CN105476973A - Felodipine sustained release tablet and preparation method thereof - Google Patents
Felodipine sustained release tablet and preparation method thereof Download PDFInfo
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- CN105476973A CN105476973A CN201510938576.7A CN201510938576A CN105476973A CN 105476973 A CN105476973 A CN 105476973A CN 201510938576 A CN201510938576 A CN 201510938576A CN 105476973 A CN105476973 A CN 105476973A
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- felodipine
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
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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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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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
- A61K9/20—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
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Abstract
The invention provides a felodipine sustained release tablet and a preparation method of the felodipine sustained release tablet. The felodipine sustained release tablet is prepared by mixing felodipine solid dispersion with a filling agent, a lubricating agent and a sustained-release material, and then tabletting; specifically, the felodipine sustained release tablet is prepared from the following components in parts by weight: the felodipine solid dispersion (containing 2.5-10 parts of felodipine and 10-100 parts of dispersion substrate), 60-160 parts of the filling agent, 0.4-8 parts of the lubricating agent, and 30-90 parts of the sustained-release material, wherein the dispersion substrate adopts polyethylene glycol, and the sustained-release material adopts hydroxypropyl methyl cellulose. Compared with the prior art, the felodipine sustained release tablet provided by the invention has the advantages that the uniform distribution is realized through the solid dispersion, so that the uniformity of the felodipine sustained release tablet is improved, and meanwhile through the interaction between the sustained-release material and the solid dispersion, the slow-release effect of the felodipine sustained release tablet is good and stable.
Description
Technical field
The present invention relates to technical field of pharmaceuticals, more particularly, relate to a kind of felodipine sustained-release tablets and preparation method thereof.
Background technology
Felodipine, chemical name is 2,6-dimethyl-4-(2,3-Dichlorobenzene base)-Isosorbide-5-Nitrae-dihydro-3,5-pyridinedicarboxylic acid methyl ethyl ester, and English name is FELODIPINE, and molecular formula is C
18h
19cl
2nO
4, molecular weight is 384.25, and chemical structural formula is as follows:
Felodipine is a kind of dihydropyridine type calcium antagonists, has the cardioselective of height, has and significantly reduces blood pressure and the effect of total periphery power-assisted.For the vascular system of some specific part, to increase the blood flow at these positions, as coronary vasodilator, cerebrovascular, conventional medicine has nifedipine, amlodipine, felodipine etc., wherein felodipine is minimum to myocardium negative effects, and the reverse of prolonged application to hypertensive patient's left ventricular hypertrophy and vascular remodeling has positive meaning.
At present, mainly felodipine ordinary tablet and slow releasing tablet on market, wherein ordinary tablet needs within one day, to take medicine 2 ~ 3 times, although this preparation can reach the effect reduced blood pressure, because its medicining times is more, large to fluctuation of blood pressure; Therefore, slow releasing tablet receives accreditation and the concern of people more.
But slow releasing tablet commercially available at present also exists release and the not good problem of the uniformity, limits the development of felodipine sustained-release tablets.
Summary of the invention
In view of this, the invention provides a kind of felodipine sustained-release tablets and preparation method thereof, felodipine sustained-release tablets release provided by the invention is good and the uniformity is high.
The invention provides a kind of felodipine sustained-release tablets, comprise following component:
Felodipine solid dispersion, described felodipine solid dispersion comprises felodipine 2.5 weight portion ~ 10 weight portion and dispersion substrate 10 weight portion ~ 100 weight portion;
Filler 60 weight portion ~ 160 weight portion;
Lubricant 0.4 weight portion ~ 8 weight portion;
Slow-release material 30 weight portion ~ 90 weight portion;
Described dispersion substrate is Polyethylene Glycol;
Described slow-release material is hydroxypropyl emthylcellulose.
Preferably, the mean molecule quantity of described Polyethylene Glycol is 1800 ~ 10500.
Preferably, particle diameter≤80 order of described felodipine solid dispersion.
Preferably, described filler is one or more in lactose, mannitol and microcrystalline Cellulose.
Preferably, described lubricant is one or both in micropowder silica gel and magnesium stearate.
Present invention also offers the preparation method of the felodipine sustained-release tablets described in a kind of technique scheme, comprise the following steps:
A) cool after felodipine being mixed with the dispersion substrate after melting, obtain felodipine solid dispersion; Described dispersion substrate is Polyethylene Glycol; The mean molecule quantity of described Polyethylene Glycol is 1800 ~ 10500;
B) tabletting after described felodipine solid dispersion, filler, lubricant being mixed with slow-release material, obtains felodipine sustained-release tablets; Described slow-release material is hydroxypropyl emthylcellulose.
