CN102316856A - Pharmaceutical preparation - Google Patents

Pharmaceutical preparation Download PDF

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Publication number
CN102316856A
CN102316856A CN2010800080129A CN201080008012A CN102316856A CN 102316856 A CN102316856 A CN 102316856A CN 2010800080129 A CN2010800080129 A CN 2010800080129A CN 201080008012 A CN201080008012 A CN 201080008012A CN 102316856 A CN102316856 A CN 102316856A
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pharmaceutical preparation
cellulose
mixture
copolymer
compartment
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金圣旭
田圣树
具滋星
金镇昱
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Hanall Biopharma Co Ltd
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Hanall Biopharma Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

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  • Life Sciences & Earth Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Engineering & Computer Science (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

The present invention relates to a pharmaceutical preparation comprising an immediate-release compartment containing a renin inhibitor as a pharmacologically active ingredient, and an extended-release compartment containing a dihydropyridine calcium channel blocker as a pharmacologically active ingredient. The pharmaceutical preparation of the present invention can avoid in vivo pharmacokinetic interaction between the renin inhibitor and the dihydropyridine calcium channel blocker, induces optimum pharmacological effects in accordance with the in vivo absorption performance of each of the active ingredients, and enables drugs to be released at the time period in which each of the active ingredients exhibits the pharmacological effects thereof, to thereby increase clinical effects, and can thus be valuably used in the prevention or treatment of metabolic syndrome, cardiovascular disease, and kidney disease.

Description

Pharmaceutical preparation
Technical field
The present invention relates to comprise the compartment of release formerly that contains as the renin inhibitor of pharmacological component; And contain pharmaceutical preparation as the slow release compartment of the dihydropyridine calcium channel blockers of pharmacological component; Relate in particular to as sending to system for the medicine that designs with specific speed sustained release medicine; Show ideal effect when absorbing in the body; Through two kinds of medicine compositionizations are improved patient's the compliance of taking medicine, thus the pharmaceutical preparation of the effect that under external factor, also can maximize.
Background technology
Hypertension is the highest disease of sickness rate in the chronic blood circulation diseases, and its sickness rate is in the trend of increase recently.And hypertension is compared in the following patient of serious symptom does not have external symptom, but may cause fatal complication such as apoplexy, mental and physical efforts are tended to end because of decline, coronary artery disease, therefore needs more positive case control and treatment.
Hypertension can be divided into agnogenic state property hypertension (disposable hypertension) and the tangible secondary hypertension of reason disease (secondary property hypertension).This state property hypertension is occupied more than 85%～90% of hyperpietic, and heredity is principal element, but detailed reason is also indeterminate.By contrast, the pathogenic factor of secondary hypertension is very various, comprise reasons such as kidney disease, kidney vascular, endocrinopathy, hormone abnormal secretion, and these reasons repeatedly causes same patient's hypertension.In view of the above, for the hypertension that is caused by a variety of causes is carried out successfully blood pressure lowering, the demand of the compound prescription of antagonism pressing is inevitable.
In order to treat the high blood pressure disease that shows with aforesaid a variety of causes and various form; From pharmaceutically also having developed various medicines, these medicines are classified as (Am J Hypertens 2005 such as renin inhibitor, calcium channel blocker, HMG-CoA reductase inhibitor, angiotensin-II-receptor blocking agent, diuretic according to the similarity or the treatment mechanism of its chemical constitution; 18; 265A-265A).
To suppressing the renin inhibitor of feritin in the starting stage and going into the calcium channel blocker of blood vessel dilating to be elaborated as follows to intracellular calcium current through inhibition.
[renin inhibitor]
Migrate in the blood at the synthetic feritin of kidney; Through the cracking proangiotensin; Release receives the angiotensin-I of the catalytic action of angiotensin converting enzyme (ACG), and angiotensin-I forms angiotensin-II in lung, kidney and other organ cracking afterwards.This angiotensin-II is along with arterial vascular contraction directly causes increased blood pressure, combine simultaneously as sodium ion keep that hormonal aldosterone can cause that increased blood pressure, left ventricular hypertrophy, blood vessel hypertrophy, atherosclerosis, renal failure are had a rest, apoplexy etc.
For the hyperpietic; Suppressing as stated, the enzymatic activity of feritin can cause the minimizing that angiotensin I forms; Its result produces the Angiotensin II of less amount and reduces the hormonal concentration of peptide class, and this mechanism may become the immediate cause that brings high blood pressure down.
Renin inhibitor based on above-mentioned biomechanism research and development; Can be used for treating diastolic dysfunction and diastole property mental and physical efforts are tended to end because of decline through controlling blood pressure and blood volume; Can delay left ventricular hypertrophy disease and the generation of the cardiac fibers hypertrophy disease that causes thus or reverse its progress through the generation that suppresses Angiotensin II, therefore be widely used as the hypertension therapeutic medicine.
And; Confirm; Renin inhibitor through individually dosed and with administering drug combinations such as diuretic such as hydrochlorothiazide, calcium channel blocker, angiotensin-convertion enzyme inhibitor and angiotensin-ii receptor blockers, have hypotensive activity more reliably and adjection [J Hypertens 2007; Jan 25 (1): 217-26, J manag Gare Pharm 2007; Oct 13 (8 Suppl B): 21-33, Cardiol Rev 2007; Nov-Dec 15 (6): 316-23, Am J Hypertens 2006; Feb 24 (2): 243-56].
In addition, as the chemistry of a kind of aliskiren of renin inhibitor 2 (S) by name, 4 (S); 5 (S); 7 (S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-2, the new amide of 7-two (1-Methylethyl)-4-hydroxyl-5-amino-8-[4-methoxyl group-3-(3-methoxyl group-propoxyl group) phenyl]; Specifically be documented among open communique EP 678503 A in Europe by the aliskiren of chemistry definition, preferably its hemifumarate.
[calcium channel blocker]
If intracellular calcium increases, the protein that then is called calmodulin combines with calcium ion and forms calcium-calmodulin complex.The interaction of hyperfunction actin of this complex and myosin and cause vasoconstriction causes hypertension and angina pectoris.So; The calcium channel of the cell membrane through blocking-up hypertension and angina pectoris pathogenic factor suppresses calcium current and goes into the effect in myocardial cell and the VSMC; Thereby blood vessel dilating and minimizing peripheral resistance are called calcium channel blocker with the medicine that reduces myocardial contraction.
Common calcium channel blocker goes into to come the diastole arterial smooth muscle in the cell through the blocking-up calcium current, and the result shows blood pressure lowering effect.And, do not influence the cardiac electric load, and reduce the resistance of coronary vasodilator, thereby increase coronary flow through coronary artery dilator.
Calcium channel blocker comprises nifedipine, amlodipine of verapamil, diltiazem and the dihydropyridines of non-dihydropyridines etc., and is more effective as the effect dihydropyridines of vasodilation.
In these dihydropyridines medicines, representative amlodipine is 3-ethyl-5-methyl 2-(2-amino ethoxy methyl)-4-(2-chlorphenyl)-1,4-dihydro-6-methyl-3,5;-picolinic acid salt belongs to and shows active persistence calcium channel blocker for a long time, proves; Its effect and safety in the hypertension therapeutic field rank the first in the world [European patent discloses the 89th, No. 167 and United States Patent (USP) the 4th, 572; No. the 4th, 879,303, No. 909, United States Patent (USP)].
Viewpoint from treatment; Can predict; The medicine of generation that is used to suppress the angiotensin of hypertension incidence reason to the cardiovascular patient administering drug combinations is a renin inhibitor and when coming the medicine of blood pressure lowering to be the calcium channel blocker of dihydropyridines through the vasodilator smooth muscle, and is effective to the patient crowd of extensive morbid state.
Relevant therewith, in International Publication communique WO2003-097098,, proposed to comprise the pharmaceutical compositions of aliskiren, amlodipine and Hydrochlorothiazide to be purpose according to the stack therapeutic effect of administering drug combinations as stated.
But, when administering drug combinations renin inhibitor and calcium channel blocker simply, have the hidden danger that produces following problem.
When taking the aliskiren as renin inhibitor, after 1～3 hour, show the highest blood level, but when absorbing food rich in fat, bioavailability is 71%, the highest blood level is reduced to 85%, receives the influence of food bigger.Aliskiren is prone to be dissolved in the water, but is difficult for absorbing, and belongs to the lower medicine of bioavailability.Moreover, also influenced according to its absorbance of medicine, so the combination of aliskiren and other drug is necessary to note when using.In addition, be Cytochrome P450 though aliskiren is apprised of to hindering or not guiding the enzyme in the liver, but carry out metabolic medicine through this enzyme.
Suppress the new generation of Cytochrome P450 3A4 as the amlodipine of calcium channel blocker.Though amlodipine as long as there is the Cytochrome P450 3A4 of liver, then can be changed over to the inactivation attitude by metabolism originally as activated state.
In view of the above; When while administration during as the aliskiren of renin inhibitor with as the amlodipine of dihydropyridine calcium channel blockers; Because the inhibitory action of amlodipine pair cell cytochrome p 450 may cause side effect when the blood level of aliskiren increases.And in contrast, because the absorption of aliskiren receives the influence of amlodipine, so the blood level of aliskiren also may reduce.Thereby, do not reach the quantitative drug effect of being brought according to the administration aliskiren.
But; Pharmaceutical compositions among the aforementioned International Publication communique WO2003-097098; Just simple combination aliskiren, amlodipine and as the Hydrochlorothiazide of diuretic; Therefore the characteristic through not considering each medicine and the simple compound preparation of principle of absorption are difficult to reach administering drug combinations and treat the synergetic therapeutic effect that machine-processed different drug is brought.
Summary of the invention
The technical task that the present invention will solve provides a kind of interaction that can avoid the biological drug disposition dynamic metabolism of renin inhibitor and dihydropyridine calcium channel blockers; Be used to guide pharmacological effect according to the best of absorbability in the body; Through in the time period of the pharmacological effect that shows each medicine, discharging medicine, the pharmaceutical preparation that can also improve clinical effectiveness.
The present invention provides and comprises the compartment of release formerly that contains as the renin inhibitor of pharmacological component, and contains the pharmaceutical preparation as the slow release compartment of the dihydropyridine calcium channel blockers of pharmacological component.
Renin inhibitor of the present invention is intended to comprise its isomer or the acceptable salt of its pharmacy, and said dihydropyridine calcium channel blockers also is intended to comprise its isomer or the acceptable salt of its pharmacy.
As long as said renin inhibitor receives the not concrete restriction of the influence of dihydropyridine calcium channel blockers, for example can be selected from aliskiren, remikiren, enalkiren, zankiren, ditekiren, terlakiren and their isomer or the acceptable salt of their pharmacy.
Said dihydropyridine calcium channel blockers can be selected from amlodipine, lercanidipine, lacidipine, felodipine, barnidipine, benidipine, cilnidipine, isradipine, Manidipine, nicardipine, nifedipine, nimodipine, nilvadipine, nisoldipine, nitrendipine, azelnidipine and their isomer or the acceptable salt of pharmacy.
