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WO2009151295A2 - Préparation pharmaceutique comprenant de l'azelnidipine et un inhibiteur de reductase hmg-coa ou un agent bloquant du récepteur de l'angiotensine ii - Google Patents

Préparation pharmaceutique comprenant de l'azelnidipine et un inhibiteur de reductase hmg-coa ou un agent bloquant du récepteur de l'angiotensine ii Download PDF

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Publication number
WO2009151295A2
WO2009151295A2 PCT/KR2009/003158 KR2009003158W WO2009151295A2 WO 2009151295 A2 WO2009151295 A2 WO 2009151295A2 KR 2009003158 W KR2009003158 W KR 2009003158W WO 2009151295 A2 WO2009151295 A2 WO 2009151295A2
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Prior art keywords
cellulose
release
pharmaceutical formulation
copolymer
formulation
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English (en)
Korean (ko)
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WO2009151295A3 (fr
Inventor
김성욱
전성수
조영관
장석영
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Hanall Pharmaceutical Co Ltd
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Hanall Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to timed dose pharmaceutical formulations comprising controlled release azelnidipine designed to control release of each drug and comprising an HMG-CoA reductase inhibitor or angiotensin II receptor blocker.
  • the present invention relates to a technology for formulating a functional combination that can suppress the decrease in drug efficacy due to drug interactions and prevent side effects from occurring when two drugs are simultaneously administered.
  • Efflux transporters, influx transporters, and metabolic enzymes are present everywhere, absorbing, metabolizing, and excreting drugs everywhere, such as when they exit the liver cells.
  • one component may interfere with the absorption, distribution, and metabolism of the other, thereby reducing the efficacy or increasing the side effects. Therefore, one component must be passed first, and the other component must be passed at a time difference to eliminate drug interaction.
  • the purpose of the present invention is to determine the dissolution order and maintain the time difference between the two components with a certain antagonistic interaction between the two components for the purpose of realizing the ideal combination method when all the drugs are heterogeneously administered. It is absorbed to enable functional combinations that maximize the efficacy and minimize side effects.
  • transporters and drug metabolizing enzymes that have been tested or reviewed for the preparation of the functional combination of the present invention are as follows.
  • P-gp P-glycoprotein
  • MDR Multidrug resistance
  • MRP Multidrug resistance associated protein
  • Influx Transporter Organic anion transport protein (OATP), Sodium taurocholate cotransporting polypeptide (NTCP), Organic cation transporter (OCT)
  • OATP Organic anion transport protein
  • NTCP Sodium taurocholate cotransporting polypeptide
  • OCT Organic cation transporter
  • Uridine-5-phophate-glucuronosyltransferase UDP-gt
  • Sulfatase Sulfotransferase (1a1, 2a1, 1e1)
  • Azelenidipine is 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3, -5-pyridinedicarboxylic acid 3-([1- (diphenylmethyl) 3-azetidinyl] 5- (methylethyl) ester, which is chemically defined and specifically described in US Pat. No. 4,772,596, there are many pharmaceutically acceptable salts depending on the purpose.
  • Azelenidipine expresses a blood pressure lowering effect by specifically binding to L-type calcium channels to dilate blood vessels.
  • the time to reach the peak blood concentration is about 3 hours, and the half-life is about 18 hours.
  • the main metabolic sites in the body are the small intestine and liver, and are mainly metabolized by cytochrome P450 3A4. [News exhibition 2002 2002 ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ Vol. 38, S-1, 2002].
  • Azelnidipine is a state-of-the-art calcium channel blocker that has many of the potential features that conventional calcium channel blockers do not have.
  • the anti-arteriosclerosis activity is strong due to its particularly high lipid affinity. This is because the high blood vessel wall penetration and anti-inflammatory action.
  • Norepinephrine_ norepinephrine
  • Azelnidipine is synergistic in combination with many types of drugs in kidney and heart conditions of diabetic hypertension (Hypertension American Heart Association 2004: 24: 263-269, Arzneistoffforschung 2007: 57 (11): 698-704 , J.Cardiovascular Pharmacol 2006 Feb: 47 (2) 314-21, Drug Exp Clin Res: 2005: 31 (5-6): 215-9)
  • Azelenidipine has been shown to have an excellent effect on lowering systolic / diastolic blood pressure without increasing or decreasing the heart rate or carbon monoxide, nor the concentrations of catecholamines such as norepinephrine and epinephrine, during exercise or after exercise [J. Cardiovascular Pharmacology Vol. 32 (2): 1999; pp 186-192]. This is different from nifedipine and other calcium channel blockers, beta blockers, diuretics, etc., acting on the sympathetic nervous system in exercise patients to further increase heart rate and blood norepinephrine levels through pharmacological action.
  • nitrotyrosine derived from the reaction with free radicals induced nitric oxide synthesis in arterial smooth muscle and causing cell damage.
  • Azelnidipine is expected to inhibit cardiomyocyte damage by inhibiting the synthesis of nitric oxide and nitirotyrosine [J. Cardiovasc. Pharmacol. Vol 47: 2006; 314-321.
  • azelnidipine has an effect of strongly inhibiting the progression of atherosclerosis compared to other calcium channel blockers due to the strong affinity and antioxidant activity of the blood vessel wall [Arzneistoffforschung. Vol. 57 (11): 2007; pp 698-704).
  • renin- angiotensin-aldosterone acts on the renin- angiotensin-aldosterone system and inhibits the expression of mRNA at the molecular level, thereby acting as a renin inhibitor [J. Pharmacol. Sci. Vol. 102: 2006; 239-242].
  • This action can be predicted to reduce the rate of reflex tachycardia, a side effect of vasodilation of existing calcium channel blockers.