Preferably, described step a) specifically comprises the following steps:
A1) dispersion substrate is heated, obtain the dispersion substrate after melting;
A2), after felodipine being joined the mixing of the dispersion substrate after melting, successively through cooling, pulverizing, felodipine solid dispersion is obtained.
Preferably, step a2) described in cooling mode be ice bath cooling; The time of described cooling is 10h ~ 15h.
Preferably, step a2) described in pulverize particle diameter≤80 order.
Preferably, step b) described in felodipine sustained-release tablets also comprise coating powder 20 weight portion ~ 30 weight portion.
The invention provides a kind of felodipine sustained-release tablets and preparation method thereof, described felodipine sustained-release tablets is obtained by tabletting after felodipine solid dispersion and filler, lubricant and slow release material mixing; Described felodipine sustained-release tablets comprises following component: felodipine solid dispersion, and described felodipine solid dispersion comprises felodipine 2.5 weight portion ~ 10 weight portion and dispersion substrate 10 weight portion ~ 100 weight portion; Filler 60 weight portion ~ 160 weight portion; Lubricant 0.4 weight portion ~ 8 weight portion; Slow-release material 30 weight portion ~ 90 weight portion; Described dispersion substrate is Polyethylene Glycol; Described slow-release material is hydroxypropyl emthylcellulose.Compared with prior art, felodipine sustained-release tablets provided by the invention realizes being uniformly distributed by solid dispersion, improve the uniformity of felodipine sustained-release tablets, interacted by slow-release material and solid dispersion simultaneously, make the had good sustained release effect of felodipine sustained-release tablets and stablize.Experimental result shows, the Accumulation dissolution of felodipine sustained-release tablets 1h provided by the invention reaches more than 90% at the Accumulation dissolution of about 10%, 4h at the Accumulation dissolution of about 50%, 10h.
Detailed description of the invention
Below in conjunction with the embodiment of the present invention, be clearly and completely described technical scheme of the present invention, obviously, described embodiment is only the present invention's part embodiment, instead of whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art, not making the every other embodiment obtained under creative work prerequisite, belong to the scope of protection of the invention.
The invention provides a kind of felodipine sustained-release tablets, comprise following component:
Felodipine solid dispersion, described felodipine solid dispersion comprises felodipine 2.5 weight portion ~ 10 weight portion and dispersion substrate 10 weight portion ~ 100 weight portion;
Filler 60 weight portion ~ 160 weight portion;
Lubricant 0.4 weight portion ~ 8 weight portion;
Slow-release material 30 weight portion ~ 90 weight portion;
Described dispersion substrate is Polyethylene Glycol;
Described slow-release material is hydroxypropyl emthylcellulose.
In the present invention, described felodipine solid dispersion comprises felodipine and dispersion substrate.In the present invention, described felodipine is principal agent composition; The source of the present invention to described felodipine is not particularly limited, and adopts commercial goods well known to those skilled in the art.In the present invention, described felodipine solid dispersion comprises the felodipine of 2.5 weight portion ~ 10 weight portions, is preferably 4 weight portion ~ 6 weight portions, is more preferably 5 weight portions.
In the present invention, described dispersion-based mass-energy is enough disperses principal agent uniform composition, significantly improves dissolubility and the wettability of principal agent composition.In the present invention, described dispersion substrate is Polyethylene Glycol.In the present invention, the mean molecule quantity of described Polyethylene Glycol is preferably 1800 ~ 10500, and the Polyethylene Glycol in above-mentioned average molecular weight range is white solid at normal temperatures, and fusing point is below 65 DEG C; Be divided into the product of different model according to the difference of mean molecule quantity, preferably include one or more in Macrogol 4000, polyethylene glycol 6000 and PEG20000, be more preferably polyethylene glycol 6000 or PEG20000; The source of the present invention to described Polyethylene Glycol is not particularly limited, and adopts commercial goods well known to those skilled in the art.In the present invention, described felodipine solid dispersion comprises the dispersion substrate of 10 weight portion ~ 100 weight portions, is preferably 30 weight portion ~ 50 weight portions.
In the present invention, the particle diameter of described felodipine solid dispersion is preferably less than or equal to 80 orders, is more preferably and is less than or equal to 70 orders.In the present invention, the principal agent composition be conducive in solid dispersion under 80 object conditions by the size controlling of described felodipine solid dispersion is dispersed in the process of further mix preparation.
