CN102600451B - Felodipine ramipril compound sustained-release preparation and preparation method thereof - Google Patents
Felodipine ramipril compound sustained-release preparation and preparation method thereof Download PDFInfo
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- CN102600451B CN102600451B CN201210020969.6A CN201210020969A CN102600451B CN 102600451 B CN102600451 B CN 102600451B CN 201210020969 A CN201210020969 A CN 201210020969A CN 102600451 B CN102600451 B CN 102600451B
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a compound sustained-release preparation containing felodipine and ramipril and a preparation method of the compound sustained-release preparation, wherein the compound sustained-release preparation is prepared by mixing felodipine sustained-release pellets and ramipril immediate-release pellets according to a specific dose proportion. The felodipine sustained-release pellets can sustainably release for 12 hours, and can be taken once a day, so as to keep the antihypertensive effect for a long time, the ramipril immediate-release pellets can be quickly absorbed so as to achieve the antihypertensive effect and treat the plasma concentration, due to the combination of the two kinds of pellets, the antihypertensive effect can be greatly enhanced, the toxic and side effect of the medicine can be reduced, the administration frequency can be reduced, sustainably stable antihypertensive effect can be achieved in a human body, the patient compliance can be enhanced, the compound sustained-release preparation consists of hundreds and thousands of pellets in uniform particle sizes, so that the damage of individual pellets will not cause burst release of the whole preparation, and compared with the sustained release tablets, the compound sustained-release preparation disclosed by the invention has the advantages of higher safety, lower irritation to gastrointestinal tract, more stable plasma concentration and capability of effectively improving the clinical effect.
Description
Technical field
The present invention relates to a kind of technical field of compound slow release preparation, relate in particular to felodipine ramipril compound slow release preparation and preparation method thereof.It belongs to a kind of compound slow release preparation of antihypertensive medicine.
Background technology
Hypertension is one of modal cardiovascular disease, is also to cause the sickness rate of congestive heart failure, apoplexy, coronary heart disease, renal failure, aortic aneurysm and the Major Risk Factors that case fatality rate raises.In recent years, along with Chinese people's living standard improves constantly, the growth of aging population, hypertension is just becoming the life that the high commonly encountered diseases of a kind of prevalence is come into us.At present the whole world there is no effective means and can effect a radical cure hypertension, once this sick suffering from will be followed lifelong and cause a lot of other relevant diseases.The press Communique of delivering recently according to International Society of Hypertension, the higher crowd of global hypertension or blood pressure has 9.72 hundred million people, accounts for world adult population's 26.4%.Along with coming out one after another and extensive use of the antihypertensive drug of new generation such as angiotensin ii receptor antagonist (ARB) of calcium antagonist (CCB), angiotensin converting enzyme inhibitor (ACEI), non-peptide class, the mortality rate of all kinds of cardiovascular disease has had decline by a relatively large margin.But the whole world still has 1,700 ten thousand people to die from the cardiovascular and cerebrovascular disease causing because of hypertension every year, wherein patient over half dies from acute myocardial infarction or cerebral vessels embolism disease, and therefore, people extraordinarily pay close attention to antihypertensive drug market.
Felodipine (Felodipine) is selectivity cerebrocrast, mainly suppresses the interior stream of the outer calcium of small artery smooth muscle cell, and selectivity expansion small artery, acts on without this vein, does not cause postural hypotension, to cardiac muscle also without obvious inhibitory action.This product, when reducing renal vascular resistance, does not affect glomerular filtration rate and creatinine clearance rate, and renal blood flow is unchanged even to be had increased slightly, and has short natruresis and diuresis.This product can increase output and cardiac index, significantly reduces afterload, and cardiac systolic function, preload and heart rate are had no significant effect.Can be used alone clinically or merge and use for hypertensive treatment with other antihypertensive drug.
