CN101627976A - Felodipine sustained-release preparation and preparation method thereof - Google Patents
Felodipine sustained-release preparation and preparation method thereof Download PDFInfo
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- CN101627976A CN101627976A CN200810116750A CN200810116750A CN101627976A CN 101627976 A CN101627976 A CN 101627976A CN 200810116750 A CN200810116750 A CN 200810116750A CN 200810116750 A CN200810116750 A CN 200810116750A CN 101627976 A CN101627976 A CN 101627976A
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Abstract
The invention discloses a felodipine-containing sustained-release preparation, which comprises a tablet core and a thin film, wherein the inside of the tablet core contains an effective curative dose of felodipine and a physiologically acceptable pharmaceutic adjuvant. The sustained-release preparation is characterized by consisting of the felodipine, a sustained-release material, a bulking agent, an adhesive, a coloring agent, a lubricant, a wetting agent and a film-forming material. The sustained-release preparation prepared can control drug release effectively to achieve ideal treatment effect, enable human bodies to obtain stable treated blood concentration and optimize the curative effect dose.
Description
Technical field
The present invention relates to a kind of is the slow releasing preparation and preparation method thereof of active substance with the felodipine.Control drug release makes human body obtain to treat blood drug level stably to reach ideal treatment effectively, makes the dosage optimization.The invention belongs to field of medicaments.
Background technology
Felodipine is a dihydropyridine calcium channel blocker, with nitrendipine and (or) other calcium channel blocker reversibilitys competition dihydropyridine binding sites, the voltage-dependent Ca of the Cor Leporis room cell of vascular smooth muscle capable of blocking and artificial culture
2+Electric current, and blocking-up K
+Inductive Mus portal vein contracture.
In vitro study shows, felodipine pushes away in to the cardiac muscle effect the vascular smooth muscle selective inhibitory; Detect negative inotropic action external, but in whole animal, do not observe this effect.Felodipine can make peripheral vascular resistance descend and the hyperamization pressure drop is low, and this pharmacological action is relevant with dosage, and follows the increase of reflexive heart rate.The hypotensive effect of felodipine is dose dependent, is proportionate with blood drug level.When first all medications, can have the reflexive heart rate to increase, but this effect reduce in time.The long term administration heart rate may increase by 5～10 times/minute, and beta-blocker can resist this effect.Felodipine single with or do not influence Electrocardiographic P-R interval when share with beta-blocker.Clinical research and electrophysiologic study show, felodipine single with or share with beta-blocker cardiac conduction (P-R, P-Q and H-V interval) had no significant effect.The antihypertensive therapy of felodipine is relevant with the obvious recovery of unborn left ventricular hypertrophy.In clinical trial, do not find clear and definite negative inotropic action to the hyperpietic that do not have left ventricular insufficiency.Find that in to hyperpietic's clinical trial felodipine can increase the plasma norepinephrine level.
Felodipine can reduce renal tubules to the heavily absorption of filterable sodium and produce sharp sodium and diuresis.This has just eliminated the common water-sodium retention effect of other vasodilation.Felodipine does not influence the drainage of daily potassium.Felodipine reduces renal vascular resistance.Normal glomerular filtration rate is constant.The patient of renal function injury, its glomerular filtration rate can increase.Felodipine does not influence the discharge of urinary albumin.
To accepting the patient of cyclosporin treatment after the renal transplantation, felodipine can bring high blood pressure down, and improves kidney blood flow and glomerular filtration rate.Felodipine also can be improved the function of early stage graft.Visible slight diuresis, natriuresis and kaliuresis effect when first all medications, short-term and long-term treatment do not influence electrolyte.
Felodipine is brought into play antianginal and ischemia resisting effect by improving myocardial oxygen.Felodipine reduces the arteria coronaria vascular resistance by expanding epicardial tremulous pulse and small artery, increases coronary blood flow and myocardial oxygen.Felodipine can effectively be alleviated coronary spasm.The decline of periphery blood pressure makes the slump in demand of afterload and myocardium oxygen of left ventricle due to the felodipine.To the stable type effort angina, felodipine can be improved the motion tolerance, reduces anginal outbreak.Felodipine can reduce the generation that symptom and silent myocardial ischemia are arranged of vasospasm patient with angina pectoris.Felodipine can be used separately or share with beta-blocker, the treatment stable angina pectoris.
No matter patient's age and race, felodipine all is effectively and better tolerance, even to congestive heart failure, asthma and other obstructive pulmonary disease, renal function injury, diabetes, gout, hyperlipemia, Reynolds disease or the patient that accepts renal transplantation good toleration being arranged also.