Have no particular limits; Preferably; Renin inhibitor in the preparation of the present invention is aliskiren, its isomer or the acceptable salt of its pharmacy (below be referred to as " aliskiren "), and dihydropyridine calcium channel blockers is amlodipine, its isomer or the acceptable salt of its pharmacy (below be referred to as " amlodipine "); Perhaps renin inhibitor is aliskiren, its isomer or the acceptable salt of its pharmacy (below be referred to as " aliskiren "), and dihydropyridine calcium channel blockers is lercanidipine, its isomer or the acceptable salt of its pharmacy (below be referred to as " lercanidipine "); Perhaps renin inhibitor is aliskiren, its isomer or the acceptable salt of its pharmacy (below be referred to as " aliskiren "), and dihydropyridine calcium channel blockers is lacidipine, its isomer or the acceptable salt of its pharmacy (below be referred to as " lacidipine "); Perhaps renin inhibitor is aliskiren, its isomer or the acceptable salt of its pharmacy (below be referred to as " aliskiren "), and dihydropyridine calcium channel blockers is felodipine, its isomer or the acceptable salt of its pharmacy (below be referred to as " felodipine "); Perhaps renin inhibitor is aliskiren, its isomer or the acceptable salt of its pharmacy (below be referred to as " aliskiren "), and dihydropyridine calcium channel blockers is barnidipine, its isomer or the acceptable salt of its pharmacy (below be referred to as " barnidipine "); Perhaps renin inhibitor is aliskiren, its isomer or the acceptable salt of its pharmacy (below be referred to as " aliskiren "), and dihydropyridine calcium channel blockers is benidipine, its isomer or the acceptable salt of its pharmacy (below be referred to as " benidipine "); Perhaps renin inhibitor is aliskiren, its isomer or the acceptable salt of its pharmacy (below be referred to as " aliskiren "), and dihydropyridine calcium channel blockers is cilnidipine, its isomer or the acceptable salt of its pharmacy (below be referred to as " cilnidipine "); Perhaps renin inhibitor is aliskiren, its isomer or the acceptable salt of its pharmacy (below be referred to as " aliskiren "), and dihydropyridine calcium channel blockers is isradipine, its isomer or the acceptable salt of its pharmacy (below be referred to as " isradipine "); Perhaps renin inhibitor is aliskiren, its isomer or the acceptable salt of its pharmacy (below be referred to as " aliskiren "), and dihydropyridine calcium channel blockers is Manidipine, its isomer or the acceptable salt of its pharmacy (below be referred to as " Manidipine "); Perhaps renin inhibitor is aliskiren, its isomer or the acceptable salt of its pharmacy (below be referred to as " aliskiren "), and dihydropyridine calcium channel blockers is nicardipine, its isomer or the acceptable salt of its pharmacy (below be referred to as " nicardipine "); Perhaps renin inhibitor is aliskiren, its isomer or the acceptable salt of its pharmacy (below be referred to as " aliskiren "), and dihydropyridine calcium channel blockers is nifedipine, its isomer or the acceptable salt of its pharmacy (below be referred to as " nifedipine "); Perhaps renin inhibitor is aliskiren, its isomer or the acceptable salt of its pharmacy (below be referred to as " aliskiren "), and dihydropyridine calcium channel blockers is nimodipine, its isomer or the acceptable salt of its pharmacy (below be referred to as " nimodipine "); Perhaps renin inhibitor is aliskiren, its isomer or the acceptable salt of its pharmacy (below be referred to as " aliskiren "), and dihydropyridine calcium channel blockers is nilvadipine, its isomer or the acceptable salt of its pharmacy (below be referred to as " nilvadipine "); Perhaps renin inhibitor is aliskiren, its isomer or the acceptable salt of its pharmacy (below be referred to as " aliskiren "), and dihydropyridine calcium channel blockers is nisoldipine (Nisulodipine), its isomer or the acceptable salt of its pharmacy (below be referred to as " nisoldipine "); Perhaps renin inhibitor is aliskiren, its isomer or the acceptable salt of its pharmacy (below be referred to as " aliskiren "), and dihydropyridine calcium channel blockers is nitrendipine, its isomer or the acceptable salt of its pharmacy (below be referred to as " nitrendipine "); Perhaps renin inhibitor is aliskiren, its isomer or the acceptable salt of its pharmacy (below be referred to as " aliskiren "), and dihydropyridine calcium channel blockers is azelnidipine, its isomer or the acceptable salt of its pharmacy (below be referred to as " azelnidipine ").
Have no particular limits, the preferred example of said renin inhibitor is the hemifumarate of aliskiren, and the preferred example of said dihydropyridine calcium channel blockers is an amlodipine benzenesulphonate.
The physics compartment of the release of preparation of the present invention through being provided for controlling two active component improves existing problem in administering drug combinations or the administration simultaneously of single preparation in the past, thereby more useful therapeutic effect is provided.
Preferably, preparation of the present invention is the preparation that is used for oral administration.
In the preparation of the present invention; The active component that formerly discharges compartment formerly discharges in the delivery formulations in it discharges back 1 hour of beginning more than the 80 weight % of active component total amount of compartment; Preferably, the active component in the preparation is released more than the 90 weight % in 1 hour.
And; In the preparation of the present invention; Till the active component of slow release compartment 2 hours after the active component that formerly discharges compartment begins to discharge, discharge below the 40 weight % of active component total amount of slow release compartment, preferably; Till the active component of slow release compartment 2 hours after the active component that formerly discharges compartment begins to discharge, discharge below the 30 weight % of active component total amount of slow release compartment.And, in the preparation of the present invention, till the active component of slow release compartment 5 hours after the active component that formerly discharges compartment begins to discharge, can discharge more than the 80 weight % of slow release compartment active component total amount, preferably, discharge more than the 90 weight %.
Preparation of the present invention provides the active component of slow release compartment than the active component time-delay that formerly discharges compartment pharmaceutical preparation at liver metabolism more than 2 hours with aforesaid release characteristics.
In the preparation of the present invention,, can contain the dihydropyridine calcium channel blockers of 0.1～400 weight portion with respect to the renin inhibitor of 100 weight portions.If be lower than 0.1 weight portion; Then possibly be difficult to bring into play obvious pharmacologically active as dihydropyridine calcium channel blockers; If surpass 400 weight portions, consider that then the character of object disease is arranged long term administration, this may cause because the inherent side effect of medicine that the high dose administration is caused.
In the preparation of the present invention, the content of renin inhibitor in each preparation can be 10～1000mg, is preferably 35～600mg.
And in the preparation of the present invention, the content of dihydropyridine calcium channel blockers in preparation can be 0.1～200mg, is preferably 2～120mg.
Compartment separately to pharmaceutical preparation of the present invention is described in more details as follows.
1, formerly discharges compartment
Formerly discharge compartment and be meant the compartment that in pharmaceutical preparation of the present invention, discharges, except pharmacological component, can also optionally append and contain the pharmacy acceptable additive prior to the slow release compartment.
(1) pharmacological component
The pharmacological component that formerly discharges compartment is a renin inhibitor, as stated.
(2) pharmacy acceptable additive
Preparation of the present invention is not damaging effect of the present invention and is not hindering in the scope of pharmacological component release, can append typical additives such as using pharmacy acceptable diluent, binding agent, disintegrating agent, lubricant, stabilizing agent, pH regulator agent and solubilizing agent.
Formerly discharge in the compartment of the present invention, with respect to the active component of 1 weight portion, content of additive can be 0.1～300 weight portion.
Formerly discharge in the compartment of the present invention, diluent can use starch, microcrystalline Cellulose, lactose, glucose, mannitol, alginate, alkali salt, clay, Polyethylene Glycol, dicalcium phosphate and their mixture etc.
Formerly discharge in the compartment of the present invention, binding agent can use starch, microcrystalline Cellulose, high dispersive silicon dioxide, mannitol, sucrose, lactose, Polyethylene Glycol, polyvinylpyrrolidone, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, natural gum, paragutta, copolyvidone (copovidone), polyvidone, gelatin or their mixture etc.
Formerly discharge in the compartment of the present invention, disintegrating agent can use starch or modified starches such as sodium starch glycollate, corn starch, potato starch or pregelatinized Starch; Bentonite, Montmorillonitum or aluminium-magnesium silicate clays such as (veegum); Celluloses such as microcrystalline Cellulose, hydroxypropyl cellulose or carboxymethyl cellulose; Algin such as sodium alginate or alginic acid; Cross-linked celluloses such as cross-linked carboxymethyl cellulose (croscarmellose) sodium; Natural gum such as guar gum or xanthan gum; Crospolyvinylpyrrolidone cross linked polymers such as (crospovidone); Foaming agent such as sodium bicarbonate or citric acid; Or their mixture.
Formerly discharge in the compartment of the present invention, lubricant can use Talcum, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, Compritol 888 ATO, glyceryl monolaurate, glyceryl monostearate, Palmic acid tristerin (glycerylpalmitostearate) and Polyethylene Glycol.
Formerly discharge in the compartment of the present invention, said stabilizing agent can use ascorbic acid, citric acid, butylated hydroxyanisole, butylated hydroxytoluene and Tocopheryl derivatives.And stabilizing agent can use alkali metal salt, alkali salt or their basifiers such as mixture, preferably can use calcium carbonate, sodium carbonate, sodium bicarbonate, magnesium oxide, magnesium carbonate, sodium citrate etc.
Formerly discharge in the compartment of the present invention, the pH regulator agent can be used acidulant such as acetic acid, adipic acid, ascorbic acid, malic acid, succinic acid, tartaric acid, fumaric acid and citric acid; And basifiers such as winnofil, ammonia and meglumine.
Formerly discharge in the compartment of the present invention, solubilizing agent can use sodium lauryl sulphate, like the polyoxyethylene sorbitan fatty acid ester of Polysorbate, docusate sodium etc.
In addition, for the various additives of from coloring agent, spice, selecting,, can prepare preparation of the present invention through selecting to use the pharmacy acceptable additive.The scope that can be used for additive of the present invention is not limited to above-mentioned additive, and above-mentioned additive can be used to prepare preparation with the routine dose of suitable selection.
2, slow release compartment
In the present invention, after the slow release compartment is meant that the active component that formerly discharges compartment is released certain hour, discharge the compartment of its active component again.The slow release compartment can contain: (1) pharmacological component; And (2) discharge control material or (3) Osmolyte regulator and semipermeable membrane coated substrate.Comprise the pharmacy acceptable additive as if needing, can appending.
(1) pharmacological component
The pharmacological component of slow release compartment is a dihydropyridine calcium channel blockers, as stated.
In the preparation of the present invention; Till the active component of slow release compartment 2 hours after the active component that formerly discharges compartment begins to discharge; Discharge below the 40 weight % of slow release compartment active component total amount; Preferably, till the active component of slow release compartment 2 hours after the active component that formerly discharges compartment begins to discharge, discharge below the 30 weight % of slow release compartment active component total amount.And, in the preparation of the present invention, till the active component of slow release compartment 5 hours after the active component that formerly discharges compartment begins to discharge, can discharge more than the 80 weight % of slow release compartment active component total amount, preferably, discharge more than the 90 weight %.
(2) discharge the control material
In the pharmaceutical preparation of the present invention, the slow release compartment comprises at least a release control material that is selected from enteric polymer, insoluble polymer, hydrophobic compound, hydrophilic polymer and their mixture.Said release control material is preferably and is selected from least a of enteric polymer, hydrophilic polymer, insoluble polymer, more preferably is selected from least a of hydrophilic polymer, insoluble polymer, HPMCP.Specifically, can for: from polyvinyl acetate, polymethacrylate copolymer, gather (ethyl acrylate, methyl methacrylate, methacrylic acid trimethyl amino ethyl ester) copolymer, ethyl cellulose, cellulose acetate and the crowd that constitutes by their mixture selected at least a insoluble polymer; Selected at least a hydrophilic polymer the crowd who constitutes from hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, carboxylic ethylene copolymer, PEO and by their mixture; Enteric polymer of from HPMCP, selecting and their combination; More preferably, can be from polymethacrylate copolymer, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, carboxylic ethylene copolymer, HPMCP, select at least a and their combination.In slow release compartment of the present invention,, contain the said release control material of 0.01～100 weight portion with respect to the dihydropyridine calcium channel blockers of 1 weight portion.Said release control material then is difficult to have sufficient time delay if be lower than 0.01 weight portion, if surpass 100 weight portions, then is difficult to reach tangible clinical effectiveness.
In slow release compartment of the present invention, enteric polymer is meant and is lower than under 5 the acid condition insolublely or stable at pH value, and is the polymer of dissolving or degraded under the specific pH value condition more than 5 at pH value.Among the present invention, spendable enteric polymer is selected at least a among enteric cellulose derivative, enteric acrylic copolymer, enteric maleic acid, enteric polyvinyl derivant and the crowd that is made up of their mixture.
At this; Preferably, the enteric cellulose derivative is at least a for what from succinic acid acetic acid hydroxypropyl emthylcellulose, HPMCP, hydroxymethyl ethyl cellulose phthalate, cellulose acetate phthalic acid ester, cellulose acetate succinate, cellulose acetate maleate, benzoic acid cellulose phthalate, cellulose propionate phthalic acid ester, methyl cellulose phthalate ester, carboxymethylethylcellulose, ethylhydroxyethylcellulose phthalic acid ester, methyl hydroxyethylcellulose and their mixture, select; Said enteric acrylic copolymer is (like Eudragit L 100, Eudragit S from styrene-propene acid copolymer, acrylic acid methyl ester-acrylic copolymer, acrylic acid methyl ester. EUDRAGIT S100, BA-St-acrylic copolymer, methacrylic acid-methylmethacrylate copolymer; Degussa; Germany), EUDRAGIT L100-55 is (like Eudragit L 100-55; Degussa, Germany), select in acrylic acid methyl ester-methacrylic acid-1-Octyl acrylate copolymer and their mixture at least a; Said enteric maleic acid is at least a for what from vinyl acetate-copolymer-maleic anhydride, styrene-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, vinyl methyl ether-copolymer-maleic anhydride, ethylene-copolymer-maleic anhydride, vinyl butyl ether-copolymer-maleic anhydride, acrylonitrile-acrylic acid methyl ester .-copolymer-maleic anhydride, BA-St-copolymer-maleic anhydride and their mixture, select; Enteric polyvinyl derivant is for gathering at least a that vinyl butyrate, phthalic acid polyvinyl alcohol contract and select acetyl acetaldehyde ester (polyvinylacetacetal phthalate) and their mixture from phthalic acid polyvinyl alcohol ester, phthalic acid polyvinyl acetal ester, phthalic acid.
