CN112618506A - Ivabramine hydrochloride single-layer osmotic pump controlled release tablet and preparation method thereof - Google Patents
Ivabramine hydrochloride single-layer osmotic pump controlled release tablet and preparation method thereof Download PDFInfo
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- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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Abstract
The invention provides an ivabrane hydrochloride single-layer osmotic pump controlled release tablet and a preparation method thereof. The single-layer osmotic pump controlled release tablet comprises a tablet core, a semipermeable coating film and a drug release pore; the tablet core comprises, by weight, 5-30% of ivabradine hydrochloride, 0-60% of a suspending agent, 30-90% of a penetration enhancer and 0.1-3% of a lubricant; the semipermeable coating film comprises 80-99% of semipermeable film-forming material and 1-20% of pore-forming agent, and the weight of the coating is increased by 3-15% of the weight of the tablet core; the aperture of the medicine release pore is 0.4mm-1.2 mm. The ivabradine hydrochloride single-layer osmotic pump controlled release tablet is orally taken once a day, has stable blood concentration and is not easily influenced by the gastrointestinal tract environment.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to an ivabrane hydrochloride single-layer osmotic pump controlled release tablet and a preparation method thereof.
Background
Resting heart rate is an important indicator of cardiovascular morbidity and mortality. Increased myocardial oxygen consumption caused by elevated heart rate (greater than 70 beats/minute) is a risk factor for heart failure and angina pectoris. Reducing heart rate is an important goal in the treatment of heart failure, thereby alleviating cardiovascular complications and reducing prognostic mortality.
Ivabradine, chemical name 7, 8-dimethoxy-3- (3- [ [ (1S) (4, 5-dimethoxybenzocyclobutan-1-yl) methyl ] -methylamino ] propyl) -1,3,4, 5-tetrahydro-2 h-benzazepin-2-one, is suitable for patients with chronic heart failure with normal sinus rhythm, or for use when beta-blocker therapy is contraindicated or intolerant.
The ivabradine hydrochloride is a first specific If channel inhibitor, and can reduce the slope of the automatic depolarization action potential of the sinoatrial node cell in the diastole and reduce the heart rate. The current-suppressing effect is dose-dependent. The action mechanism has no influence on other cardiovascular functions such as blood pressure, myocardial contraction, atrioventricular conduction velocity and the like. The patient shows good tolerance to the ivabradine hydrochloride, and is also suitable for chronic heart failure patients with complications such as diabetes, myocardial infarction, hypertension and the like.
The Schweiya company developed the Ivabradine hydrochloride tablet at the earliest, and the current products on the market are all quick-release preparations which are taken twice a day with meals. After oral administration, ivabradine is rapidly and almost completely absorbed, peaking at plasma levels around 1 hour in the fasted state, eliminating the half-life of 2 hours. Due to the first pass effect in the intestine and liver, the absolute bioavailability of the film-coated tablets is about 40%. Food delays absorption by approximately 1 hour and plasma exposure increases by 20% to 30%. 80% of ivabradine hydrochloride is metabolized by the liver, the main active metabolite is N-demethyl derivative, and 20% is renal clearance. Ivabradine hydrochloride exhibits pharmacokinetic linearity, CmaxAUC and heart rate decline were linearly related to the mean dose in the range of 0.5 to 24 mg.
The most common adverse reactions in clinical medication are bradycardia, hypertension, atrial fibrillation and dysphoria. Bradycardia was reported in 3.3% of patients, and severe bradycardia occurred in 0.5% (40 or fewer times per minute). The Ivabradine hydrochloride osmotic pump controlled release tablet is developed, can avoid the peak valley phenomenon of blood concentration, reduce the influence of food on absorption, reduce the administration frequency and has clinical value.
CN102908327 discloses an ivabradine sustained release preparation, which selects a plurality of framework materials to slow down the dissolution of a medicament, but the release rate of a sustained release framework tablet is gradually slowed down and is easily influenced by the gastrointestinal tract environment.
