization pressure is 2.0-2.5bar, and 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 above 95.7%, the content uniformity is good, the medicine feeding time of 600g urapidil is within 30min, the speed and the efficiency are high, and the process parameters are the optimal conditions in the medicine feeding link. The atomization pressure is too low, which causes the fog drops to be too large, the pill cores are adhered, the atomization pressure is too large, the powder is blown away by air pressure, and the medicine feeding rate is low. The experiment improves the medicine feeding efficiency and the medicine feeding yield by optimizing the technological parameters of the medicine feeding link.
And preparing the drug-loading pellets according to the preferable drug-loading link process parameters, and then further inspecting the coating link process parameters.
TABLE 4 influence of coating process parameters on urapidil sustained-release capsules
And (4) conclusion:
experimental example 2 studies the release conditions of pH1.2 and pH5.5, and we have obtained the formulation conditions of sustained release preparation suitable for gastrointestinal absorption, and experimental example 3 further examines the release behavior of another main absorption site, the absorption rate of urapidil in human body is 90.82 ± 1.80% in the jejunum, the pH of jejunum is 6-7, and the medium pH6.8 is selected for examination of release curve, so as to ensure the full and stable release of the drug in jejunum. Through the investigation of coating parameters, the blanking rate is 8g/min, the guniting rate is 3.5g/min, the atomization pressure is 1.5-2.5bar, the coating is carried out when the rotating speed of a turntable is 250-300r/min, the release curve of the coated urapidil sustained-release capsule in a medium with the pH value of 6.8 is similar to that of the original preparation, the characteristic of absorption of urapidil in a human body is met, and the release effect of the urapidil sustained-release capsule is further accurately controlled.
Test example 4: quality research of urapidil sustained-release capsule
The quality of the urapidil sustained release capsule samples prepared in the embodiments 1-10 of the invention is studied, the content uniformity, the drug delivery rate and the in vitro release degree (pH6.8 medium) are detected, the detection method is the same as that in the test example 3, the F2 factor value is calculated according to the release data, the specific calculation method can refer to the dissolution curve guiding principle published by the State administration of medicine, and the research results are shown in Table 5.
TABLE 5 study on the quality of urapidil sustained-release capsules prepared in examples 1 to 10
And (4) conclusion:
the drug application rates of the examples 1-10 are all above 90%, and the F2 value is greater than 50, which shows that the release curve is similar to the original release curve of the preparation, the larger the F2 value is, the higher the similarity degree of the release curve is, so that the examples 1-10 have the double effects of both the drug application rate and the release behavior. Examples 1-4 had the best results, the drug delivery rate was above 95%, the pellets were round and smooth, and the F2 value was above 75, indicating that the release behavior was closer to that of the original formulation, the content uniformity was better, and the RSD was below 1.5.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. The sustained-release urapidil 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, the sustained-release pellets are characterized in that the medicine feeding 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 mass of urapidil, and the coating part comprises ethyl cellulose with the viscosity of 3-14CP and the particle size D90 of 70-90 mu m.
2. The urapidil sustained-release capsule according to claim 1, wherein the upper part comprises ethyl cellulose with viscosity of 9-11CP and particle size D90 of 90-110 μm, the amount of ethyl cellulose is 4-6% of the mass of urapidil, and the coating part comprises ethyl cellulose with viscosity of 3-9CP and particle size D90 of 70-90 μm.
3. The urapidil sustained-release capsule according to claim 1, wherein the upper part comprises ethyl cellulose with viscosity of 9-11CP and particle size D90 of 110-130 μm, the dosage of the ethyl cellulose is 4-6% of the mass of urapidil, and the coating part comprises ethyl cellulose with viscosity of 9-14CP and particle size D90 of 70-90 μm.
4. The urapidil sustained-release capsule according to claim 1, wherein the upper part comprises ethyl cellulose with viscosity of 11-14CP and particle size D90 of 90-110 μm, the amount of the ethyl cellulose is 4-6% of the mass of urapidil, and the coating part comprises ethyl cellulose with viscosity of 9-14CP and particle size D90 of 70-90 μm.
5. The urapidil sustained-release capsule according to any one of claims 1 to 4, wherein the sustained-release pellets are prepared by coating and loading pellets, and specifically comprise:
spraying the powder of the upper medicine layer and the adhesive of the upper medicine layer on the pellet core at the same time to obtain the micro-pellets of the upper medicine;
and (3) spraying the coating material powder and the coating plasticizer onto the drug-loaded pellets simultaneously to obtain the sustained-release pellets.