At this, with respect to the active component of 1 weight portion, can contain the enteric polymer of 0.1 weight portion～20 weight portions, preferably can contain 0.5 weight portion～10 weight portions.If be lower than 0.5 weight portion, then pH less than 5 condition under dissolving easily, if surpass 10 weight portions, then possibly cause the release of the unnecessary increase of total formulation weight amount or its excessive deferral ground.
In slow release compartment of the present invention, said insoluble polymer is meant the acceptable water-insoluble polymer of the pharmacy of control drug release.Among the present invention, spendable insoluble polymer for from polyvinyl acetate, polymethacrylate copolymer, gather (ethyl acrylate, methyl methacrylate) copolymer, gather (ethyl acrylate, methyl methacrylate, methacrylic acid trimethyl amino ethyl ester) copolymer, select ethyl cellulose, cellulose esters, cellulose ether, acylated cellulose, two acylated celluloses, three acylated celluloses, cellulose acetate, cellulose diacetate, cellulose triacetate and the crowd that constitutes by their mixture at least a.At this, with respect to the active component of 1 weight portion, can contain the insoluble polymer of 0.1 weight portion～30 weight portions, preferably can contain 0.1 weight portion～20 weight portions.If be lower than 0.1 weight portion, the then release of the uncontrollable medicine of possibility, if surpass 30 weight portions, then the release of medicine may be by excessive deferral.
In slow release compartment of the present invention, hydrophobic compound is meant the acceptable water-fast material of the pharmacy of control drug release.Among the present invention, spendable hydrophobic compound can be at least a for what select the crowd who constitutes from fatty acid and fatty acid ester, fatty acid alcohol, wax, inorganic matter and by their mixture.At this; Preferably, fatty acid and fatty acid ester are at least a for what from Palmic acid tristerin (glycerylpalmitostearate), tristerin, Compritol 888 ATO, cetyl palmitate, glyceryl monooleate, stearic acid and their mixture, select; Fatty acid alcohol is at least a for what from cetostearyl alcohol, hexadecanol, octadecanol and their mixture, select; Wax is at least a for what from Brazil wax, Cera Flava, microwax and their mixture, select; Inorganic matter is at least a for what from Talcum, winnofil, calcium hydrogen phosphate, zinc oxide, titanium oxide, Kaolin, bentonite, Montmorillonitum, aluminium-magnesium silicate (veegum) and their mixture, select.
At this, with respect to the active component of 1 weight portion, can contain the hydrophobic compound of 0.1 weight portion～50 weight portions, preferably can contain 0.1 weight portion～40 weight portions.If be lower than 0.1 weight portion, the then release of the uncontrollable medicine of possibility, if surpass 50 weight portions, then the release of medicine may be by excessive deferral.
In slow release compartment of the present invention, hydrophilic polymer is meant the acceptable water-soluble polymer substance of the pharmacy of control drug release.Among the present invention, spendable hydrophilic polymer can be at least a for what select the crowd who constitutes from saccharide, cellulose derivative, natural gum, protein, polyvinyl derivant, polymethacrylate copolymer, polythene derivative, carboxylic ethylene copolymer and by their mixture.At this; Preferably, saccharide is from dextrin, gathers select dextrin, glucosan, pectin and pectin derivant, alginate, polygalacturonic acid, xylan, araboxylan, arabinogalactan, starch, hydroxypropyl starch, amylose, amylopectin and their mixture at least a; Cellulose derivative is at least a for what from hydroxypropyl emthylcellulose, hydroxypropyl cellulose, hydroxy methocel, hydroxyethyl-cellulose, methylcellulose, sodium carboxymethyl cellulose, succinic acid acetic acid hydroxypropyl emthylcellulose, hydroxyethylmethyl-cellulose and their mixture, select; Natural gum is at least a for what from guar gum, locust bean gum, Tragacanth, carrageenin, the joyous natural gum of alloy (gum acacia), arabic gum (gum arabic), gellan gum, xanthan gum and their mixture, select; Protein is at least a for what from gelatin, casein, zein and their mixture, select; The polyvinyl derivant is at least a for what from polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl acetal diethyl amino yl acetate (polyvinylacetal diethylaminoacetate) and their mixture, select; Polymethacrylate copolymer is from gathering (butyl methacrylate; (2-dimethyl aminoethyl) methacrylate, methyl methacrylate) copolymer, gather (methacrylic acid-methyl methacrylate) copolymer, gather select in (methacrylic acid-ethyl acrylate) copolymer and their mixture at least a; Polythene derivative is at least a for what from Polyethylene Glycol, PEO and their mixture, select; The carboxylic ethylene copolymer is a carbomer.
At this, with respect to the active component of 1 weight portion, can contain the hydrophilic polymer of 0.05 weight portion～50 weight portions, preferably can contain 0.5 weight portion～30 weight portions.If be lower than 0.05 weight portion, the then release of the uncontrollable medicine of possibility, if surpass 50 weight portions, then the release of medicine may be by excessive deferral.
In pharmaceutical preparation of the present invention; The slow release compartment contains at least a release control material of from enteric polymer, insoluble polymer, hydrophobic compound, hydrophilic polymer and their mixture, selecting; Preferably contain enteric polymer and hydrophilic polymer, perhaps contain insoluble polymer.
And; In the slow release compartment of preparation of the present invention; As the preferred exemplary of the insoluble polymer that discharges the control material for from polyvinyl acetate, polymethacrylate copolymer, gather (ethyl acrylate; That methyl methacrylate, methacrylic acid trimethyl amino ethyl ester) selects among copolymer, ethyl cellulose, cellulose acetate and the crowd that is made up of their mixture is at least a.
And, in the slow release compartment of preparation of the present invention,, can contain the release control material of 0.01～100 weight portion with respect to the active component of 1 weight portion.Discharge and control material if be lower than 0.01 weight portion, then possibly can't have sufficient time delay, if surpass 100 weight portions, then medicine possibly not be released perhaps and possibly become long time delay.
(3) Osmolyte regulator and semipermeable membrane coated substrate
Slow release compartment of the present invention can comprise Osmolyte regulator, and can be the compartment that coats with the semipermeable membrane coated substrate.
In slow release compartment of the present invention, Osmolyte regulator is preferably select the crowd who constitutes from magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, lithium sulfate, sodium sulfate and by their mixture at least a.
At this, with respect to the active component of 1 weight portion, can contain the Osmolyte regulator of 0.01 weight portion～10 weight portions, preferably can contain 0.05 weight portion～5 weight portions.If be lower than 0.01 weight portion, it is poor then possibly to be difficult to obtain discharging adequate time, if surpass 10 weight portions, then the release of medicine possibly is difficult to obtain tangible clinical effectiveness by delay.
In the present invention, the semipermeable membrane coated substrate is the material of blend in the coatings of pharmaceutical preparation, and mean be used to form can make some composition through and can not make the material of the film that other compositions pass through.Semipermeable membrane coated substrate among the present invention can be used foregoing insoluble polymer.
At this, with respect to the active component of 1 weight portion, can contain the semipermeable membrane coated substrate of 0.1 weight portion～20 weight portions, preferably can contain 1 weight portion～10 weight portions.If be lower than 0.1 weight portion, then possibly be difficult to obtain adequate time and postpone, if surpass 20 weight portions, then maybe medicine be not released or time delay elongated.
(4) pharmacy acceptable additive
Preparation of the present invention; In the scope of not damaging effect of the present invention; Except that pharmacy acceptable (2) discharges the control material; Do not breaking away under the situation that delays the releasing properties scope, can also append typical additives such as using diluent, binding agent, disintegrating agent, lubricant, pH regulator agent, defoamer, solubilizing agent and prepare preparation.
For example, can use starch, microcrystalline Cellulose, lactose, glucose, mannitol, alginate, alkali salt, clay, Polyethylene Glycol, dicalcium phosphate and their mixture etc. as diluent; Can use starch, microcrystalline Cellulose, high dispersive silicon dioxide, mannitol, sucrose, lactose, Polyethylene Glycol, polyvinylpyrrolidone, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, natural gum, paragutta, copolyvidone, polyvidone, gelatin and their mixture etc. as binding agent.
Can use starch or modified starches such as sodium starch glycollate, corn starch, potato starch or pregelatinized Starch as disintegrating agent; Bentonite, Montmorillonitum or aluminium-magnesium silicate clays such as (veegum); Celluloses such as microcrystalline Cellulose, hydroxypropyl cellulose or carboxymethyl cellulose; Algin such as sodium alginate or alginic acid; Cross-linked celluloses such as cross-linked carboxymethyl cellulose (croscarmellose) sodium; Natural gum such as guar gum or xanthan gum; Crospolyvinylpyrrolidone cross linked polymers such as (crospovidone); Foaming agent such as sodium bicarbonate or citric acid; Or their mixture.
Can use Talcum, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, sodium benzoate, silica sol, sodium stearyl fumarate, Compritol 888 ATO, glyceryl monolaurate, glyceryl monostearate, Palmic acid tristerin (glycerylpalmitostearate) and/or Polyethylene Glycol etc. as lubricant.
As pharmacy acceptable additive of the present invention, the pH regulator agent can be used like acidulant such as acetic acid, adipic acid, ascorbic acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acids and like basifiers such as winnofil, ammonia, meglumines.
As pharmacy acceptable additive of the present invention, defoamer can use simethicone, oleyl alcohol, propylene glycol alginate, like the Simethicone of Simethicone emulsion.
In pharmacy acceptable additive of the present invention, solubilizing agent can use sodium lauryl sulphate, like the polyoxyethylene sorbitan fatty acid ester of Polysorbate, docusate sodium etc.
In addition, for the various additives of from coloring agent, spice, selecting,, can prepare preparation of the present invention through selecting to use the pharmacy acceptable additive.The scope that can be used for additive of the present invention is not limited to above-mentioned additive, and above-mentioned additive can be used to prepare preparation with the routine dose of suitable selection.
And, in preparation of the present invention,, can use pure water, ethanol, dichloromethane etc. as combining solvent and the solvent that is used for sustained release additives.More preferably pure water and ethanol.
In pharmacy acceptable additive of the present invention, the scope of spendable additive is not limited to above-mentioned additive, and above-mentioned additive can be used to prepare preparation with the routine dose of suitable selection.
Pharmaceutical preparation of the present invention can prepare becomes several formulations, for example can be prepared into like tablet, powder, granule or capsules etc. such as uncoated tablets, coated tablet, multilayer tablet or pressed coated tablets.
Pharmaceutical preparation of the present invention can be with the slow release compartment with formerly discharge the form of carrying out the resulting two-phase matrix tablet of tabletting (two-phase matrix tablet) behind the compartment uniform mixing.
In addition; Pharmaceutical preparation of the present invention can be the form of film coated tablet; This film coated tablet comprise the tablet formed by the slow release compartment and by the outside of sealing this tablet formerly discharge the film coating layer that compartment is formed, at first discharge the active component of film coating layer thus along with the dissolving of film coating layer.
In addition; Pharmaceutical preparation of the present invention can be the form of multilayer tablet; Said multilayer tablet has the slow release compartment and formerly discharges the multiple structure of compartment; Its each compartment all obtains in the following manner: the granule that will constitute the slow release compartment and formerly discharge compartment mixes with medicated premix, and utilizes the multilamellar tablet machine that mixture is pressed into bilayer or tri-layer tablets.The preparation of gained is the tablet that is used for oral administration, and it is configured to release formerly and the slow release of realizing medicine according to independent layer.
In addition, pharmaceutical preparation of the present invention can be the form of compression coated tablets agent, and this pressed coated tablet comprises the inner core that formed by the slow release compartment and formerly discharges the skin that compartment forms by the outer surface of sealing this inner core.Said pressed coated tablet can be infiltration compacting coated tablet (osmoticpress-coated tablet).This infiltration compacting coated tablet is following tablet; Wherein tablet mixture is pressed into tablet through the mode of mixing Osmolyte regulator for medicament slow release; Tablet surface is coated with the preparation inner core with the semipermeable membrane coated substrate; Mix with medicated premix to prepare skin constituting the granule that formerly discharges compartment, carry out tabletting has the slow release inner core and the releasing layer formerly on the surface of sealing this inner core with formation preparation then.