CN104398486 discloses an ivabradine hydrochloride double-layer osmotic pump controlled release tablet, which is prepared with a medicine-containing layer and a boosting layer respectively, and has high requirements on instruments and equipment, complex preparation process and higher production cost.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide an ivabrane hydrochloride single-layer osmotic pump controlled release tablet and a preparation method thereof, so as to reduce blood concentration fluctuation and gastrointestinal environment influence, reduce administration times and improve medicine safety and patient compliance.
The invention provides an ivabrane hydrochloride single-layer osmotic pump controlled release tablet which is realized by the following technical scheme: the single-layer osmotic pump controlled release tablet comprises a tablet core, a semipermeable coating film and a drug release pore. The tablet core comprises, by weight, 5-30% of ivabradine hydrochloride, 0-60% of a suspending agent, 30-90% of a penetration enhancer and 0.1-3% of a lubricant; the semipermeable coating film comprises 80-99% of semipermeable film-forming material and 1-20% of pore-forming agent, and the weight of the coating is increased by 3-15% of the weight of the tablet core; the aperture of the medicine release pore is 0.4mm-1.2 mm.
The suspending agent is selected from one or more of polyoxyethylene, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and polyvinylpyrrolidone.
The penetration enhancer is selected from one or more of sodium chloride, potassium chloride, sorbitol, mannitol and lactose.
The lubricant is selected from one or more of magnesium stearate, talcum powder, magnesium lauryl sulfate, superfine silica gel powder and polyethylene glycol.
The semipermeable membrane forming material is selected from one or a combination of more of cellulose acetate, acrylic resin and ethyl cellulose.
The pore-forming agent is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, propylene glycol, water-soluble inorganic salt and polyvinylpyrrolidone.
The invention provides a preparation method of an ivabrane hydrochloride single-layer osmotic pump controlled release tablet, which comprises the following specific preparation processes:
(1) uniformly mixing ivabradine hydrochloride, a penetration enhancer and a suspending agent, adding a wetting agent to prepare a soft material, sieving with a 20-mesh sieve, carrying out wet granulation, drying in an oven at 40 ℃ for 2 hours, and sieving with a 20-mesh sieve, carrying out dry granulation; adding a lubricant and mixing uniformly; pressing by a circular shallow concave punching die with the diameter of 8 mm;
(2) weighing a semipermeable membrane forming material and a pore-forming agent according to the prescription amount, adding the semipermeable membrane forming material and the pore-forming agent into an acetone-water solution, and forming a clear and transparent coating solution after completely dissolving; coating the tablet core in a coating pan; after coating, placing the mixture in a drying oven at 40 ℃ for aging for 12 hours to remove acetone; the center of the circle of one side of the coated tablet is provided with a drug release pore with the diameter of 0.4mm to 1.2 mm.
The wetting agent is preferably absolute ethyl alcohol, water or ethanol solution with different concentrations.
The positive progress effects of the invention are as follows: by using the single-layer osmotic pump technology, the drug release time is prolonged to more than 16 hours, and the constant-speed release of the drug is realized. Effectively avoids the peak valley phenomenon of the blood concentration of the quick-release preparation, is not easily influenced by factors such as gastrointestinal tract peristalsis, environment and the like, reduces the administration frequency to once a day, and improves the compliance of patients and the safety and the effectiveness of medicaments.
Drawings
FIG. 1 is a graph of percentage in vitro cumulative release versus time for example 1-example 3 of ivabradine hydrochloride single layer osmotic pump controlled release tablets;
FIG. 2 is a graph of percentage in vitro cumulative release versus time for example 4-example 6 ivabradine hydrochloride single layer osmotic pump controlled release tablets;
FIG. 3 is a graph of percentage in vitro cumulative release versus time for the Ivabradine hydrochloride single layer osmotic pump controlled release tablets of examples 7-11.
Detailed Description
The invention will be further described below by means of specific examples. It should be understood that: the embodiments of the present invention are given for illustration only and not for limitation, and any simple modification of the present invention based on the technical solution of the present invention falls within the protection scope of the present invention.
