CN106727435B - Metoprolol sustained-release capsule and preparation method thereof - Google Patents
Metoprolol sustained-release capsule and preparation method thereof Download PDFInfo
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- 239000002775 capsule Substances 0.000 title claims abstract description 58
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 229960002237 metoprolol Drugs 0.000 title claims abstract description 37
- 238000013268 sustained release Methods 0.000 title claims abstract description 37
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000000576 coating method Methods 0.000 claims abstract description 73
- 239000011248 coating agent Substances 0.000 claims abstract description 71
- 239000003814 drug Substances 0.000 claims abstract description 23
- 239000004014 plasticizer Substances 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000007902 hard capsule Substances 0.000 claims abstract description 15
- 229940079593 drug Drugs 0.000 claims abstract description 12
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 10
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 10
- 239000007903 gelatin capsule Substances 0.000 claims abstract description 10
- 239000008101 lactose Substances 0.000 claims abstract description 10
- 229960001375 lactose Drugs 0.000 claims abstract description 10
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 10
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 10
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 10
- 239000000843 powder Substances 0.000 claims abstract description 10
- 238000002156 mixing Methods 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims abstract description 6
- 238000011049 filling Methods 0.000 claims abstract description 4
- 239000000463 material Substances 0.000 claims description 19
- 239000011812 mixed powder Substances 0.000 claims description 18
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 17
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 15
- 239000007921 spray Substances 0.000 claims description 15
- 238000005507 spraying Methods 0.000 claims description 15
- 239000007788 liquid Substances 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 9
- 230000032683 aging Effects 0.000 claims description 9
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical group 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 8
- 239000000945 filler Substances 0.000 claims description 8
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical group CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 7
- 239000001069 triethyl citrate Substances 0.000 claims description 7
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 7
- 235000013769 triethyl citrate Nutrition 0.000 claims description 7
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims description 4
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 4
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims description 4
- 229920002562 Polyethylene Glycol 3350 Polymers 0.000 claims description 3
- 238000010902 jet-milling Methods 0.000 claims description 3
- 229920003156 Eudragit® RL PO Polymers 0.000 claims description 2
- 229920003160 Eudragit® RS PO Polymers 0.000 claims description 2
- 238000001125 extrusion Methods 0.000 claims description 2
- 238000002844 melting Methods 0.000 claims description 2
- 230000008018 melting Effects 0.000 claims description 2
- 239000000080 wetting agent Substances 0.000 claims description 2
- 238000013265 extended release Methods 0.000 claims 4
- USFMMZYROHDWPJ-UHFFFAOYSA-N trimethyl-[2-(2-methylprop-2-enoyloxy)ethyl]azanium Chemical compound CC(=C)C(=O)OCC[N+](C)(C)C USFMMZYROHDWPJ-UHFFFAOYSA-N 0.000 claims 2
- 238000000338 in vitro Methods 0.000 abstract description 11
- 239000003960 organic solvent Substances 0.000 abstract description 8
- 208000024172 Cardiovascular disease Diseases 0.000 abstract description 3
- 239000003125 aqueous solvent Substances 0.000 abstract description 3
- 238000005265 energy consumption Methods 0.000 abstract description 2
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 108010010803 Gelatin Proteins 0.000 description 6
- 208000021017 Weight Gain Diseases 0.000 description 6
- 229920000159 gelatin Polymers 0.000 description 6
- 239000008273 gelatin Substances 0.000 description 6
- 235000019322 gelatine Nutrition 0.000 description 6
- 235000011852 gelatine desserts Nutrition 0.000 description 6
- 230000004584 weight gain Effects 0.000 description 6
- 235000019786 weight gain Nutrition 0.000 description 6
- 239000008213 purified water Substances 0.000 description 5
- 238000002835 absorbance Methods 0.000 description 3
- 238000009792 diffusion process Methods 0.000 description 3
- SUPCQIBBMFXVTL-UHFFFAOYSA-N ethyl 2-methylprop-2-enoate Chemical compound CCOC(=O)C(C)=C SUPCQIBBMFXVTL-UHFFFAOYSA-N 0.000 description 2
- 238000004880 explosion Methods 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 238000009474 hot melt extrusion Methods 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000002431 foraging effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012943 hotmelt Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
Images
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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
- A61K9/4891—Coated capsules; Multilayered drug free capsule shells