In the present invention, described filler is the adjunct ingredient of felodipine sustained-release tablets provided by the invention, mainly plays dilution principal agent composition, fills the effect of slow releasing tablet.In the present invention, described filler be preferably in lactose, mannitol and microcrystalline Cellulose one or more, be more preferably lactose and microcrystalline Cellulose; The source of the present invention to described filler is not particularly limited, and adopts the commercial goods of above-mentioned lactose well known to those skilled in the art, mannitol and microcrystalline Cellulose.In the present invention, the particle diameter of described filler is preferably less than or equal to 100 orders, is more preferably and is less than or equal to 90 orders.In the present invention, described felodipine sustained-release tablets comprises the filler of 60 weight portion ~ 160 weight portions, is preferably 80 weight portion ~ 100 weight portions.In the preferred technical scheme of the present invention, described filler is lactose and microcrystalline Cellulose, described felodipine sustained-release tablets preferably includes the lactose of 40 weight portion ~ 100 weight portions and the microcrystalline Cellulose of 10 weight portion ~ 40 weight portions, is more preferably the lactose of 48 weight portion ~ 68 weight portions and the microcrystalline Cellulose of 20 weight portion ~ 32 weight portions.
In the present invention, described lubricant is the adjunct ingredient of felodipine sustained-release tablets provided by the invention.In the present invention, described lubricant be preferably in micropowder silica gel and magnesium stearate one or both, be more preferably micropowder silica gel and magnesium stearate; The source of the present invention to described lubricant is not particularly limited, and adopts the commercial goods of above-mentioned micropowder silica gel well known to those skilled in the art and magnesium stearate.In the present invention, described felodipine sustained-release tablets comprises the lubricant of 0.4 weight portion ~ 8 weight portion, is preferably 6 weight portions.In the preferred technical scheme of the present invention, described lubricant is micropowder silica gel and magnesium stearate, described felodipine sustained-release tablets preferably includes the micropowder silica gel of 0.2 weight portion ~ 3 weight portion and the magnesium stearate of 0.2 weight portion ~ 5 weight portion, is more preferably the micropowder silica gel of 2 weight portions and the magnesium stearate of 4 weight portions.
In the present invention, described slow-release material is the adjunct ingredient of felodipine sustained-release tablets provided by the invention, described slow-release material can interact with the felodipine solid dispersion described in technique scheme, makes the had good sustained release effect of felodipine sustained-release tablets and stablizes.In the present invention, described slow-release material is hydroxypropyl emthylcellulose, preferably include in hydroxypropyl emthylcellulose K250, hydroxypropyl emthylcellulose K750 and hydroxypropyl emthylcellulose K1500 one or more, be more preferably hydroxypropyl emthylcellulose K250 and hydroxypropyl emthylcellulose K750; The source of the present invention to described hydroxypropyl emthylcellulose is not particularly limited, and adopts commercial goods well known to those skilled in the art.In the present invention, described felodipine sustained-release tablets comprises the slow-release material of 30 weight portion ~ 90 weight portions, is preferably 60 weight portion ~ 70 weight portions, is more preferably 63 weight portions.In the preferred technical scheme of the present invention, described slow-release material is hydroxypropyl emthylcellulose K250 and hydroxypropyl emthylcellulose K750, described felodipine sustained-release tablets preferably includes the hydroxypropyl emthylcellulose K250 of 10 weight portion ~ 30 weight portions and the hydroxypropyl emthylcellulose K750 of 20 weight portion ~ 60 weight portions, is more preferably the hydroxypropyl emthylcellulose K250 of 18 weight portion ~ 21 weight portions and the hydroxypropyl emthylcellulose K750 of 42 weight portion ~ 45 weight portions.
Present invention also offers the preparation method of the felodipine sustained-release tablets described in a kind of technique scheme, comprise the following steps:
A) cool after felodipine being mixed with the dispersion substrate after melting, obtain felodipine solid dispersion; Described dispersion substrate is Polyethylene Glycol;
B) tabletting after described felodipine solid dispersion, filler, lubricant being mixed with slow-release material, obtains felodipine sustained-release tablets; Described slow-release material is hydroxypropyl emthylcellulose.
In the present invention, cool after felodipine is mixed with the dispersion substrate after melting, obtain felodipine solid dispersion.In the present invention, described felodipine is principal agent composition; The source of the present invention to described felodipine is not particularly limited, and adopts commercial goods well known to those skilled in the art.In the present invention, described felodipine solid dispersion comprises the felodipine of 2.5 weight portion ~ 10 weight portions, is preferably 4 weight portion ~ 6 weight portions, is more preferably 5 weight portions.
In the present invention, described dispersion-based mass-energy is enough disperses principal agent uniform composition, significantly improves dissolubility and the wettability of principal agent composition.In the present invention, described dispersion substrate is Polyethylene Glycol.In the present invention, the mean molecule quantity of described Polyethylene Glycol is preferably 1800 ~ 10500, and the Polyethylene Glycol in above-mentioned average molecular weight range is white solid at normal temperatures, and fusing point is below 65 DEG C; Be divided into the product of different model according to the difference of mean molecule quantity, preferably include one or more in Macrogol 4000, polyethylene glycol 6000 and PEG20000, be more preferably polyethylene glycol 6000 or PEG20000; The source of the present invention to described Polyethylene Glycol is not particularly limited, and adopts commercial goods well known to those skilled in the art.In the present invention, described felodipine solid dispersion comprises the dispersion substrate of 10 weight portion ~ 100 weight portions, is preferably 30 weight portion ~ 50 weight portions.
