CN103169704A - Compound slow-release capsule preparation of nicotinic acid and simvastatin as well as preparation method of preparation - Google Patents
Compound slow-release capsule preparation of nicotinic acid and simvastatin as well as preparation method of preparation Download PDFInfo
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- CN103169704A CN103169704A CN2011104421735A CN201110442173A CN103169704A CN 103169704 A CN103169704 A CN 103169704A CN 2011104421735 A CN2011104421735 A CN 2011104421735A CN 201110442173 A CN201110442173 A CN 201110442173A CN 103169704 A CN103169704 A CN 103169704A
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Abstract
The invention provides a capsule containing a nicotinic acid slow-release tablet and a simvastatin mixture. The compound slow-release capsule preparation includes the nicotinic acid slow-release tablet and the simvastatin mixture, wherein the content of the nicotinic acid is 50%-80%. The simvastatin mixture includes the simvastatin and other medical auxiliary materials, wherein the content of the simvastatin is 20%-80%. The invention provides the preparation method of the compound slow-release capsule preparation of nicotinic acid and simvastatin. The preparation method comprises the following steps of: preparing the simvastatin and the medical auxiliary materials into a simvastatin mixture; preparing the nicotinic acid and the medical auxiliary materials into a slow-release tablet; filling the simvastatin mixture to the capsule by using a capsule filling machine; filling the nicotinic acid slow-release tablet to the capsule to obtain the nicotinic acid-simvastatin slow release capsule. The compound slow-release capsule preparation disclosed by the invention is good in stability, controllable in quality, simple in preparation method, suitable for industrial production and large in application value.
Description
Technical field
The present invention relates to pharmaceutical preparation, be specifically related to compound preparation, relate in particular to compound sustained release capsules preparation of a kind of nicotinic acid and simvastatin and preparation method thereof.
Background technology
Blood fat is the general name of contained lipid in human plasma, comprising cholesterol, triglyceride, cholesterol ester, beta lipoprotein, phospholipid, not esterified fat acid etc.When cholesterol, triglyceride, beta lipoprotein surpass normal value, can be referred to as hyperlipidemia.According to statistics, the number of middle national trouble hyperlipidemia has reached 1.6 hundred million, and annual still up to ten million speed is increasing.On February 15th, 2008 drugs approved by FDA Abbott nicotinic acid+simvastatin compound slow-release tablet (niacin extended-release+simvastatin, Simcor) listing, be used in conjunction with keeping on a diet, reduce and adopt separately niacin sustained-release preparation or simvastatin sheet to treat the invalid patient of mixed type lipid metabolism disease, reduce its T-CHOL, low density lipoprotein, LDL and triglyceride, and high density lipoprotein increasing.Product is thin membrane coated tablet, the dosage specification: slow release nicotinic acid/simvastatin 500mg/20mg/ sheet, 750mg/20mg/ sheet, 1000mg/20mg/ sheet.In clinical research, the patient that the patient who takes compound sustained-released nicotinic acid/simvastatin 1000mg/20mg sheet takes more separately simvastatin sheet 20mg has significantly reduced cholesterolemia.Have obvious characteristics and advantages: (1) effect for reducing blood fat is had complementary advantages: simvastatin has remarkable result for reducing low density lipoprotein, LDL and T-CHOL, can reduce triglyceride simultaneously; Nicotinic acid can effectively increase hdl level, reduce the level of triglyceride and LP(a), thereby both share the effect that can reach mutual supplement with each other's advantages, and side effect does not increase.(2) reduce a day dosage: due to coupling action compensatings both, therefore consumption per day all reduces separately, and the simvastatin consumption is down to 20mg/ day, and the nicotinic acid consumption is down to maximum 1g/ day; The medication number of times is reduced to every day 1 time, facilitates medication.(3) reduce the side effect incidence rate: due to the consumption per day that has reduced simvastatin and nicotinic acid, so greatly reduce the risk that side effect occurs, after nicotinic acid is made slow releasing preparation simultaneously, reduced the peak valley fluctuation of this medicine, reduce the incidence rate of nicotinic acid untoward reaction, all be better than existing lipid lowerers aspect safety and ease of use.