Felodipine sustained-release tablets has following advantage:
1, do not cause postural hypotension.Felodipine sustained-release tablets reduces arteriotony by reducing peripheral vascular resistance, and owing to the high selectivity to the small artery smooth muscle, felodipine sustained-release tablets does not have direct effect to myocardial contraction and cardiac conduction in the therapeutic dose scope; Again because of vein smooth muscle and adrenergic antiotasis are regulated the nothing influence, so do not cause postural hypotension;
2, felodipine sustained-release tablets has slight natriuretic diuretic effect, so do not cause fluid retention;
3, felodipine sustained-release tablets is all effective to each phase hypertension;
4, felodipine sustained-release tablets can use separately, also can share with other antihypertensive drug;
5, the patient is good to the toleration of felodipine sustained-release tablets, even suffer from angina pectoris and congestive heart failure, also can use this product;
6, felodipine sustained-release tablets can be kept effective blood drug concentration in 24 hours after medication.
Summary of the invention
The invention discloses a kind of slow releasing preparation that contains felodipine and preparation method thereof, control drug release makes human body obtain to treat blood drug level stably to reach ideal treatment effectively, makes the dosage optimization.
Felodipine sustained-release preparation of the present invention, it includes label and thin film, label contains the felodipine and the physiologically acceptable pharmaceutic adjuvant of effective therapeutic dose, wherein said slow releasing preparation demonstrates the character in following simultaneously: (1) release in vitro curve, wherein within an hour, the burst size of felodipine is below 20% according to the test of standard release for slow releasing preparation; (2) for absorption curve in the felodipine body of normal adults single dose, the blood drug level of felodipine through the time process and calculating tried and the main pharmacokinetic parameter of reference preparation Chinese medicine as follows: Cmax is respectively 2.41 ± 0.87ng/mL and 2.81 ± 1.68ng/mL, Tmax is respectively 3.9 ± 1.3h and 3.3 ± 0.9h, t
1/2(Kel) be respectively 19.53 ± 8.16h and 18.53 ± 7.31h, MRT is respectively 25.20 ± 6.15h and 24.66 ± 4.36h.
Wherein said slow releasing preparation, it is characterized in that forming by felodipine, slow-release material, filler, binding agent, coloring agent, lubricant, wetting agent, filmogen, count by weight percentage: felodipine 1～20%, slow-release material 0～60%, filler 0～55%, binding agent 0～20%, coloring agent 0～5%, lubricant 0.1～5%, wetting agent 0～45%, filmogen 0.5～10%.
Wherein said slow releasing preparation comprises about 0.5mg to about 40mg felodipine, and preferably about 1mg is to the felodipine of about 20mg.The felodipine consumption accounts for 1～20% of recipe quantity.
Wherein said slow releasing preparation is characterized in that described slow-release material can select one or more in hydroxypropyl methylcellulose, Sulisi aqueous dispersion, ethyl cellulose, methylcellulose, Hydroxypropyl Methylcellulose Phathalate, cellulose acetate-phthalate, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl-cellulose, cellulose acetate, cellulose diacetate, Triafol T, hexadecanol, glyceryl monostearate, Brazil wax, the hydroxy methocel for use.
Wherein said slow releasing preparation is characterized in that described filler can select polyvinyl alcohol for use, poly-phthalic acid vinyl acetate, polystyrene, carbopol, polrvinyl chloride, octadecanol, diethyl phthalate, dioctyl phthalate, Polyethylene Glycol, sodium alginate, chitosan, gelatin, Lac, pectin, guar gum, sucrose, lactose, starch, dextrin, Icing Sugar, low-substituted hydroxypropyl cellulose, cross linked polyvinyl pyrrolidone, cross-linking sodium carboxymethyl cellulose, mannitol, microcrystalline Cellulose, pregelatinized Starch, in the titanium dioxide one or more.
Wherein said slow releasing preparation is characterized in that in the optional water of described binding agent, ethanol, dehydrated alcohol, starch slurry, polyvidone, crospolyvinylpyrrolidone, hydroxypropyl methylcellulose and/or other cellulose families one or more.
Wherein said slow releasing preparation, it is characterized in that described coloring agent can select ferrum oxide, amaranth, carmine, erythrosine, newly red, the lemon yellow of red, the red pigment of cowberry of red, beet red, lac, capsanthin, red rice, sunset yellow, indigo Huang, light blue for use, and for the various pigments that strengthen the acid pigment of above-mentioned water solublity dispersibility in oils and fats one or more.
