KR20090107960A - Pharmaceutical formulation for treating cardiovascular disease - Google Patents

Abstract

PURPOSE: A pharmaceutical formulation for treating cardiovascular diseases is provided to enhance drug effect than administering two components of drug separately and reduce side effects. CONSTITUTION: A pharmaceutical formulation for treating cardiovasclular diseases contains a immediate release compartment and sustained release compartment. The immediate release compartment comprises an irbesartan as a pharmacologically active ingredient or its pharmaceutically acceptable salt. The sustained release compartment contains an amlodipine as a pharmacologically active ingredient and its isomer or its pharmaceutically acceptable salt. 80 % or more of irbesartan is released within 30 minutes after releasing the irbesartan.

Description

Pharmaceutical formulation for treating cardiovascular disease

The present invention relates to pharmaceutical formulations containing ibesatan and amlodipine.

Ibesatan is a representative drug of non-peptide angiotensin-2-receptor blocker, which relaxes blood vessels by selectively inhibiting angiotensin-2 binding to receptors in tissues such as vascular smooth muscle cells and adrenal glands [M burnier et al., The Lancet. vol.355 (2000), p637-645], which has been used to treat nephropathy in Type 2 Diabetic Patients as well as hypertension.

Amlodipine is a calcium channel blocker that prevents calcium ions from entering the cell membranes of the heart and peripheral vascular smooth muscle, and directly relaxes vascular smooth muscle, resulting in an antihypertensive effect. The exact mechanism of action that relieves amlodipine angina is not fully established but has been shown to reduce overall ischemic symptoms by two mechanisms:

First, amlodipine dilates the peripheral arteries, reducing total peripheral vascular resistance (afterload), reducing the burden on the heart, and stabilizing heart rate to reduce the energy consumption and oxygen demand of the myocardium.

Second, amlodipine is thought to dilate the main coronary arteries and other coronary arteries in the ischemic and normal areas. This vasodilation increases oxygen transport in the myocardial ischemic region of patients with coronary artery spasms (prinzmetal's or angina).

In general, calcium channel blockers such as amlodipine are useful for hyporenin patients by dilatating the arteries and reducing myocardial ischemia, but have little effect on renal failure and chronic heart failure by generating angioedema and activating the renin angiotensin system. However, angiotensin-2-receptor blockers such as Ibesartan, unlike amlodipine, dilate veins, reduce angioedema, are useful for patients with gorenin, block the renin-angiotensin system, and have chronic heart failure.

Through this, the combination and combination administration of calcium channel blocker amlodipine and angiotensin-2-receptor blocker ivesartan may be more effective for cardiovascular disease and reduce side effects.

On the other hand, the development of a simple combination of ibesatan and amlodipine can be expected to improve patient compliance by taking medication. However, while Ibesatan is mainly metabolized by cytochrome P450 (CYP450) -based enzymes, amlodipine inhibits the new production of cytochrome P450-based enzymes. Therefore, if ibesatan is transferred to the liver at the same time as amlodipine, or if amlodipine is introduced into the liver before ibesatan, ibesatan is inhibited from metabolism, thereby increasing the blood concentration of the drug. That is, the simple combination agent cannot take into consideration the pharmacological mechanisms such as metabolism of absorption distribution of the drug using biorhythms, and thus has side problems such as lowering the therapeutic effect, inducing drug interactions, and increasing side effects.

Accordingly, the present inventors have completed the present invention as a result of recognizing and solving problems of the simple drug complex of ibesatan and amlodipine.

An object of the present invention is very effective in treating hypertension and hyperlipidemia and preventing complications, and selectively release-controlled amlodipine and ibe, which can improve patient compliance, optimize drug delivery time, avoid drug interactions and reduce side effects. To provide a pharmaceutical formulation containing satan.

The present invention relates to a prior-release compartment comprising an angiotensin-2-receptor blocker, Irbesartan or a pharmaceutically acceptable salt thereof, as a pharmacologically active ingredient, and amlodipine (Amlodipine), which is a calcium channel blocker as a pharmacologically active ingredient, A pharmaceutical formulation is provided which is a time release release formulation comprising a delayed release compartment comprising an isomer thereof or a pharmaceutically acceptable salt thereof.

In the following, “ibesartan” means including its pharmaceutically acceptable salts unless otherwise indicated, and “amlodipine” includes both its isomers and pharmaceutically acceptable salts thereof unless otherwise noted. Means that.

In the present invention, pharmaceutically acceptable salts mean salts commonly used in the pharmaceutical industry, for example, inorganic ion salts, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, prepared with calcium, potassium, sodium and magnesium, Inorganic acid salts, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid prepared from iodic acid, perchloric acid, tartaric acid and sulfuric acid , Benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid, vanic acid, Organic acid salts prepared with hydroiodic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and nathalenesulfonic acid, sulfonic acid salts, glycine, arginine, Amino acid salts made with lysine and the like, and amine salts made with trimethylamine, triethylamine, ammonia, pyridine, picoline and the like, are not limited by the listed salts.

 The formulation according to the present invention provides a more effective therapeutic effect by providing a physical compartment controlling the release between two active ingredients, thereby improving the problem of co-administration or co-administration of existing single agents.

The present invention provides a pharmaceutical formulation wherein at least 80% and preferably at least 90% of the total amount of ibesatan is released within 30 minutes after initiation of ibesatan elution.