  • Calcium channel blockers typified by dihydropyridine are metabolized by cytochrome P450, but mainly inhibit the action of cytochrome P450 3A4, and azelnidipine is a drug that mainly inhibits cytochrome P450 3A4. Therefore, when the drug requiring cytochrome P450 3A4 enzyme and azelnidipine are administered together, the activation of electrons is suppressed, thereby reducing the efficacy of the electrons or causing side effects.
  • statin compounds such as simvastatin, widely used as HMG-CoA reductase inhibitors, are metabolized and activated by cytochrome P450 3A4 in the liver to inhibit lipid synthesis in the liver. Therefore, when administered with such statin drugs and cytochrome P450 3A4 inhibitory calcium channel blockers such as azelnidipine, even if they are not metabolized with a non-metabolized statin drug, the partially metabolized intermediate is more than twice as high in the blood and has side effects. Can lead to [Drug Metab. Pharmacokinet. Vol. 22 (3): 2007; pp 199-205.
  • valsartan an angiotensin II receptor blocker
  • cytochrome P450 2D6 and 3A4 in combination with azelnidipine, which has an inhibitory effect on cytochrome P450 3A4. It is possible to inhibit the pharmacological action of Valsartan by inhibiting the conversion to 4-hydroxyvalsartan.
  • losartan which is metabolized by cytochrome P450 3A4, it is metabolized by cytochrome P450 3A4 into active losartan.
  • human liver metabolism enzymes differ in metabolism of a single drug due to the genetic polymorphism of individual metabolase enzymes, and it is often necessary to observe continuously during drug administration. It is difficult to predict the clinical changes that will occur if they are acted upon.
  • the present inventors have led to the present invention as a result of research efforts to solve the above problems and to reduce the side effects while increasing the clinical therapeutic effect when combined administration.
  • the HMG-CoA reductase inhibitor component in combination with azelnidipine promotes sufficient activity and suppresses unnecessary blood concentration.
  • the angiotensin II receptor blocker component a sufficiently activated metabolite is released into the blood. To provide.
  • the present invention relates to delayed-release compartments and angiotensin II receptor blockers, pharmaceutically acceptable salts thereof, or isomers or HMG-CoA reductase inhibitors thereof, comprising azelnidipine or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a pharmaceutical formulation comprising a pre-release compartment comprising a pharmaceutically acceptable salt or isomer thereof as an active ingredient.
  • the present invention also provides an immediate release of an HMG-CoA reductase inhibitor or angiotensin II receptor blocker upon oral administration so that at least 80%, preferably at least 90%, of the drug is eluted within one hour, and the release of azelnidipine is HMG-CoA.
  • pharmaceutical preparations that are initiated between 2 and 4 hours after the onset of release of a reductase inhibitor or angiotensin II receptor blocker.
  • the present invention uses a combination of azelnidipine and HMG-CoA reductase inhibitor or angiotensin II receptor blocker, which are drugs that inhibit cytochrome P 450-based enzymes, as an effective drug, constituting different release rates thereof to antagonize each other.
  • the present invention provides a pharmaceutical preparation comprising a new concept of azelnidipine, an HMG-CoA reductase inhibitor, or angiotensin II receptor blocker, which can prevent synergism and at the same time obtain synergistic effects, and exhibit an easy effect on the patient's medication.
  • the present invention provides a delayed-release compartment consisting of azelnidipine, its pharmaceutically acceptable salts and the desired excipients and a HMG-CoA reductase inhibitor or angiotensin II so as to be physically separated or compartmentalized to obtain different release rates of the two drugs.
  • a formulation consisting of a receptor-releasing agent, each pharmaceutically acceptable salt thereof and a pre-release compartment consisting of the desired excipient.
  • the pre-release compartment and the delayed-release compartment according to the present invention, and the preparation according to the present invention can be implemented in various formulations.
  • the pharmaceutical preparations of the invention exert a more effective effect when taken once daily, in the evening, preferably between 5 pm and 11 pm.
  • Pre-release compartment refers to the compartment that is released earlier than the delayed-release compartment in the pharmaceutical formulation of the present invention.
  • the pharmacologically active ingredient of the prior release compartment comprises an HMG-CoA reductase inhibitor, an isomer thereof or a pharmaceutically acceptable salt thereof, and may further comprise a pharmaceutically acceptable additive as necessary.
  • HMG-CoA reductase inhibitors are mostly metabolized by cytochrome P450 3A4 in the liver to perform lipid inhibitory action.
  • the HMG-CoA reductase inhibitor may be simvastatin, lovastatin, atorvastatin, pravastatin, pitavastatin, roschvastatin, fluvastatin, cerivastatin, isomers thereof, or a pharmaceutically acceptable salt thereof, and is preferred.
  • the following may be selected and used from atorvastatin calcium, simvastatin and isomers thereof and pharmaceutically acceptable salts.
  • the present invention uses 5 to 160 mg, preferably 5 to 80 mg, in the composition (200 to 1500 mg total).
  • the pharmacologically active ingredient of the prior release compartment comprises an angiotensin II receptor blocker, an isomer thereof or a pharmaceutically acceptable salt thereof, and may further comprise a pharmaceutically acceptable additive as necessary.
  • Angiotensin II receptor blockers are compounds that bind and interfere with angiotensin II receptors and are widely used in the treatment of cardiovascular diseases effective for patients with essential hypertension and heart failure.
  • the angiotensin II receptor blocker may be losartan, valsartan, candesartan, irbesartan, eprosartan, olmesartan, telmisartan and its isomers or pharmaceutically acceptable salts thereof.
  • the present invention uses 5 to 1200 mg, preferably 8 to 600 mg, in the composition (200 to 1500 mg total).
  • the pre-release compartment may release within about 2 hours, preferably within 1 hour, of release of at least about 80%, preferably at least 90%, of the total amount of active ingredient in the unit formulation, thereby rapidly exhibiting medicinal efficacy.
  • formulations of the present invention may also be formulated using additives such as pharmaceutically acceptable diluents, binders, disintegrants, lubricants, stabilizers and the like without departing from the effects of the present invention.