Wherein said slow releasing preparation is characterized in that described lubricant can select magnesium stearate, micropowder silica gel, Pulvis Talci, hydrogenated vegetable oil, polyethylene glycols for use, month hang in the pure magnesium sulfate one or more.
Wherein said slow releasing preparation is characterized in that in the optional water of described wetting agent, ethanol, dehydrated alcohol, starch slurry, chloroform, acetone, polyvidone, crospolyvinylpyrrolidone, hydroxypropyl methylcellulose and/or other cellulose families one or more.
Wherein said slow releasing preparation is characterized in that described filmogen can select one or more in ethyl cellulose, starch, Aquacoat, methylcellulose, cellulose acetate, acrylic resin, Opadry, the Sulisi for use.
Wherein said slow releasing preparation, it is characterized in that the release in vitro curve, according to drug release determination method (two appendix XD first methods of Chinese Pharmacopoeia version in 2005), apparatus is pressed dissolution method second subtraction unit, with 0.4% cetyl trimethyl ammonium bromide phosphate buffer (pH6.5) 500ml is solvent, rotating speed is that per minute 200 changes, under the condition that temperature is 37 ℃, or carry out release under the suitable substantially condition and test, carry out release at the placement slow releasing preparation and test in back 1 hour, the burst size of felodipine is below 20%.
Wherein said slow releasing preparation, in 0.5 hour of described test, the burst size of felodipine is below 8%.
Wherein said slow releasing preparation, burst size is 40%～70% when 4 hours of described test, is preferably 50%～60%.
Wherein said slow releasing preparation, burst size is being more than 80 when 7 hours of described test, preferably more than 90%.
Wherein said slow releasing preparation, absorption curve in the felodipine body behind normal adults single dose oral administration, the blood drug level of felodipine through the time process and calculating tried and the main pharmacokinetic parameter of reference preparation Chinese medicine as follows: Cmax is respectively 2.41 ± 0.87ng/mL and 2.81 ± 1.68ng/mL, Tmax is respectively 3.9 ± 1.3h and 3.3 ± 0.9h, t
1/2(Kel) be respectively 19.53 ± 8.16h and 18.53 ± 7.31h, MRT is respectively 25.20 ± 6.15h and 24.66 ± 4.36h.
Wherein said slow releasing preparation only needed oral medicine once on 1st, had obviously reduced the administration number of times of felodipine, had improved patient's compliance.Clinical trial simultaneously proves, with felodipine sustained-release tablets (Plendil) bioequivalence that has gone on the market at present.
Wherein said slow releasing preparation, the felodipine maximum plasma concentration (Cmax) that it demonstrates behind single dose administration 10mg is 3.28ng/mL.
Wherein said slow releasing preparation, the time that felodipine reaches maximum plasma concentration (Cmax) after administration is at least about 6 hours, preferably at least about 4 hours.
Wherein said slow releasing preparation, its pharmacokinetic curve meets steady plasma-drug concentration, and its stability bandwidth is not more than the stability bandwidth of felodipine sustained-release tablets (Plendil) the contrast medicine of equal daily dose basically.
Wherein said slow releasing preparation, it comprises the release improved procedure that felodipine absorption curve in described external felodipine release profiles and/or the described body can effectively be provided.
Wherein said slow releasing preparation, the amount of felodipine is enough to provide daily dose according to mode to several dosage units of single administration in each dosage unit.
Be used for active component and acceptable accessories composition that the present invention prepares felodipine sustained-release preparation:
| Felodipine | ??1～20％ |
| Slow-release material | ??0～60％ |
| Filler | ??0～55％ |
| Binding agent | ??0～20％ |
| Coloring agent | ??0～5％ |
| Lubricant | ??0.1～5％ |
| Wetting agent | ??0～45％ |
| Filmogen | ??0.5～10％ |
The preparation method of felodipine sustained-release preparation of the present invention comprises following steps:
1 plain sheet preparation technology
1.1 preparation contains the principal agent binding agent
Get the stirring of recipe quantity felodipine guiding humid medium and make dissolving, add the binding agent stirring again and make dissolving, lucifuge is placed standby.
1.2 granulate
Filler and framework material stirring are made mix homogeneously, add the binding agent that contains principal agent behind the mixing and granulate, with an amount of wetting agent eluant container wall; and in the adding granulator; continue to stir and to make into granule, take out granule with the 12 mesh sieves granulate that wets, granule is in aeration-drying below 50 ℃.Dried particles is carried out moisture content detect, detect qualified (granule moisture content is less than 3%) back with 12 mesh sieve granulate, standby.
1.3 tabletting
With the granule that makes and the lubricant of recipe quantity, behind the mix homogeneously, detection level determines that sheet is heavy, and with the stamping of 9mm scrobicula, Hardness Control is in 3～7KG scope.