Pharmaceutical preparation of the present invention can be the form of capsule, and said capsule contains microgranule (particle), granule (granule), piller or the sheet that is formed by the slow release compartment, and by formerly discharging microgranule, granule, piller or the sheet that compartment forms.
Preparation of the present invention can also append the formation coatings at slow release compartment and/or the outside that formerly discharges compartment.For the release control or the stability of formulation of medicine, can be to by the slow release compartment and/or formerly discharge microgranule, granule, piller or the sheet that compartment constitutes and wrap up.In addition, pharmaceutical preparation of the present invention can be for comprising the slow release compartment and formerly discharging the form of the medicine box of compartment.Specifically, said medicine box can comprise (a) and formerly discharges compartment; (b) slow release compartment; And (c) be used to fill the said container that formerly discharges compartment and slow release compartment.Said medicine box can be prepared as following form; Wherein preparation constitutes microgranule, granule, piller or the sheet that formerly discharges compartment; Preparation constitutes granule, piller or the sheet of slow release compartment in addition, and two kinds of release compartments that will prepare thus are filled in paper tinsel, bubble (blister), the bottle and are used for the dosage form with different pharmaceutical administration simultaneously with preparation.
Preparation of the present invention can be provided as does not have the uncoated tablets of additional coating form, perhaps can optionally be provided as the form of coated tablet, and said coated tablet also is included in the coatings that the preparation outside forms.Through forming coatings, the preparation that can guarantee the stability of active component more can be provided.
Those skilled in the art can suitably select to form the method for coatings from the method that can form the film like coatings on the surface of tablet layer, for example fluidized bed coating and pan coating method are preferably used the pan coating method.
Can utilize film former, coalescents or their mixture to prepare coatings.Particularly; Film former can use like cellulose derivatives such as hydroxypropyl emthylcellulose, hydroxypropyl cellulose, carbohydrate derivative, polythene derivative, wax, fat, gelatin and their mixture etc., and the film forming auxiliary agent can use Polyethylene Glycol, ethyl cellulose, glyceride, titanium oxide, Talcum, diethyl phthalate and their mixture etc.
The content of coatings can be 0.5～15 weight % (%w/w) with respect to the tablet total weight amount.
If the content of coatings is lower than 0.5 weight %, then possibly be difficult to guarantee the protection of product and depend on stability of formulation, if the content of coatings surpasses 15 weight %, then possibly influence the release appearance attitude of active component.
In addition, the present invention provides the pharmaceutical preparation that is used for the administration in night according to of the present invention.
Preparation of the present invention can be administered once in one day, especially in (during 17-23) administration in night, the effect and the minimized side effect of maximized each active component can be provided thus.The present invention can prevent hindering the reduction like the pharmacological effect that absorption caused of renin inhibitors such as aliskiren like the high-absorbility of dihydropyridine calcium channel blockers such as amlodipine, can suppress to take simultaneously like renin inhibitor such as aliskiren and the side effect that rising caused of the aliskiren blood level that may take place during like calcium channel blockers such as amlodipines.In the present invention, postpone to discharge the high dihydropyridine calcium channel blockers of absorbance, and formerly discharge the low renin inhibitor of absorbance, thereby can guide pharmacological effect based on the best of the absorption of human body ability of each medicine.In addition, be 24 hours like the acting duration of renin inhibitors such as aliskiren, so it is effective to reach morning of peak for blood pressure when taking night, thereby can shows the rising of clinical effectiveness through the administration in night.
In view of the above, preparation of the present invention can be designed for the administration in night.
In addition, can also use and take slow release compartment of the present invention and the commercially available medication that formerly discharges the active component of compartment simultaneously.
The invention provides the method for at least a disease in prevention and treatment metabolic syndrome, cardiovascular disease and the nephropathy, it comprises to the step that comprises human mammal administration pharmaceutical preparation of the present invention.
Said cardiovascular disease comprises hypertension and complication of the patient who suffers from metabolic syndrome etc.Said metabolic syndrome association list reveals hypertension or diabetes, obesity, hyperlipemia and coronary artery disease etc.
Pharmaceutical preparation of the present invention; Preferably can pass through this area appropriate method; For example be utilized in Chronotherapeutics (2003, Peter Redfern, PhP) in disclosed time difference administration principle; Assign to prepare preparation according to each disease or one-tenth, specifically can be according to the method preparation that comprises following steps.
First step is; Releases control material through the active component of slow release compartment and one or both being selected from enteric polymer, insoluble polymer, hydrophobic compound and hydrophilic polymer and the conventional additives that is used in pharmaceutics mix, mediate, drying, pelletize or coating, and tabletting obtains sustained-release granular formulation or tablet; Perhaps through said active component and Osmolyte regulator and the conventional additives that is used in pharmaceutics are mixed, mediate, dry, pelletize or tabletting, carry out coating with the semipermeable membrane coated substrate afterwards and obtain sustained-release granular formulation or tablet.
Second step is, through the active component and the acceptable conventional additives of pharmacy that will formerly discharge compartment mix, mediate, the conventional method of the preparation oral solid formulation of dry, pelletize or coating and tabletting obtains formerly release granules or tablet.
Third step is, after the mixed with excipients with the granule separately that obtains in the first step and second step or tablet and pharmaceutics, carries out tabletting or filling and obtains to be used for the preparation of oral administration.
The said first step and second step can replacing order, perhaps carry out simultaneously.
Can prepare pharmaceutical preparation of the present invention through aforesaid method, the compounding method of preparation of third step specified as follows, but be not to be defined in this.
The preparation of [A] two-phase matrix tablet
With microgranule that obtains in the first step or granule, perhaps, mix with the granule for preparing in second step with behind this microgranule or the granule usefulness release control material coating, be pressed into certain weight then, thus the preparation tablet.In order to improve stability or shape, can optionally carry out film coating to the tablet that obtains.
[B] contains the preparation of the film coated tablet of active component
With coated tablet that obtains in the first step or granule, perhaps with this coated tablet or granule with after discharging control material coating, carry out drying and be pressed into a certain amount ofly, and it is perhaps carried out coating and is prepared into tablet it.In addition, after the active component dissolving that formerly discharges compartment and being scattered in water-soluble film coating solution, be coated on the skin of the tablet that obtains in the first step, thereby can be prepared in the oral type film coated tablet that contains active component in the film coating.
The preparation of [C] multilayer tablet
With the granule that obtains in the first step, perhaps with this granule with after discharging control material coating, carry out drying and obtain granule, and utilize tablet machine that the preparation of granules that obtains in dried granules and second step is become bilayer tablet.According to preparation design or optionally, discharge auxiliary layer and prepare three layers or more multiwalled tablet, perhaps prepare the coating multilayer tablet through coating through appending.
The preparation of [D] pressed coated tablet
With coated tablet that obtains in the first step or granule; Perhaps with behind this coated tablet or the granule usefulness release control material coating; Carry out drying and be prepared into a certain amount ofly, and carry out coating and as inner core, utilize the pressed coated tablet machine that the granule that obtains in the inner core and second step is together carried out tabletting then with it or to it; Thereby the pressed coated tablet that the surface of the tablet of preparation first step is sealed by releasing layer formerly perhaps prepares the pressed coated tablet of coating through coating.
The preparation of [E] capsule (containing granule or sheet)
With the granule that obtains in the first step or with behind this granule usefulness release control material coating; The granule or the tablet that carry out obtaining in dry resulting granules or tablet and second step are put into capsule filling machine; And be filled in a certain size the capsule, thereby preparation capsule with the effective dose of each main component.
The preparation of [F] capsule (piller)
(1) with the active component of slow release compartment, discharge the control material and the pharmacy acceptable additive of optionally adding is dissolved in or is suspended in water, organic solvent or the mixed solvent; And it is coated on carries out drying on the sugar pill; Then optionally with in water-soluble, organic solvent or the mixed solvent separately or the control of the release more than 2 kinds material carry out coating and dry; Then will it with second step in the tablet that obtains in the granule that obtains or the third step mix, utilize capsule filling machine to be filled in the capsule then and prepare capsule.
Active component and the pharmacy acceptable additive that (2) will formerly discharge compartment is dissolved in or is suspended in water, organic solvent or the mixed solvent; And it is coated on carries out drying on the sugar pill; Then with after the release control piller of the active component of the slow release compartment that contains said (1) mixes mutually, utilize capsule filling machine to be filled in the capsule and the preparation capsule.
The preparation of [G] medicine box
To contain the formulations of active ingredients of the slow release compartment that obtains in the first step and contain the formulations of active ingredients that formerly discharges compartment that obtains in second step and together be filled in paper tinsel, bubble, the bottle, thus the medicine box that preparation can be taken simultaneously.
Pharmaceutical preparation of the present invention can prevent the interaction of renin inhibitor and dihydropyridine calcium channel blockers pharmacokinetics in vivo; And guiding is based on the pharmacological effect of the best of absorbability in the body; And improve clinical effectiveness, thereby can effectively prevent or treat metabolic syndrome, cardiovascular disease, nephropathy etc. through discharging medicine in the time period that shows pharmacological effect at each active component.
Description of drawings
Fig. 1 is the aliskiren-amlodipine preparation that illustrates according to first embodiment preparation, and as the figure of the comparison stripping curve of the single preparation Tekturna of aliskiren of control drug and the single preparation Norvasc of amlodipine (Norvasc);
Fig. 2 is the aliskiren-amlodipine preparation that illustrates according to second embodiment preparation, and as the figure of the comparison stripping curve of the single preparation Tekturna of aliskiren of control drug and the single preparation Norvasc of amlodipine;
Fig. 3 is the aliskiren-amlodipine preparation that illustrates according to the 3rd to the 6th embodiment preparation, and as the figure of the comparison stripping curve of the single preparation Tekturna of aliskiren of control drug;
Fig. 4 is the aliskiren-amlodipine preparation that illustrates according to the 3rd to the 6th embodiment preparation, and as the figure of the comparison stripping curve of the single preparation Norvasc of amlodipine of control drug;
Fig. 5 is the aliskiren-amlodipine preparation that illustrates according to the 9th embodiment preparation, and as the figure of the comparison stripping curve of the single preparation Tekturna of aliskiren of control drug and the single preparation Norvasc of amlodipine;
Fig. 6 is the aliskiren-lercanidipine preparation that illustrates according to the 11 embodiment preparation, and rather puts down the figure of the comparison stripping curve of (Zanidip) again as the single preparation Tekturna of aliskiren and the single preparation of lercanidipine of control drug;
Fig. 7 is the aliskiren-lacidipine preparation that illustrates according to the 12 embodiment preparation, and as the figure of the comparison stripping curve of the single preparation Tekturna of aliskiren of control drug and the single preparation Vaxar of lacidipine.
The specific embodiment
In order to help understanding of the present invention that embodiment is provided.Following embodiment just provides in order to be more prone to understand the present invention, is not to be used to limit content of the present invention.
Embodiment 1: the preparation of aliskiren-amlodipine two-phase matrix tablet
Utilize the composition and the content of table 1, prepare the two-phase matrix tablet as follows.
1) contains the preparation that formerly discharges compartment of aliskiren
With aliskiren hemifumarate with as the microcrystalline Cellulose (JRS of excipient; Vivapur.), lactose, corn starch, sodium starch glycollate (DMV; Primojel) sieve with No. 35; And with super mixer (Lab.Pharma Mixer P, Diosna Germany) mixes.In addition, with the hydroxypropyl cellulose adhesive solution (5%W-W) for preparing soluble in water, and this adhesive solution and main constituent mixture together put in the super mixer mediate.After accomplishing kneading, (Erweka Germany) carries out pelletize, and utilizes the hot water exsiccator under 60 ℃, to carry out drying to utilize the agitator with No. 18 sieves.After accomplishing drying, sieve through No. 20 once more and be prepared into release particles formerly.
2) contain the preparation of the slow release compartment of amlodipine
Amlodipine Besylate Tablet, microcrystalline Cellulose are sieved with No. 35, and (Lab.Pharma Mixer P, Diosna Germany) mixed 5 minutes and the preparation mixture with super mixer.With said mixture put into fluidized bed granulation coating machine (GPCG-1, Glatt, Germany) in, spray simultaneously hydroxypropyl emthylcellulose prepared adhesive solution soluble in water (5%W-W) and form granule, carry out drying again.Afterwards, be sprayed at dissolving polymethacrylates RS PO in 1: 1 mixed liquor of ethanol and dichloromethane (Eudragit RS PO, Evonik-Degussa) resulting solution (5%W-W) and coated particle to said granule.