6. The urapidil sustained-release capsule according to claim 5, wherein the upper layer powder comprises urapidil, ethyl cellulose and talc; the upper medicine layer adhesive is an aqueous dispersion of oleic acid, dibutyl sebacate and polysorbate 80, and the solid content of the upper medicine layer adhesive is 39% -41%; the coating material powder comprises ethyl cellulose, AS-LF type hypromellose 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%.
7. The urapidil sustained-release capsule according to claim 2, wherein the drug delivery pellets comprise the following components in percentage by mass: 30% urapidil, 1.2% -1.8% ethyl cellulose, 0.4% -0.8% talcum powder, 5.5% -6.5% oleic acid, 1.5% -2.5% dibutyl sebacate, 0.02% polysorbate 80 and the balance of sucrose pill cores; the sustained-release pellet comprises the following components in percentage by mass: 2.2 to 3.2 percent of ethyl cellulose, 5.7 to 6.7 percent of AS-LF type hydroxypropyl methylcellulose acetate succinate, 0.3 to 0.4 percent of talcum powder, 1.1 to 1.3 percent of oleic acid, 0.4 to 0.7 percent of dibutyl sebacate, 0.02 percent of polysorbate 80, and the balance of the medicine-feeding pellets.
8. The urapidil sustained-release capsule according to claim 3, wherein the drug delivery pellets comprise the following components in percentage by mass: 30% urapidil, 1.2% -1.8% ethyl cellulose, 0.2% -0.8% talcum powder, 5.5% -6.5% oleic acid, 1.5% -2.5% dibutyl sebacate, 0.02% polysorbate 80 and the balance of sucrose pill cores; the sustained-release pellet comprises the following components in percentage by mass: 2.7 to 2.8 percent of ethyl cellulose, 6.0 to 6.2 percent of AS-LF type hydroxypropyl methylcellulose acetate succinate, 0.3 to 0.4 percent of talcum powder, 0.9 to 1.5 percent of oleic acid, 0.3 to 0.9 percent of dibutyl sebacate, 0.02 percent of polysorbate 80 and the balance of the medicine-loading pellets.
9. The urapidil sustained-release capsule according to claim 4, wherein the drug delivery pellets comprise the following components in percentage by mass: 30% urapidil, 1.2% -1.8% ethyl cellulose, 0.2% -0.8% talcum powder, 5.0% -5.7% oleic acid, 2.3% -3.2% dibutyl sebacate and 0.02% polysorbate 80, and the balance being sucrose pill cores; the sustained-release pellet comprises the following components in percentage by mass: 2.4 to 3.0 percent of ethyl cellulose, 5.7 to 6.2 percent of AS-LF type hydroxypropyl methylcellulose acetate succinate, 0.6 to 0.7 percent of talcum powder, 1.1 to 1.2 percent of oleic acid, 0.5 to 0.7 percent of dibutyl sebacate, 0.02 percent of polysorbate 80, and the balance of the medicine-feeding pellets.
10. The method for preparing urapidil sustained release capsules according to any one of claims 1 to 4, characterized in that: the method comprises the following steps:
(1) micronizing ethyl cellulose to a first preset particle size to obtain first ethyl cellulose micropowder; weighing a formula amount of sucrose pill core, urapidil, first ethyl cellulose micro powder and talcum powder;
(2) uniformly mixing the first ethyl cellulose micro powder, urapidil and talcum powder according to the prescription amount to obtain upper medicine layer powder;
(3) respectively preparing oleic acid, dibutyl sebacate and polysorbate with the prescription amount into aqueous dispersion with the solid content of 40 percent to obtain an upper medicine layer adhesive and a coating plasticizer;
(4) spraying the powder of the upper drug layer and the adhesive of the upper drug layer on the pellet core at the same time, and drying to obtain the micro-pellets;
(6) micronizing ethyl cellulose to a second preset particle size to obtain second diethyl cellulose micropowder; weighing the prescription amount of the medicine-loading pellets, the second diethyl cellulose micropowder, AS-LF type hydroxypropyl methylcellulose acetate succinate and talcum powder;
(7) uniformly mixing the second diethyl cellulose micro powder, AS-LF type hydroxypropyl methylcellulose acetate succinate and talcum powder according to the formula amount to obtain coating material powder;
(8) spraying the coating material powder and the coating plasticizer onto the drug-loaded pellets simultaneously to obtain the sustained-release pellets;
(9) aging the sustained-release pellets, and filling to obtain urapidil sustained-release capsules;
in the step (4), the process parameters of the medicine feeding procedure are as follows: the rotating speed of the turntable of the centrifugal granulator is 200-;
in the step (8), the technological parameters of the coating procedure are as follows: the rotating speed of the turntable of the centrifugal granulator is 250-300r/min, the blanking speed is 7-9g/min, the liquid spraying speed is 3-4g/min, and the atomizing pressure is 1.5-2.5 bar.
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