2 art for coating
2.1 the preparation of coating solution
The recipe quantity filmogen is added in the water, and it is an amount of to add water, stirred 45 minutes, whole dissolvings are disperseed, standby.
2.2 coating
The plain sheet that makes is put in the high-efficiency coating pot, and inlet temperature is heated to about 50 ℃～80 ℃, at the uniform velocity sprays into the coating solution coating, and the sheet bed tempertaure remains on 35～45 ℃, and it is about 3% that coating increases weight, promptly.
In order to investigate release in vitro effect of the present invention,
According to drug release determination method (two appendix XD first methods of Chinese Pharmacopoeia version in 2005), apparatus is pressed dissolution method second subtraction unit, has measured the release in vitro degree of the felodipine sustained-release tablets of the embodiment of the invention 3 preparations.
(get 1mol/L sodium dihydrogen phosphate 206ml with 0.4% cetyl trimethyl ammonium bromide phosphate buffer (pH6.5), 0.5mol/L disodium phosphate soln 196ml, cetyl trimethyl ammonium bromide 20.0g, adding water to 5000ml) 500ml is solvent, rotating speed is that per minute 200 changes, operation in accordance with the law, got solution 5ml respectively filtered at 1,4 and 7 hour, and in process container, replenish same solution 5ml immediately, and get subsequent filtrate, measure according to the method under the assay item.Other precision takes by weighing through 105 ℃ of felodipine reference substances that are dried to constant weight an amount of, adds the mobile phase dissolving and quantitatively is diluted to the solution that every 1ml contains 10 μ g, measures with method.
Calculate every burst size respectively at different time.Every burst size in the time of 0.5 hour, 1 hour, 4 hours, 7 hours, 9 hours of this product.
According to the felodipine sustained-release tablets of embodiment 3 preparations and the result of felodipine sustained-release tablets (Plendil) release profiles comparative study in different pH value release medium, see accompanying drawing 1～4.
Result of the test shows that the felodipine sustained-release tablets and the behavior of felodipine sustained-release tablets (Plendil) release in vitro that prepare according to embodiment 3 have concordance.
In order further to verify, carried out the bioequivalence test according to the felodipine sustained-release tablets curative effect of embodiment 3 preparations.20 men's health experimenters divide two groups to carry out the single dose test, measure the felodipine sustained-release tablets Plendil of producing with respect to AstraZeneca pharmaceutical Co. Ltd according to the felodipine sustained-release tablets of embodiment 3 preparations) bioavailability.Behind single oral dose felodipine sustained-release test film and the reference sheet (be felodipine 5mg/ sheet * 2), the blood drug level of measuring felodipine through the time process and calculating tried and the main pharmacokinetic parameter of reference preparation Chinese medicine as follows: Cmax is respectively 2.41 ± 0.87ng/mL and 2.81 ± 1.68ng/mL, Tmax is respectively 3.9 ± 1.3h and 3.3 ± 0.9h, t
1/2(Kel) be respectively 19.53 ± 8.16h and 18.53 ± 7.31h, MRT is respectively 25.20 ± 6.15h and 24.66 ± 4.36h; AUC
0-60Be respectively 31.27 ± 9.54ngh/mL and 29.48 ± 6.90ngh/mL, AUC
0-∞Be respectively 34.52 ± 9.28ngh/mL and 32.55 ± 7.48ngh/mL.20 experimenter's single oral dose reference preparation felodipine sustained-release tablets 10mg (5mg/ sheet * 2 slice) and be subjected to the average blood plasma drug-time curve of test preparation felodipine sustained-release tablets 10mg (5mg/ sheet * 2 slice) back felodipine to see accompanying drawing 5.
The result shows, according to the felodipine sustained-release tablets and the felodipine sustained-release tablets Plendil of embodiment 3 preparations), press AUC
0-60Calculate, during the single dose test in the test preparation relative bioavailability of felodipine be 106.5 ± 14.9%.The sharp Cmax of AUC is through to the check of number conversion rear difference analysis, and Tmax is through the Wilcoxon signed rank test, the difference that shows that there are no significant.AUC and Cmax to number conversion after two one-side t-check shows test preparation and reference preparation bioequivalence.