Ramipril (Ramipril) is a prodrug, after gastrointestinal absorption, in liver hydrolysis, generates activated, potent and long-acting angiotensin converting enzyme (ACE) inhibitor of ramiprilat-tool.Take ramipril and can cause the rising of plasma renin activity and the decline of Angiotensin II and aldosterone plasma concentration.Because the minimizing of Angiotensin II, ACE inhibitor can cause peripheral blood vessel expansion and vascular resistance to decline, thereby produces useful hemodynamic Effects.Evidence show, organize ACE, especially vascular system-rather than circulation in ACE, be the principal element that determines hemodynamic Effects.With kininase, II is the same, the angiotensin converting enzyme Kallidin I of also degrading.Evidence show, the ACE that ramiprilat causes suppresses, and to kallikrein-kassinin kinin-prostaglandin system, can produce some effect.Someone infers that this mechanism has participated in blood pressure lowering and the metabolism of ramipril.Hyperpietic takes clinostatism and orthostatic blood pressure after ramipril and all declines.In 1～2 hour after taking medicine, just produce obvious pressure reduction effect; 3-6 hour after peak effect appears at and takes medicine; The pressure reduction effect that has shown therapeutic dose at least can maintain 24 hours.Clinically for the treatment of essential hypertension and congestive heart failure.
The dissolubility of felodipine in water approximately 0.58 μ g/ml, is low dissolving high osmosis (ClassII class) medicine, and oral absorption is complete and experience extensive first pass metabolism, and bioavailability is about 20%.After peak reaching time of blood concentration appears at and takes medicine 2.5～5 hours, plasma protein binding rate was greater than 99%, and medium effective concentration is 4～6nmol/L, and a small amount of light diet does not affect the characteristics of pharmacokinetics of this product.Clearance rate in hepatic insufficiency patient body is normal young experimenter's 60%.Conventional therapeutic dose is 2.5mg～10mg/ day clinically.
The about 10mg/ml of the dissolubility of ramipril in water, for height dissolves high osmosis (Class1 class) medicine, can, by promptly from gastrointestinal absorption, can reach peak serum concentration after oral administration within an hour.The peak plasma concentrations of its active metabolite ramiprilat appears in 2～4 hours after medication, the peak serum concentration of ramiprilat declines in heterogeneous mode, as 1 administration ramipril 5～10mg every day, after a few days, be 13～17 hours the effective half-life of ramiprilat.Almost can be by fully metabolism, its metabolite is mainly from renal excretion, and about 60% drains from urine, and 40% from defecate.Conventional therapeutic dose is 1.5mg～10mg/ day clinically.
Oral solid pharmaceutical formulation (the patent No.: IL115059 of a kind of ramipril and dihydropyridine compounds combination, Astrazeneca AB), what describe is the drug regimen of a kind of ACE inhibitor ramipril of rapid release and the calcium antagonist dihydropyridine compounds of slow release (as felodipine, nitrendipine, nifedipine and lacidipine), this drug regimen can be made into sustained-release double-layer tablet, capsule or other oral solid formulations, the effectively treatment hypertension of taking medicine once a day.Breakage and the defect of slow releasing tablet part when producing can cause the prominent of whole preparation to release generation, so safety is poor.
The felodipine ramipril slow releasing tablet of being produced by Sanofi-Aventis company (trade name: Triapin), in the approval listing of 1998 Nian European Union, be used for the treatment of hypertension.The current domestic single preparations of ephedrine that only has felodipine sustained-release tablets, felodipine sustained-release capsule and ramipril tablet having gone on the market, temporarily do not have felodipine ramipril compound slow release preparation production listing and registration to declare, the felodipine ramipril compound slow release preparation develop once a day, 12 hours discharging has good clinical practice advantage.
Summary of the invention
The object of the invention is to overcome the shortcoming and defect of prior art, provide a kind of and have that effect is lasting, medicining times is few, blood drug level is steady, safety is higher, the better felodipine ramipril of stability compound slow release preparation.Based on this, the present invention also provides a kind of preparation method of felodipine ramipril compound slow release preparation.
The diameter that micropill is comprised of medicine and adjuvant is about the miniature spherical entity of 1mm, according to different therapeutic doses and requirement, micropill is that the medicine of dose is dispersed in 1,100 miniature spherical compartments, error or the defect of indivedual micropills in preparation is unlikely to the drug release behavior of whole preparation to affect greatly, and greatly reduced the generation of burst drug release.There is larger contact surface on after micropill is oral and gastrointestinal tract surface, and absorption is good and little to local zest, and meanwhile, micropill is different from tablet, and the former is not affected by gastric emptying factor substantially, therefore the infiltration rate of medicine is even, individual bioavailability difference is also little.Micropill has the advantages such as particle diameter is even, good fluidity, difficult crushing, particularly fine pellet core surface coatings, to make location, sustained-release preparation, technique simple, can avoid other solid preparations as inhomogeneous in coatings such as tablets, may cause that medicine sky is released, the risk of pulse.The compound slow release preparation being formed by the micropill of different pharmaceutical, can increase medicine stability, improve curative effect, reduce the advantages such as poisonous side effect of medicine.