  • Pharmaceutically acceptable diluents may include starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol, dicalcium phosphate, mixtures thereof, and the like.
  • binders include starch, microcrystalline cellulose, highly dispersible silica, mannitol, sucrose, lactose, polyethylene glycol, polyvinylpyrrolidone, hypromellose, hydroxypropyl cellulose, natural gums, synthetic gums, nasal Povidone, gelatin, mixtures thereof and the like can be used.
  • Pharmaceutically acceptable disintegrants include starch or modified starches such as sodium starch glycolate, corn starch, potato starch or starch gelatinized starch; Clay such as bentonite, montmorillonite, or veegum; Celluloses such as microcrystalline cellulose, hydroxypropyl cellulose or carboxymethyl cellulose; Algins such as sodium alginate or alginic acid; Crosslinked celluloses such as croscarmellose sodium; Gums such as guar gum and xanthan gum; Crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone); Effervescent agents such as sodium bicarbonate, citric acid, or mixtures thereof can be used.
  • Clay such as bentonite, montmorillonite, or veegum
  • Celluloses such as microcrystalline cellulose, hydroxypropyl cellulose or carboxymethyl cellulose
  • Algins such as sodium alginate or alginic acid
  • Crosslinked celluloses such as croscarmel
  • Pharmaceutically acceptable lubricants include talc, stearic acid, magnesium stearate, calcium stearate, and the like, sodium lauryl sulfate, hydrogenated vegetable oils, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monorate, glyceryl Monostearate, glyceryl palmitostearate, polyethylene glycol and the like can be used.
  • Pharmaceutically acceptable stabilizers may include ascorbic acid, citric acid, butylhydroxy anisole, butylhydroxy toluene, tocopherol derivatives and the like.
  • formulation of the present invention may be formulated by selecting and using a pharmaceutically acceptable additive as various additives selected from colorants and fragrances.
  • the range of additives usable in the present invention is not limited to the use of such additives, and the above additives may be formulated to contain a range of dosages, usually by selection.
  • Delayed-release compartment refers to the compartment in which the active ingredient is released after a certain time after the release of the prior-release compartment active ingredient in the pharmaceutical formulation according to the present invention.
  • the delayed-release compartment comprises (1) azelnidipine, a pharmacologically active ingredient or a pharmaceutically acceptable salt thereof, and (2-1) release controlling substance or (2-2) osmotic pressure regulator and semipermeable membrane coating base, If necessary, it may further include a pharmaceutically acceptable additive.
  • Pharmacologically active ingredients of the delayed-release compartment include azelnidipine, and / or pharmaceutically acceptable salts thereof.
  • the pharmaceutically acceptable salt of azelnidipine may be selected from the group consisting of hydrochloride, bromate, benzenesulfonate, citrate, methanesulfonate, tosylate, naphthalenesulfonate, tri-methanesulfonate and addition salts thereof.
  • the present invention is not limited thereto.
  • Azelenidipine the active ingredient in the delayed-release compartment, may be included as about 2 to 64 mg of the unit preparation (200 to 1500 mg total) based on an adult (65 to 75 kg adult male), preferably 4 to 32 mg, More preferably 8 to 16 mg.
  • the azelnidipine in the delayed-release compartment is delayed to 0-20% or less of the total amount of azelnidipine for 2 hours after the initiation of the release of the prior-release compartment, and the release of azelnidipine within 2 hours after the initiation of release More than 90% of the total amount of nidipine is released, indicating the desired efficacy.
  • the delayed-release compartment in the formulation of the present invention refers to a pharmaceutically acceptable substance for controlling the release of the active ingredient, selected from the group consisting of enteric polymers, water insoluble polymers, hydrophobic compounds, hydrophilic polymers, and mixtures thereof. It includes a release control material, preferably may be selected from the group consisting of enteric polymers, water insoluble polymers, hydrophilic polymers and mixtures thereof.
  • the release controlling substance comprises 0.05 to 100 parts by weight, preferably 0.01 to 20 parts by weight, based on 1 part by weight of azelnidipine. If the release control material is less than 0.05 parts by weight it may be difficult to have a sufficient delay time, there is a problem that the release of the drug does not occur or the delay time is too long when more than 100 parts by weight.
  • the enteric polymer is insoluble or stable under acidic conditions of less than pH 5, and refers to a polymer that is dissolved or decomposed under conditions of pH 5 or higher, such as an enteric cellulose derivative, an enteric acrylic acid copolymer, or an enteric polymethacrylate. It may be selected from the group consisting of copolymers, enteric maleic acid copolymers, enteric polyvinyl derivatives, and mixtures thereof.
  • the enteric cellulose derivatives include hypromellose acetate succinate, hypromellose phthalate, hydroxymethylethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, and cellulose propionate phthalate.
  • the enteric acrylic acid copolymers include styrene-acrylic acid copolymers, methyl acrylate-acrylic acid copolymers, methyl methacrylate acrylic acid copolymers (Acryl-eze Colorcon USA), butyl acrylate-styrene-acrylic acid copolymers, and methyl methacrylate acrylates.
  • the enteric polymethacrylate copolymer is a methacrylic acid-methyl methacrylate copolymer (e.g. Eudragit L 100, Eudragit S, Evonik, Germany), methacrylic acid-ethyl acrylate copolymer (e.g.
  • the enteric maleic acid copolymers include vinyl acetate-maleic anhydride copolymers, styrene-maleic anhydride copolymers, styrene-maleic acid monoester copolymers, vinylmethyl ether-maleic anhydride copolymers, ethylene-maleic anhydride copolymers, and vinyl butyl ether- At least one selected from maleic anhydride copolymer, acrylonitrile-methyl acrylate maleic anhydride copolymer, and butyl styrene-maleic-maleic anhydride copolymer;
  • the enteric polyvinyl derivative is at least one selected from polyvinyl alcohol phthalate, polyvinylacetate phthalate, polyvinyl butyrate phthalate and polyvinylacetacetal phthalate.