In the present invention, the described process cooled afterwards that felodipine mixed with the dispersion substrate after melting preferably specifically comprises the following steps:
A1) dispersion substrate is heated, obtain the dispersion substrate after melting;
A2), after felodipine being joined the mixing of the dispersion substrate after melting, successively through cooling, pulverizing, felodipine solid dispersion is obtained.
In the present invention, first dispersion substrate is heated, obtain the dispersion substrate after melting.The mode of the present invention to described heating is not particularly limited, and preferably adopts heating in water bath.In the present invention, the temperature of described heating is preferably 68 DEG C ~ 72 DEG C, is more preferably 70 DEG C.
After obtaining the dispersion substrate after melting, after felodipine is joined the mixing of the dispersion substrate after melting by the present invention, successively through cooling, pulverizing, obtain felodipine solid dispersion.In the present invention, felodipine is joined the dispersion substrate after melting, felodipine can be made to be uniformly distributed in dispersion substrate.
In the present invention, the mode of described cooling is preferably ice bath cooling; In described cooling procedure, mixture constantly solidifies, last completely brittle, obtains solid product.In the present invention, the time of described cooling is preferably 10h ~ 15h, is more preferably 12h.
After obtaining completely brittle solid product, above-mentioned solid product is pulverized by the present invention, obtains felodipine solid dispersion.The method of the present invention to described pulverizing is not particularly limited, and adopts polishing well known to those skilled in the art.In the present invention, the particle diameter of described pulverizing is preferably less than or equal to 80 orders, is more preferably and is less than or equal to 70 orders.
After obtaining described felodipine solid dispersion, tabletting after described felodipine solid dispersion, filler, lubricant mix with slow-release material by the present invention, obtains felodipine sustained-release tablets.In the present invention, identical with described in technique scheme of described felodipine solid dispersion, does not repeat them here.
In the present invention, described filler is the adjunct ingredient of felodipine sustained-release tablets provided by the invention, mainly plays dilution principal agent composition, fills the effect of slow releasing tablet.In the present invention, described filler be preferably in lactose, mannitol and microcrystalline Cellulose one or more, be more preferably lactose and microcrystalline Cellulose; The source of the present invention to described filler is not particularly limited, and adopts the commercial goods of above-mentioned lactose well known to those skilled in the art, mannitol and microcrystalline Cellulose.In the present invention, the particle diameter of described filler is preferably less than or equal to 100 orders, is more preferably and is less than or equal to 90 orders.In the present invention, described felodipine sustained-release tablets comprises the filler of 60 weight portion ~ 160 weight portions, is preferably 80 weight portion ~ 100 weight portions.In the preferred technical scheme of the present invention, described filler is lactose and microcrystalline Cellulose, described felodipine sustained-release tablets preferably includes the lactose of 40 weight portion ~ 100 weight portions and the microcrystalline Cellulose of 10 weight portion ~ 40 weight portions, is more preferably the lactose of 48 weight portion ~ 68 weight portions and the microcrystalline Cellulose of 20 weight portion ~ 32 weight portions.
In the present invention, described lubricant is the adjunct ingredient of felodipine sustained-release tablets provided by the invention.In the present invention, described lubricant be preferably in micropowder silica gel and magnesium stearate one or both, be more preferably micropowder silica gel and magnesium stearate; The source of the present invention to described lubricant is not particularly limited, and adopts the commercial goods of above-mentioned micropowder silica gel well known to those skilled in the art and magnesium stearate.In the present invention, described felodipine sustained-release tablets comprises the lubricant of 0.4 weight portion ~ 8 weight portion, is preferably 6 weight portions.In the preferred technical scheme of the present invention, described lubricant is micropowder silica gel and magnesium stearate, described felodipine sustained-release tablets preferably includes the micropowder silica gel of 0.2 weight portion ~ 3 weight portion and the magnesium stearate of 0.2 weight portion ~ 5 weight portion, is more preferably the micropowder silica gel of 2 weight portions and the magnesium stearate of 4 weight portions.