The concrete technical solution of the present invention is: felodipine ramipril compound slow release preparation is comprised of felodipine sustained-release micropill and ramipril fast release micropill.
Described felodipine sustained-release micropill is by forming containing pill core and slow release coatings two parts, and ramipril fast release micropill is by forming containing pill core and stomach dissolution type film coating layer two parts.
Composition and the percentage by weight of described felodipine sustained-release micropill are as follows:
Containing pill core, comprise: felodipine 1～10%, excipient or celphere 75～95.5%, binding agent 3～10%, solubilizing agent 0.5～5%.The percentage by weight of each component is all with the total weight containing pill core above.
Sustained release coating layer comprises: slow-release material 3～25%, antiplastering aid 15～80%, plasticizer 10～30%, porogen 3～30% and opacifier 0.5～5%.In each component, the percentage by weight of slow-release material is with the total weight containing pill core above, and the percentage by weight of antiplastering aid, plasticizer, porogen and opacifier is with the total weight of slow-release material.
Composition and the percentage by weight of described ramipril fast release micropill are as follows:
Containing pill core, comprise: ramipril 1～10%, excipient or celphere 80～96%, binding agent 3～10%.The percentage by weight of each component is all with the total weight containing pill core above.
Stomach dissolution type film coating layer comprises: coating material 3～15%, plasticizer 5～25% and opacifier 0.5～5%.In each component, the percentage by weight of coating material is with the total weight containing pill core above, and the percentage by weight of plasticizer and opacifier is with the total weight of coating material.
Preferably, described excipient is one or more the mixture in lactose, microcrystalline Cellulose, mannitol, starch, dextrin, sucrose.
Preferably, described celphere is microcrystalline Cellulose ball core or starch ball core.
Preferably, described binding agent is one or more the mixture in polyvinylpyrrolidone, hydroxypropyl emthylcellulose, carboxymethyl cellulose.
Preferably, described solubilizing agent is one or more the mixture in sodium lauryl sulphate, tween, Polyethylene Glycol.
Described slow-release material is methacrylic resin polymer or ethyl cellulose.Preferably, methacrylic resin polymer is one or more the mixture in Eudragit NE30D, Eudragit RS30D, Eudragit RL30D, Eudragit RS, Eudragit RL, and ethyl cellulose is Surelease or Aquacoat.
Described coating material is cellulose ethers or polyethylene kind.Preferably, cellulose ethers is one or more the mixture in hydroxypropyl emthylcellulose, hydroxypropyl cellulose, ethyl cellulose, and polyethylene kind is polyvinylpyrrolidone.
Preferably, described antiplastering aid is one or more the mixture in Pulvis Talci, magnesium stearate, silicon dioxide, titanium dioxide.
Preferably, described plasticizer is one or more the mixture in diethyl phthalate, dibutyl phthalate, triethyl citrate, tributyl citrate, dibutyl sebacate, glycerol.
Preferably, described porogen is one or more the mixture in lactose, polyvinylpyrrolidone, polyethylene glycols, hydroxypropyl emthylcellulose.
Preferably, described opacifier is one or more the mixture in titanium dioxide, color lake, ferrum oxide.
Preferably, describedly containing pill core, adopt and extrude spheronization or medicine-feeding legal system is standby.
After dose ratio is mixed in accordance with regulations by above-mentioned non-promise Horizon slow-release micro-pill and ramipril fast release micropill, adopt pharmaceutically customary way directly to pack in hard capsule, also can add other pharmaceutic adjuvants and be pressed into tablet.
In above-mentioned optimization formula, the vitro release of two kinds of medicament pellet preparations and dissolution are about:
The release of non-promise Horizon slow-release micro-pill: 2 hours 10～30%, 6 hours 40～70%, > 75% in 10 hours.
The dissolution of ramipril fast release micropill: > 80% in 30 minutes.