Chinese patent 200810238273,200810240879,200910033397 discloses a kind of compound simvastatin niacin sustained release tablet and preparation method thereof, this patent use coating medicine-feeding method with the simvastatin bag to slow release nicotinic acid label.Chinese patent 200810239882,200910036107 discloses a kind of compound simvastatin nicolar sustained release capsule and preparation method thereof, and this patent incapsulates simvastatin fast release micropill and niacin sustained release micropill and obtains compound simvastatin nicolar sustained release capsule.Chinese patent 200910232861 discloses a kind of niacin simvastatin double-layer sustained release tablets, and simvastatin is made the rapid release lamella, is pressed into double-layer sustained release tablets with niacin slow-release tablet.Chinese patent 200810137477 discloses a kind of niacin simvastatin sustained-release sheet, during tabletting, the simvastatin fast-release tablet is wrapped in inside niacin slow-release tablet, forms compound slow-release tablet.Stable bad due to simvastatin easily degraded by hydrolysis and oxidation, and the lactone bond open loop of rupturing generates its active metabolite simvastatin hydroxy acid under super-humid conditions; The generation dimer of oxidation copolymerization reaction slowly or polymer occur in intramolecule two ethylene linkages under hot conditions.In preparation process at present commonly used, be easy to cause the degraded of simvastatin, as the easily heat production or need to use the technique of water such as tabletting, coating.Simultaneously, because the simvastatin relative dosage is less, the method for compacting double-layer tablet or slow release label medicine-feeding coating all may cause simvastatin content uniformity undesirable.Therefore, find a kind ofly can make the stable unaffected of simvastatin, the easier satisfactory process conditions of content uniformity are just very necessary simultaneously, and effectiveness and the safety of medicine also is of great significance.Therefore, need to be resolved hurrily stability and the content homogeneity question of simvastatin.The present invention just will propose a kind of new preparation method to this compound slow release preparation, to solve stability problem and the content homogeneity question of simvastatin.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned weak point, research design good stability, the compound sustained release capsules preparation of the uniform nicotinic acid of content and simvastatin.
The invention provides the compound sustained release capsules preparation of a kind of nicotinic acid and simvastatin.Wherein Nicotinic Acid Content is 250 milligrams-1500 milligrams, preferred 500 milligrams-1000 milligrams; Simvastatin content is 10 milligrams-50 milligrams, preferred 20 milligrams-40 milligrams.
Preparation of the present invention is by niacin slow-release tablet and simvastatin compositions of mixtures.Wherein, niacin slow-release tablet accounts for 55.6%-99.6%, preferred 83%-99%; The simvastatin mixture accounts for 0.4%-44.4%, preferred 1%-17%.
The described niacin slow-release tablet of preparation of the present invention is comprised of nicotinic acid and pharmaceutic adjuvant, and wherein, Nicotinic Acid Content is 40%-80%, preferred 55%-75%.
The described simvastatin mixture of preparation of the present invention is comprised of simvastatin mixture and pharmaceutic adjuvant, and wherein, simvastatin content is 20%-80%, preferred 30%-70%.
Pharmaceutic adjuvant in the described niacin slow-release tablet of preparation of the present invention comprises binding agent, fluidizer, lubricant and gellant (gelling agent).Described gellant is a kind of material that can form gel in water when dissolving, and is selected from one or more in hypromellose, hyprolose, polyoxyethylene or sodium alginate.Binding agent is selected from one or more in hypromellose, polyvidone or hyprolose.Fluidizer is micropowder silica gel.Lubricant is selected from one or more in stearic acid, magnesium stearate, sodium stearyl fumarate or polyethylene glycol 6000.