In the present invention, described slow-release material is the adjunct ingredient of felodipine sustained-release tablets provided by the invention, described slow-release material can interact with the felodipine solid dispersion described in technique scheme, makes the had good sustained release effect of felodipine sustained-release tablets and stablizes.In the present invention, described slow-release material is hydroxypropyl emthylcellulose, preferably include in hydroxypropyl emthylcellulose K250, hydroxypropyl emthylcellulose K750 and hydroxypropyl emthylcellulose K1500 one or more, be more preferably hydroxypropyl emthylcellulose K250 and hydroxypropyl emthylcellulose K750; The source of the present invention to described hydroxypropyl emthylcellulose is not particularly limited, and adopts commercial goods well known to those skilled in the art.In the present invention, described felodipine sustained-release tablets comprises the slow-release material of 30 weight portion ~ 90 weight portions, is preferably 60 weight portion ~ 70 weight portions, is more preferably 63 weight portions.In the preferred technical scheme of the present invention, described slow-release material is hydroxypropyl emthylcellulose K250 and hydroxypropyl emthylcellulose K750, described felodipine sustained-release tablets preferably includes the hydroxypropyl emthylcellulose K250 of 10 weight portion ~ 30 weight portions and the hydroxypropyl emthylcellulose K750 of 20 weight portion ~ 60 weight portions, is more preferably the hydroxypropyl emthylcellulose K250 of 18 weight portion ~ 21 weight portions and the hydroxypropyl emthylcellulose K750 of 42 weight portion ~ 45 weight portions.
In the present invention, tabletting after described felodipine solid dispersion, filler, lubricant being mixed with slow-release material, the device of the present invention to described mixing is not particularly limited, and adopts mixer well known to those skilled in the art.In the present invention, the mode of described mixing is preferably and stirs, and the speed of described stirring is preferably 2r/min ~ 5r/min, is more preferably 3r/min ~ 4r/min; The time of described stirring is preferably 30min ~ 60min, is more preferably 30min.The device of the present invention to described tabletting is not particularly limited, and adopts tablet machine well known to those skilled in the art; The mould of φ 9mm is adopted to carry out tabletting; Hardness is preferably 5kg ~ 7kg, is more preferably 6kg.
In the present invention, described felodipine sustained-release tablets preferably also comprises coating powder 20 weight portion ~ 30 weight portion, is more preferably 25 weight portions.In the present invention, described coating powder is preferably Opadry coating powder; The source of the present invention to described coating powder is not particularly limited, and adopts commercial goods well known to those skilled in the art.
The invention provides a kind of felodipine sustained-release tablets and preparation method thereof, described felodipine sustained-release tablets is obtained by tabletting after felodipine solid dispersion and filler, lubricant and slow release material mixing; Described felodipine sustained-release tablets comprises following component: felodipine solid dispersion, and described felodipine solid dispersion comprises felodipine 2.5 weight portion ~ 10 weight portion and dispersion substrate 10 weight portion ~ 100 weight portion; Filler 60 weight portion ~ 160 weight portion; Lubricant 0.4 weight portion ~ 8 weight portion; Slow-release material 30 weight portion ~ 90 weight portion; Described dispersion substrate is Polyethylene Glycol; Described slow-release material is hydroxypropyl emthylcellulose.Compared with prior art, felodipine sustained-release tablets provided by the invention realizes being uniformly distributed by solid dispersion, improve the uniformity of felodipine sustained-release tablets, interacted by slow-release material and solid dispersion simultaneously, make the had good sustained release effect of felodipine sustained-release tablets and stablize.Experimental result shows, the Accumulation dissolution of felodipine sustained-release tablets 1h provided by the invention reaches more than 90% at the Accumulation dissolution of about 10%, 4h at the Accumulation dissolution of about 50%, 10h.
In addition, first the preparation method of felodipine sustained-release tablets provided by the invention prepares felodipine solid dispersion by the dispersion substrate after melting, can reduce its related substances in slow releasing tablet, the stability of improving the quality of products.
In order to further illustrate the present invention, be described in detail below by following examples.As shown in table 1, in following examples of the present invention, supplementary material used all meets standards of pharmacopoeia, and wherein lactose and mannitol were through pulverizing 100 mesh sieve process.
The kind of supplementary material used and source in table 1 embodiment of the present invention
| Supplementary material title | Specification | Material category | Manufacturer |
| Volume in Felodipine Raw Material | Medicinal | Raw material | Changzhou Rui Ming pharmaceutical Co. Ltd |
| Macrogol 4000,6000,10000 | Medicinal | Adjuvant | Haidian, Beijing fellow member of an association or organization's Fine Chemical Works |
| Lactose | Medicinal | Adjuvant | Mei Jile group of Germany |
| Mannitol | Medicinal | Adjuvant | Merck KGaA company |
| Microcrystalline Cellulose | Medicinal | Adjuvant | Asahi Kasei Corporation |
| Micropowder silica gel | Medicinal | Adjuvant | Huzhou Zhanwang Pharmaceutical Co., Ltd. |
| Magnesium stearate | Medicinal | Adjuvant | Qufu City pharmaceutic adjuvant company limited |
| Hydroxypropyl emthylcellulose K250, K750 | Medicinal | Adjuvant | Ya Shilan group (ASLAND) |
| Opadry coating powder | Medicinal | Adjuvant | Shanghai Colorcon Coating Technology Co., Ltd |
Embodiment 1
(1) 50g polyethylene glycol 6000 is carried out heating in water bath at 70 DEG C, to complete melting, then add the mixing of 5g Volume in Felodipine Raw Material, then ice bath cooling 12h is carried out, obtain completely brittle solid product, finally pulverized 80 mesh sieves, and obtained felodipine solid dispersion.
