CN112206234A - Ivabradine preparation and preparation method thereof - Google Patents

Ivabradine preparation and preparation method thereof Download PDF

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Publication number
CN112206234A
CN112206234A CN201910631071.4A CN201910631071A CN112206234A CN 112206234 A CN112206234 A CN 112206234A CN 201910631071 A CN201910631071 A CN 201910631071A CN 112206234 A CN112206234 A CN 112206234A
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Prior art keywords
ivabradine hydrochloride
stirring
preparation
polyethylene glycol
ivabradine
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CN112206234B (en
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郝贵周
孟凡亮
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Lunan Pharmaceutical Group Corp
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Lunan Pharmaceutical Group Corp
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an ivabradine hydrochloride tablet and a preparation method thereof. Adding the molten liquid into the mixed powder of the filler, stirring uniformly, adding the lubricant, mixing uniformly, and tabletting. Compared with the prior art, the tablet prepared by the invention has the advantages of good drug stability, no crystal transformation phenomenon in the storage process, rapid dissolution, simple process and suitability for industrial production.

Description

Ivabradine preparation and preparation method thereof
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an ivabradine hydrochloride preparation and a preparation method thereof.
Background
Ivabradine hydrochloride is the hydrochloride of ivabradine, is the first selective specific IF (controlling spontaneous diastolic depolarization in the sinoatrial node and regulating heart rate) inhibitor, and has selective effect on the sinoatrial node but no effect on intracardiac conduction, myocardial contraction or ventricular repolarization. The product is different from the most commonly used beta receptor blocker for treating angina pectoris, and does not cause adverse reaction or rebound phenomenon such as respiratory tract contraction or spasm, bradycardia, etc. At present, the heart rate is slowed down to be an important way for preventing and treating the angina, and the product opens up a new way with bright prospect for treating the angina.
The chemical name of the ivabradine hydrochloride is 7, 8-dimethoxy-3- (3- [ [ (1S) (4, 5-dimethoxybenzocyclobutane-1-yl) methyl ] -methylamino ] propyl) -1, 3, 4, 5-tetrahydro-2H-benzazepine-2-ketone, and the compound is a polymorphic medicine. In order to pursue the stability of the raw materials, the prior art reports a great deal of research on the raw materials of the crystalline form of ivabradine hydrochloride, and the patent literature discloses and protects the polymorphic form of ivabradine hydrochloride and the preparation process thereof.
The ivabradine stable drug has the characteristic of poor solubility, and in order to improve the dissolution rate of the crystal form drug in a preparation, the prior art usually adopts a micronization technology, a solid dispersion technology, a surfactant solubilization technology, an inclusion technology and the like. However, micronization tends to cause aggregation of the drug, resulting in limited improvement in solubility; solid dispersions are susceptible to aging, also resulting in a decrease in drug solubility; the surfactant is solubilized, so that gastrointestinal irritation is easily caused; the inclusion technology is complex in process. In the prior art, although there is a technology for preparing a preparation by utilizing an amorphous ivabradine hydrochloride raw material, no report for improving the stability of the amorphous ivabradine hydrochloride raw material is found. If the preparation is stored, the medicine is converted into a crystal form, which not only influences the dissolution of the medicine, but also causes the difference of curative effect of the medicine and brings hidden danger to clinical medication.
CN03802711.9 discloses an ivabradine pharmaceutical composition capable of being dispersed in the mouth, and the auxiliary materials are lactose and starch, which can be rapidly disintegrated and take effect in the mouth. However, rapid disintegration does not represent rapid dissolution and no stability test results are published.
CN201610792496.X discloses Ivabradine hydrochloride tablet and its preparation method, and adjuvant including lactose, starch, polyvidone K30, silica gel micropowder, and magnesium stearate. The dissolution rate is lower and is less than 50% in 10 min.
CN201310339181.6 discloses an ivabradine hydrochloride tablet and a preparation method thereof, and the preparation is prepared by uniformly mixing amorphous ivabradine hydrochloride, guar gum and other pharmaceutically acceptable auxiliary materials and tabletting. The amorphous ivabradine hydrochloride has lower stability and is easy to be transformed into crystals in the long-term storage process. The process is only suitable for amorphous state of the medicine, and slow medicine dissolution can be caused in the process of storing the medicine material which is changed into a crystal form.