  • Enteric polymer according to the present invention may be included in 5 to 80% by weight, preferably 10 to 30% by weight based on the total weight of the formulation, when less than 5% by weight has a problem that is not dissolved or stable under acidic conditions, 80 In the case of more than% by weight, there is a problem that does not dissolve even under basic conditions.
  • a water-insoluble polymer refers to a polymer which does not dissolve in pharmaceutically acceptable water that controls the release of the drug, such as polyvinyl acetate, water-insoluble polymethacrylate copolymer [eg, poly (ethylacrylate- Methyl methacrylate) copolymers (eg Eudragit NE30D), poly (ethylacrylate-methyl methacrylate-trimethylaminoethylmethacrylate chloride) copolymers (eg Eudragit RS PO) and the like], ethyl It may be selected from the group consisting of cellulose, cellulose acetate, and mixtures thereof, preferably polyvinyl acetate, poly (ethylacrylate-methyl methacrylate) copolymer, poly (ethylacrylate-methyl methacrylate- Trimethylaminoethyl methacrylate) copolymer, ethyl cellulose, cellulose acetate It may be
  • the water-insoluble polymer according to the present invention may be included in 5 to 80% by weight, preferably 10 to 30% by weight based on the total weight of the formulation, when less than 5% by weight has a problem that it is difficult to have a sufficient delay time, 80% In the case of more than%, there is a problem that the release of the drug does not occur or the delay time is too long.
  • the hydrophobic compound refers to a substance which does not dissolve in pharmaceutically acceptable water that controls the release of the drug, and includes, for example, fatty acids and fatty acid esters, fatty alcohols, waxes, inorganic substances, and mixtures thereof. It may be selected from the group.
  • the fatty acid and fatty acid esters may be at least one selected from glyceryl palmitostearate, glyceryl stearate, glyceryl behenate, cetyl palmitate, glyceryl monooleate and threric acid;
  • the fatty acid alcohol is at least one selected from cetostearyl alcohol, cetyl alcohol and stearyl alcohol; Waxes are one or more selected from carnauba wax, beeswax, and microcrystalline wax;
  • the inorganic material may be at least one selected from talc, precipitated calcium carbonate, calcium dihydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite, and non-gum.
  • it may be at least one selected from glyceryl palmitostearate, glyceryl behenate, spirinic acid, cetyl alcohol, carnauba wax, and gum.
  • Hydrophobic compound according to the present invention may be included in 5 to 80% by weight, preferably 10 to 30% by weight relative to the total weight of the formulation, if less than 5% by weight has a problem that does not affect the release of the drug at all, If it is more than 80% by weight there is a problem that the release of the drug does not occur or difficult to formulate.
  • the hydrophilic polymer refers to a polymer material which is dissolved in pharmaceutically acceptable water for controlling the release of the drug, such as sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, hydrophilic polymethacrylate copolymers, It may be selected from the group consisting of polyethylene derivatives, carboxyvinyl polymers, and mixtures thereof.
  • the saccharide is one selected from dextrin, polydextrin, dextran, pectin and pectin derivative, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropylstarch, amylose, and amylopectin More than;
  • the cellulose derivatives include hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl methyl cellulose acetate succinate, and hydride.
  • the gum is at least one selected from guar gum, locust bean gum, tragacanta, carrageenan, acacia gum, arabic gum, gellan gum, and xanthan gum;
  • the protein is at least one selected from gelatin, casein, and zein;
  • the polyvinyl derivative is at least one selected from polyvinyl alcohol, polyvinyl pyrrolidone, and polyvinyl acetal diethylamino acetate;
  • the hydrophilic polymethacrylate copolymers include poly (butyl methacrylate- (2-dimethylaminoethyl) methacrylate-methylmethacrylate) copolymers (eg Eudragit E100, Evonik, Germany);
  • the polyethylene derivative is at least one selected from polyethylene glycol, and polyethylene oxide;
  • the carboxyvinyl polymer may be a carbomer, preferably hypromellose, hydroxypropylcellulose, guar gum
  • Hydrophilic polymer according to the present invention may be included in 5 to 80% by weight, preferably 10 to 30% by weight based on the total weight of the formulation, if less than 5% by weight has a problem that does not affect the disintegration of the tablet at all, If more than 80% by weight there is a problem that is difficult to control the disintegration and release.
  • Preferred release controlling substances in the present invention include hypromellose acetate succinate, hypromellose phthalate, methyl methacrylate acrylic acid copolymer, polyvinylacetate, ethyl cellulose, cellulose acetate, carnauba wax, hypromellose , Hydroxypropyl cellulose, polyvinyl pyrrolidone, and mixtures thereof; More preferably polyvinylacetate, hypromellose acetate succinate, hypromellose, hydroxypropyl cellulose, ethyl cellulose, and mixtures thereof; Polyvinylacetate, hypromellose acetate succinate, hypromellose, and mixtures thereof.
  • the delayed-release compartment of the present invention includes an osmotic pressure regulator and may be a compartment coated with a semipermeable membrane coating base.
  • the semi-permeable membrane coating base is a pharmaceutically usable coating base, and refers to a substance used in forming a membrane which is blended into the coating layer of the pharmaceutical formulation and passes some components but does not pass other components.
  • Water insoluble polymethacrylate copolymer ethylcellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, and mixtures thereof It may be selected from the group, preferably at least one selected from polyvinyl acetate, water-insoluble polymethacrylate copolymer, ethyl cellulose, cellulose triacetate.
  • Semi-permeable membrane coating base according to the present invention may be included in 5 to 80% by weight, preferably 10 to 30% by weight based on the total weight of the formulation, when less than 5% by weight has a problem that it is difficult to form the desired semi-permeable membrane, 80 In the case of more than% by weight, there is a problem that all components may not pass.