Description of drawings:
Accompanying drawing 1 is that release compares in the 0.4% CTAB phosphate buffer (PH6.5)
Accompanying drawing 2 is that release compares in the 0.4% CTAB aqueous solution
Accompanying drawing 3 is that release compares in the 0.4% cetyl trimethyl ammonium bromide 9-1000 hydrochloric acid solution
Accompanying drawing 4 is that 0.4% CTAB PH4.0 citric acid sodium hydrogen phosphate buffer soln release compares
Accompanying drawing 5 is 20 experimenter's single oral dose reference preparation felodipine sustained-release tablets 10mg (5mg/ sheet * 2 slice) and the average blood plasma drug-time curve that is subjected to test preparation felodipine sustained-release tablets 10mg (5mg/ sheet * 2 slice) back felodipine
The specific embodiment
Prescription:
Plain tablet recipe:
Felodipine 5g
Copolyvidone 20g
Microcrystalline Cellulose 41
Sucrose 82g
Hypromellose 50g
Magnesium stearate 2g
Ethanol is an amount of
Coating fluid prescription:
Opadry 30g
Water is an amount of
Make 1000
Preparation process:
1 plain sheet preparation technology
1.1 preparation contains the principal agent binding agent
Get felodipine 5g and add ethanol 60g and stir and to make dissolving, add the 20g copolyvidone again and stir and make dissolving, lucifuge is placed standby.
1.2 granulate
Sucrose is pulverized; cross 80 mesh sieves; together pack in the wet mixing pelletizer with microcrystalline Cellulose, hypromellose again; stirring makes mix homogeneously, adds the binding agent that contains principal agent behind the mixing and granulates, with an amount of alcohol flushing chamber wall; and in the adding granulator; continue to stir and to make into granule, take out granule with the 12 mesh sieves granulate that wets, granule is in aeration-drying below 50 ℃.Dried particles is carried out moisture content detect, detect qualified (granule moisture content is less than 3%) back with 12 mesh sieve granulate, standby.
1.3 tabletting
With the granule that makes and the magnesium stearate of recipe quantity, behind the mix homogeneously, detection level determines that sheet is heavy, and with the stamping of 9mm scrobicula, Hardness Control is in 5～10KG scope.
2 art for coating
2.1 the preparation of coating solution
The recipe quantity Opadry is added in the water, and it is an amount of to add water, stirred 45 minutes, whole dissolvings are disperseed, be mixed with Opadry concentration and be 15% homogeneous aqueous dispersion, standby.
2.2 coating
The plain sheet that makes is put in the high-efficiency coating pot, and inlet temperature is heated to about 60 ℃～90 ℃, at the uniform velocity sprays into the coating solution coating, and the sheet bed tempertaure remains on 30～45 ℃, and it is about 4% that coating increases weight, promptly.
Prescription:
Plain tablet recipe:
Felodipine 5g
Polyvidone 20g
Microcrystalline Cellulose 40g
Sucrose 40g
Hypromellose 40g
Starch 40g
Magnesium stearate 2g
Ethanol is an amount of
Coating fluid prescription:
Opadry 20g
Water is an amount of
Make 1000
Preparation process:
1 plain sheet preparation technology
1.1 preparation contains the principal agent binding agent
Get felodipine 5g and add ethanol 70g and stir and to make dissolving, add the 20g polyvidone again and stir and make dissolving, lucifuge is placed standby.
1.2 granulate
Sucrose is pulverized; cross 80 mesh sieves; together pack in the wet mixing pelletizer with microcrystalline Cellulose, hypromellose, starch again; stirring makes mix homogeneously, adds the binding agent that contains principal agent behind the mixing and granulates, with an amount of alcohol flushing chamber wall; and in the adding granulator; continue to stir and to make into granule, take out granule with the 12 mesh sieves granulate that wets, granule is in aeration-drying below 60 ℃.Dried particles is carried out moisture content detect, detect qualified (granule moisture content is less than 3%) back with 12 mesh sieve granulate, standby.
1.3 tabletting
With the granule that makes and the magnesium stearate of recipe quantity, behind the mix homogeneously, detection level determines that sheet is heavy, and with the stamping of 9mm scrobicula, Hardness Control is in 6～14KG scope.
2 art for coating
2.1 the preparation of coating solution
The recipe quantity Opadry is added in the water, and it is an amount of to add water, stirred 60 minutes, whole dissolvings are disperseed, be mixed with Opadry concentration and be 20% homogeneous aqueous dispersion, standby.
2.2 coating
The plain sheet that makes is put in the high-efficiency coating pot, and inlet temperature is heated to about 60 ℃～80 ℃, at the uniform velocity sprays into the coating solution coating, and the sheet bed tempertaure remains on 30～45 ℃, and it is about 4% that coating increases weight, promptly.