At present, the problem of dissolution rate and stability of the ivabradine tablet prepared in the prior art cannot be solved.
Disclosure of Invention
In view of the defects of the prior art, the inventor provides an Ivabradine hydrochloride tablet which is fast in dissolution and stable in quality.
In order to achieve the above object of the present invention, the inventors tried to prepare a solid dispersion by a solvent evaporation method, but the dispersion material itself is highly viscous, and the dissolution rate is not high although the solubility can be improved like hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, and the like.
Further, the inventors considered that the melt granulation method is adopted, but the melting point of the raw materials is about 194 ℃, and the raw materials are easily degraded in the production process at such a high temperature. The inventor considers that the low-melting-point polyethylene glycol is selected, amorphous or crystalline bulk drugs are added into the molten polyethylene glycol, and the bulk drugs can be dissolved and cooled to form amorphous solid dispersion.
However, the above dispersion was still standing for a long period of time, and further, the inventors tried to add various transcrystallization inhibitors, and although the transcrystallization could be suppressed, the dissolution rate was decreased. When citric acid is added into the composition, the composition inhibits the crystal transformation of the medicine, improves the solubility of the medicine in polyethylene glycol, and further improves the dissolution rate in a dissolution medium. The unexpected effect is achieved.
The invention is realized by the following scheme:
the ivabradine hydrochloride tablet is prepared by melting ivabradine hydrochloride, polyethylene glycol and citric acid, mixing with pharmaceutically acceptable adjuvants, and tabletting.
Preferably, the weight ratio of the ivabradine hydrochloride to the polyethylene glycol is 1: 2-6.
Further preferably, the weight ratio of the ivabradine hydrochloride to the polyethylene glycol is 1: 4.
Preferably, the weight ratio of the ivabradine hydrochloride to the citric acid is 1: 0.2-0.6.
Further preferably, the weight ratio of the ivabradine hydrochloride to the citric acid is 1: 0.4.
The polyethylene glycol is one or more of PEG2000, PEG4000, PEG6000 and PEG 8000.
Preferably, the polyethylene glycol is PEG 4000.
The pharmaceutically acceptable auxiliary materials comprise a filler and a lubricant.
Preferably, the filler is selected from one or more of lactose, mannitol, sorbitol, microcrystalline cellulose, and compressible starch.
Preferably, the lubricant is selected from one or more of magnesium stearate, aerosil and talcum powder.
Preferably, the ivabradine hydrochloride tablet specifically comprises the following components in parts by weight:
Figure BDA0002128722930000031
the invention also provides a preparation method of the ivabradine hydrochloride tablet.
The ivabradine hydrochloride tablet is prepared by adopting the following method: firstly, heating and melting polyethylene glycol, adding citric acid, stirring to dissolve, then adding a prescription amount of ivabradine hydrochloride raw material, and stirring to dissolve; adding the molten liquid into the mixed powder of the filler, stirring uniformly, adding the lubricant, mixing uniformly, and tabletting.
Compared with the prior art, the ivabradine hydrochloride tablet and the preparation process thereof have the following advantages and remarkable progressions:
(1) the raw material of the ivabradine hydrochloride is selected to be in an amorphous form or a crystal form, so that the prepared tablet can be stored and transported for a long time, and the medicine is quickly dissolved out and has good stability;
(2) the preparation process is simple and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples. It should be properly understood that: the examples of the present invention are given solely for the purpose of illustration and not as limitations of the present invention, and therefore, simple modifications of the present invention in the context of the methods of the present invention are intended to fall within the scope of the claims.
Example 1
1) Prescription
Figure BDA0002128722930000032
2) Preparation method
Heating polyethylene glycol to 400060 deg.C for melting, adding citric acid, stirring for dissolving, adding Ivabradine hydrochloride raw material, and stirring for dissolving. Adding the molten liquid into mixed powder of lactose and microcrystalline cellulose, stirring uniformly, adding magnesium stearate according to the prescription amount, mixing uniformly, and tabletting.