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- 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
- A61K9/4816—Wall or shell material
- A61K9/4825—Proteins, e.g. gelatin
-
- 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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides a metoprolol sustained-release capsule and a preparation method thereof. The preparation method of the sustained-release capsule comprises the following steps: uniformly mixing metoprolol, microcrystalline cellulose and lactose, and filling the mixture into a hollow gelatin capsule shell to prepare a medicine-containing capsule inner core; dry powder coating is carried out on the inner core of the medicine-containing capsule by adopting an internal addition method or an external addition method of a plasticizer to prepare a coated sustained-release capsule, and the coated sustained-release capsule is aged for 2 to 12 hours at the temperature of between 60 and 70 ℃ to obtain the metoprolol sustained-release capsule. The metoprolol sustained-release capsule disclosed by the invention has the first-stage drug release behavior after 24 hours of in-vitro drug release, and provides a product which is convenient to swallow and is used for treating cardiovascular diseases. The metoprolol sustained-release capsule is prepared by adopting the dry powder coating, any aqueous and organic solvent is not used in the preparation process, the operation is simple and convenient, and the problems of instability, energy consumption, time consumption, environmental pollution and the like existing in the aqueous and organic solution coating of the hard capsule can be solved.
Description
Technical Field
The invention belongs to the technical field of pharmacy, and particularly relates to a metoprolol sustained-release capsule and a dry powder coating preparation method thereof.
Background
the metoprolol is a β 1 receptor blocker and is widely used for treating cardiovascular diseases such as hypertension, angina, myocardial infarction and the like.
The existing metoprolol sustained-release capsule is realized by firstly preparing sustained-release pellets and then filling the sustained-release pellets into a hollow hard capsule shell, and the process is complex. The slow release coating of the hard capsule is always a preparation difficulty, because the gelatin capsule shell is unstable when meeting water, the water-based coating technology has high difficulty, and an isolating layer needs to be added or the coating conditions need to be strictly controlled; and the organic solvent coating not only consumes energy and time, but also has the problems of explosion prevention, organic solvent pollution and the like.
The capsule is coated with dry powder, so that the problems of gelatin stability and organic solvent pollution caused by aqueous or organic solvent coating can be solved, and the capsule has the advantages of simplicity and convenience in operation, environmental friendliness, high integration and industrialization degree and the like. By adjusting the addition method of the plasticizer, the type and the dosage of the coating material, the coating process and the aging condition, the coating material can be ensured to be adsorbed on the surface of the capsule, and a coating film is formed by aging, thereby achieving good slow release effect.
Disclosure of Invention
The invention provides a metoprolol sustained-release capsule which has a first-stage drug release behavior, the main release mechanism is diffusion, and a clinical sustained-release preparation formulation convenient to swallow is provided. The capsule is prepared by a dry powder coating method, and is efficient, energy-saving and environment-friendly; the influence of the water-based coating solvent on the hard capsule shell is avoided, and the problems of explosion prevention of equipment and organic solvent residue caused by the organic solvent coating solvent are avoided.
The technical scheme adopted by the invention for solving the technical problem is as follows:
a metoprolol sustained-release capsule, which consists of 100 to 300 parts by weight of drug-containing filler, 60 to 100 parts by weight of gelatin capsule shell and 20 to 120 parts by weight of sustained-release coating; the drug-containing filler consists of 10-50 parts by weight of metoprolol and 50-90 parts by weight of filler; wherein the filler is microcrystalline cellulose, lactose or a mixture of both; the gelatin capsule shell is conventional No. 2, No. 1 and No. 0 hollow hard capsule shell; the slow release coating is coated outside the gelatin capsule shell and consists of 100 parts by weight of acrylic acid slow release coating material, 5-40 parts by weight of plasticizer and 5-15 parts by weight of anti-sticking agent.
Preferably, the acrylic acid slow-release coating material consists of Ewing RS PO and Ewing RL PO, wherein the Ewing RS PO is polymerized by ethyl acrylate, methyl methacrylate and chlorinated trimethylamine-based ethyl methacrylate in a mass ratio of 1:2:0.1, the Ewing RL PO is polymerized by ethyl acrylate, methyl methacrylate and chlorinated trimethylamine-based ethyl methacrylate in a mass ratio of 1:2:0.2, and the plasticizer is triethyl citrate; the antisticking agent is talcum powder.