Prescription:
Plain tablet recipe:
Felodipine 5g
Copolyvidone 20g
Starch 40g
Sucrose 52g
Hypromellose 75g
Micropowder silica gel 5g
Stearic acid 2g
Ethanol is an amount of
Coating fluid prescription:
Opadry 20g
Water is an amount of
Make 1000
Preparation process:
1 plain sheet preparation technology
1.1 preparation contains the principal agent binding agent
Get felodipine 5g and add ethanol 53g and stir and to make dissolving, add the 20g copolyvidone again and stir and make dissolving, lucifuge is placed standby.
1.2 granulate
Sucrose is pulverized, and it is standby to cross 80 mesh sieves.Get the cane sugar powder and the micropowder silica gel of recipe quantity and cross 40 mesh sieve premixs; together pack in the wet mixing pelletizer with starch, hypromellose again; stirring makes mix homogeneously; adding the binding agent that contains principal agent behind the mixing granulates; with an amount of alcohol flushing chamber wall, and add in the granulator, continue stirring and make into granule; take out granule with the 12 mesh sieves granulate that wets, granule is in aeration-drying below 50 ℃.Dried particles is carried out moisture content detect, detect qualified (granule moisture content is less than 3%) back with 12 mesh sieve granulate, standby.
1.3 tabletting
With the granule that makes and the stearic acid of recipe quantity, behind the mix homogeneously, detection level determines that sheet is heavy, and with the stamping of 9mm scrobicula, Hardness Control is in 3～7KG scope.
2 art for coating
2.1 the preparation of coating solution
The recipe quantity Opadry is added in the water, and it is an amount of to add water, stirred 45 minutes, whole dissolvings are disperseed, be mixed with Opadry concentration and be 18% homogeneous aqueous dispersion, standby.
2.2 coating
The plain sheet that makes is put in the high-efficiency coating pot, and inlet temperature is heated to about 50 ℃～80 ℃, at the uniform velocity sprays into the coating solution coating, and the sheet bed tempertaure remains on 35～45 ℃, and it is about 3% that coating increases weight, promptly.
Prescription:
Plain tablet recipe:
Felodipine 5g
Polyvidone 20g
Sucrose 110g
Hypromellose 65g
Hydroxypropyl emthylcellulose 5g
Polyethylene glycol 6000 0.5g
Magnesium stearate 2g
Ferrum oxide 0.5g
Ethanol is an amount of
Make 1000
Preparation technology:
Get the recipe quantity felodipine and pulverize ultrasonic dissolution in the adding 90ml ethanol, add recipe quantity polyvinylpyrrolidone (K30), standby after the stirring and dissolving.Will recipe quantity sucrose pulverize back and hydroxypropyl emthylcellulose (K4M) and drop into the wet-mixed comminutor and do and mix 2min, add felodipine polyvinylpyrrolidone (K30) solution and make granule, 9mm stamping behind the magnesium stearate mixing is sneaked in 60 ℃ of oven dry behind the granulate.Get hydroxypropyl emthylcellulose (5 centipoise) 5g, polyethylene glycol 6000 0.5g is dissolved in 100ml 70% ethanol, and it is standby to sneak into ferrum oxide 0.5g.Begin to spray into coating solution when the pot temperature reaches 40 ℃, cooperate hot blast drying, packing promptly behind the coating.
Claims (13)
1, a kind of slow releasing preparation that contains felodipine, it includes label and thin film, label contains the felodipine and the physiologically acceptable pharmaceutic adjuvant of effective therapeutic dose, wherein said slow releasing preparation demonstrates the character in following simultaneously: (1) release in vitro curve, within an hour, the burst size of felodipine is below 20% according to the test of standard release; (2) for absorption curve in the felodipine body of normal adults single dose, the blood drug level of felodipine through the time process and calculating tried and the main pharmacokinetic parameter of reference preparation Chinese medicine as follows: Cmax is respectively 2.41 ± 0.87ng/mL and 2.81 ± 1.68ng/mL, Tmax is respectively 3.9 ± 1.3h and 3.3 ± 0.9h, t
1/2(Kel) be respectively 19.53 ± 8.16h and 18.53 ± 7.31h, MRT is respectively 25.20 ± 6.15h and 24.66 ± 4.36h.
2, claim 1 described slow releasing preparation, it is characterized in that forming by felodipine, slow-release material, filler, binding agent, coloring agent, lubricant, wetting agent, filmogen, count by weight percentage: felodipine 1～20%, slow-release material 0～60%, filler 0～55%, binding agent 0～20%, coloring agent 0～5%, lubricant 0.1～5%, wetting agent 0～45%, filmogen 0.5～10%.
3, each described slow releasing preparation in the above-mentioned claim comprises about 0.5mg to about 40mg felodipine, and preferably about 1mg is to the felodipine of about 20mg.