Example 2
1) Prescription
Figure BDA0002128722930000041
2) Preparation method
Heating polyethylene glycol to 800060 deg.C for melting, adding citric acid, stirring for dissolving, adding Ivabradine hydrochloride raw material, and stirring for dissolving. Adding the molten liquid into mannitol, stirring, adding talcum powder according to the prescription amount, mixing uniformly, and tabletting.
Example 3
1) Prescription
Figure BDA0002128722930000042
2) Preparation method
Heating polyethylene glycol to 200060 deg.C for melting, adding citric acid, stirring for dissolving, adding Ivabradine hydrochloride raw material, and stirring for dissolving. Adding the molten liquid into sorbitol, stirring uniformly, adding the micropowder silica gel according to the prescription amount, mixing uniformly, and tabletting.
Example 4
1) Prescription
Figure BDA0002128722930000051
2) Preparation method
Heating polyethylene glycol to 600060 deg.C for melting, adding citric acid, stirring for dissolving, adding Ivabradine hydrochloride raw material, and stirring for dissolving. Adding the molten liquid into the compressible starch, stirring uniformly, adding the micro-powder silica gel according to the prescription amount, mixing uniformly, and tabletting.
Example 5
1) Prescription
Figure BDA0002128722930000052
2) Preparation method
Heating polyethylene glycol to 200060 deg.C for melting, adding citric acid, stirring for dissolving, adding Ivabradine hydrochloride raw material, and stirring for dissolving. Adding the molten liquid into lactose, stirring, adding the micropowder silica gel according to the prescription amount, mixing uniformly, and tabletting.
Example 6
1) Prescription
Figure BDA0002128722930000053
2) Preparation method
Heating polyethylene glycol to 1000060 deg.C for melting, adding citric acid, stirring for dissolving, adding Ivabradine hydrochloride raw material, and stirring for dissolving. Adding the molten liquid into microcrystalline cellulose, stirring uniformly, adding the micro-powder silica gel according to the prescription amount, mixing uniformly, and tabletting.
Example 7
1) Prescription
Figure BDA0002128722930000061
2) Preparation method
Heating polyethylene glycol at 100060 deg.C for melting, adding citric acid, stirring for dissolving, adding Ivabradine hydrochloride raw material, and stirring for dissolving. Adding the molten liquid into sorbitol, stirring uniformly, adding the micropowder silica gel according to the prescription amount, mixing uniformly, and tabletting.
Example 8
1) Prescription
Figure BDA0002128722930000062
2) Preparation method
Heating polyethylene glycol to 200060 deg.C for melting, adding citric acid, stirring for dissolving, adding Ivabradine hydrochloride raw material, and stirring for dissolving. Adding the molten liquid into sorbitol, stirring uniformly, adding the micropowder silica gel according to the prescription amount, mixing uniformly, and tabletting.
Example 9
1) Prescription
Figure BDA0002128722930000071
2) Preparation method
Heating polyethylene glycol to 200060 deg.C for melting, adding citric acid, stirring for dissolving, adding Ivabradine hydrochloride raw material, and stirring for dissolving. Adding the molten liquid into sorbitol, stirring uniformly, adding the micropowder silica gel according to the prescription amount, mixing uniformly, and tabletting.
Example 10
1) Prescription
Figure BDA0002128722930000072
2) Preparation method
Heating polyethylene glycol to 200060 deg.C for melting, adding citric acid, stirring for dissolving, adding Ivabradine hydrochloride raw material, and stirring for dissolving. Adding the molten liquid into sucrose, stirring, adding the micropowder silica gel according to the prescription amount, mixing uniformly, and tabletting.
Example 11
1) Prescription
Figure BDA0002128722930000073
2) Preparation method
Heating polyethylene glycol to 200060 deg.C for melting, adding citric acid, stirring for dissolving, adding Ivabradine hydrochloride raw material, and stirring for dissolving. Adding the molten liquid into dextrin, stirring uniformly, adding the sodium fumarate with the prescription amount, mixing uniformly, and tabletting.
Example 12
1) Prescription
Figure BDA0002128722930000081
2) Preparation method
Heating polyethylene glycol to 200060 deg.C for melting, adding citric acid, stirring for dissolving, adding Ivabradine hydrochloride raw material, and stirring for dissolving. Adding the molten liquid into the compressible starch, stirring uniformly, adding the micro-powder silica gel according to the prescription amount, mixing uniformly, and tabletting.