Pharmaceutic adjuvant in the described simvastatin mixture of preparation of the present invention comprises filler, binding agent, cosolvent, pH adjusting agent, antioxidant and fluidizer.Described filler is selected from one or more in microcrystalline Cellulose, lactose, starch, sucrose or calcium hydrogen phosphate.Binding agent is selected from one or several in polyvidone, hypromellose or hyprolose.Cosolvent is selected from one or more in Polyethylene Glycol, polyoxyethylene hydrogenated Oleum Ricini or polysorbate.PH adjusting agent is selected from one or several in citric acid, tartaric acid or vitamin C.Antioxidant is selected from one or several in butylhydroxy anisole, propyl gallate or vitamin C.Fluidizer is micropowder silica gel.
Another object of the present invention has been to provide the preparation method of the compound sustained release capsules preparation of a kind of nicotinic acid and simvastatin.The inventive method is made mixture with simvastatin and suitable adjuvant, separately nicotinic acid and suitable adjuvant are made slow releasing tablet, use capsule filling machine first the simvastatin mixture to be poured into capsule, then niacin slow-release tablet is poured into capsule, make the niacin simvastatin sustained-release capsule.
Concrete, the inventive method comprises the following steps:
(1) preparation niacin slow-release tablet;
(2) preparation simvastatin mixture;
(3) the compound sustained release capsules preparation of preparation nicotinic acid and simvastatin.
Niacin slow-release tablet of the present invention is grouped into by the one-tenth of following weight percent proportioning:
| Title | The weight percent proportioning |
| Nicotinic acid | 40％-80％ |
| Gellant | 15％-55％ |
| Binding agent | 0％-10％ |
| Fluidizer | 0.5％-2％ |
| Lubricant | 0％-2％ |
。
The invention provides the preparation method of described niacin slow-release tablet: be selected from one of following method:
(1) use mixer that nicotinic acid is directly mixed with at least a gellant (gelling agent) and binding agent, fluidizer, lubricant, tabletting is made slow releasing tablet; Or
(2) water is granulated nicotinic acid and adjuvant binding agent, fluidizer, lubricant except gellant (gelling agent) with mixer granulator, after drying again with at least a gellant (gelling agent) mix homogeneously, tabletting is made slow releasing tablet; Or
(3) use the ethanol of 1%-100% that nicotinic acid, at least a gellant (gelling agent) and binding agent, fluidizer, lubricant are granulated with mixer granulator, dry rear tabletting is made slow releasing tablet.
Simvastatin mixture of the present invention is grouped into by the one-tenth of following weight percent proportioning:
| Title | The weight percent proportioning |
| Simvastatin | 20％-80％ |
| Filler | 20％-70％ |
| Binding agent | 0％-10％ |
| Cosolvent | 0％-30％ |
| PH adjusting agent | 0％-0.25％ |
| Antioxidant | 0％-1％ |
| Fluidizer | 0％-2％ |
The preparation method of the preparation of simvastatin mixture of the present invention: be selected from one of following method:
(1) use mixer that simvastatin and filler, binding agent, cosolvent, pH adjusting agent, antioxidant and fluidizer are directly mixed, make mixture; Or
(2) use ethanol that simvastatin and filler, binding agent, cosolvent, pH adjusting agent, antioxidant and fluidizer are granulated with mixer granulator, make mixture after drying; Or
(3) use ethanol to use the squeezing roll circule method to granulate simvastatin and filler, binding agent, cosolvent, pH adjusting agent, antioxidant and fluidizer, make mixture after drying; Or
(4) use fluid bed medicine-feeding technology, use ethanol that simvastatin and filler, binding agent, cosolvent, pH adjusting agent, antioxidant and fluidizer are granulated, make mixture after drying.
Concrete steps of the invention process are as follows:
10 parts or 20 parts of simvastatins, 0.02-0.08 part butylhydroxy anisole, 20-60 part lactose are mixed directly, make mixture; With 250 parts of nicotinic acid, 70-130 part hypromellose and 7-8 part stearic acid mix homogeneously, be pressed into slow releasing tablet; Use capsule filling machine first the simvastatin mixture to be poured in capsule, then niacin slow-release tablet is poured in capsule, make slow releasing capsule.