3) tabletting and coating
With said 1) and 2) product put into double-cone mixer and mix.In this mixture, add magnesium stearate and carry out final mixed.Utilize rotary tablet machine (MRC-33:Sejong Pharmatech Co., Ltd., South Korea) that final mixture is carried out tabletting.Simultaneously; With METHOCEL E15LV, hydroxypropyl cellulose, titanium oxide and Talcum dissolving and be dispersed in ethanol and the pure water and preparation coating solution (20%W/W); And utilize Hi-coating machine (SFC-30N, Sejong Pharmatech Co., Ltd.; South Korea) forms the film coating layer to coating coating solution on the sheet of compacting, prepare the two-phase matrix tablet thus.
Embodiment 2: the preparation of aliskiren-amlodipine multilayer tablet
Utilize the composition and the content of table 1, prepare multilayer tablet as follows.
1) contains the preparation that formerly discharges compartment of aliskiren
With aliskiren hemifumarate with sieve with No. 35, and mix as microcrystalline Cellulose, D-mannitol, the lactose of excipient with super mixer.In addition, with the hydroxypropyl cellulose adhesive solution (5%W-W) for preparing soluble in water, and this adhesive solution and main constituent mixture together mediated.After accomplishing kneading, utilize agitator to carry out pelletize, and utilize the hot water exsiccator under 60 ℃, to carry out drying with No. 18 sieves.After accomplishing drying, sieve through No. 20 once more.Material mixing sodium starch glycollate after screening, and after adding magnesium stearate, utilize double-cone mixer to carry out final mixed.
2) contain the preparation of the slow release compartment of amlodipine
Amlodipine Besylate Tablet, microcrystalline Cellulose are sieved with No. 35, and mixed 5 minutes and the preparation mixture with super mixer.Said mixture is put in the fluidized bed granulation coating machine, sprayed simultaneously hydroxypropyl emthylcellulose prepared adhesive solution soluble in water (5%W-W) and form granule, carry out drying again.Afterwards, be sprayed at the dissolving resulting solution of HPMCP (5%W-W) in 1: 1 mixed liquor of ethanol and dichloromethane and coated particle to said granule.And after it adds magnesium stearate, utilize double-cone mixer (Dasan Pharmatech, South Korea) to carry out final mixed.
3) tabletting and coating
Use multilamellar tablet machine (MRC-37T, Sejong Pharmatech Co., Ltd., South Korea) to carry out tabletting.With said 2) in contain Amlodipine Besylate Tablet constituent put into first powder feeder, said 1) in contain aliskiren hemifumarate constituent put into second powder feeder after, carry out tabletting can minimize the condition that interlayer mixes.Simultaneously; With METHOCEL E15LV, hydroxypropyl cellulose, titanium oxide and Talcum dissolving and be dispersed in ethanol and the pure water and preparation coating solution (20%W/W); And utilize Hi-coating machine to form the film coating layer to coating coating solution on the sheet of compacting, prepare the preparation of multilayer tablet form thus.
Embodiment 3: the preparation (granule-piller) of aliskiren-amlodipine capsule
Utilize the composition and the content of table 1, prepare capsule as follows.
1) contains the preparation that formerly discharges compartment of aliskiren
Aliskiren hemifumarate, microcrystalline Cellulose, D-mannitol are sieved with No. 35, and mixes with super mixer.In addition, with the hydroxypropyl cellulose adhesive solution (5%W-W) for preparing soluble in water, and this adhesive solution and main constituent mixture together mediated.After accomplishing kneading, utilize agitator to carry out pelletize, and utilize the hot water exsiccator under 60 ℃, to carry out drying with No. 18 sieves.After accomplishing drying, sieve through No. 20 once more.
2) contain the preparation of the slow release compartment of amlodipine
Amlodipine Besylate Tablet, microcrystalline Cellulose, hydroxypropyl methylcellulose mixtures are dissolved in 1: 1 mixed liquor of ethanol and dichloromethane and as medicine layer coating solution (20%W/W); After the granulating coated machine of co-current flow bed is put into sugar pill, coat with said medicine layer coating solution.Afterwards, be utilized in again that the dissolving resulting solution of HPMCP (5%W-W) appends coating in 1: 1 mixed liquor of ethanol and dichloromethane, thus preparation amlodipine piller.
3) mixing and capsule are filled
Utilize double-cone mixer mixed process 1) and 2) end product.After mixture adds sodium starch glycollate, utilize double-cone mixer to mix.Then add magnesium stearate and carry out final mixed to mixture.The mixture of final mixed is placed powder feeder, utilize capsule filling machine (SF-40N, Sejong Pharmatech Co., Ltd., South Korea) to fill and prepare the release control preparation of capsule shape.
Embodiment 4: the preparation (tablet-piller) of aliskiren-amlodipine capsule
Utilize the composition and the content of table 1, prepare capsule as follows.
1) contains the preparation that formerly discharges compartment of aliskiren
Aliskiren hemifumarate, microcrystalline Cellulose, D-mannitol, lactose are sieved with No. 35, and mix with super mixer.In addition, with the hydroxypropyl cellulose adhesive solution (5%W-W) for preparing soluble in water, and this adhesive solution and main constituent mixture together mediated.After accomplishing kneading, utilize agitator to carry out pelletize, and utilize the hot water exsiccator under 60 ℃, to carry out drying with No. 18 sieves.After accomplishing drying, sieve through No. 20 once more.Material after screening adds sodium starch glycollate, and utilizes double-cone mixer to mix.Then, add magnesium stearate and carry out final mixed to mixture.And utilize rotary tablet machine that said final mixture is carried out tabletting.
2) contain the preparation of the slow release compartment of amlodipine
Amlodipine Besylate Tablet, microcrystalline Cellulose, hydroxypropyl methylcellulose mixtures are distributed in 8: 2 mixed liquors of ethanol and pure water and as medicine layer coating solution (20%W/W); After the granulating coated machine of co-current flow bed is put into sugar pill, coat with said medicine layer coating solution.Afterwards, be utilized in that the dissolving resulting solution of HPMCP (5%W-W) appends coating in 1: 1 mixed liquor of ethanol and dichloromethane, thus preparation amlodipine piller.
3) capsule is filled
Utilize capsule filling machine to process 1) and 2) final constituent fill and prepare the preparation of capsule shape.
Embodiment 5: the preparation (granule-granule) of aliskiren-amlodipine capsule
Utilize the composition and the content of table 1, prepare capsule as follows.
1) contains the preparation that formerly discharges compartment of aliskiren
Aliskiren hemifumarate, microcrystalline Cellulose, D-mannitol are sieved with No. 35, and mixes with super mixer.In addition, with the hydroxypropyl cellulose adhesive solution (5%W-W) for preparing soluble in water, and this adhesive solution and main constituent mixture together mediated.After accomplishing kneading, utilize agitator to carry out pelletize, and utilize the hot water exsiccator under 60 ℃, to carry out drying with No. 18 sieves.After accomplishing drying, sieve through No. 20 once more.
2) contain the preparation of the slow release compartment of amlodipine
Amlodipine Besylate Tablet, microcrystalline Cellulose are sieved with No. 35, and mix 5 minutes preparation mixture with super mixer.Said mixture is put into fluidized bed granulation coating machine, spray simultaneously hydroxypropyl emthylcellulose resulting adhesive solution soluble in water (5%W-W) and form granule, and carry out drying.Afterwards, be sprayed at the dissolving resulting solution of HPMCP (5%W-W) in 1: 1 mixed liquor of ethanol and dichloromethane and coated particle to said granule.
3) mixing and capsule are filled
Utilize double-cone mixer mixed process 1) and 2) end product.After mixture adds sodium starch glycollate, utilize double-cone mixer to mix.Then add magnesium stearate and carry out final mixed to mixture.The mixture of final mixed is placed powder feeder, utilize capsule filling machine to fill and prepare the preparation of capsule shape.
Embodiment 6: the preparation (granule-tablet) of aliskiren-amlodipine capsule
Utilize the composition and the content of table 1, prepare capsule as follows.
1) contains the preparation that formerly discharges compartment of aliskiren
Aliskiren hemifumarate, microcrystalline Cellulose, D-mannitol, sodium starch glycollate are sieved with No. 35, and mix with super mixer.In addition, with the hydroxypropyl cellulose adhesive solution (5%W-W) for preparing soluble in water, and this adhesive solution and main constituent mixture together mediated.After accomplishing kneading, utilize agitator to carry out pelletize, and utilize the hot water exsiccator under 60 ℃, to carry out drying with No. 18 sieves.After accomplishing drying, sieve through No. 20 once more.
2) contain the preparation of the slow release compartment of amlodipine
Amlodipine Besylate Tablet, microcrystalline Cellulose are sieved with No. 35, and mix 5 minutes preparation mixture with super mixer.Said mixture is put into fluidized bed granulation coating machine, spray simultaneously hydroxypropyl emthylcellulose resulting adhesive solution soluble in water (5%W-W) and form granule, and carry out drying.Afterwards, after said granule adds pulverous carbomer 71G, put into magnesium stearate, finally mix with double-cone mixer at this.
It is that 7～9kp, thickness are that 3.0mm, length are the sheet of 5.5mm that the speed of utilizing rotary tablet machine to change with per minute 30 is pressed into hardness with said final mixture.Afterwards, be utilized in that the dissolving resulting solution of HPMCP (5%W-W) carries out coating and prepares amlodipine sustained release coating tablet in 1: 1 mixed liquor of ethanol and dichloromethane.
3) capsule is filled
Utilize capsule filling machine to process 1) and 2) end product fill and prepare the preparation of capsule shape.
Embodiment 7: the preparation (tablet-tablet) of aliskiren-amlodipine capsule
Utilize the composition and the content of table 2, prepare capsule as follows.
1) contains the preparation that formerly discharges compartment of aliskiren
Aliskiren hemifumarate, microcrystalline Cellulose, D-mannitol are sieved with No. 35, and mixes with super mixer.In addition, with the hydroxypropyl cellulose adhesive solution (5%W-W) for preparing soluble in water, and this adhesive solution and main constituent mixture together mediated.After accomplishing kneading, utilize agitator to carry out pelletize, and utilize the hot water exsiccator under 60 ℃, to carry out drying with No. 18 sieves.After accomplishing drying, sieve through No. 20 once more.Material after screening adds sodium starch glycollate, and utilizes double-cone mixer to mix.Then, add magnesium stearate and carry out final mixed to mixture.And utilize rotary tablet machine that said final mixture is carried out tabletting.
2) contain the preparation of the slow release compartment of amlodipine
Amlodipine Besylate Tablet, microcrystalline Cellulose are sieved with No. 35, and mix 5 minutes preparation mixture with super mixer.Said mixture is put into fluidized bed granulation coating machine, spray simultaneously hydroxypropyl emthylcellulose resulting adhesive solution soluble in water (5%W-W) and form granule, and carry out drying.Afterwards, after said granule adds pulverous carbomer 71G, put into magnesium stearate, finally mix with double-cone mixer at this.
It is that 7～9kp, thickness are that 3.0mm, length are the sheet of 5.5mm that the speed of utilizing rotary tablet machine to change with per minute 30 is pressed into hardness with said final mixture.Afterwards, be utilized in that the dissolving resulting solution of HPMCP (5%W-W) carries out coating and prepares the sustained release coating tablet in 1: 1 mixed liquor of ethanol and dichloromethane.
3) capsule is filled
Utilize capsule filling machine to process 1) and 2) end product fill and prepare the release control preparation of capsule shape.
Embodiment 8: the preparation of aliskiren-Amlodipine Besylate Tablet pressed coated tablet
Utilize the composition and the content of table 2, prepare the pressed coated tablet as follows.
1) contains the preparation that formerly discharges compartment of aliskiren
Aliskiren hemifumarate, microcrystalline Cellulose, D-mannitol are sieved with No. 35, and mixes with super mixer.In addition, with the hydroxypropyl cellulose adhesive solution (5%W-W) for preparing soluble in water, and this adhesive solution and main constituent mixture together mediated.After accomplishing kneading, utilize agitator to carry out pelletize, and utilize the hot water exsiccator under 60 ℃, to carry out drying with No. 18 sieves.After accomplishing drying, sieve through No. 20 once more.Material after screening adds sodium starch glycollate, and utilizes double-cone mixer to mix.Then, after mixture adds magnesium stearate, carry out final mixed.
2) contain the preparation of the slow release compartment of amlodipine
Amlodipine Besylate Tablet, microcrystalline Cellulose are sieved with No. 35, and mix 5 minutes preparation mixture with super mixer.Said mixture is put into fluidized bed granulation coating machine, spray simultaneously hydroxypropyl emthylcellulose resulting adhesive solution soluble in water (5%W-W) and form granule, and carry out drying.Afterwards, after said granule adds pulverous carbomer 71G, put into magnesium stearate, finally mix with double-cone mixer at this.