Preferably, the mass ratio of the Eudragit RS PO to the Eudragit RL PO in the acrylic acid sustained-release coating material is 1-10: 1; the mass of the plasticizer is 5-30% of that of the acrylic acid slow-release coating material; the mass of the talcum powder is 10 percent of that of the acrylic acid slow-release coating material.
A preparation method of metoprolol sustained-release capsules comprises the following steps: uniformly mixing metoprolol, microcrystalline cellulose and lactose, and filling the mixture into a hollow gelatin capsule shell to prepare a medicine-containing capsule inner core; dry powder coating is carried out on the inner core of the medicine-containing capsule by adopting an internal addition method or an external addition method of a plasticizer to prepare a coated sustained-release capsule, and the coated sustained-release capsule is aged for 2 to 12 hours at the temperature of between 60 and 70 ℃ to obtain the metoprolol sustained-release capsule.
Preferably, the plasticizer internal addition method comprises the following steps: mixing plasticizer and acrylic acid sustained-release coating material, performing hot melting extrusion at 60-110 ℃, performing jet milling, adding an anti-sticking agent, and preparing preplasticized mixed powder; placing the inner core of the medicine-containing capsule in a coating pan, spraying a wetting agent PEG 3350 with the mass of 0.5-3% of that of the acrylic acid sustained-release coating material by a liquid spray gun, and spraying pre-plasticized mixed powder by an electrostatic gun, wherein the operating process conditions of the electrostatic spray gun are as follows: 0.35g/min, voltage 60KV, air pressure 15 psi.
Preferably, the plasticizer addition method comprises the steps of: mixing the acrylic acid slow-release coating material and the anti-sticking agent to prepare coating mixed powder. The inner core of the medicine-containing capsule is placed in a coating pan, a liquid spray gun sprays plasticizer, an electrostatic gun sprays coating mixed powder, and the flow rate of the liquid spray gun is 25 percent of that of the electrostatic gun.
Preferably, the plasticizer addition method comprises the steps of: mixing the acrylic acid sustained-release coating material and the anti-sticking agent to prepare coating mixed powder, placing the inner core of the medicine-containing capsule in a coating pan, spraying the plasticizer by a liquid spray gun, and spraying the coating mixed powder by an electrostatic gun, wherein the flow rate of the liquid spray gun is 25 percent of that of the electrostatic gun.
The invention has the beneficial effects that:
the metoprolol sustained-release capsule disclosed by the invention can release drugs in vitro for 24 hours in a first-stage drug release behavior, the main release mechanism is diffusion, and a product which is convenient to swallow and is used for treating cardiovascular diseases can be provided for clinic. The metoprolol sustained-release capsule is prepared by adopting the dry powder coating, any aqueous and organic solvent is not used in the preparation process, the operation is simple and convenient, the problems of instability, energy consumption, time consumption, environmental pollution and the like existing in the aqueous and organic solution coating of the hard capsule can be solved, and the method has good industrialization prospect.
Drawings
FIG. 1 shows the effect of the ratio of RS and RL on the in vitro release profile.
FIG. 2 is a graph showing the effect of coating weight gain on in vitro release profiles.
FIG. 3 is a graph showing the effect of aging time on in vitro release profiles.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
100g of metoprolol, 300g of microcrystalline cellulose and 400g of lactose are mixed uniformly, and a No. 2 capsule plate is used for preparing an inner core of a gelatin hard capsule, wherein each capsule contains about 25mg of metoprolol on average.
420g of Ewing RS, 42g of Ewing RL and 46.2g of triethyl citrate are mixed, hot-melt extrusion is carried out at 100 ℃, air flow grinding is carried out, and 46.2g of talcum powder is added for mixing to prepare preplasticized mixed powder with RS: RL =10: 1. Placing the hard capsule inner core in a coating pan with the rotation speed of 30rpm and the temperature of 70 ℃, and spraying 4.6g of a moisture-inducing agent PEG 3350 by a liquid spray gun; spraying the preplasticized mixed powder by an electrostatic gun (0.35 g/min, voltage 60KV, air pressure 15 psi). Preparing a coating capsule with the coating weight increased by about 15 percent, and placing the coating capsule in an oven at 65 ℃ for aging for 6 h.