Nicotinic acid provided by the invention and simvastatin compound sustained release capsules preparation have the following advantages:
(1) preparation of simvastatin mixture does not need the tabletting process, and technique is simpler, is conducive to the stability of simvastatin.
(2) preparation process of simvastatin mixture is more easily controlled with respect to the organic solvent coating, and technique is simpler, does not produce the inhomogeneity problem of content; Contrast aqueous coatings, more be conducive to the stability of simvastatin.
Better stability of preparation of the present invention, quality controllable, preparation method is simple, is suitable for suitability for industrialized production, and larger using value is arranged.
The specific embodiment
Embodiment 1:
100 gram simvastatins, 0.8 gram butylhydroxy anisole, 60 gram lactose are mixed directly, make mixture; Separately with 250 gram nicotinic acid, 80 gram hypromelloses, 10 gram polyvidones and 5 gram stearic acid mix homogeneously, be pressed into 500 slow releasing tablet; Use capsule filling machine (IN-CAP) first 32.16 milligrams of simvastatin mixture to be poured in capsule, then 1 niacin slow-release tablet is poured in capsule, make 300 slow releasing capsule (every capsules contains 20 milligrams of simvastatins, 500 milligrams, nicotinic acid).
Embodiment 2:
50 gram simvastatins, 100 gram microcrystalline Cellulose and 5 gram micropowder silica gels are mixed, the 50 gram ethanol that are dissolved with 0.1 gram butylhydroxy anisole are sprayed in said mixture, dry under 35 ℃
2-4Hour, dry rear 18 mesh sieves of crossing make mixture; Separately with 250 gram nicotinic acid, 90 gram hypromelloses and 5 gram stearic acid mix homogeneously, be pressed into 500 slow releasing tablet; Use capsule filling machine (IN-CAP) first 62.04 milligrams of simvastatin mixture to be poured in capsule, then 1 niacin slow-release tablet is poured in capsule, make 500 slow releasing capsule (every capsules contains 20 milligrams of simvastatins, 500 milligrams, nicotinic acid).
Embodiment 3:
100 gram simvastatins and 200 gram microcrystalline Cellulose are mixed, the 90 gram ethanol that are dissolved with 0.2 gram butylhydroxy anisole and 0.05 gram citric acid are sprayed in said mixture, dry under 35 ℃
2-4Hour, dry rear 20 mesh sieves of crossing make mixture; Separately with 250 gram nicotinic acid, 125 gram polyoxyethylene, 13 gram microcrystalline Cellulose, 2 gram micropowder silica gels, 2.5 gram magnesium stearate mix homogeneously, be pressed into 250 slow releasing tablet; Use capsule filling machine (IN-CAP) first 120.1 milligrams of simvastatin mixture to be poured in capsule, then 1 niacin slow-release tablet is poured in capsule, make 250 slow releasing capsule (every capsules contains 40 milligrams of simvastatins, 1000 milligrams, nicotinic acid).Use USP device I, the corbeil method, under 100rpm, in 37 ℃ of water, the nicotinic acid sustained release discharges as follows at each setting-up time point: release in 3 hours release in 23%, 6 hour release in 39%, 12 hour discharged 94%, 24 hour in 70%, 20 hour and discharges 98%.Use USP device I, the corbeil method, under 100rpm, in 37 ℃ of pH7.0 buffer that added 0.5% sodium lauryl sulphate, simvastatin discharged 88% in 30 minutes.
Embodiment 4:
With 250 gram nicotinic acid, 125 gram polyoxyethylene and 13 gram microcrystalline Cellulose mix homogeneously, use 75% alcohol granulation, with 2.5 gram magnesium stearate mix homogeneously, be pressed into 500 slow releasing tablet after dry 2-4 under 40 ℃ hour; Use capsule filling machine (IN-CAP) first 120.1 milligrams, simvastatin mixture in embodiment 3 to be poured in capsule; again 1 niacin slow-release tablet is poured in capsule, makes 500 slow releasing capsule (every capsules contains 40 milligrams of simvastatins, 500 milligrams, nicotinic acid).