It is that 7～9kp, thickness are that 3.0mm, length are the sheet of 5.5mm that the speed of utilizing rotary tablet machine to change with per minute 30 is pressed into hardness with said final mixture.Afterwards, be utilized in that the dissolving resulting solution of HPMCP (5%W-W) carries out coating and prepares amlodipine sustained release coating inner core in 1: 1 mixed liquor of ethanol and dichloromethane.
3) tabletting and coating
Use pressed coated tablet machine (RUD-1; Kilian; Germany) with amlodipine sustained release coating inner core tablet as inner core and the constituent that will contain aliskiren hemifumarate as outer and accomplish preparation to the pressed coated tablet; Afterwards, with METHOCEL E15LV, hydroxypropyl cellulose, titanium oxide and Talcum dissolving and be dispersed in ethanol and the pure water and preparation coating solution (20%W/W).After said pressed coated tablet put into Hi-coating machine, coat with coating solution and prepare the pressed coated tablet of coating.
Embodiment 9: the preparation of aliskiren-amlodipine maleate pressed coated tablet
Utilize the composition and the content of table 2, prepare the pressed coated tablet as follows.
1) contains the preparation that formerly discharges compartment of aliskiren
Aliskiren hemifumarate, microcrystalline Cellulose, D-mannitol are sieved with No. 35, and mixes with super mixer.In addition, with the hydroxypropyl cellulose adhesive solution (5%W-W) for preparing soluble in water, and this adhesive solution and main constituent mixture together mediated.After accomplishing kneading, utilize agitator to carry out pelletize, and utilize the hot water exsiccator under 60 ℃, to carry out drying with No. 18 sieves.After accomplishing drying, sieve through No. 20 once more.Material after screening adds sodium starch glycollate, and utilizes double-cone mixer to mix.Then, after mixture adds magnesium stearate, carry out final mixed.
2) contain the preparation of the slow release compartment of amlodipine
Amlodipine maleate, microcrystalline Cellulose are sieved with No. 35, and mix 5 minutes preparation mixture with super mixer.Said mixture is put into fluidized bed granulation coating machine, spray simultaneously hydroxypropyl emthylcellulose resulting adhesive solution soluble in water (5%W-W) and form granule, and carry out drying.Afterwards, after said granule adds pulverous carbomer 71G, put into magnesium stearate, finally mix with double-cone mixer at this.
It is that 7～9kp, thickness are that 3.0mm, length are the sheet of 5.5mm that the speed of utilizing rotary tablet machine to change with per minute 30 is pressed into hardness with said final mixture.Afterwards, be utilized in that the dissolving resulting solution of HPMCP (5%W-W) carries out coating and prepares the coated inner cores that discharges amlodipine by time difference in 1: 1 mixed liquor of ethanol and dichloromethane.
3) tabletting and coating
Use pressed coated tablet machine (RUD-1; Kilian; Germany) with Amlodipine Besylate Tablet coated inner cores tablet as inner core and the constituent that will contain aliskiren hemifumarate as outer and accomplish preparation to the pressed coated tablet; Afterwards, with METHOCEL E15LV, hydroxypropyl cellulose, titanium oxide and Talcum dissolving and be dispersed in 8: 2 mixed liquors of ethanol and pure water and preparation coating solution (20%W/W).After said pressed coated tablet put into Hi-coating machine, coat with coating solution and prepare the pressed coated tablet of coating.
Embodiment 10: the preparation of aliskiren-(S)-Amlodipine Besylate Tablet pressed coated tablet
Utilize the composition and the content of table 2, prepare the pressed coated tablet as follows.
1) contains the preparation that formerly discharges compartment of aliskiren
Aliskiren hemifumarate, microcrystalline Cellulose, D-mannitol are sieved with No. 35, and mixes with super mixer.In addition, with the hydroxypropyl cellulose adhesive solution (5%W-W) for preparing soluble in water, and this adhesive solution and main constituent mixture together mediated.After accomplishing kneading, utilize agitator to carry out pelletize, and utilize the hot water exsiccator under 60 ℃, to carry out drying with No. 18 sieves.After accomplishing drying, sieve through No. 20 once more.Material after screening adds sodium starch glycollate, and utilizes double-cone mixer to mix.Then, after mixture adds magnesium stearate, carry out final mixed.
2) contain the preparation of the slow release compartment of amlodipine
(S)-Amlodipine Besylate Tablet, microcrystalline Cellulose are sieved with No. 35, and mix 5 minutes preparation mixture with super mixer.Said mixture is put into fluidized bed granulation coating machine, spray simultaneously hydroxypropyl emthylcellulose resulting adhesive solution soluble in water (5%W-W) and form granule, and carry out drying.Afterwards, after said granule adds pulverous carbomer 71G, put into magnesium stearate, finally mix with double-cone mixer at this.
It is that 7～9kp, thickness are that 3.0mm, length are the sheet of 5.5mm that the speed of utilizing rotary tablet machine to change with per minute 30 is pressed into hardness with said final mixture.Afterwards, be utilized in that the dissolving resulting solution of HPMCP (5%W-W) carries out coating and prepares amlodipine sustained release coating inner core in 1: 1 mixed liquor of ethanol and dichloromethane.
3) tabletting and coating
Use pressed coated tablet machine (RUD-1; Kilian; Germany) with Amlodipine Besylate Tablet coated inner cores tablet as inner core and the constituent that will contain aliskiren hemifumarate as outer and accomplish preparation to the pressed coated tablet; Afterwards, with METHOCEL E15LV, hydroxypropyl cellulose, titanium oxide and Talcum dissolving and be dispersed in 8: 2 mixed liquors of ethanol and pure water and preparation coating solution (20%W/W).After said pressed coated tablet put into Hi-coating machine, coat with coating solution and prepare the pressed coated tablet of coating.
Embodiment 11: the preparation of aliskiren-lercanidipine multilayer tablet
Utilize the composition and the content of table 2, prepare multilayer tablet as follows.
1) contains the preparation that formerly discharges compartment of aliskiren
With aliskiren hemifumarate with sieve with No. 35, and mix as microcrystalline Cellulose, the D-mannitol of excipient with super mixer.In addition, with the hydroxypropyl cellulose adhesive solution (5%W-W) for preparing soluble in water, and this adhesive solution and main constituent mixture together mediated.After accomplishing kneading, utilize agitator to carry out pelletize, and utilize the hot water exsiccator under 60 ℃, to carry out drying with No. 18 sieves.After accomplishing drying, sieve through No. 20 once more.Material mixing sodium starch glycollate after screening, and after adding magnesium stearate, utilize double-cone mixer to carry out final mixed.
2) contain the preparation of the slow release compartment of lercanidipine
Lercanidipine hydrochloride, microcrystalline Cellulose are sieved with No. 35, and mixed 5 minutes and the preparation mixture with super mixer.Said mixture is put in the fluidized bed granulation coating machine, sprayed simultaneously hydroxypropyl emthylcellulose prepared adhesive solution soluble in water (5%W-W) and form granule, carry out drying again.Afterwards, be sprayed at the dissolving resulting solution of HPMCP (5%W-W) in 1: 1 mixed liquor of ethanol and dichloromethane and coated particle to said granule.And after it adds magnesium stearate, utilize double-cone mixer (Dasan Pharmatech, South Korea) to carry out final mixed.
3) tabletting and coating
Use multilamellar tablet machine (MRC-37T, Sejong Pharmatech Co., Ltd., South Korea) to carry out tabletting.The constituent that will contain lercanidipine is put into first powder feeder, after the constituent that contains aliskiren hemifumarate is put into second powder feeder, carries out tabletting can minimize the condition that interlayer mixes.Simultaneously; With METHOCEL E15LV, hydroxypropyl cellulose, titanium oxide and Talcum dissolving and be dispersed in 8: 2 mixed liquors of ethanol and pure water and preparation coating solution (20%W/W); And utilize Hi-coating machine to form the film coating layer to coating coating solution on the said tablet, prepare multilayer tablet thus.
Embodiment 12: the preparation of aliskiren-lacidipine pressed coated tablet
Utilize the composition and the content of table 2, prepare the pressed coated tablet as follows.
1) contains the preparation that formerly discharges compartment of aliskiren
Aliskiren hemifumarate, microcrystalline Cellulose, D-mannitol are sieved with No. 35, and mixes with super mixer.In addition, with the hydroxypropyl cellulose adhesive solution (5%W-W) for preparing soluble in water, and this adhesive solution and main constituent mixture together mediated.After accomplishing kneading, utilize agitator to carry out pelletize, and utilize the hot water exsiccator under 60 ℃, to carry out drying with No. 18 sieves.After accomplishing drying, sieve through No. 20 once more.Material after screening adds sodium starch glycollate, and utilizes double-cone mixer to mix.Then, after mixture adds magnesium stearate, carry out final mixed.
2) contain the preparation of the slow release compartment of lacidipine
Lacidipine, microcrystalline Cellulose are sieved with No. 35, and mix 5 minutes preparation mixture with super mixer.Said mixture is put into fluidized bed granulation coating machine, spray simultaneously hydroxypropyl emthylcellulose resulting adhesive solution soluble in water (5%W-W) and form granule, and carry out drying.Afterwards, after said granule adds pulverous carbomer 71G, put into magnesium stearate, finally mix with double-cone mixer at this.
It is that 7～9kp, thickness are that 3.0mm, length are the sheet of 5.5mm that the speed of utilizing rotary tablet machine to change with per minute 30 is pressed into hardness with said final mixture.Afterwards, be utilized in that the dissolving resulting solution of HPMCP (5%W-W) carries out coating and prepares Lacidipine sustained-release coated inner cores tablet in 1: 1 mixed liquor of ethanol and dichloromethane.
3) tabletting and coating
Use pressed coated tablet machine (RUD-1; Kilian; Germany) with Lacidipine sustained-release coated inner cores tablet as inner core and the constituent that will contain aliskiren hemifumarate as outer and accomplish preparation to the pressed coated tablet; Afterwards, with METHOCEL E15LV, hydroxypropyl cellulose, titanium oxide and Talcum dissolving and be dispersed in 8: 2 mixed liquors of ethanol and pure water and preparation coating solution (20%W/W).After said pressed coated tablet put into Hi-coating machine (SFC-30N:Sejong), coat with coating solution and prepare the pressed coated tablet of coating.
Embodiment 13: aliskiren-amlodipine blister package medicine box
Utilize the composition and the content of table 2, prepare the pressed coated tablet as follows.
Replace among the embodiment 5 1) aliskiren release particles and 2 formerly) the amlodipine slow-releasing granules mixes and carries out the process of tabletting; Process 1 with embodiment 5) with 2) after identical composition, content and method prepare granule; Use rotary tablet machine (MRC-33:Sejong) that the final constituent of each process is carried out tabletting respectively, and utilize suction plastic packing machine (Minister A, Heung-A Engineering) to be packaged in blister package container (paper tinsel, Dong-il Corporation; PVDC; Jeon Min Industry Co., Ltd.) in so that can take them simultaneously.
[table 1]
Figure BPA00001422680900301
Figure BPA00001422680900311
[table 2]
Figure BPA00001422680900312
Figure BPA00001422680900321
Experimental example 1: relatively stripping curve test (comparative dissolution profile test)
Utilize the aliskiren-amlodipine two-phase matrix tablet and the control drug (Norvasc: the single preparation of amlodipine, Tekturna: the single preparation of aliskiren) compare the stripping curve test of preparation among the said embodiment 1.The test of the stripping curve of aliskiren composition is carried out based on the general dissolution test method described in the Da Han pharmacopeia (the 8th edition), and the stripping curve test of amlodipine composition is 120 minutes being that benchmark changes to simulated intestinal fluid with dissolution fluid from simulated gastric fluid and came to carry out altogether 480 minutes.The method of each composition stripping curve test is following, and its result is presented among Fig. 1.
Fig. 1 is the aliskiren-amlodipine preparation that illustrates according to first embodiment preparation; And as the figure of the comparison stripping curve of the single preparation Tekturna of aliskiren of control drug and the single preparation Norvasc of amlodipine; Wherein, the x axle is represented elapsed time, and the y axle is represented dissolution rate (%).
According to shown in Figure 1; Two-phase matrix tablet of the present invention is when stripping curve is tested; The aliskiren composition shows the dissolution characteristic that almost is equal to than control formulation Tekturna, but the stripping of amlodipine composition is very slow than the control formulation Norvasc.Aliskiren of the present invention-amlodipine two-phase matrix tablet is till 1 hour, and the dissolution rate of amlodipine composition is lower than 5%, and hence one can see that, and is very slow than the dissolution rate of control formulation about 99%.