Example 2
100g of metoprolol, 300g of microcrystalline cellulose and 400g of lactose are mixed uniformly, and a No. 2 capsule plate is used for preparing an inner core of a gelatin hard capsule, wherein each capsule contains about 25mg of metoprolol on average.
385g of EquidrS, 77g of EquidrRL and 46.2g of triethyl citrate are mixed, hot-melt extrusion is carried out at 100 ℃, air flow grinding is carried out, 46.2g of talcum powder is mixed, and preplasticizing mixed powder with RS: RL =5:1 is prepared.
Example 3
100g of metoprolol, 300g of microcrystalline cellulose and 400g of lactose are mixed uniformly, and a No. 2 capsule plate is used for preparing an inner core of a gelatin hard capsule, wherein each capsule contains about 25mg of metoprolol on average.
231g of EquidrS, 231g of EquidrRL and 46.2g of triethyl citrate are mixed, hot-melt extruded at 100 ℃, jet milled and mixed with 46.2g of talc to prepare a preplasticized mixed powder with RS: RL =1: 1.
The metoprolol sustained release capsule obtained in example 1-3 was added to water using 500mL of purified water as the release medium at a speed of 75 rpm and a temperature of 37. + -. 0.5 ℃ and sampled at regular intervals at 10mL, filtered through a 0.45 μm filter and the absorbance measured at 274 nm. Concentrations were calculated from standard curves and in vitro release curves were plotted (see figure 1). The results show that: the proportion of RS and RL has obvious influence on the in vitro release curve, and when RS: RL =10:1, the 24h slow release effect is better.
Example 4
200g of metoprolol, 300g of microcrystalline cellulose and 500g of lactose are mixed uniformly, and the inner core of the gelatin hard capsule is prepared by a # 1 capsule plate, wherein each capsule contains about 50mg of metoprolol on average.
420g of Ewing RS, 42g of Ewing RL and 46.2g of talcum powder are mixed to prepare coating mixed powder. Placing the hard capsule core in a coating pan with 30rpm, spraying triethyl citrate (0.05 g/min, air pressure 5 psi) with a liquid spray gun, and spraying the coating mixed powder (0.2 g/min, voltage 60KV, air pressure 15 psi) with an electrostatic gun. Spraying powder for a certain time, sampling, measuring the coating weight gain of the capsule, preparing the coating capsule with different coating weight gains, and aging in an oven at 60 ℃ for 6 h.
500mL of purified water is used as a release medium, the rotation speed is 75 rpm, the temperature is 37 +/-0.5 ℃, 10mL of purified water is sampled at regular time, the purified water is filtered by a 0.45 mu m filter membrane, and the absorbance at 274nm is measured. Concentrations were calculated from standard curves and in vitro release curves were plotted (FIG. 2). The results show that: the weight gain of the coating has a significant effect on the in vitro release profile. When the weight gain of the coating is 16%, the coating has a 24-hour slow release effect. The fitting of a drug release curve proves that the drug release curve shows a first-order drug release behavior (ln (1-Q) = -0.134t-0.123, R = 0.997), and the main release mechanism is diffusion.
Example 5
200g of metoprolol, 360g of microcrystalline cellulose and 640g of lactose are uniformly mixed, and a No. 0 capsule plate is used for preparing an inner core of a gelatin hard capsule, wherein each capsule contains about 50mg of metoprolol on average.
420g of Ewing RS, 42g of Ewing RL and 46.2g of talcum powder are mixed to prepare coating mixed powder. Placing the hard capsule core in a coating pan with 30rpm, spraying triethyl citrate (0.05 g/min, air pressure 5 psi) with a liquid spray gun, and spraying the coating mixed powder (0.2 g/min, voltage 60KV, air pressure 15 psi) with an electrostatic gun. Coated capsules with coating weight gain of about 16% were prepared and placed in an oven at 60 ℃ for 2h each.
Example 6
The same procedure as in example 5 was followed, except that the aging time was 6 hours.