The preparation method of non-promise Horizon ramipril compound slow release preparation, comprises the steps:
(1) by the gentle excipient mix homogeneously in non-promise ground, add purified water (or ethanol) solution of binding agent and solubilizing agent to make soft material, or non-promise Horizon, binding agent and solubilizing agent are dissolved in purified water (or ethanol) and are made containing drug solns, then adopt and extrude spheronization or the centrifugal ball method or fluid bed pill method or celphere medicine-feeding method made made 20～40 objects containing pill core, standby.Preparation slow release layer coating solution is also sprayed onto containing on pill core, makes non-promise Horizon slow-release micro-pill;
(2) by ramipril and excipient mix homogeneously, add purified water (or ethanol) solution of binding agent to make soft material, or ramipril and binding agent are dissolved in purified water (or ethanol) and are made containing drug solns, then adopt and extrude spheronization or the centrifugal ball method or fluid bed pill method or celphere medicine-feeding method made made 20～40 objects containing pill core, standby.Formulate thin rete coating solution is also sprayed onto containing on pill core, makes ramipril fast release micropill;
(3) the non-promise Horizon slow-release micro-pill and the ramipril fast release micropill that above-mentioned (1) step and (2) step are made, dose ratio mix homogeneously, makes non-promise Horizon ramipril compound slow release preparation in accordance with regulations.
The compound slow release preparation that the present invention makes by non-promise Horizon slow-release micro-pill and ramipril fast release micropill in accordance with regulations dose ratio be mixed.Non-promise Horizon slow-release micro-pill can lasting release in 12 hours, take every day once, keep lasting hypotensive effect, and ramipril fast release micropill can absorb fast and reaches hypotensive effect, both use in conjunction are strengthened antihypertensive effect greatly, can reduce the toxic and side effects of medicine, reduce medicining times, reach in vivo continual and steady antihypertensive effect, improved patient's compliance, compound slow release preparation is comprised of 1,100 uniform micropills of particle diameter simultaneously, the breakage of indivedual micropills can not cause the prominent of whole preparation to be released, more safer than slow releasing tablet, less to gastrointestinal zest, blood drug level is more steady, effectively improved clinical efficacy.
Accompanying drawing explanation
Fig. 1～Fig. 8: the non-promise Horizon slow-release micro-pill making for the embodiment of the present invention one～embodiment tetra-is the releasing curve diagram of 2,4,6,8,10,12 hours and the ramipril fast release micropill stripping curve figure of 5,10,15,20,30,45 minutes in multiple release medium in vitro in multiple release medium in vitro.
The specific embodiment
In order to make those skilled in the art understand better technical scheme of the present invention, below in conjunction with specific embodiment, the present invention is described in further detail.
Embodiment mono-:
1, the preparation of non-promise Horizon slow-release micro-pill:
Prescription: non-promise Horizon 15g, microcrystalline Cellulose 180g, lactose 150g, sodium lauryl sulphate 6g, Aquacoat (Sulisi) 140.4g, titanium dioxide 2g.
Preparation technology: non-promise Horizon is mixed homogeneously with the method that microcrystalline Cellulose and lactose adopt equivalent to increase progressively, and mixed powder is standby.Sodium lauryl sulphate is dissolved in 35% alcoholic solution, adds in above-mentioned mixed powder and make soft material, adopt and extrude round as a ball legal system pastille ball core, dry, sieve and choose 20～30 orders containing pill core, coating is used.It is 15% sustained release coating solution that the Sulisi of recipe quantity and titanium dioxide are mixed with to solid content by purified water, dissolves, stirs 45min, and it is fully disperseed.By 300g be placed in fluid bed containing pill core, adjusting process parameter, guarantees fluidized state, and sustained release coating liquid is sprayed on containing pill wicking surface, makes coating weightening finish to 10%, stops hydrojet, takes out micropill and puts in 50 ℃ of baking ovens ripening 12 hours.Make non-promise Horizon slow-release micro-pill.
2, the preparation of ramipril fast release micropill:
Prescription: ramipril 15g, microcrystalline Cellulose 180g, lactose 150g, Opadry 17.25g.
Preparation technology: ramipril is mixed homogeneously with the method that microcrystalline Cellulose and lactose adopt equivalent to increase progressively, by purified water, make soft material, adopt and extrude round as a ball legal system pastille ball core, dry, sieve and choose 20～30 orders containing pill core, coating is used.It is 15% film coating solution that the Opadry of recipe quantity is mixed with to solid content by purified water, dissolves, stirs 45min, and it is fully disperseed.The pill core that contains of 300g is placed in to fluid bed, and adjusting process parameter, guarantees fluidized state, and film coating liquid is sprayed on containing pill wicking surface, makes coating weightening finish to 5%, stops hydrojet, continues fluidized drying 15 minutes.Make ramipril fast release micropill.