4, each described slow releasing preparation in the above-mentioned claim is characterized in that:
Described slow-release material can be selected one or more in hydroxypropyl methylcellulose, Sulisi aqueous dispersion, ethyl cellulose, methylcellulose, Hydroxypropyl Methylcellulose Phathalate, cellulose acetate-phthalate, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl-cellulose, cellulose acetate, cellulose diacetate, Triafol T, hexadecanol, glyceryl monostearate, Brazil wax, the hydroxy methocel for use.
Described filler can be selected polyvinyl alcohol for use, poly-phthalic acid vinyl acetate, polystyrene, carbopol, polrvinyl chloride, octadecanol, diethyl phthalate, dioctyl phthalate, Polyethylene Glycol, sodium alginate, chitosan, gelatin, Lac, pectin, guar gum, sucrose, lactose, starch, dextrin, Icing Sugar, low-substituted hydroxypropyl cellulose, cross linked polyvinyl pyrrolidone, cross-linking sodium carboxymethyl cellulose, mannitol, microcrystalline Cellulose, pregelatinized Starch, in the titanium dioxide one or more.
In the optional water of described binding agent, ethanol, dehydrated alcohol, starch slurry, polyvidone, crospolyvinylpyrrolidone, hydroxypropyl methylcellulose and/or other cellulose families one or more.
Described coloring agent can be selected ferrum oxide, amaranth, carmine, erythrosine, newly red, the lemon yellow of red, the red pigment of cowberry of red, beet red, lac, capsanthin, red rice, sunset yellow, indigo Huang, light blue for use, and for the various pigments that strengthen the acid pigment of above-mentioned water solublity dispersibility in oils and fats one or more.
Described lubricant can select magnesium stearate, micropowder silica gel, Pulvis Talci, hydrogenated vegetable oil, polyethylene glycols for use, month hang in the pure magnesium sulfate one or more makes.
In the optional water of wetting agent, ethanol, dehydrated alcohol, starch slurry, chloroform, acetone, polyvidone, crospolyvinylpyrrolidone, hydroxypropyl methylcellulose and/or other cellulose families one or more.
Described filmogen can be selected one or more in ethyl cellulose, starch, Aquacoat, methylcellulose, cellulose acetate, acrylic resin, Opadry, the Sulisi for use.
5, the preparation method of each described slow releasing preparation in the above-mentioned claim comprises following steps:
(1) plain sheet preparation technology
(1.1) preparation contains the principal agent binding agent and gets recipe quantity felodipine guiding humid medium and stir and to make dissolving, adds binding agent again and stirs and make dissolving, and lucifuge is placed standby.
(1.2) granulation makes mix homogeneously with filler and framework material stirring, adds the binding agent that contains principal agent behind the mixing and granulates, with an amount of wetting agent eluant container wall; and in the adding granulator; continue to stir and to make into granule, take out granule with the 12 mesh sieves granulate that wets, granule is in aeration-drying below 50 ℃.Dried particles is carried out moisture content detect, detect qualified (granule moisture content is less than 3%) back with 12 mesh sieve granulate, standby.
(1.3) tabletting is with the granule that makes and the lubricant of recipe quantity, and behind the mix homogeneously, detection level determines that sheet is heavy, and with the stamping of 9mm scrobicula, Hardness Control is in 3～7KG scope.
(2) art for coating
(2.1) preparation of coating solution adds to the recipe quantity filmogen in the water, and it is an amount of to add water, stirs 45 minutes, and whole dissolvings are disperseed, and is standby.
(2.2) the coating plain sheet that will make is put in the high-efficiency coating pot, and inlet temperature is heated to about 50 ℃～80 ℃, at the uniform velocity sprays into the coating solution coating, and the sheet bed tempertaure remains on 35～45 ℃, and it is about 3% that coating increases weight, promptly.
6, each described slow releasing preparation in the above-mentioned claim, it is characterized in that the release in vitro curve, according to drug release determination method (two appendix X of Chinese Pharmacopoeia version in 2005 D, first method), apparatus is pressed dissolution method second subtraction unit, with 0.4% cetyl trimethyl ammonium bromide phosphate buffer (pH6.5) 500ml is solvent, rotating speed is that per minute 200 changes, under the condition that temperature is 37 ℃, or carry out release under the suitable substantially condition and test, carry out release in the placement compositions and test in back 0.5 hour, the burst size of felodipine is below 8%;
Carry out release in the placement compositions and test in back 1 hour, the burst size of felodipine is below 20%.
Place compositions carry out release when testing back 4 hours burst size be 40%～70%, be preferably 50%～60%.