Example 7
The same procedure as in example 5 was followed, except that the aging time was 12 hours.
The metoprolol sustained release capsule obtained in example 4-6 was added to water using 500mL of purified water as the release medium at a speed of 75 rpm and a temperature of 37. + -. 0.5 ℃ and sampled at regular intervals for 10mL, filtered through a 0.45 μm filter and measured for absorbance at 274 nm. Concentrations were calculated from standard curves and in vitro release curves were plotted (see figure 3). The results show that: the aging time had a significant effect on the in vitro release profile. When the aging time is 6h and 12h, the coating film is fully aged and fused, and the slow release effect is good. In view of efficiency, 6h is preferable.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any way, and all simple modifications and equivalent variations of the above embodiments according to the technical spirit of the present invention are included in the scope of the present invention.
Claims (3)
1. The metoprolol sustained-release capsule is characterized by consisting of 100-300 parts by weight of drug-containing filler, 60-100 parts by weight of gelatin capsule shell and 20-120 parts by weight of sustained-release coating; the drug-containing filler consists of 10-50 parts by weight of metoprolol and 50-90 parts by weight of filler; wherein the filler is microcrystalline cellulose, lactose or a mixture of both; the gelatin capsule shell is conventional No. 2, No. 1 and No. 0 hollow hard capsule shell; the slow release coating is coated outside the gelatin capsule shell and consists of 100 parts by weight of acrylic acid slow release coating material, 5-40 parts by weight of plasticizer and 5-15 parts by weight of anti-sticking agent;
the preparation method of the metoprolol sustained-release capsule comprises the following steps: uniformly mixing metoprolol, microcrystalline cellulose and lactose, and filling the mixture into a hollow gelatin capsule shell to prepare a medicine-containing capsule inner core; dry powder coating is carried out on the inner core of the medicine-containing capsule by adopting an internal addition method or an external addition method of a plasticizer to prepare a coated sustained-release capsule, and the coated sustained-release capsule is aged for 2 to 12 hours at the temperature of between 60 and 70 ℃ to obtain the metoprolol sustained-release capsule;
the plasticizer internal addition method comprises the following steps: mixing plasticizer and acrylic acid sustained-release coating material, performing hot melting extrusion at 60-110 ℃, performing jet milling, adding an anti-sticking agent, and preparing preplasticized mixed powder; placing the inner core of the medicine-containing capsule in a coating pan, spraying a wetting agent PEG 3350 with the mass of 0.5-3% of that of the acrylic acid sustained-release coating material by a liquid spray gun, and spraying pre-plasticized mixed powder by an electrostatic gun, wherein the operating process conditions of the electrostatic spray gun are as follows: 0.35g/min, 60KV voltage and 15psi air pressure;
the plasticizer external addition method comprises the following steps: mixing the acrylic acid sustained-release coating material and the anti-sticking agent to prepare coating mixed powder, placing the inner core of the medicine-containing capsule in a coating pan, spraying the plasticizer by a liquid spray gun, and spraying the coating mixed powder by an electrostatic gun, wherein the flow rate of the liquid spray gun is 25 percent of that of the electrostatic gun;
the dry coating comprises the following specific process parameters: the rotating speed of a coating pan is 30rpm, the electrostatic voltage is 60KV, the air pressure is 15psi, the flow rate of a plasticizer is 0.05g/min, and the flow rate of powder is 0.2 g/min; the aging time was 6 hours.
2. The metoprolol extended release capsule of claim 1, wherein the acrylic extended release coating material consists of Ewing RS PO polymerized from ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate in a mass ratio of 1:2:0.1 and Ewing RL PO polymerized from ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate in a mass ratio of 1:2:0.2, the plasticizer is triethyl citrate; the antisticking agent is talcum powder.
3. The metoprolol extended release capsule of claim 2, wherein the mass ratio of the eudragit RS PO to the eudragit RL PO in the acrylic extended release coating material is 1-10: 1; the mass of the plasticizer is 5-30% of that of the acrylic acid slow-release coating material; the mass of the talcum powder is 10 percent of that of the acrylic acid slow-release coating material.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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CN201611216206.3A CN106727435B (en) | 2016-12-26 | 2016-12-26 | Metoprolol sustained-release capsule and preparation method thereof |
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