Embodiment 5:
With 250 gram nicotinic acid and 10 gram polyvidone mix homogeneously, water is granulated, with 80 gram hypromelloses, 5 gram stearic acid mix homogeneously, be pressed into 500 slow releasing tablet after dry 2-4 under 40 ℃ hour; Use capsule filling machine (IN-CAP) first 62.04 milligrams, simvastatin mixture in embodiment 2 to be poured in capsule; again 2 niacin slow-release tablets are poured in capsule, make 500 slow releasing capsule (every capsules contains 20 milligrams of simvastatins, 1000 milligrams, nicotinic acid).
Embodiment 6:
100 gram simvastatins, 25 gram polyvidones and 200 gram microcrystalline Cellulose are mixed, the 150 gram ethanol that are dissolved with 0.2 gram butylhydroxy anisole and 100 gram PEG400s are sprayed in said mixture, make wet stock, use the spheronizator of extruding of 0.6 millimeter screen cloth that wet stock is made piller, under 35 ℃ dry 2-4 hour, cross 14 mesh sieves after dry, make mixture; Use capsule filling machine (IN-CAP) first 85.04 milligrams of simvastatin mixture to be poured in capsule; again 1 niacin slow-release tablet in embodiment 1 is poured in capsule, makes 50 slow releasing capsule (every capsules contains 20 milligrams of simvastatins, 500 milligrams, nicotinic acid).
Embodiment 7:
100 gram simvastatins, 25 gram hydroxypropyl celluloses, 0.2 gram butylhydroxy anisole and 100 gram PEG400s are dissolved in 550 gram alcoholic solution, using fluid bed (Ge Late GPCG2) to be sprayed onto on 200 gram microcrystalline Cellulose mentioned solution granulates, cross 18 mesh sieves after dry, make mixture; Separately with 750 gram nicotinic acid, 450 gram polyoxyethylene, 45 gram polyvidones, 7.5 gram magnesium stearate mix homogeneously, be pressed into 1000 slow releasing tablet; Use capsule filling machine (IN-CAP) first 85.04 milligrams of simvastatin mixture to be poured in capsule, then 1 niacin slow-release tablet is poured in capsule, make 1000 slow releasing capsule (every capsules contains 20 milligrams of simvastatins, 750 milligrams, nicotinic acid).Use USP device I, the corbeil method, under 100rpm, in 37 ℃ of water, the nicotinic acid sustained release discharges as follows at each setting-up time point: release in 3 hours release in 18%, 6 hour release in 33%, 12 hour discharged 90%, 24 hour in 63%, 20 hour and discharges 97%.Use USP device I, the corbeil method, under 100rpm, in 37 ℃ of pH7.0 buffer that added 0.5% sodium lauryl sulphate, simvastatin discharged 83% in 30 minutes.
Claims (8)
1. the compound sustained release capsules preparation of a nicotinic acid and simvastatin, is characterized in that, described compound sustained release capsules preparation is by niacin slow-release tablet and simvastatin compositions of mixtures; Wherein Nicotinic Acid Content is 50%-80%, preferred 55%-75%; Described simvastatin mixture is comprised of simvastatin mixture and pharmaceutic adjuvant, and wherein, simvastatin content is 20%-80%, preferred 30%-70%.
2. the compound sustained release capsules preparation of a kind of nicotinic acid according to claim 1 and simvastatin, is characterized in that, described niacin slow-release tablet is comprised of nicotinic acid and pharmaceutic adjuvant, and wherein Nicotinic Acid Content is 250 milligrams-1500 milligrams, preferred 500 milligrams-1000 milligrams; Simvastatin content is 10 milligrams-50 milligrams, preferred 20 milligrams-40 milligrams.