3, dose ratio in accordance with regulations, takes non-promise Horizon slow-release micro-pill and ramipril fast release micropill mix homogeneously, fill in blank capsules, i.e. get Fei Nuo Horizon ramipril slow releasing capsule.
4, vitro release (dissolution) is measured:
Non-promise Horizon slow-release micro-pill: adopt respectively pH1.2 hydrochloric acid solution, pH4.5 phosphate buffer, pH6.8 phosphate buffer, pH7.2 phosphate buffer and water as release medium, with turning basket method, with 100 revs/min, respectively sampling in 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, by UV method, at 238nm wavelength place, measure trap, calculate cumulative release degree.Result is as follows:
Ramipril fast release micropill: adopt respectively pH1.2 hydrochloric acid solution, pH4.5 phosphate buffer, pH6.8 phosphate buffer, pH7.2 phosphate buffer and water as dissolution medium, with turning basket method, with 100 revs/min, respectively sampling in 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, by HPLC method, at 238nm wavelength place, measure trap, calculate cumulative release degree.Result is as follows:
Embodiment bis-:
1, the preparation of non-promise Horizon slow-release micro-pill:
Prescription: non-promise Horizon 15g, microcrystalline Cellulose 180g, lactose 150g, sodium lauryl sulphate 6g, Aquacoat (Aquacoat) 182.5g, dibutyl phthalate 4.5g, titanium dioxide 2g.
Preparation technology: non-promise Horizon is mixed homogeneously with the method that microcrystalline Cellulose and lactose adopt equivalent to increase progressively, and mixed powder is standby.Sodium lauryl sulphate is dissolved in 35% alcoholic solution, adds in above-mentioned mixed powder and make soft material, adopt and extrude round as a ball legal system pastille ball core, dry, sieve and choose 20～30 orders containing pill core, coating is used.It is 15% sustained release coating solution that the Aquacoat of recipe quantity, dibutyl phthalate and titanium dioxide are mixed with to solid content by purified water, dissolves, stirs 45min, and it is fully disperseed.By 300g be placed in fluid bed containing pill core, adjusting process parameter, guarantees fluidized state, and sustained release coating liquid is sprayed on containing pill wicking surface, makes coating weightening finish to 13%, stops hydrojet, takes out micropill and puts in 50 ℃ of baking ovens ripening 12 hours.Make non-promise Horizon slow-release micro-pill.
2, the preparation of ramipril fast release micropill:
Prescription: ramipril 15g, microcrystalline Cellulose 180g, lactose 150g, Opadry 17.25g.
Preparation technology: ramipril is mixed homogeneously with the method that microcrystalline Cellulose and lactose adopt equivalent to increase progressively, by purified water, make soft material, adopt and extrude round as a ball legal system pastille ball core, dry, sieve and choose 20～30 orders containing pill core, coating is used.It is 15% film coating solution that the Opadry of recipe quantity is mixed with to solid content by purified water, dissolves, stirs 45min, and it is fully disperseed.The pill core that contains of 300g is placed in to fluid bed, and adjusting process parameter, guarantees fluidized state, and film coating liquid is sprayed on containing pill wicking surface, makes coating weightening finish to 5%, stops hydrojet, continues fluidized drying 15 minutes.Make ramipril fast release micropill.
3, dose ratio in accordance with regulations, takes non-promise Horizon slow-release micro-pill and ramipril fast release micropill mix homogeneously, fill in blank capsules, i.e. get Fei Nuo Horizon ramipril slow releasing capsule.