Examples 1-11 preparation methods: weighing the medicines and the auxiliary materials (except the magnesium stearate) according to the prescription amount, sieving by a 30-mesh sieve and uniformly mixing. Adding appropriate amount of wetting agent anhydrous ethanol, granulating, sieving with 20 mesh sieve, drying in oven at 40 deg.C for 2 hr, sieving with 20 mesh sieve, and drying. Adding magnesium stearate, and mixing. The round shallow concave film-punching tablet with the diameter of 8mm has the hardness of 5-9 kg. Weighing cellulose acetate and polyethylene glycol 3350 according to the formula, heating in a constant-temperature water bath at 35 ℃, adding into an acetone-water solution (99.5: 0.5) under magnetic stirring, and after completely dissolving, clarifying and transparent the coating solution. And placing the tablet core in a coating pot, controlling the temperature of the tablet bed to be 22-28 ℃, and increasing the weight of the coating by 5-6%. After coating, the coating was aged in an oven at 40 ℃ for 12 hours to remove acetone. A medicine releasing hole with the diameter of 0.6mm is punched on the semipermeable membrane at the center position of one side of the osmotic pump by using a laser drilling machine.
According to the second method of the determination method of the dissolution rate and the release rate of 0931 in the four-part general rule of the 2020 edition of Chinese pharmacopoeia, 900mL of phosphate buffer solution with the pH value of 6.8 is taken as a release medium at the rotating speed of 100rpm and the temperature of (37 +/-0.5) DEG C for 2h, 4h, 6h, 8h, 12h, 16h, 20h and 24h respectively, 10mL of the solution is taken, and meanwhile, an equal amount of a same-temperature fresh medium is supplemented. The sample was filtered through a 0.45 μm microporous membrane, and 1mL of the subsequent filtrate was taken as a test solution. Measuring peak area by high performance liquid chromatograph external standard method, detecting wavelength 286nm, and calculating cumulative release percentage by external standard method.
Example 1
Tablet core prescription
| Composition of | Dosage (each tablet) |
| Ivabradine hydrochloride | 10.8mg |
| Hydroxyethyl cellulose LR | 30mg |
| Hydroxypropyl methylcellulose E5 | 10mg |
| Mannitol | 147.2mg |
| Magnesium stearate | 2mg |
Coating film prescription
| Composition of | Dosage (per 100 tablets) |
| Cellulose acetate | 0.9g |
| Polyethylene glycol 3350 | 0.1g |
| Acetone (II) | 19.9g |
| Water (W) | 0.1g |
Example 2
Tablet core prescription
| Composition of | Dosage (each tablet) |
| Ivabradine hydrochloride | 10.8mg |
| Hydroxypropyl methylcellulose E50 | 30mg |
| Hydroxypropyl methylcellulose E5 | 10mg |
| Mannitol | 147.2mg |
| Magnesium stearate | 2mg |
Coating film prescription
| Composition of | Dosage (per 100 tablets) |
| Cellulose acetate | 0.9g |
| Polyethylene glycol 3350 | 0.1g |
| Acetone (II) | 19.9g |
| Water (W) | 0.1g |
Example 3
Tablet core prescription
| Composition of | Dosage (each tablet) |
| Ivabradine hydrochloride | 10.8mg |
| Polyoxyethylene N80 | 30mg |
| Hydroxypropyl methylcellulose E5 | 10mg |
| Mannitol | 147.2mg |
| Magnesium stearate | 2mg |
Coating film prescription
| Composition of | Dosage (per 100 tablets) |
| Cellulose acetate | 0.9g |
| Polyethylene glycol 3350 | 0.1g |
| Acetone (II) | 19.9g |
| Water (W) | 0.1g |
It can be seen from figure 1 that polyoxyethylene, hydroxyethyl cellulose and hydroxypropylmethyl cellulose all act as suspending agents to delay drug release.