Place compositions carry out release when testing back 7 hours burst size be more than 80, preferably to know more than 90%.
7, each described slow releasing preparation in the above-mentioned claim, absorption curve in the felodipine body behind normal adults single dose oral administration, the blood drug level of felodipine through the time process and calculating tried and the main pharmacokinetic parameter of reference preparation Chinese medicine as follows: Cmax is respectively 2.41 ± 0.87ng/mL and 2.81 ± 1.68ng/mL, Tmax is respectively 3.9 ± 1.3h and 3.3 ± 0.9h, t
1/2(Kel) be respectively 19.53 ± 8.16h and 18.53 ± 7.31h, MRT is respectively 25.20 ± 6.15h and 24.66 ± 4.36h.
8, each described slow releasing preparation in the above-mentioned claim only needed oral medicine once on 1st, had obviously reduced the administration number of times of felodipine, had improved patient's compliance.Clinical trial simultaneously proves, with felodipine sustained-release tablets (Plendil) bioequivalence that has gone on the market at present.
9, each described slow releasing preparation in the above-mentioned claim, the felodipine maximum plasma concentration (Cmax) that it demonstrates behind single dose administration 10mg is 3.28ng/mL.
10, each described slow releasing preparation in the above-mentioned claim, the time that felodipine reaches maximum plasma concentration (Cmax) after administration is at least about 6 hours, preferably at least about 4 hours.
11, each described slow releasing preparation in the above-mentioned claim, its pharmacokinetic curve meets steady plasma-drug concentration, and its stability bandwidth is not more than the stability bandwidth of felodipine sustained-release tablets (Plendil) the contrast medicine of equal daily dose basically.
12, each described slow releasing preparation in the above-mentioned claim, it comprises the release improved procedure that felodipine absorption curve in described external felodipine release profiles and/or the described body can effectively be provided.
13, each described slow releasing preparation in the above-mentioned claim, the amount of felodipine is enough to provide daily dose according to mode to several dosage units of single administration in each dosage unit.
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| CN200810116750A CN101627976A (en) | 2008-07-17 | 2008-07-17 | Felodipine sustained-release preparation and preparation method thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102188401A (en) * | 2011-05-10 | 2011-09-21 | 山东威高药业有限公司 | Felodipine sustained-release tablet and preparation method thereof |
| CN102920677A (en) * | 2011-08-12 | 2013-02-13 | 重庆药友制药有限责任公司 | Felodipine sustained release preparation and its preparation method |
| CN104758938A (en) * | 2015-04-01 | 2015-07-08 | 贾红瑞 | Felodipine tablet for treating high blood pressure and preparation method of Felodipine tablet |
| CN105476973A (en) * | 2015-12-15 | 2016-04-13 | 西南药业股份有限公司 | Felodipine sustained release tablet and preparation method thereof |
| CN107982236A (en) * | 2018-01-05 | 2018-05-04 | 西南医科大学 | A kind of felodipine sustained-release tablets |
-
2008
- 2008-07-17 CN CN200810116750A patent/CN101627976A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102188401A (en) * | 2011-05-10 | 2011-09-21 | 山东威高药业有限公司 | Felodipine sustained-release tablet and preparation method thereof |
| CN102188401B (en) * | 2011-05-10 | 2013-07-03 | 山东威高药业有限公司 | Felodipine sustained-release tablet and preparation method thereof |
| CN102920677A (en) * | 2011-08-12 | 2013-02-13 | 重庆药友制药有限责任公司 | Felodipine sustained release preparation and its preparation method |
| CN102920677B (en) * | 2011-08-12 | 2016-06-08 | 重庆药友制药有限责任公司 | A kind of felodipine sustained-release preparation and preparation method thereof |
| CN104758938A (en) * | 2015-04-01 | 2015-07-08 | 贾红瑞 | Felodipine tablet for treating high blood pressure and preparation method of Felodipine tablet |
| CN104758938B (en) * | 2015-04-01 | 2017-08-29 | 新乡医学院第一附属医院 | It is a kind of to treat felodipine tablet of hypertension and preparation method thereof |
| CN105476973A (en) * | 2015-12-15 | 2016-04-13 | 西南药业股份有限公司 | Felodipine sustained release tablet and preparation method thereof |
| CN105476973B (en) * | 2015-12-15 | 2018-10-16 | 西南药业股份有限公司 | A kind of felodipine sustained-release tablets and preparation method thereof |
| CN107982236A (en) * | 2018-01-05 | 2018-05-04 | 西南医科大学 | A kind of felodipine sustained-release tablets |
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