  • Osmotic pressure control agent in the present invention refers to a component used to control the release rate of the drug using the principle of osmotic pressure, for example magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, lithium sulfate, sodium sulfate, and their It may be selected from the group consisting of a mixture, preferably using sodium chloride.
  • Osmotic pressure control agent according to the present invention may be included in 1 to 80% by weight, preferably 2 to 50% by weight relative to the total weight of the formulation, there is a problem that the osmotic pressure is not formed when less than 1% by weight.
  • the formulations of the present invention may also be formulated using additives such as pharmaceutically acceptable diluents, binders, disintegrants, lubricants, etc., within the scope of not impairing the effects of the present invention, preferably 1 to 95% by weight of the total weight of the formulation, preferably Preferably it may be included in 5 to 90% by weight, if less than 1% by weight has a problem of formulating, in the case of more than 95% by weight there is a problem that is difficult to oral administration.
  • additives such as pharmaceutically acceptable diluents, binders, disintegrants, lubricants, etc.
  • Pharmaceutically acceptable diluents may include starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol, dicalcium phosphate, mixtures thereof, and the like.
  • binders include starch, microcrystalline cellulose, highly dispersible silica, mannitol, sucrose, lactose, polyethylene glycol, polyvinylpyrrolidone, hypromellose, hydroxypropyl cellulose, natural gums, synthetic gums, nasal Povidone, gelatin, mixtures thereof and the like can be used.
  • Pharmaceutically acceptable disintegrants include starch or modified starches, such as sodium starch glycolate, corn starch, potato starch or starch gelatinized starch; Clay such as bentonite, montmorillonite, or veegum; Celluloses such as microcrystalline cellulose, hydroxypropyl cellulose or carboxymethyl cellulose; Algins such as sodium alginate or alginic acid; Crosslinked celluloses such as croscarmellose sodium; Gums such as guar gum and xanthan gum; Crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone); Effervescent agents such as sodium bicarbonate, citric acid, or mixtures thereof can be used.
  • starch or modified starches such as sodium starch glycolate, corn starch, potato starch or starch gelatinized starch
  • Clay such as bentonite, montmorillonite, or veegum
  • Celluloses such as microcrystalline cellulose, hydroxypropyl cellulose or carboxymethyl
  • Pharmaceutically acceptable lubricants include talc, stearic acid, magnesium stearate, calcium stearate and the like, sodium laurylsulfate, hydrogenated vegetable oils, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monostearate, glycerol Reel palmitostearate, polyethylene glycol and the like can be used.
  • additives selected from colorants and flavorings may be selected and used to formulate the formulations of the present invention.
  • the range of the additives usable in the present invention is not limited to the use of the additives, and the above additives may be formulated to contain a range of dosages by selection.
  • the pharmaceutical preparations of the present invention may be prepared in various formulations, and may be formulated, for example, in tablets, powders, granules, capsules, and the like, such as uncoated tablets, coated tablets, multi-layered tablets, or nucleated tablets. It can be formulated into capsules, including tablets consisting of bilayer tablets, nucleated tablets, or delayed-release compartments.
  • the pharmaceutical formulation of the present invention may be in the form of a two-phase matrix tablet obtained by tableting after the delayed-release compartment and the prior-release compartment are uniformly mixed.
  • the pharmaceutical formulation of the present invention may be in the form of a film coated tablet consisting of a tablet consisting of a delayed-release compartment and a film-coating layer composed of a pre-release compartment surrounding the outside of the tablet, the film coating layer of the film coating layer as it is dissolved HMG-CoA reductase inhibitor will be eluted first.
  • Preferred delayed-release compartments of the film-coated tablets according to the invention comprise those which are drycoated with an emission control material.
  • the pharmaceutical preparation of the present invention is obtained by mixing the pharmaceutical additives in the granules constituting the delayed-release compartment and the prior-release compartment and tableting each layer in parallel two-layer or three-layer tablets using a multiple tableting machine.
  • the release compartment and the pre-release compartment may be in the form of a multi-layered tablet in which the multilayered structure is balanced.
  • This formulation is a tablet for oral administration which is formulated to enable pre-release and delayed release in layers.
  • the pharmaceutical formulation of the present invention may be in the form of a nucleated tablet consisting of an inner core consisting of a delayed-release compartment and an outer layer composed of a prior-release compartment surrounding the outer surface of the inner core.
  • the nucleated tablet may be an osmotic nucleated tablet, and the osmotic nucleated tablet contains an osmotic pressure regulator within the tablet for delayed release, followed by tableting. Then, the surface of the tablet is coated with a semipermeable membrane coating base to make it an inner nuclear tablet.
  • the granules constituting the prior-release compartment are mixed with pharmaceutical additives and compressed into an outer layer to have a delayed-release inner-core tablet, and a dosage form in which the front-release layer surrounds the surface of the inner core tablet.
  • compositions of the invention may be in the form of particles, granules, pellets, or tablets comprising delayed-release compartments, or capsules comprising particles, granules, pellets, or tablets, consisting of pre-release compartments.
  • the delayed-release compartment of the capsule according to the present invention may be coated with a release control material, the release control material may be hypromellose acetate succinate, hypromellose phthalate, methyl methacrylate copolymer, poly It may be selected from the group consisting of vinyl acetate, ethyl cellulose, cellulose acetate, carnauba wax, hypromellose, hydroxypropyl cellulose, polyvinyl pyrrolidone, or mixtures thereof.
  • the formulations of the present invention may further form a coating layer on the outside of the delayed release compartment and / or the prior release compartment. That is, the surface of the particles, granules, pellets, or tablets composed of delayed-release compartments and / or pre-release compartments may be coated for the purpose of release control or formulation stability.