So; Be different from the stripping curve when taking simultaneously as the single preparation of aliskiren of control drug and the single preparation of amlodipine; In aliskiren of the present invention-amlodipine two-phase sustained release preparation; Because the initial release of amlodipine is much slower than aliskiren, therefore can fully guarantee aliskiren resorbent time after liver can be at first by metabolism.
[aliskiren hemifumarate test method]
The basis of stripping curve test: the general dissolution test method in the Da Han pharmacopeia the 8th edition
Test method: oar method (Paddle method), 50 rev/mins
Testing liquid: pure water, 900mL
Analytical method: UV-Vis spectrophotography
[amlodipine test method]
The basis of stripping curve test: the general dissolution test method in the Da Han pharmacopeia the 8th edition
Test method: oar method (Paddle method), 50 rev/mins
Testing liquid: 0.01M hydrochloric acid solution, 750mL (simulated gastric fluid)
PH6.8 phosphate buffer, 1000mL (simulated intestinal fluid) altogether
Analytical method: UV-Vis spectrophotography
Experimental example 2: relatively stripping curve test (comparative dissolution profile test)
Utilize the aliskiren-amlodipine multilayer tablet and the control drug (Norvasc: the single preparation of amlodipine, Tekturna: the single preparation of aliskiren) compare the stripping curve test of preparation among the said embodiment 2.The test of the stripping curve of aliskiren is carried out based on the general dissolution test method described in the Da Han pharmacopeia the 8th edition, and the stripping curve test of amlodipine composition is 120 minutes being that benchmark changes to simulated intestinal fluid with dissolution fluid from simulated gastric fluid and came to carry out altogether 480 minutes.The method of each composition stripping curve test is identical with experimental example 1, and its result is presented among Fig. 2.
Fig. 2 is the aliskiren-amlodipine preparation that illustrates according to second embodiment preparation; And as the figure of the comparison stripping curve of the single preparation Tekturna of aliskiren of control drug and the single preparation Norvasc of amlodipine; Wherein, the x axle is represented elapsed time, and the y axle is represented dissolution rate (%).
According to shown in Figure 2, the multilayer tablet of embodiment 2 is when stripping curve is tested, and the aliskiren composition shows the dissolution characteristic that almost is equal to than control formulation Tekturna, but the stripping of amlodipine is very slow than the control formulation Norvasc.Aliskiren of the present invention-amlodipine multilayer tablet is till 1 hour, and the dissolution rate of amlodipine composition is lower than 10%, and hence one can see that, and is very slow than the dissolution rate of control formulation about 99%.
So; Be different from the stripping curve when taking simultaneously as the single preparation of aliskiren of control drug and the single preparation of amlodipine; In aliskiren of the present invention-amlodipine multilayer tablet; Because the initial release of amlodipine is much slower than aliskiren, therefore can fully guarantee aliskiren resorbent time after liver can be at first by metabolism.
Experimental example 3: relatively stripping curve test (comparative dissolution profile test)
Utilize the aliskiren-amlodipine capsule and the control drug (Norvasc: the single preparation of amlodipine, Tekturna: the single preparation of aliskiren) compare the stripping curve test of preparation among the said embodiment 3～6.The test of the stripping curve of aliskiren is carried out based on the general dissolution test method described in the Da Han pharmacopeia the 8th edition, and its result is presented among Fig. 3.
Fig. 3 is the aliskiren-amlodipine preparation that illustrates according to the 3rd to the 6th embodiment preparation; And as the figure of the comparison stripping curve of the single preparation Tekturna of aliskiren of control drug; Wherein, the x axle is represented elapsed time, and the y axle is represented dissolution rate (%).
In addition, the stripping curve of amlodipine composition test is 120 minutes to be that benchmark changes to simulated intestinal fluid with dissolution fluid from simulated gastric fluid and came to carry out altogether 480 minutes, and its result is presented among Fig. 4.
Fig. 4 is the aliskiren-amlodipine preparation that illustrates according to the 3rd to the 6th embodiment preparation, and as the figure of the comparison stripping curve of the single preparation Norvasc of amlodipine of control drug, wherein, the x axle is represented elapsed time, and the y axle is represented dissolution rate (%).
The method of each composition stripping curve test is identical with experimental example 1.
According to shown in Figure 3, capsule of the present invention is when stripping curve is tested, and the aliskiren composition shows the dissolution characteristic that almost is equal to than control formulation Tekturna, and is as shown in Figure 4, and the stripping of amlodipine is very slow than the control formulation Norvasc.Aliskiren of the present invention-amlodipine capsule is till 1 hour, and the dissolution rate of amlodipine composition is lower than 10%, and hence one can see that, and is very slow than the dissolution rate of control formulation about 99%.
So; Be different from the stripping curve when taking simultaneously as the single preparation of aliskiren of control drug and the single preparation of amlodipine; In aliskiren of the present invention-amlodipine capsule; Because the initial release of amlodipine is much slower than aliskiren, therefore can fully guarantee aliskiren resorbent time after liver can be at first by metabolism.
Experimental example 4: relatively stripping curve test (comparative dissolution profile test)
Utilize the aliskiren-amlodipine pressed coated tablet and the control drug (Norvasc: the single preparation of amlodipine, Tekturna: the single preparation of aliskiren) compare the stripping curve test of preparation among the said embodiment 9.The test of the stripping curve of aliskiren composition is carried out based on the general dissolution test method of record in the Da Han pharmacopeia the 8th edition, and the stripping curve test of amlodipine composition is 120 minutes being that benchmark changes to simulated intestinal fluid with dissolution fluid from simulated gastric fluid and came to carry out altogether 480 minutes.The method of each composition stripping curve test is identical with experimental example 1, and its result is presented among Fig. 5.
Fig. 5 is the aliskiren-amlodipine preparation that illustrates according to the 9th embodiment preparation; And as the figure of the comparison stripping curve of the single preparation Tekturna of aliskiren of control drug and the single preparation Norvasc of amlodipine; Wherein, the x axle is represented elapsed time, and the y axle is represented dissolution rate (%).
According to shown in Figure 5, the pressed coated tablet of embodiment 5 is when stripping curve is tested, and the aliskiren composition shows the dissolution characteristic that almost is equal to than control formulation Tekturna, but the stripping of amlodipine is very slow than the control formulation Norvasc.Aliskiren of the present invention-amlodipine pressed coated tablet is till 1 hour, and the dissolution rate of amlodipine composition is lower than 5%, and hence one can see that, and is very slow than the dissolution rate of control formulation about 99%.
So; Be different from the stripping curve when taking simultaneously as the single preparation of aliskiren of control drug and the single preparation of amlodipine; In aliskiren of the present invention-amlodipine pressed coated tablet; Because the initial release of amlodipine is much slower than aliskiren, therefore can fully guarantee aliskiren resorbent time after liver can be at first by metabolism.
Experimental example 5: relatively stripping curve test (comparative dissolution profile test)
Utilize the aliskiren-lercanidipine multilayer tablet and the control drug of preparation among the said embodiment 11 (rather flat again: the single preparation of lercanidipine, Tekturna: the single preparation of aliskiren) compare the stripping curve test.The test of the stripping curve of aliskiren is carried out based on the general dissolution test method of record in the Da Han pharmacopeia the 8th edition, and the stripping curve test of lercanidipine composition is 120 minutes being that benchmark changes to simulated intestinal fluid with dissolution fluid from simulated gastric fluid and came to carry out altogether 480 minutes.In the method for each composition stripping curve test, aliskiren is identical with experimental example 1, and lercanidipine is following.Its result is presented among Fig. 6.
Fig. 6 is the aliskiren-lercanidipine preparation that illustrates according to the 11 embodiment preparation; And as the single preparation Tekturna of aliskiren of control drug and the single preparation of the lercanidipine peaceful figure of flat comparison stripping curve again; Wherein, The x axle is represented elapsed time, and the y axle is represented dissolution rate (%).
According to shown in Figure 6, multilayer tablet of the present invention is when stripping curve is tested, and the aliskiren composition shows the dissolution characteristic that almost is equal to than control formulation Tekturna, but the stripping of lercanidipine is rather flat more very slow than control formulation.Aliskiren of the present invention-lercanidipine multilayer tablet is till 1 hour, and the dissolution rate of lercanidipine composition is lower than 10%, and hence one can see that, and is very slow than the dissolution rate of control formulation about 99%.
So; Be different from the stripping curve when taking simultaneously as the single preparation of aliskiren of control drug and the single preparation of lercanidipine; In aliskiren of the present invention-lercanidipine multilayer tablet; Because the initial release of lercanidipine is much slower than aliskiren, therefore can fully guarantee aliskiren resorbent time after liver can be at first by metabolism.
[lercanidipine test method]
The basis of stripping curve test: the general dissolution test method in the Da Han pharmacopeia the 8th edition
Test method: oar method (Paddle method), 50 rev/mins
Testing liquid: 0.01M hydrochloric acid solution, 750mL (simulated gastric fluid)
Analytical method: high-speed liquid chromatography
Experimental example 6: relatively stripping curve test (comparative dissolution profile test)
Utilize among the said embodiment 12 preparation aliskiren-lacidipine pressed coated tablet and control drug (Vaxar:; The single preparation of lacidipine, Tekturna: the single preparation of aliskiren) compare the stripping curve test.The test of the stripping curve of aliskiren is carried out based on the general dissolution test method of record in the Da Han pharmacopeia the 8th edition, and the stripping curve test of lacidipine composition is 120 minutes being that benchmark changes to simulated intestinal fluid with dissolution fluid from simulated gastric fluid and came to carry out altogether 480 minutes.In the method for each composition stripping curve test, aliskiren is identical with experimental example 1, and lacidipine is following.Its result is presented among Fig. 7.
Fig. 7 is the aliskiren-lacidipine preparation that illustrates according to the 12 embodiment preparation; And as the figure of the comparison stripping curve of the single preparation Tekturna of aliskiren of control drug and the single preparation Vaxar of lacidipine; Wherein, the x axle is represented elapsed time, and the y axle is represented dissolution rate (%).
According to shown in Figure 7, pressed coated tablet of the present invention is when stripping curve is tested, and the aliskiren composition shows the dissolution characteristic that almost is equal to than control formulation Tekturna, but the stripping of lacidipine is very slow than control formulation Vaxar.Aliskiren of the present invention-lacidipine pressed coated tablet is till 1 hour, and the dissolution rate of lacidipine composition is lower than 10%, and hence one can see that, and is very slow than the dissolution rate of control formulation about 99%.
So; Be different from the stripping curve when taking simultaneously as the single preparation of aliskiren of control drug and the single preparation of lacidipine; In aliskiren of the present invention-lacidipine pressed coated tablet; Because the initial release of lacidipine is much slower than aliskiren, therefore can fully guarantee aliskiren resorbent time after liver can be at first by metabolism.
[lacidipine test method]
The basis of stripping curve test: the general dissolution test method in the Da Han pharmacopeia the 8th edition
Test method: oar method (Paddle method), 75 rev/mins
Testing liquid: 0.01M hydrochloric acid solution, 750mL (simulated gastric fluid)
Analytical method: high-speed liquid chromatography
Utilizability on the industry
The present invention provides and comprises the compartment of release formerly that contains as the renin inhibitor of pharmacological component, and contains the pharmaceutical preparation as the slow release compartment of the dihydropyridine calcium channel blockers of pharmacological component.Pharmaceutical preparation of the present invention can prevent the interaction of renin inhibitor and dihydropyridine calcium channel blockers pharmacokinetics in vivo; And guiding is based on the pharmacological effect of the best of absorbability in the body of each active component; And improve clinical effectiveness through discharging medicine in the time period that shows pharmacological effect at each active component; Thereby can effectively prevent or treat metabolic syndrome, cardiovascular disease, nephropathy, therefore have the utilizability on the industry.

Claims (34)

1. pharmaceutical preparation comprises: contain the compartment of release formerly as the renin inhibitor of pharmacological component; And contain slow release compartment as the dihydropyridine calcium channel blockers of pharmacological component.
2. pharmaceutical preparation according to claim 1 is characterized in that said renin inhibitor is for selected at least a from aliskiren, remikiren, enalkiren, zankiren, ditekiren, terlakiren, their isomer or their the acceptable salt of pharmacy.
3. pharmaceutical preparation according to claim 1 is characterized in that said dihydropyridine calcium channel blockers is for selected at least a from amlodipine, lercanidipine, lacidipine, felodipine, barnidipine, benidipine, cilnidipine, isradipine, Manidipine, nicardipine, nifedipine, nimodipine, nilvadipine, nisoldipine, nitrendipine, azelnidipine, their isomer or their the acceptable salt of pharmacy.