4, vitro release (dissolution) is measured:
Non-promise Horizon slow-release micro-pill: adopt respectively pH1.2 hydrochloric acid solution, pH4.5 phosphate buffer, pH6.8 phosphate buffer, pH7.2 phosphate buffer and water as release medium, with turning basket method, with 100 revs/min, respectively sampling in 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, by UV method, at 238nm wavelength place, measure trap, calculate cumulative release degree.Result is as follows:
Ramipril fast release micropill: adopt respectively pH1.2 hydrochloric acid solution, pH4.5 phosphate buffer, pH6.8 phosphate buffer, pH7.2 phosphate buffer and water as dissolution medium, with turning basket method, with 100 revs/min, respectively sampling in 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, by HPLC method, at 238nm wavelength place, measure trap, calculate cumulative release degree.Result is as follows:
Embodiment tri-:
1, the preparation of non-promise Horizon slow-release micro-pill:
Prescription: non-promise Horizon 15g, microcrystalline Cellulose celphere 300g, PVP-K30 10g, tween 5g, Eudragit NE30D 65.2g, Pulvis Talci 15.6g, titanium dioxide 2g.
Preparation technology: non-promise Horizon, PVP-K30 and tween are dissolved in 50% alcoholic solution, stir and use CL, make containing drug solns.Microcrystalline Cellulose celphere is placed in fluid bed, by above-mentioned, containing drug solns, is sprayed on celphere surface, adopts medicine-feeding legal system must contain pill core, dry, sieves and chooses 20～30 orders containing pill core, and coating is used.Eudragit NE30D, Pulvis Talci and the titanium dioxide of recipe quantity are added to purified water dissolved dilution, and to be mixed with solid content be 20% sustained release coating solution, stirs 45min, and it is fully disperseed.By 300g be placed in fluid bed containing pill core, adjusting process parameter, guarantees fluidized state, and sustained release coating liquid is sprayed on containing pill wicking surface, makes coating weightening finish to 6%, stops hydrojet, takes out micropill and puts in 40 ℃ of baking ovens ripening 24 hours.Make non-promise Horizon slow-release micro-pill.
2, the preparation of ramipril fast release micropill:
Prescription: ramipril 15g, microcrystalline Cellulose celphere 300g, PVP-K30 10g, Opadry 17.25g.
Preparation technology: ramipril and PVP-K30 are dissolved in purified water, stir and use CL, make containing drug solns.Microcrystalline Cellulose celphere is placed in fluid bed, by above-mentioned, containing drug solns, is sprayed on celphere surface, adopts medicine-feeding legal system must contain pill core, dry, sieves and chooses 20～30 orders containing pill core, and coating is used.It is 15% film coating solution that the Opadry of recipe quantity is mixed with to solid content by purified water, dissolves, stirs 45min, and it is fully disperseed.The pill core that contains of 300g is placed in to fluid bed, and adjusting process parameter, guarantees fluidized state, and film coating liquid is sprayed on containing pill wicking surface, makes coating weightening finish to 5%, stops hydrojet, continues fluidized drying 15 minutes.Make ramipril fast release micropill.
3, dose ratio in accordance with regulations, takes non-promise Horizon slow-release micro-pill and ramipril fast release micropill mix homogeneously, fill in blank capsules, i.e. get Fei Nuo Horizon ramipril slow releasing capsule.
4, vitro release (dissolution) is measured:
Non-promise Horizon slow-release micro-pill: adopt respectively pH1.2 hydrochloric acid solution, pH4.5 phosphate buffer, pH6.8 phosphate buffer, pH7.2 phosphate buffer and water as release medium, with turning basket method, with 100 revs/min, respectively sampling in 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, by UV method, at 238nm wavelength place, measure trap, calculate cumulative release degree.Result is as follows:
Ramipril fast release micropill: adopt respectively pH1.2 hydrochloric acid solution, pH4.5 phosphate buffer, pH6.8 phosphate buffer, pH7.2 phosphate buffer and water as dissolution medium, with turning basket method, with 100 revs/min, respectively sampling in 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, by HPLC method, at 238nm wavelength place, measure trap, calculate cumulative release degree.Result is as follows:
Embodiment tetra-:
1, the preparation of non-promise Horizon slow-release micro-pill:
Prescription: non-promise Horizon 15g, microcrystalline Cellulose celphere 300g, PVP-K30 10g, tween 5g, Eudragit RS30D 23.3g, Eudragit RL30D 70g, Pulvis Talci 16.8g, titanium dioxide 2g.