Example 13
1) Prescription
Figure BDA0002128722930000082
2) Preparation method
Heating polyethylene glycol to 200060 deg.C for melting, adding citric acid, stirring for dissolving, adding Ivabradine hydrochloride raw material, and stirring for dissolving. Adding the molten liquid into the compressible starch, stirring uniformly, adding the micro-powder silica gel according to the prescription amount, mixing uniformly, and tabletting.
Comparative example 1
1) Prescription
Figure BDA0002128722930000091
2) Preparation method
Heating and melting polyethylene glycol 400060 ℃, stirring to dissolve, adding the Ivabradine hydrochloride raw material with the prescription amount, and stirring to dissolve. Adding the molten liquid into mixed powder of lactose and microcrystalline cellulose, stirring uniformly, adding magnesium stearate according to the prescription amount, mixing uniformly, and tabletting.
Comparative example 2
1) Prescription
Figure BDA0002128722930000092
2) Preparation method
The amorphous ivabradine hydrochloride is sieved by a 100-mesh sieve, and is uniformly mixed with the guar gum, the sodium carboxymethyl starch, the microcrystalline cellulose and the magnesium stearate which are sieved by the 100-mesh sieve, and then the mixture is tabletted.
Comparative example 3
1) Prescription
Figure BDA0002128722930000093
2) Preparation method
Weighing 10% PVPK30 according to the prescription amount, and dissolving the PVPK30 by using 50% ethanol solution to be used as a bonding agent for later use; weighing and progressively mixing the prescription amount of ivabradine hydrochloride with the prescription amount of lactose monohydrate in an equivalent amount; adding the starch with the prescription amount and mixing evenly. Adding adhesive, mixing, sieving with 20 mesh sieve, and granulating; drying wet granules at 60 ℃, adding magnesium stearate and aerosil according to the prescription amount, and uniformly mixing; detecting the particle content, and adopting a flat-punch die-pressed sheet with a nick in the middle according to the content; coating the tablet core with film coat, and packaging with aluminum plastic.
Comparative example 4
1) Prescription
Figure BDA0002128722930000101
2) Preparation method
Respectively crushing the citric acid and the ivabradine hydrochloride, sieving by a 100-mesh sieve, weighing according to the prescription, adding into the mixed powder of the lactose and the microcrystalline cellulose, uniformly stirring, adding the magnesium stearate according to the prescription, uniformly mixing, and tabletting.
Comparative example 5
1) Prescription
Figure BDA0002128722930000102
2) Preparation method
Heating and melting polyethylene glycol at 200060 ℃, adding maleic acid, stirring to dissolve, adding the Ivabradine hydrochloride raw material with the prescription amount, and stirring to dissolve. Adding the molten liquid into sucrose, stirring, adding the micropowder silica gel according to the prescription amount, mixing uniformly, and tabletting.
Comparative example 6
1) Prescription
Figure BDA0002128722930000111
2) Preparation method
Heating and melting povidone at 195 ℃, adding citric acid, stirring to dissolve, adding the Ivabradine hydrochloride raw material with the prescription amount, and stirring to dissolve. Adding the molten liquid into sucrose, stirring, adding the micropowder silica gel according to the prescription amount, mixing uniformly, and tabletting.
Comparative example 7
1) Prescription
Figure BDA0002128722930000112
2) Preparation method
Heating and melting polyethylene glycol at 200060 ℃, adding cholic acid, stirring to dissolve, adding the Ivabradine hydrochloride raw material with the prescription amount, and stirring to dissolve. Adding the molten liquid into sucrose, stirring, adding the micropowder silica gel according to the prescription amount, mixing uniformly, and tabletting.
Comparative example 8
1) Prescription
Figure BDA0002128722930000113
Figure BDA0002128722930000121
2) Preparation method
Heating and melting polyethylene glycol at 200060 ℃, adding the Ivabradine hydrochloride raw material with the prescription amount, and stirring to dissolve. Adding the molten liquid into the mixed powder of citric acid and lactose, stirring uniformly, adding the micropowder silica gel according to the prescription amount, mixing uniformly, and tabletting.