  • the pharmaceutical formulation of the present invention may be in the form of a kit comprising a delayed-release compartment, and a prior-release compartment, specifically the present invention to prepare the particles, granules, pellets, or tablets constituting the prior-release compartment,
  • the granules, pellets or tablets constituting the delayed-release compartment may be separately prepared, and may be in the form of a kit prepared in a form that can be taken at the same time by filling together with a foil, a blister, a bottle, and the like.
  • the kit may be composed of a unit dosage form of the delayed-release compartment, a unit dosage form of the pre-release compartment, and a packaging container for packaging the unit dosage form of the delayed-release compartment and the pre-release compartment, wherein the packaging container may be formed of a delayed-release compartment.
  • the packaging container may be formed of a delayed-release compartment.
  • Each of the unit dosage form and the pre-release compartment may be packed separately or together.
  • the formulation according to the present invention is also provided in a state such as uncoated tablets without additional coating, but if necessary, a coating layer is formed on the outside of the formulation to form a coating tablet or coating capsule further comprising a coating layer. Can be.
  • a coating layer By forming the coating layer, it is possible to provide a formulation that can further ensure the stability of the active ingredient.
  • the method of forming the coating layer can be appropriately selected by the choice of a person skilled in the art from the method of forming a film-like coating layer on the surface of the tablet layer, a method such as fluidized bed coating method, fan coating method, dry coating method can be applied. .
  • the coating layer may be formed by using a coating agent, a coating aid, or a mixture thereof.
  • the coating agent may be a cellulose derivative such as hypromellose or hydroxypropyl cellulose, a sugar derivative, a polyvinyl derivative, waxes, fats, gelatin, Or a mixture thereof, and the like
  • a coating aid may be polyethylene glycol, ethyl cellulose, glycerides, titanium oxide, talc, diethyl phthalate, or a mixture thereof.
  • the coating layer may include 0.5 to 100% by weight based on the total weight of the tablet.
  • the present invention provides a pharmaceutical formulation for evening administration.
  • the present invention provides a method for treating cardiovascular disease comprising administering the pharmaceutical formulation of the present invention to a mammal.
  • the present invention provides a composition for treating cardiovascular disease, comprising administering the pharmaceutical formulation of the present invention to a mammal.
  • the invention also provides for the use of the pharmaceutical preparations of the invention for the treatment of cardiovascular diseases.
  • the cardiovascular disease refers to diseases that may occur in the heart and vascular system such as angina pectoris, myocardial infarction, stroke, cerebral hemorrhage, heart failure, hypertension, hypotension, arteriosclerosis, and hyperlipidemia; It also includes hypertension or complications of those with metabolic syndrome, which is a combination of high blood pressure, diabetes, obesity, hyperlipidemia, and coronary artery disease.
  • the pharmaceutical formulation of the present invention may be suitably formulated according to each disease using methods disclosed in Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA, as appropriate methods in the art, and specifically This can be done by the following steps.
  • azelnidipine is administered by one or two release controlling substances selected from an enteric polymer, a water-insoluble polymer, a hydrophobic compound, a hydrophilic polymer, a semipermeable membrane coating base, and an osmotic pressure control agent, and a conventional additive used in pharmaceuticals. It is a step of obtaining delayed-release granules or tablets through mixing, granulation or coating.
  • the second step is to obtain the pre-release granules, tablets obtained through a conventional procedure for producing oral solids such as mixing, associating, drying and granulating the HMG-CoA reductase inhibitor with conventional pharmaceutically acceptable additives. to be.
  • the granules or tablets obtained in the first step and the second step are mixed with pharmaceutical excipients, tableted or filled to obtain a preparation for oral administration.
  • the first step and the second step may be reversed or executed simultaneously.
  • the pharmaceutical formulation of the present invention may be prepared by the above process, and the formulation method is described in more detail as follows, but is not limited thereto.
  • the particles or granules obtained in the first step are further coated as they are or with a release controlling material, and then mixed with the granules prepared in the second step and compressed into a certain amount of weight to prepare a tablet.
  • the obtained tablet can be film coated as necessary for the purpose of improving stability or property.
  • the coated tablets or granules obtained in the first step are additionally coated as they are or with a release control material, dried and then compressed into a predetermined amount to produce tablets as they are or additionally coated, and then the drug of the prior release compartment is separately added to the water-soluble film coating solution.
  • the tablet outer layer obtained in the first step may be coated to prepare an oral dosage form film-coated tablet containing the active ingredient in the film coating.
  • the granules obtained in the first step may be further coated as they are or with a release control material, and the dried granules and the granules obtained in the second step may be added to produce two-layer tablets using a multi-layer tablet press.
  • Coated multi-layered tablets can be prepared by formulating or coating three or more multi-layered tablets by adding a release aid layer as needed or by formulation.
  • the coated tablet or granules obtained in the first step are additionally coated as it is or with a release control material, dried, and then compressed into a predetermined amount to be coated as it is or additionally to the inner core, followed by a nucleated tableting machine together with the granules obtained in the second step.
  • the coated nucleated tablet may be prepared by preparing or coating a nucleated tablet in a form in which a pre-release layer surrounds the surface of the first-stage tablet.
  • the granules obtained in the first step are additionally coated as is or with a release controlling substance, and the dried granules or tablets and the granules or tablets obtained in the second step are placed in a capsule charger and filled into capsules of a predetermined size by an effective amount of each active ingredient in an appropriate amount.
  • HMG-CoA reductase inhibitor and pharmaceutically acceptable additives are dissolved or suspended in water, organic solvent, or mixed solvent, coated on spherical granules of sugar, dried and controlled to release beta adrenergic blocker Capsules may be prepared by mixing the pellets and filling the capsules.
  • the granules obtained in the first step are additionally coated as is or with a release controlling substance and the dried granules or tablets are filled into capsules.
  • the granules or tablets obtained in the second step may be put in a capsule charger, and capsules may be prepared by inserting a corresponding amount of the active ingredient into the capsule of a predetermined size and the capsule prepared in (1) above.
