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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- CN106727435B CN106727435B CN201611216206.3A CN201611216206A CN106727435B CN 106727435 B CN106727435 B CN 106727435B CN 201611216206 A CN201611216206 A CN 201611216206A CN 106727435 B CN106727435 B CN 106727435B
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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- 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
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- A—HUMAN NECESSITIES
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- 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
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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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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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.
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| US20190099378A1 (en) * | 2017-10-02 | 2019-04-04 | Powder Pharma Coating Inc. | Method for dry powder coating capsules |
| CN108619523B (en) * | 2018-03-23 | 2020-06-30 | 浙江工业大学 | Coated film for rapid thermoplastic coating preparation and preparation method thereof |
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| US20090068260A1 (en) * | 2006-02-24 | 2009-03-12 | Tomer Gold | Beta-1-selective adrenoceptor blocking agent compositions and methods for their preparation |
| CN102365083A (en) * | 2009-03-18 | 2012-02-29 | 赢创罗姆有限公司 | Controlled release pharmaceutical composition with resistance against the influence of ethanol employing a coating comprising a polymer mixture and excipients |
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