(2) the felodipine solid dispersion obtained and 48g lactose, 12g mannitol, 20g microcrystalline Cellulose, 2g micropowder silica gel, 4g magnesium stearate, 21g hydroxypropyl emthylcellulose K250 and 42g hydroxypropyl emthylcellulose K750 are added in mixer, 30min is stirred under 4r/min, tablet machine is finally adopted to carry out tabletting, tabletting parameter is φ 9mm, hardness 6kg, obtains felodipine sustained-release tablets (1000).
(3) adopt 25g Opadry coating powder to carry out coating, obtain felodipine sustained-release tablets product.
Embodiment 2
(1) 30g PEG20000 is carried out heating in water bath at 70 DEG C, to complete melting, then add the mixing of 5g Volume in Felodipine Raw Material, then ice bath cooling 12h is carried out, obtain completely brittle solid product, finally pulverized 80 mesh sieves, and obtained felodipine solid dispersion.
(2) the felodipine solid dispersion obtained and 68g lactose, 32g microcrystalline Cellulose, 2g micropowder silica gel, 4g magnesium stearate, 18g hydroxypropyl emthylcellulose K250 and 45g hydroxypropyl emthylcellulose K750 are added in mixer, 30min is stirred under 3r/min, tablet machine is finally adopted to carry out tabletting, tabletting parameter is φ 9mm, hardness 6kg, obtains felodipine sustained-release tablets (1000).
(3) adopt 25g Opadry coating powder to carry out coating, obtain felodipine sustained-release tablets product.
Embodiment 3
(1) 40g Macrogol 4000 is carried out heating in water bath at 68 DEG C, to complete melting, then add the mixing of 5g Volume in Felodipine Raw Material, then ice bath cooling 10h is carried out, obtain completely brittle solid product, finally pulverized 80 mesh sieves, and obtained felodipine solid dispersion.
(2) the felodipine solid dispersion obtained and 60g lactose, 30g microcrystalline Cellulose, 2g micropowder silica gel, 4g magnesium stearate, 21g hydroxypropyl emthylcellulose K250 and 42g hydroxypropyl emthylcellulose K750 are added in mixer, 30min is stirred under 4r/min, tablet machine is finally adopted to carry out tabletting, tabletting parameter is φ 9mm, hardness 6kg, obtains felodipine sustained-release tablets (1000).
(3) adopt 25g Opadry coating powder to carry out coating, obtain felodipine sustained-release tablets product.
Embodiment 4
(1) 50g polyethylene glycol 6000 is carried out heating in water bath at 70 DEG C, to complete melting, then add the mixing of 5g Volume in Felodipine Raw Material, then ice bath cooling 12h is carried out, obtain completely brittle solid product, finally pulverized 80 mesh sieves, and obtained felodipine solid dispersion.
(2) the felodipine solid dispersion obtained and 48g lactose, 20g microcrystalline Cellulose, 2g micropowder silica gel, 4g magnesium stearate, 21g hydroxypropyl emthylcellulose K250 and 42g hydroxypropyl emthylcellulose K750 are added in mixer, 30min is stirred under 4r/min, tablet machine is finally adopted to carry out tabletting, tabletting parameter is φ 9mm, hardness 6kg, obtains felodipine sustained-release tablets (1000).
(3) adopt 25g Opadry coating powder to carry out coating, obtain felodipine sustained-release tablets product.
Comparative example
The felodipine sustained-release tablets (Plendil) that AstraZeneca pharmaceutical Co. Ltd produces.
High performance liquid chromatography is adopted to carry out release test experience to the felodipine sustained-release tablets in embodiment 1 ~ 4 and comparative example.Experiment condition is: high performance liquid chromatograph is Agilent 1200 type high performance liquid chromatograph, detector is Agilent 1200LC UV-detector, data process machine is chemstation chromatographic work station, chromatographic column is WondasilTMC18 post (150 × 4.6mm, 5 μm), column temperature is room temperature, and determined wavelength is 245nm, sampling volume 20 μ L, flow velocity is 1.0mL/min.Chromatographic condition and system suitability are tested and are: take octadecylsilane chemically bonded silica as filler, with acetonitrile-methanol-phosphate buffer (pH=3.0)-(2:1:2) for mobile phase, determined wavelength is 245nm, theoretical cam curve calculates should be not less than 1500 by felodipine peak, and the separating degree of felodipine peak and other impurity peaks should meet the requirements.Specific experiment is operating as: sample thief respectively, according to drug release determination method (Chinese Pharmacopoeia version in 2010 two annex XD first methods), with the Tween 80 of 1% (w/v) (with water for solvent) 500mL for release medium, rotating speed 100r/min, operate in accordance with the law, got solution 5mL respectively to filter at 1,2,4,6,8,10 hour, and instant release medium of supplementing same volume in process container, get subsequent filtrate as need testing solution; It is appropriate that another precision takes the felodipine being dried to constant weight through 105 DEG C, dissolves and be quantitatively diluted to the solution of every 1mL containing 10 μ g, as need testing solution with dissolution medium; Get above-mentioned two kinds of solution, measure according to the method under drug release determination item, calculate the burst size of every sheet at different time.Experimental result is in table 2.