Comparative example 9
1) Prescription
Figure BDA0002128722930000122
2) Preparation method
Heating and melting polyethylene glycol at 200060 ℃, adding deoxycholic acid, stirring to dissolve, adding the Ivabradine hydrochloride raw material with the prescription amount, and stirring to dissolve. Adding the molten liquid into sucrose, stirring, adding the micropowder silica gel according to the prescription amount, mixing uniformly, and tabletting.
Verification examples
1. Stability detection
The ivabradine hydrochloride bare chips prepared in each example and comparative example were placed for 6 months at 40 ℃ and 75% RH without aluminium-plastic packaging for stability experiments:
chromatographic conditions for the measurement of relevant substances: octadecylsilane chemically bonded silica is used as chromatographic column filler, and KH is 0.01mol/L2PO4The solution (with 0.5% triethylamine and phosphoric acid to adjust the pH to 6.0) and methanol 80: 20 as mobile phase A and methanol as mobile phase B, the detection wavelength was 230nm, the column temperature was 30 ℃ and the flow rate was 0.75 ml/min. The gradient elution conditions are shown in Table 1, and the results of the measurements are shown in Table 2.
TABLE 1 mobile phase gradient elution conditions
t(min) A(％) B(％)
0 90 10
10 70 30
12 55 45
35 55 45
2. Dissolution testing
Chromatographic conditions for dissolution determination: eighteen in weightThe alkylsilane bonded silica gel is used as a chromatographic column filler and is (0.01 mol/LKH)2PO4The solution (containing 0.5% triethylamine, pH adjusted to 6.0 with phosphoric acid, 80: 20 with methanol, 60: 40 with methanol) was used as mobile phase, the detection wavelength was 230nm, the column temperature was 30 ℃ and the flow rate was 0.65 ml/min. Dissolution medium: water, paddle method, 25 rpm, 10 minutes sampling detection, the limit is 85% of the labeled amount. The results are shown in Table 2.
TABLE 2 measurement results of examples
Figure BDA0002128722930000131

Claims (8)

1. The ivabradine hydrochloride tablet is characterized in that the ivabradine hydrochloride tablet is prepared by melting ivabradine hydrochloride, polyethylene glycol and citric acid, mixing with pharmaceutically acceptable auxiliary materials, and tabletting.
2. Ivabradine hydrochloride tablet according to claim 1, wherein the weight ratio of ivabradine hydrochloride to polyethylene glycol is from 1:2 to 6.
3. The ivabradine hydrochloride tablet according to claim 1, wherein the weight ratio of the ivabradine hydrochloride to the citric acid is 1: 0.2-0.6.
4. Ivabradine hydrochloride tablet according to claim 1, wherein the polyethylene glycol type is one or more of PEG2000, PEG4000, PEG6000, PEG 8000.
5. Ivabradine hydrochloride tablet according to claim 1, wherein the pharmaceutically acceptable excipients comprise fillers and lubricants.
6. Ivabradine hydrochloride tablet according to claim 5, wherein the filler is selected from one or more of lactose, mannitol, sorbitol, microcrystalline cellulose, compressible starch.
7. Ivabradine hydrochloride tablet according to claim 5, wherein the lubricant is selected from one or more of magnesium stearate, aerosil, talc.
8. A process for the preparation of the ivabradine hydrochloride tablet according to any one of claims 1 to 7, characterized in that it is prepared by a process comprising: firstly heating and melting polyethylene glycol, adding citric acid, stirring to dissolve, then adding the Ivabradine hydrochloride raw material according to the prescription amount, stirring to dissolve, adding the molten liquid into the mixed powder of the filler, stirring uniformly, then adding the lubricant, mixing uniformly, and tabletting.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011157722A2 (en) * 2010-06-14 2011-12-22 Ratiopharm Gmbh Solid ivabradine-containing composition
CN103211781A (en) * 2013-03-21 2013-07-24 青岛正大海尔制药有限公司 Etoposide soft capsule

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011157722A2 (en) * 2010-06-14 2011-12-22 Ratiopharm Gmbh Solid ivabradine-containing composition
CN103211781A (en) * 2013-03-21 2013-07-24 青岛正大海尔制药有限公司 Etoposide soft capsule

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