Example 4
Tablet core prescription
| Composition of | Dosage (each tablet) |
| Ivabradine hydrochloride | 16.2mg |
| Polyoxyethylene 303 | 30mg |
| Hydroxypropyl methylcellulose E5 | 10mg |
| Mannitol | 141.8mg |
| Magnesium stearate | 2mg |
Coating film prescription
| Composition of | Dosage (per 100 tablets) |
| Cellulose acetate | 0.9g |
| Polyethylene glycol 3350 | 0.1g |
| Acetone (II) | 19.9g |
| Water (W) | 0.1g |
Example 5
Tablet core prescription
| Composition of | Dosage (each tablet) |
| Ivabradine hydrochloride | 16.2mg |
| Polyoxyethylene N750 | 30mg |
| Hydroxypropyl methylcellulose E5 | 10mg |
| Mannitol | 141.8mg |
| Magnesium stearate | 2mg |
Coating film prescription
| Composition of | Dosage (per 100 tablets) |
| Cellulose acetate | 0.9g |
| Polyethylene glycol 3350 | 0.1g |
| Acetone (II) | 19.9g |
| Water (W) | 0.1g |
Example 6
Tablet core prescription
| Composition of | Dosage (each tablet) |
| Ivabradine hydrochloride | 16.2mg |
| Polyoxyethylene N10 | 30mg |
| Hydroxypropyl methylcellulose E5 | 10mg |
| Mannitol | 141.8mg |
| Magnesium stearate | 2mg |
Coating film prescription
| Composition of | Dosage (per 100 tablets) |
| Cellulose acetate | 0.9g |
| Polyethylene glycol 3350 | 0.1g |
| Acetone (II) | 19.9g |
| Water (W) | 0.1g |
Figure 2 shows that low molecular weight polyethylene oxide (10000 to 300000 daltons) is more suitable as a suspending agent, with a constant and moderate release rate. The high molecular weight polyoxyethylene has high viscosity, increased swelling degree and reduced release end point, and is not suitable for single-layer osmotic pump tablets.
Example 7
Tablet core prescription
| Composition of | Dosage (each tablet) |
| Ivabradine hydrochloride | 16.2mg |
| Polyoxyethylene N10 | 30mg |
| Polyvinylpyrrolidone K30 | 10mg |
| Lactose | 141.2mg |
| Magnesium stearate | 2mg |
Coating film prescription
| Composition of | Dosage (per 100 tablets) |
| Cellulose acetate | 0.9g |
| Polyethylene glycol 3350 | 0.1g |
| Acetone (II) | 19.9g |
| Water (W) | 0.1g |
Example 8
Tablet core prescription
| Composition of | Dosage (each tablet) |
| Ivabradine hydrochloride | 16.2mg |
| Polyoxyethylene N10 | 30mg |
| Polyvinylpyrrolidone K30 | 10mg |
| Sorbitol | 141.2mg |
| Magnesium stearate | 2mg |
Coating film prescription
| Composition of | Dosage (per 100 tablets) |
| Cellulose acetate | 0.9g |
| Polyethylene glycol 3350 | 0.1g |
| Acetone (II) | 19.9g |
| Water (W) | 0.1g |
Example 9
Tablet core prescription
| Composition of | Dosage (each tablet) |
| Ivabradine hydrochloride | 16.2mg |
| Polyoxyethylene N10 | 30mg |
| Polyvinylpyrrolidone K30 | 10mg |
| Mannitol | 141.2mg |
| Magnesium stearate | 2mg |
Coating film prescription
| Composition of | Dosage (per 100 tablets) |
| Cellulose acetate | 0.9g |
| Polyethylene glycol 3350 | 0.1g |
| Acetone (II) | 19.9g |
| Water (W) | 0.1g |
Example 10
Tablet core prescription
| Composition of | Dosage (each tablet) |
| Ivabradine hydrochloride | 16.2mg |
| Polyoxyethylene N10 | 30mg |
| Polyvinylpyrrolidone K30 | 10mg |
| Mannitol | 141.8mg |
| Magnesium stearate | 2mg |
Coating film prescription
| Composition of | Dosage (per 100 tablets) |
| Cellulose acetate | 0.85g |
| Polyethylene glycol 3350 | 0.15g |
| Acetone (II) | 19.9g |
| Water (W) | 0.1g |
Example 11
Tablet core prescription
| Composition of | Dosage (each tablet) |
| Ivabradine hydrochloride | 16.2mg |
| Polyoxyethylene N10 | 30mg |
| Polyvinylpyrrolidone K30 | 10mg |
| Mannitol | 141.8mg |
| Magnesium stearate | 2mg |
Coating film prescription
| Composition of | Dosage (per 100 tablets) |
| Cellulose acetate | 0.8g |
| Polyethylene glycol 3350 | 0.2g |
| Acetone (II) | 19.9g |
| Water (W) | 0.1g |
Figure 3 shows that when the tablet core is added with penetration enhancer such as sorbitol, lactose, mannitol, etc., the medicine can be completely pushed out from the medicine releasing small hole. The dosage of the pore-forming agent in the coating film has a remarkable adjusting effect on the release speed, the dosage is increased, the release speed is too high, the effect of sustained and controlled release is difficult to achieve, and 10 percent of polyethylene glycol 3350 is preferred.