The detection data of the felodipine sustained-release tablets release in table 2 embodiment 1 ~ 4 and comparative example
As shown in Table 2, the felodipine sustained-release tablets in embodiment 1 ~ 4 is respectively more than 5% ~ 30%, 45% ~ 75% and 80% of labelled amount in the burst size of 1h, 4h, 8h, and conform with the regulations standard; And compared with comparative example, the Accumulation dissolution of felodipine sustained-release tablets 1h provided by the invention reaches more than 90% at the Accumulation dissolution of about 10%, 4h at the Accumulation dissolution of about 50%, 10h, has better slow release effect.
High performance liquid chromatography is adopted to carry out uniformity of dosage units test experience to the felodipine sustained-release tablets in embodiment 1 ~ 4 and comparative example.Experiment condition is: high performance liquid chromatograph is Agilent 1200 type high performance liquid chromatograph, detector is Agilent 1200LC UV-detector, data process machine is chemstation chromatographic work station, chromatographic column is WondasilTMC18 post (150 × 4.6mm, 5 μm), column temperature is room temperature, and determined wavelength is 238nm, sampling volume 20 μ L, flow velocity is 1.0mL/min.Specific experiment is operating as: sample thief 1 respectively, is placed in 50mL measuring bottle, makes sample dissolution with EtOH Sonicate, and be diluted to scale, shake up, and filter, precision measures subsequent filtrate as need testing solution; Separately get felodipine reference substance 10mg, accurately weighed, be placed in 50mL measuring bottle, dissolve with mobile phase and be diluted to scale, shaking up, precision measures 5mL, is placed in 50mL measuring bottle, is diluted to scale with mobile phase, shake up, in contrast product solution; Precision measures need testing solution and each 20 μ L of reference substance solution respectively, injection liquid chromatography, and record chromatogram, by external standard method with calculated by peak area and get final product.Experimental result is in table 3, and wherein X is labelled amount meansigma methods, and S is standard deviation, and A is the absolute value of labelled amount and meansigma methods X difference, and B is uniformity of dosage units.
The detection data of the felodipine sustained-release tablets uniformity of dosage units in table 3 embodiment 1 ~ 4 and comparative example
As shown in Table 3, the uniformity of dosage units of the felodipine tablet in embodiment 1 ~ 4 is within 4, show that the content of felodipine tablet provided by the invention every sheet principal agent composition departs from the degree of labelled amount low, namely the degree that felodipine sustained-release tablets every sheet content that felodipine tablet provided by the invention compares ratio and provides meets labelled amount is high, good evenness.
High performance liquid chromatography is adopted to carry out related substance test experience to the felodipine sustained-release tablets in embodiment 1 ~ 4 and comparative example.Experiment condition is: high performance liquid chromatograph is Agilent 1200 type high performance liquid chromatograph, detector is Agilent 1200LC UV-detector, data process machine is chemstation chromatographic work station, chromatographic column is WondasilTMC18 post (150 × 4.6mm, 5 μm), column temperature is room temperature, and determined wavelength is 238nm, sampling volume 20 μ L, flow velocity is 1.0mL/min.Chromatographic condition and system suitability are tested and are: take octadecylsilane chemically bonded silica as filler, with methanol-acetonitrile-water (50:15:35) for mobile phase, determined wavelength is 238nm, the separating degree of impurity I and felodipine should be greater than 3.0, and theoretical cam curve calculates by felodipine peak and is not less than 3500.Specific experiment is operating as: sample thief fine powder appropriate (being about equivalent to felodipine 12.5mg), be placed in 25mL measuring bottle, add the ultrasonic sample dissolution that makes of mobile phase and also quantitatively dilute the solution made containing felodipine 0.5mg in every 1mL, filter, get subsequent filtrate as need testing solution; Separately get impurity I reference substance, accurately weighed, add mobile phase and dissolve and quantitatively dilute the solution made about containing 0.15mg in every 1mL, precision measures 1mL, is placed in 100mL measuring bottle, and precision adds need testing solution 1mL, be diluted to scale with mobile phase, shake up, in contrast solution; Get contrast solution 20 μ L and inject high performance liquid chromatograph, regulate detector sensitivity, make the peak height of felodipine chromatographic peak be about 50% of full scale; Precision measures contrast solution and each 20 μ L of need testing solution again, measures according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex VD), and record chromatogram is to 3 times of main constituent peak retention time; If any the chromatographic peak consistent with impurity I retention time in the chromatogram of need testing solution, by external standard method with calculated by peak area, 0.3% of felodipine labelled amount must not be exceeded, other single impurity peak area must not be greater than 1.0% of felodipine peak area in contrast solution, and total impurities must not cross 1.5%.Experimental result is in table 4.