4. according to any described pharmaceutical preparation in the claim 1 to 3, it is characterized in that said renin inhibitor is an aliskiren hemifumarate.
5. according to any described pharmaceutical preparation in the claim 1 to 3, it is characterized in that said dihydropyridine calcium channel blockers is an amlodipine benzenesulphonate.
6. according to any described pharmaceutical preparation in the claim 1 to 3, it is characterized in that the said active component that formerly discharges compartment begins to be released within an hour at it, in the delivery formulations more than the 80 weight % of active component total amount.
7. according to any described pharmaceutical preparation in the claim 1 to 3; Till the active component that it is characterized in that the slow release compartment 2 hours after the active component that formerly discharges compartment begins to discharge; Release is lower than 40 weight % of slow release compartment active component total amount; Till 5 hours after the active component that formerly discharges compartment begins to discharge, discharge more than the 80 weight % of slow release compartment active component total amount.
8. according to any described pharmaceutical preparation in the claim 1 to 3, it is characterized in that the said renin inhibitor with respect to 100 weight portions, said dihydropyridine calcium channel blockers is 0.1～400 weight portion.
9. according to any described pharmaceutical preparation in the claim 1 to 3, it is characterized in that the content of said renin inhibitor in pharmaceutical preparation is 10～1000mg.
10. according to any described pharmaceutical preparation in the claim 1 to 3, it is characterized in that the content of said dihydropyridine calcium channel blockers in pharmaceutical preparation is 0.1～200mg.
11., it is characterized in that said slow release compartment contains selected at least a release control material from enteric polymer, insoluble polymer, hydrophobic compound, hydrophilic polymer and their mixture according to any described pharmaceutical preparation in the claim 1 to 3.
12. pharmaceutical preparation according to claim 11 is characterized in that the dihydropyridine calcium channel blockers with respect to 1 weight portion, the content of said release control material is 0.01～100 weight portion.
13. pharmaceutical preparation according to claim 11 is characterized in that said enteric polymer is for selected at least a the crowd who constitutes from enteric cellulose derivative, enteric acrylic copolymer, enteric maleic acid, enteric polyvinyl derivant and by their mixture.
14. pharmaceutical preparation according to claim 13 is characterized in that said enteric cellulose derivative is at least a for what from succinic acid acetic acid hydroxypropyl emthylcellulose, HPMCP, hydroxymethyl ethyl cellulose phthalate, cellulose acetate phthalic acid ester, cellulose acetate succinate, cellulose acetate maleate, benzoic acid cellulose phthalate, cellulose propionate phthalic acid ester, methyl cellulose phthalate ester, carboxymethylethylcellulose, ethylhydroxyethylcellulose phthalic acid ester, methyl hydroxyethylcellulose and their mixture, select; Said enteric acrylic copolymer is at least a for what from styrene-propene acid copolymerization, acrylic acid methyl ester-acrylic copolymer, acrylic acid methyl ester. EUDRAGIT S100, BA-St-acrylic copolymer, methacrylic acid-methylmethacrylate copolymer, EUDRAGIT L100-55, acrylic acid methyl ester-methacrylic acid-1-Octyl acrylate copolymer and their mixture, select; Said enteric maleic acid is at least a for what from vinyl acetate-copolymer-maleic anhydride, styrene-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, vinyl methyl ether-copolymer-maleic anhydride, ethylene-copolymer-maleic anhydride, vinyl butyl ether-copolymer-maleic anhydride, acrylonitrile-acrylic acid methyl ester .-copolymer-maleic anhydride, BA-St-copolymer-maleic anhydride and their mixture, select; Said enteric polyvinyl derivant is for gathering at least a that vinyl butyrate, phthalic acid polyvinyl alcohol contract and select acetyl acetaldehyde ester and their mixture from phthalic acid polyvinyl alcohol ester, phthalic acid polyvinyl acetal ester, phthalic acid.
15. pharmaceutical preparation according to claim 11 is characterized in that the active component with respect to 1 weight portion, said enteric polymer is 0.1 weight portion to 20 weight portion.
16. pharmaceutical preparation according to claim 11, it is characterized in that said insoluble polymer for from polyvinyl acetate, polymethacrylate copolymer, gather (ethyl acrylate, methyl methacrylate) copolymer, gather (ethyl acrylate, methyl methacrylate, methacrylic acid trimethyl amino ethyl ester) copolymer, select ethyl cellulose, cellulose esters, cellulose ether, acylated cellulose, two acylated celluloses, three acylated celluloses, cellulose acetate, cellulose diacetate, cellulose triacetate and the crowd that constitutes by their mixture at least a.
17. pharmaceutical preparation according to claim 16, it is characterized in that said insoluble polymer for from polyvinyl acetate, polymethacrylate copolymer, gather (ethyl acrylate, methyl methacrylate, methacrylic acid trimethyl amino ethyl ester) copolymer, ethyl cellulose, cellulose acetate and the crowd that constitutes by their mixture select at least a.
18. pharmaceutical preparation according to claim 11 is characterized in that the active component with respect to 1 weight portion, said insoluble polymer is 0.1 weight portion to 30 weight portion.
19. pharmaceutical preparation according to claim 11 is characterized in that at least a for selection the crowd who constitutes from fatty acid and fatty acid ester, fatty acid alcohol, wax, inorganic matter and by their mixture of said hydrophobic compound.
20. pharmaceutical preparation according to claim 19 is characterized in that said fatty acid and fatty acid ester are at least a for what from Palmic acid tristerin, tristerin, Compritol 888 ATO, cetyl palmitate, glyceryl monooleate, stearic acid and their mixture, select; Said fatty acid alcohol is at least a for what from cetostearyl alcohol, hexadecanol, octadecanol and their mixture, select; Said wax is at least a for what from Brazil wax, Cera Flava, microwax and their mixture, select; Said inorganic matter is at least a for what from Talcum, winnofil, calcium hydrogen phosphate, zinc oxide, titanium oxide, Kaolin, bentonite, Montmorillonitum, aluminium-magnesium silicate and their mixture, select.
21. pharmaceutical preparation according to claim 11 is characterized in that the active component with respect to 1 weight portion, said hydrophobic compound is 0.1 weight portion to 50 weight portion.
22. pharmaceutical preparation according to claim 11 is characterized in that said hydrophilic polymer is at least a for what select the crowd who constitutes from saccharide, cellulose derivative, natural gum, protein, polyvinyl derivant, polymethacrylate copolymer, polythene derivative, carboxylic ethylene copolymer and by their mixture.
23. pharmaceutical preparation according to claim 22 is characterized in that said saccharide is from dextrin, gathers select dextrin, glucosan, pectin and pectin derivant, alginate, polygalacturonic acid, xylan, araboxylan, arabinogalactan, starch, hydroxypropyl starch, amylose, amylopectin and their mixture at least a; Said cellulose derivative is at least a for what from hydroxypropyl emthylcellulose, hydroxypropyl cellulose, hydroxy methocel, hydroxyethyl-cellulose, methylcellulose, sodium carboxymethyl cellulose, succinic acid acetic acid hydroxypropyl emthylcellulose, hydroxyethylmethyl-cellulose and their mixture, select; Said natural gum is at least a for what from guar gum, locust bean gum, Tragacanth, carrageenin, acacia gum, arabic gum, gellan gum, xanthan gum and their mixture, select; Said protein is at least a for what from gelatin, casein, zein and their mixture, select; Said polyvinyl derivant is at least a for what from polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl acetal diethyl amino yl acetate and their mixture, select; Said polymethacrylate copolymer is from gathering (butyl methacrylate, (2-dimethyl aminoethyl) methacrylate-methyl methacrylate) copolymer, gather (methacrylic acid-methyl methacrylate) copolymer, gathering select in (methacrylic acid-ethyl acrylate) copolymer and their mixture at least a; Said polythene derivative is at least a for what from Polyethylene Glycol, PEO and their mixture, select; The carboxylic ethylene copolymer is a carbomer.
24. pharmaceutical preparation according to claim 11 is characterized in that the active component with respect to 1 weight portion, said hydrophilic polymer is 0.05 weight portion～50 weight portions.
25. pharmaceutical preparation according to claim 11 is characterized in that said hydrophilic polymer is at least a for what select the crowd who constitutes from hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, carboxylic ethylene copolymer, PEO and by their mixture.
26. pharmaceutical preparation according to claim 11 is characterized in that said release control material is for selected at least a from polymethacrylate copolymer, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, carboxylic ethylene copolymer and HPMCP.
27. according to any described pharmaceutical preparation in the claim 1 to 3, it is characterized in that said pharmaceutical preparation is choice of formulation from following form,
With the slow release compartment with after formerly discharging the compartment uniform mixing, carry out tabletting and the two-phase matrix tablet that obtains;
The sheet that constitutes by the slow release compartment and by seal said the outside formerly discharge the film coated tablet that film coating layer that compartment constitutes is constituted;
Said slow release compartment and the said stratified multilayer tablet of compartment structure that formerly discharges;
Comprise the microgranule, granule, piller or the sheet that constitute by the slow release compartment and by the capsule that formerly discharges microgranule, granule, piller or sheet that compartment constitutes;
Comprise the slow release compartment and reach the medicine box that formerly discharges compartment; Or
The inner core that constitutes by the slow release compartment and formerly discharge the pressed coated tablet that skin constituted that compartment constitutes by the outside of sealing said inner core.
28. pharmaceutical preparation according to claim 27 is characterized in that said pressed coated tablet is infiltration compacting coated tablet.
29., it is characterized in that said slow release compartment comprises Osmolyte regulator, and by semipermeable membrane coated substrate institute coating according to any described pharmaceutical preparation in the claim 1 to 3.
30. pharmaceutical preparation according to claim 29 is characterized in that said Osmolyte regulator is at least a for what select the crowd who constitutes from magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, lithium sulfate, sodium sulfate and by their mixture.
31. pharmaceutical preparation according to claim 29, it is characterized in that said semipermeable membrane coated substrate for from polyvinyl acetate, polymethacrylate copolymer, gather (ethyl acrylate, methyl methacrylate) copolymer, gather (ethyl acrylate, methyl methacrylate, methacrylic acid trimethyl amino ethyl ester) copolymer, select ethyl cellulose, cellulose esters, cellulose ether, acylated cellulose, two acylated celluloses, three acylated celluloses, cellulose acetate, cellulose diacetate, cellulose triacetate and the crowd that constitutes by their mixture at least a.
32. according to any described pharmaceutical preparation in the claim 1 to 3, it is characterized in that formerly discharging in the compartment outside of at least one, further comprise coatings at said slow release compartment or said.
33., it is characterized in that said preparation is the pharmaceutical preparation that is used for the administration in night according to any described pharmaceutical preparation in the claim 1 to 3.
34. prevention and treatment are selected from the method for at least a disease in metabolic syndrome, cardiovascular disease and the nephropathy, comprise: will be according to any described pharmaceutical preparation in the claim 1 to 3 to the step that comprises human mammals administration.
CN2010800080129A 2009-02-27 2010-02-26 Pharmaceutical preparation Pending CN102316856A (en)

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CN107550881A (en) * 2017-09-28 2018-01-09 南京易亨制药有限公司 A kind of felodipine sustained-release tablets and its preparation technology
CN109432039A (en) * 2015-06-03 2019-03-08 南京三迭纪医药科技有限公司 Pharmaceutical formulation and its use
CN111494387A (en) * 2012-12-07 2020-08-07 法国诗华动物保健公司 Triazine formulations with a second active ingredient and a surfactant

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CN101374505A (en) * 2006-01-27 2009-02-25 Cj第一制糖株式会社 Multiple unit type sustained release oral formulation and process for the preparation thereof
CN101505737A (en) * 2006-08-24 2009-08-12 韩兀制药株式会社 Combined pharmaceutical formulation with controlled-release comprising dihydropyridine calcium channel blockers and HMG-CoA reductase inhibitors

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CN101374505A (en) * 2006-01-27 2009-02-25 Cj第一制糖株式会社 Multiple unit type sustained release oral formulation and process for the preparation thereof
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CN111494387A (en) * 2012-12-07 2020-08-07 法国诗华动物保健公司 Triazine formulations with a second active ingredient and a surfactant
CN109432039A (en) * 2015-06-03 2019-03-08 南京三迭纪医药科技有限公司 Pharmaceutical formulation and its use
CN107550881A (en) * 2017-09-28 2018-01-09 南京易亨制药有限公司 A kind of felodipine sustained-release tablets and its preparation technology

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Application publication date: 20120111