Preparation technology: non-promise Horizon, PVP-K30 and tween are dissolved in 50% alcoholic solution, stir and use CL, make containing drug solns.Microcrystalline Cellulose celphere is placed in fluid bed, by above-mentioned, containing drug solns, is sprayed on celphere surface, adopts medicine-feeding legal system must contain pill core, dry, sieves and chooses 20～30 orders containing pill core, and coating is used.The Eudragit RS30D of recipe quantity, Eudragit RL30D, Pulvis Talci and titanium dioxide are added to purified water dissolved dilution, and to be mixed with solid content be 20% sustained release coating solution, stirs 45min, and it is fully disperseed.By 300g be placed in fluid bed containing pill core, adjusting process parameter, guarantees fluidized state, and sustained release coating liquid is sprayed on containing pill wicking surface, makes coating weightening finish to 8%, stops hydrojet, takes out micropill and puts in 40 ℃ of baking ovens ripening 24 hours.Make non-promise Horizon slow-release micro-pill.
2, the preparation of ramipril fast release micropill:
Prescription: ramipril 15g, microcrystalline Cellulose celphere 300g, PVP-K30 10g, Opadry 17.25g.
Preparation technology: ramipril and PVP-K30 are dissolved in purified water, stir and use CL, make containing drug solns.Microcrystalline Cellulose celphere is placed in fluid bed, by above-mentioned, containing drug solns, is sprayed on celphere surface, adopts medicine-feeding legal system must contain pill core, dry, sieves and chooses 20～30 orders containing pill core, and coating is used.It is 15% film coating solution that the Opadry of recipe quantity is mixed with to solid content by purified water, dissolves, stirs 45min, and it is fully disperseed.The pill core that contains of 300g is placed in to fluid bed, and adjusting process parameter, guarantees fluidized state, and film coating liquid is sprayed on containing pill wicking surface, makes coating weightening finish to 5%, stops hydrojet, continues fluidized drying 15 minutes.Make ramipril fast release micropill.
3, dose ratio in accordance with regulations, takes non-promise Horizon slow-release micro-pill and ramipril fast release micropill mix homogeneously, fill in blank capsules, i.e. get Fei Nuo Horizon ramipril slow releasing capsule.
4, vitro release (dissolution) is measured:
Non-promise Horizon slow-release micro-pill: adopt respectively pH1.2 hydrochloric acid solution, pH4.5 phosphate buffer, pH6.8 phosphate buffer, pH7.2 phosphate buffer and water as release medium, with turning basket method, with 100 revs/min, respectively sampling in 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, by UV method, at 238nm wavelength place, measure trap, calculate cumulative release degree.Result is as follows:
Ramipril fast release micropill: adopt respectively pH1.2 hydrochloric acid solution, pH4.5 phosphate buffer, pH6.8 phosphate buffer, pH7.2 phosphate buffer and water as dissolution medium, with turning basket method, with 100 revs/min, respectively sampling in 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, by HPLC method, at 238nm wavelength place, measure trap, calculate cumulative release degree.Result is as follows:
Compliance test result
Extracorporeal releasing test:
Get embodiment mono-, two, three, four slow-release micro-pill that make and fast release micropill are as sample, according to the detection method of UV, adopt pH1.2 hydrochloric acid solution, pH4.5 phosphate buffer, pH6.8 phosphate buffer, pH7.2 phosphate buffer and water are as dissolution medium, respectively at 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, vitro release and dissolution determination are carried out in sampling in 12 hours, by detecting data, can find out, 4 batch samples of slow-release micro-pill discharge in 12 hours evenly in multiple release medium, all approach first-order release, show to have in vitro slow release characteristic.Fast release micropill 4 batch samples in multiple dissolution medium in 15 minutes dissolution all reach more than 90%, there is good dissolution.According to test result, this product can further be carried out the research of release in body.
Above the present invention is described in detail, applies specific case principle of the present invention and embodiment are set forth in literary composition, the explanation of above embodiment is just for helping to understand method of the present invention and core concept thereof.It should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improvement and modification also fall in the protection domain of the claims in the present invention.
Claims (4)
1. a felodipine ramipril compound slow release preparation, is characterized in that, it is comprised of felodipine sustained-release micropill and ramipril fast release micropill, wherein:
Felodipine sustained-release micropill is by forming containing pill core and slow release layer, by weight, containing pill core, contain felodipine 1～10%, excipient 75～95.5%, binding agent 3～10%, solubilizing agent 0.5～5%, in slow release layer the consumption of slow-release material account for containing pill core weight ratio be 3%～25%, the consumption of antiplastering aid accounts for that slow-release material weight ratio is 15～80%, the consumption of plasticizer accounts for that slow-release material weight ratio is 10～30%, the consumption of porogen accounts for that slow-release material weight ratio is 3～30%, to account for slow-release material weight ratio be 0.5～5% to the consumption of opacifier.