The detection data of the related substances of felodipine sustained-release tablets in table 4 embodiment 1 ~ 4 and comparative example
As shown in Table 4, the felodipine sustained-release tablets in embodiment 1 ~ 4 compares the felodipine sustained-release tablets in ratio, and its related substances is lower, and 40 DEG C ± 2 DEG C, accelerate 6 months under RH75% ± 5% condition after its related substances more stable.
The above-mentioned explanation of the disclosed embodiments, enables professional and technical personnel in the field realize or uses the present invention.To be apparent for those skilled in the art to the multiple amendment of these embodiments, General Principle as defined herein can without departing from the spirit or scope of the present invention, realize in other embodiments.Therefore, the present invention can not be restricted to these embodiments shown in this article, but will meet the widest scope consistent with principle disclosed herein and features of novelty.
Claims (10)
1. a felodipine sustained-release tablets, is characterized in that, comprises following component:
Felodipine solid dispersion, described felodipine solid dispersion comprises felodipine 2.5 weight portion ~ 10 weight portion and dispersion substrate 10 weight portion ~ 100 weight portion;
Filler 60 weight portion ~ 160 weight portion;
Lubricant 0.4 weight portion ~ 8 weight portion;
Slow-release material 30 weight portion ~ 90 weight portion;
Described dispersion substrate is Polyethylene Glycol;
Described slow-release material is hydroxypropyl emthylcellulose.
2. felodipine sustained-release tablets according to claim 1, is characterized in that, the mean molecule quantity of described Polyethylene Glycol is 1800 ~ 10500.
3. felodipine sustained-release tablets according to claim 1, is characterized in that, particle diameter≤80 order of described felodipine solid dispersion.
4. felodipine sustained-release tablets according to claim 1, is characterized in that, described filler is one or more in lactose, mannitol and microcrystalline Cellulose.
5. felodipine sustained-release tablets according to claim 1, is characterized in that, described lubricant is one or both in micropowder silica gel and magnesium stearate.
6. a preparation method for the felodipine sustained-release tablets described in any one of Claims 1 to 5, is characterized in that, comprises the following steps:
A) cool after felodipine being mixed with the dispersion substrate after melting, obtain felodipine solid dispersion; Described dispersion substrate is Polyethylene Glycol;
B) tabletting after described felodipine solid dispersion, filler, lubricant being mixed with slow-release material, obtains felodipine sustained-release tablets; Described slow-release material is hydroxypropyl emthylcellulose.
7. preparation method according to claim 6, is characterized in that, described step a) specifically comprises the following steps:
A1) dispersion substrate is heated, obtain the dispersion substrate after melting;
A2), after felodipine being joined the mixing of the dispersion substrate after melting, successively through cooling, pulverizing, felodipine solid dispersion is obtained.
8. preparation method according to claim 7, is characterized in that, step a2) described in cooling mode be ice bath cooling; The time of described cooling is 10h ~ 15h.
9. preparation method according to claim 7, is characterized in that, step a2) described in pulverize particle diameter≤80 order.
10. preparation method according to claim 6, is characterized in that, step b) described in felodipine sustained-release tablets also comprise coating powder 20 weight portion ~ 30 weight portion.
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Citations (2)
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|---|---|---|---|---|
| US20030190356A1 (en) * | 2002-04-08 | 2003-10-09 | Yea-Sheng Yang | Process for preparing oral sustained-release formulation of felodipine |
| CN101627976A (en) * | 2008-07-17 | 2010-01-20 | 北京科信必成医药科技发展有限公司 | Felodipine sustained-release preparation and preparation method thereof |
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| US20030190356A1 (en) * | 2002-04-08 | 2003-10-09 | Yea-Sheng Yang | Process for preparing oral sustained-release formulation of felodipine |
| CN101627976A (en) * | 2008-07-17 | 2010-01-20 | 北京科信必成医药科技发展有限公司 | Felodipine sustained-release preparation and preparation method thereof |
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| 张聪等: "固体分散体技术提高难溶性药物溶出度的研究新进展", 《中国医药指南》 * |
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