3. the compound sustained release capsules preparation of a kind of nicotinic acid according to claim 1 and simvastatin, is characterized in that, described niacin slow-release tablet is grouped into by the one-tenth of following weight percent proportioning:
Described simvastatin mixture is grouped into by the one-tenth of following weight percent proportioning:
4. compound sustained release capsules preparation according to claim 3, is characterized in that, described gellant is selected from one or more in hypromellose, hyprolose, polyoxyethylene or sodium alginate; Binding agent is selected from one or more in hypromellose, polyvidone or hyprolose; Fluidizer is micropowder silica gel; Lubricant is selected from one or more in stearic acid, magnesium stearate, sodium stearyl fumarate or polyethylene glycol 6000;
Described filler is selected from one or more in microcrystalline Cellulose, lactose, starch, sucrose or calcium hydrogen phosphate; Binding agent is selected from one or several in polyvidone, hypromellose or hyprolose; Cosolvent is selected from one or more in Polyethylene Glycol, polyoxyethylene hydrogenated Oleum Ricini or polysorbate; PH adjusting agent is selected from one or several in citric acid, tartaric acid or vitamin C; Antioxidant is selected from one or several in butylhydroxy anisole, propyl gallate or vitamin C
5. the preparation method of the compound sustained release capsules preparation of a kind of nicotinic acid as claimed in claim 1 and simvastatin, is characterized in that, described method is made mixture with simvastatin and pharmaceutic adjuvant; Separately nicotinic acid and pharmaceutic adjuvant are made slow releasing tablet, use capsule filling machine first the simvastatin mixture to be poured into capsule, then niacin slow-release tablet is poured into capsule, make the niacin simvastatin sustained-release capsule.
6. preparation method according to claim 5, is characterized in that, described method is mixed directly 10 parts or 20 parts of simvastatins, 0.02-0.08 part butylhydroxy anisole, 20-60 part lactose, makes the simvastatin mixture; Separately with 250 parts of nicotinic acid, 70-130 part hypromellose and 7-8 part stearic acid mix homogeneously, be pressed into niacin slow-release tablet; Use capsule filling machine first the simvastatin mixture to be poured in capsule, then niacin slow-release tablet is poured in capsule, make the compound sustained release capsules of nicotinic acid and simvastatin.
7. according to claim 5 or 6 described preparation methoies, is characterized in that, the preparation method of described niacin slow-release tablet is selected from one of following method:
(1) use mixer that nicotinic acid is directly mixed with at least a gellant and binding agent, fluidizer, lubricant, tabletting is made slow releasing tablet; Or
(2) water is granulated nicotinic acid and adjuvant binding agent, fluidizer, lubricant except gellant with mixer granulator, after drying again with at least a gellant mix homogeneously, tabletting is made slow releasing tablet; Or
(3) use the ethanol of 1%-100% that nicotinic acid, at least a gellant and binding agent, fluidizer, lubricant are granulated with mixer granulator, dry rear tabletting is made slow releasing tablet.
8. according to claim 5 or 6 described preparation methoies, is characterized in that, the preparation method of the preparation of described simvastatin mixture is selected from one of following method:
(1) use mixer that simvastatin and filler, binding agent, cosolvent, pH adjusting agent, antioxidant and fluidizer are directly mixed, make mixture; Or
(2) use ethanol that simvastatin and filler, binding agent, cosolvent, pH adjusting agent, antioxidant and fluidizer are granulated with mixer granulator, make mixture after drying; Or
(3) use ethanol to use the squeezing roll circule method to granulate simvastatin and filler, binding agent, cosolvent, pH adjusting agent, antioxidant and fluidizer, make mixture after drying; Or
(4) use fluid bed medicine-feeding technology, use ethanol that simvastatin and filler, binding agent, cosolvent, pH adjusting agent, antioxidant and fluidizer are granulated, make mixture after drying.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101674811A (en) * | 2007-02-09 | 2010-03-17 | 阿尔法制药有限公司 | A dosage form containing two or more active pharmaceutical ingredients in different physical forms |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101674811A (en) * | 2007-02-09 | 2010-03-17 | 阿尔法制药有限公司 | A dosage form containing two or more active pharmaceutical ingredients in different physical forms |
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Application publication date: 20130626 |