While the preferred embodiments and principles of this invention have been described in detail, it will be apparent to those skilled in the art that variations may be made in the embodiments based on the teachings of the invention and such variations are considered to be within the scope of the invention.
Claims (8)
1. The ivabrane hydrochloride single-layer osmotic pump controlled release tablet is characterized by comprising a tablet core, a semipermeable coating film and a drug release pore;
the tablet core comprises, by weight, 5-30% of ivabradine hydrochloride, 0-60% of a suspending agent, 30-90% of a penetration enhancer and 0.1-3% of a lubricant;
the semipermeable coating film comprises 80-99% of semipermeable film forming material and 1-20% of pore-forming agent, and the weight of the coating is increased by 3-15% of the weight of the tablet core;
the aperture of the medicine release pore is 0.4mm-1.2 mm.
2. The ivabradine hydrochloride single-layer osmotic pump controlled release tablet according to claim 1, wherein the suspending agent is selected from one or more of polyoxyethylene, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and polyvinylpyrrolidone.
3. The ivabradine hydrochloride mono-layer osmotic pump controlled release tablet of claim 1, wherein the penetration enhancer is selected from one or a combination of sodium chloride, potassium chloride, sorbitol, mannitol and lactose.
4. The ivabradine hydrochloride mono-layer osmotic pump controlled release tablet according to claim 1, wherein the lubricant is selected from one or more of magnesium stearate, talcum powder, magnesium lauryl sulfate, silica gel micropowder and polyethylene glycol.
5. The ivabradine hydrochloride single-layer osmotic pump controlled release tablet according to claim 1, wherein the semipermeable polymer material is selected from one or more of cellulose acetate, acrylic resin and ethyl cellulose.
6. The ivabradine hydrochloride single-layer osmotic pump controlled release tablet according to claim 1, wherein the pore-forming agent is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, propylene glycol, water-soluble inorganic salts, and polyvinylpyrrolidone.
7. A process for the preparation of the ivabradine hydrochloride mono-layer osmotic pump controlled release tablet according to any of claims 1 to 6, characterized in that it comprises the following steps:
(1) uniformly mixing ivabradine hydrochloride, a penetration enhancer and a suspending agent, adding a wetting agent to prepare a soft material, sieving with a 20-mesh sieve, carrying out wet granulation, drying in an oven at 40 ℃ for 2 hours, and sieving with a 20-mesh sieve, carrying out dry granulation; adding a lubricant and mixing uniformly; pressing by a circular shallow concave punching die with the diameter of 8 mm;
(2) weighing a semipermeable membrane forming material and a pore-forming agent according to the prescription amount, adding the semipermeable membrane forming material and the pore-forming agent into an acetone-water solution, and forming a clear and transparent coating solution after completely dissolving; coating the tablet core in a coating pan; after coating, placing the mixture in a drying oven at 40 ℃ for aging for 12 hours to remove acetone; the center of the circle of one side of the coated tablet is provided with a drug release pore with the diameter of 0.4mm to 1.2 mm.
8. The method of claim 7, wherein the wetting agent is preferably absolute ethanol, water or ethanol solution of different concentrations.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116983272A (en) * | 2023-09-08 | 2023-11-03 | 江苏诺和必拓新药研发有限公司 | Ivabradine hydrochloride sustained release tablet and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104398486A (en) * | 2014-12-08 | 2015-03-11 | 武汉武药科技有限公司 | Ivabradine hydrochloride osmotic pump controlled-release tablet and preparation method thereof |
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