  • Controlled release materials selected from enteric polymers, water-insoluble polymers, hydrophobic compounds, hydrophilic polymers, semipermeable membrane coating bases, and osmotic pressure regulators of the first step after filling into capsules with fibric acid derivatives and pharmaceutically acceptable additives 1 It can be prepared by the coating method using a conventional additive used in pharmaceuticals with the species or two species.
  • Capsules can be prepared by putting the granules or tablets obtained in step 2 into the capsule charger and putting the capsules prepared in (1) above with the effective amount of each main ingredient in a capsule of a certain size.
  • the fibric acid derivative-containing preparation obtained in the first step and the HMG-CoA reductase inhibitor-containing preparation obtained in the second step can be prepared together with a foil, blister, bottle, or the like to be used as a kit.
  • the present invention is to formulate a so-called Chronotherapy that maximizes the therapeutic effect on the basis of Xenobiotics to improve the reduction in drug efficacy that may occur in the combination of different drugs from the pharmacokinetic point of view.
  • an active ingredient agelnidipine, a component that inhibits cytochrome P450 3A4, and an HMG-CoA reductase inhibitor or angiotensin II receptor blocker, which require this enzyme, are used as an active ingredient to control the elution time in the body.
  • controlled release materials allows the active ingredients to be delivered at a certain rate and at a certain rate, thus controlling the amount of time they are eluted in the body rather than in the case of complex prescriptions in which the drug components are taken separately at the same time.
  • the composition can be realized.
  • the pharmaceutical preparation can be taken at a time, the medication guide and the medication for the patient are easy.
  • blood pressure lowering effect and lipid lowering effect are superior to those of simple combinations, and the combinations exhibiting the optimal effect at the time of risk of complications. This can save you time on medication guidance.
  • simvastatin an HMG-CoA reductase inhibitor
  • azelnidipine simvastatin is not metabolized by cytochrome P450 due to the inhibitory effect of cytochrome P450 3A4 of azelnidipine in the liver.
  • Cmax blood peak concentrations
  • AUC area under the curve
  • the drug selected from HMG-CoA reductase inhibitor or angiotensin II receptor blocker as an active ingredient is eluted and absorbed first in the small intestine so that it does not interfere with the action of azelnidipine in the liver, which is an angiotensin II receptor blocker. If letan or valsartan and azelnidipine are simultaneously transferred to the liver, they are not metabolized by cytochrome P450 and inactivated substances are leaked into the blood, thereby reducing the problem of the drug.
  • FIG. 1 shows comparative dissolution curves of a pharmaceutical preparation of azelnidipine / simvastatin prepared according to Example 1 and a control agent (calblock: azelnidipine single agent, joco: simvastatin single agent).
  • Example 1 Preparation of azelnidipine-simvastatin nucleated tablets
  • azelnidipine hydrochloride and 50.25 g of microcrystalline cellulose were appled in a No. 35 sieve, mixed in a high-speed mixer, and combined with 20 g of Colicoat SR30D (polyvinyl acetate aqueous solution, BASF, Germany). It was granulated using, dried at 60 ° C. using a hot water dryer, and then sieved to No. 20 sieve again. 0.75 g of magnesium stearate was added thereto, followed by final mixing in a double cone mixer, and the final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong Pharmatech) to obtain a core tablet.
  • Colicoat SR30D polyvinyl acetate aqueous solution, BASF, Germany
  • simvastatin 20 g of simvastatin, 57 g of microcrystalline cellulose, and 112.46 g of mannitol were appled in a No. 35 sieve and mixed with a high speed mixer. Separately, 5 g of hydroxypropyl cellulose and 2 g of citric acid were dissolved in purified water to prepare a binding solution, which was added to a high-speed mixer with a main ingredient mixture, and then combined, and granulated using No. 20 sieve using an oscillator. It was dried at and then reconstituted with No. 20 sieve. 0.04 g of butylated hydroxyanisole, 1 g of starch glyconate, and 1 g of colloidal silicon dioxide were mixed, and 1.5 g of magnesium stearate was added thereto, followed by final mixing in a double cone mixer.
  • nucleated tablet tableting machine (RUD-1: Kilian) as the inner core of azelnidipine hydrochloric acid hydrochloride and a composition containing simvastatin as an outer layer
  • hydroxypropyl using a high coater (SFC-30N, Sejong Pharmatech)
  • Nucleated tablets were prepared by forming a methylcellulose 3% (w / w) film coating layer.
  • MRC-37T Sejong Pharmatech
  • the composition containing the atorvastatin is placed in the primary powder feeder
  • the composition containing azelnidipine is placed in the secondary powder feeder and compressed
  • hydroxypropyl methyl is used by using a high coater (SFC-30N, Sejong Pharmatech).
  • SFC-30N Sejong Pharmatech
  • a cellulose 3% (w / w) film coating layer was formed to prepare a pharmaceutical formulation in the form of a multilayer tablet.
  • valsartan 80 g of valsartan, 1.5 g of colloidal silicon oxide, and 56.23 g of microcrystalline cellulose were appled into a No. 35 sieve and mixed with a double cone mixer.
  • the mixture was prepared dry using a roller compactor, and then granulated using No. 20 sieve using an oscillator.
  • This formulation is mixed with 0.5 g of sodium starch glycolate in a double cone mixer, and 0.75 g of magnesium stearate is mixed with a double cone mixer, and the final mixture is mixed with a rotary tablet press (MRC-33: Sejong). It was tableted using.
  • Each one of the gel nidipine hydrochloride tablets of 1) and the valsartan tablets of 2) were filled in the hydroxypropyl methylcellulose hard capsules of No. 0 using a capsule charger.
  • Azelnidipine delayed-release granules were prepared according to the same process except for the final mixing of magnesium stearate in Example 3).
  • the final compositions of 1) and 2) were placed in a double cone mixer, and 1 g of sodium starch glycolate and 1 g of colloidal silicon dioxide were added and mixed together, and 0.75 g of magnesium stearate was added to the final mixture.