Ramipril fast release micropill is by forming containing pill core and stomach dissolution type thin layer, by weight, containing pill core, contain felodipine 1～10%, excipient 80～96%, binding agent 3～10%, in stomach dissolution type thin layer the consumption of thin-film material account for containing pill core weight ratio be 3%～15%, the consumption of plasticizer accounts for that thin-film material weight ratio is 5～25%, to account for thin-film material weight ratio be 0.5～5% to the consumption of opacifier.
Described excipient is mixture or the microcrystalline Cellulose ball core of lactose and microcrystalline Cellulose.
Described binding agent is polyvinylpyrrolidone or hydroxypropyl emthylcellulose.
Described solubilizing agent is sodium lauryl sulphate or tween.
Described slow-release material is one or more in EudragitNE30D, EudragitRS30D, EudragitRL30D and ethyl cellulose.
Described thin-film material is Opadry or hydroxypropyl emthylcellulose.
Described antiplastering aid is Pulvis Talci or silicon dioxide.
Described plasticizer is dibutyl phthalate or triethyl citrate.
Described porogen is polyvinylpyrrolidone or hydroxypropyl emthylcellulose.
Described opacifier is titanium dioxide.
2. felodipine ramipril compound slow release preparation according to claim 1, is characterized in that, after dose ratio is mixed in accordance with regulations by non-promise Horizon slow-release micro-pill and ramipril fast release micropill, adopts pharmaceutically customary way directly to pack in hard capsule.
3. felodipine ramipril compound slow release preparation according to claim 1, is characterized in that, in optimization formula, the vitro release of two kinds of medicament pellet preparations and dissolution are about:
The release of non-promise Horizon slow-release micro-pill: 2 hours 10～30%, 6 hours 40～70%, 10 hours >75%.
The dissolution of ramipril fast release micropill: 30 minutes >80%.
4. the preparation method of felodipine ramipril compound slow release preparation according to claim 1, comprises the steps:
(1), by the gentle excipient mix homogeneously in non-promise ground, spheronization is extruded in employing or fluid bed ball core medicine-feeding method is made 20～40 objects containing pill core.Preparation sustained release coating liquid is also sprayed onto containing on pill core, makes non-promise Horizon slow-release micro-pill;
(2), by ramipril and excipient mix homogeneously, spheronization is extruded in employing or fluid bed ball core medicine-feeding method is made 20～40 objects containing pill core.Preparation thin film coating solution is also sprayed onto containing on pill core, makes ramipril fast release micropill;
(3) the non-promise Horizon slow-release micro-pill and the ramipril fast release micropill that above-mentioned (1) step and (2) step are made, dose ratio mix homogeneously, makes non-promise Horizon ramipril compound slow release preparation in accordance with regulations.
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| CN201210020969.6A CN102600451B (en) | 2012-01-17 | 2012-01-17 | Felodipine ramipril compound sustained-release preparation and preparation method thereof |
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| CN103142618B (en) * | 2013-02-22 | 2017-12-12 | 广州科的信医药技术有限公司 | A kind of Metroprolol succinate hydrochlorothiazide sustained-release pellet capsule and preparation method thereof |
| CN104758266B (en) * | 2015-04-02 | 2017-07-25 | 常州市第四制药厂有限公司 | A kind of felodipine sustained-release tablets and its preparation technology |
| CN107149598A (en) * | 2017-03-27 | 2017-09-12 | 广西厚德大健康产业股份有限公司 | A kind of preparation method of felodipine sustained-release compaction of pellet |
| CN107213138B (en) * | 2017-08-07 | 2020-12-18 | 北京罗诺强施医药技术研发中心有限公司 | Method and pharmaceutical composition for treating hypertension by timed release of drugs |
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| CN101239036A (en) * | 1994-09-02 | 2008-08-13 | 阿斯特拉公司 | Novel pharmaceutical composition containing the ACE inhibitor ramipril and a dihydropyridine compound |
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| CN101239036A (en) * | 1994-09-02 | 2008-08-13 | 阿斯特拉公司 | Novel pharmaceutical composition containing the ACE inhibitor ramipril and a dihydropyridine compound |
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