  • the final mixed mixture was put into a powder feeder and filled into No. 1 gelatin hard capsules using a capsule charger.
  • a delayed-release layer granule of azelnidipine hydrochloride was prepared in the same process as in Example 1).
  • Each final composition prepared above was mixed with a double cone mixer, 1 g of starch glyconate and 1 g of colloidal silicon dioxide were mixed, and 1.5 g of magnesium stearate was added to the final mixture.
  • the final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) and then a hydroxypropyl methylcellulose 3% (w / w) film coating layer was formed as a high coater (SFC-30N, Sejong Machinery, South Korea). Phase matrix tablets were prepared.
  • the azelnidipine / simvastatin preparation prepared according to Example 1 was eluted.
  • the dissolution test was performed for 2 hours in 0.1 N hydrochloric acid solution, and then further dissolution test in pH 6.8 (phosphate solution) buffer.
  • Dissolution test method for each component is as follows, the results are shown in Figure 1 attached.
  • the azelnidipine / simvastatin preparation of the present invention is formulated so that simvastatin is rapidly eluted and absorbed as intended by the present invention, and azelnidipine is eluted and absorbed after simvastatin is absorbed.
  • the preparations according to the invention can be prepared in a variety of formulations to facilitate the taking of the patient.
  • Dissolution test basis Dissolution test method of General Test Method
  • Test method Paddle method, 50 revolutions / minute
  • Test solution 0.1N-hydrochloric acid solution, 750mL (0 ⁇ 2 hours)
  • Test method Paddle method, 50 revolutions / minute
  • the present invention relates to a complex controlled release of a drug selected from azelnidipine and an HMG-CoA reductase inhibitor or angiotensin II receptor blocker, which is most effective in the prevention or treatment of metabolic syndrome, cardiovascular disease or kidney disease. It provides a suitable pharmaceutical complex composition form.
  • Azelnidipine, HMG-CoA Reductase Inhibitor, or Angiotensin II Receptor Blocker Differently use controlled-release and immediate-release substances to control the elution time in the body so that each drug can It is a drug delivery system designed to release and deliver to the body, which is provided once a day in the evening to provide a complex controlled release formulation considering the absorption, metabolism and pharmacological mechanism of the drug to have the most ideal effect in the body.

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Abstract

La présente invention concerne une préparation pharmaceutique à libération lente comprenant de l'azelnidipine et un inhibiteur de réductase HMG-CoA ou un agent bloquant du récepteur de l'angiotensine II. Plus spécifiquement, un principe d'administration est appliqué selon lequel le temps nécessaire à l'action pharmacologique de chaque composant complexe pour réagir dans le corps est différent et chaque composant est conçu de sorte que les composants peuvent être libérés de manière lente à une vitesse spécifique afin d'avoir un effet optimal lorsqu'ils sont absorbés dans le corps. La préparation pharmaceutique décrite dans cette invention est extrêmement effficace pour traiter l'hypertension et empêcher les complications chez des personnes présentant un syndrome dit métabolique, tel qu'une hyperlipidémie, une coronaropathie, une cardiopathie, une néphropathie ou une maladie cérébrovasculaire, etc.; le fait d'augmenter la tolérance du patient permettant de maximiser les effets sur les facteurs extérieurs.
PCT/KR2009/003158 2008-06-13 2009-06-12 Préparation pharmaceutique comprenant de l'azelnidipine et un inhibiteur de reductase hmg-coa ou un agent bloquant du récepteur de l'angiotensine ii Ceased WO2009151295A2 (fr)

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US12109223B2 (en) 2020-12-03 2024-10-08 Battelle Memorial Institute Polymer nanoparticle and DNA nanostructure compositions and methods for non-viral delivery
US12441996B2 (en) 2023-12-08 2025-10-14 Battelle Memorial Institute Use of DNA origami nanostructures for molecular information based data storage systems
US12458606B2 (en) 2023-09-29 2025-11-04 Battelle Memorial Institute Polymer nanoparticle compositions for in vivo expression of polypeptides

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KR20010022508A (ko) * 1997-07-31 2001-03-15 추후보정 3-히드록시-3-메틸글루타릴 조효소 ａ 환원 효소 억제제와니코틴산 화합물의 조성물 및 야간에 1일 1회 투여하여고지질혈증을 치료하는 방법
KR101384841B1 (ko) * 2005-06-27 2014-04-15 다이이찌 산쿄 가부시키가이샤 안지오텐신 ⅱ 수용체 길항제 및 칼슘 채널 차단제를함유한 약학 제제
KR100762847B1 (ko) * 2006-01-27 2007-10-04 씨제이 주식회사 멀티플 유닛 타입 서방성 경구 제제 및 그 제조방법
WO2008023869A1 (fr) * 2006-08-24 2008-02-28 Hanall Pharmaceutical Co., Ltd. PRÉPARATION PHARMACEUTIQUE COMBINÉE À LIBÉRATION CONTRÔLÉE COMPRENANT DES INHIBITEURS CALCIQUES À BASE DE DIHYDROPYRIDINE ET DES INHIBITEURS DE HMG-CoA RÉDUCTASE

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US12433910B2 (en) 2020-12-03 2025-10-07 Battelle Memorial Institute Polymer nanoparticle and DNA nanostructure compositions and methods for non-viral delivery
US12031128B2 (en) 2021-04-07 2024-07-09 Battelle Memorial Institute Rapid design, build, test, and learn technologies for identifying and using non-viral carriers
US12458606B2 (en) 2023-09-29 2025-11-04 Battelle Memorial Institute Polymer nanoparticle compositions for in vivo expression of polypeptides
US12441996B2 (en) 2023-12-08 2025-10-14 Battelle Memorial Institute Use of DNA origami nanostructures for molecular information based data storage systems

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