In addition, the present invention provides a pharmaceutical formulation in which amlodipine is eluted 1 hour after the start of ibessatan elution, preferably 1 hour and 30 minutes after oral administration.

In addition, the present invention provides a pharmaceutical formulation in which amlodipine is released at 20% or less, preferably 10% or less, or more preferably, at least 20% of the total amount of amlodipine in the unit preparation within 2 hours after the start of ebesatan elution. to provide.

The present invention provides a pharmaceutical formulation that is absorbed in the liver 2 to 4 hours later than amlodipine ibesatan.

The pharmaceutical formulations of the present invention for implementing such drug delivery systems are delayed with amlodipine or its pharmaceutically acceptable salts and desired excipients, so that they can be physically separated or partitioned to obtain different release times and rates of the two drugs. It consists of a release compartment and a pre-release compartment consisting of ibesatan or a pharmaceutically acceptable salt thereof and the desired excipient. In addition, the presently disclosed and delayed-release compartments can be implemented in various formulations.

Each component of the pharmaceutical formulation of the present invention will be described in more detail as follows.

1.Preventive compartment

Pre-release compartment refers to the compartment that is released earlier than the delayed-release compartment in the pharmaceutical formulation of the present invention, and includes pharmacologically active ingredient ibesatan and may further include a pharmaceutically acceptable additive as necessary. Can be.

In the present invention, the prior-release compartment is prepared in the form of a mixture, granules, pellets, or tablets through a conventional procedure for preparing oral administration agents such as mixing, coalescing, drying, and granulation together with pharmaceutically acceptable additives in addition to Ibesatan. can do. In addition, in the case where the fluidity is not good and tableting is not possible directly, it may be compressed, granulated, and granulated to granulate.

(1) pharmaceutical active ingredients

Pre-release compartments include ibesatan or a pharmaceutically acceptable salt as the pharmacologically active ingredient.

In the preparation of the present invention, the active ingredient in the prior-release compartment, ivesartan, contains 1 to 1000 mg of the preparation (200 mg to 1,200 mg in total), preferably 50, based on an adult (65-75 kg adult male). To 400 mg.

Ibesatan in the prior-release compartment is released within 30 minutes after the initiation of release, and releases about 80% or more of the total amount of ibesatan in the unit formulation, thereby exhibiting rapid drug efficacy.

(2) pharmaceutically acceptable additives

The pre-release compartment of the present invention may use additives such as pharmaceutically acceptable diluents, binders, disintegrants, lubricants, pH adjusting agents, stabilizers, dissolution aids, etc. without departing from the effects of the present invention.

In the pre-release compartment of the present invention, the additive comprises 0.01-100 parts by weight with respect to 1 part by weight of ibesatan.

The diluent in the pre-release compartment of the present invention may use starch, microcrystalline cellulose, lactose monohydrate, glucose, di-mannitol, alginate, alkaline earth metal salts, clays, polyethylene glycols, anhydrous calcium hydrogen phosphate, or mixtures thereof. .

In the pre-release compartment of the present invention, the binder is starch, microcrystalline cellulose, highly dispersible silica, mannitol, sucrose, lactose monohydrate, polyethylene glycol, polyvinylpyrrolidone (povidone), hypromellose, hydroxypropyl cellulose, natural gum, Synthetic gums, copovidone, gelatin, mixtures thereof, and the like.

The disintegrating agent in the prior-release compartment of the present invention may be a starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized 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.

In the prior release compartment of the present invention, the lubricant is talc, stearic acid, magnesium stearate, calcium stearate, sodium laurylsulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monolate , Glyceryl monostearate, glyceryl palmitostearate, or a mixture thereof can be used.

In the pre-release compartment of the present invention, the pH adjusting agent may use acidifying agents such as acetic acid, adipic acid, ascorbic acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid, and basicizing agents such as precipitated calcium carbonate, aqueous ammonia, meglumine, and the like. have.

In the pre-release compartment of the present invention, stabilizers may be used alkalizing agents which are salts of alkali metals, salts of alkaline earth metals, or mixtures thereof. As the salt of the alkali metal and the salt of the alkaline earth metal, calcium carbonate, sodium carbonate, sodium hydrogen carbonate, magnesium oxide, magnesium carbonate, sodium citrate, tribasic calcium phosphate, and the like can be used.

In the pre-release compartment of the present invention, the dissolution aid may be polyoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate, polysorbate, docusate sodium, poloxamer and the like.

In addition to the various additives selected from colorants and flavorings, pharmaceutically acceptable additives may be selected and used to formulate the formulations of the present invention.

The range of additives usable in the pre-release compartments of the present invention is not limited to the use of such additives, and the additives described above may be formulated containing a range of doses in a usual range by selection.

2. Delayed release block

In the present invention, the delayed-release compartment refers to a compartment in which the active ingredient is released after a certain time of release of the prior-release compartment active ingredient. The delayed-release compartment comprises (1) the pharmacologically active ingredient amlodipine, an isomer thereof or a pharmaceutically acceptable salt thereof, and (2-1) a release controlling substance or (2-2) an osmotic pressure regulator and a semipermeable membrane coating base. If necessary, (3) may further include a pharmaceutically acceptable additive.

(1) pharmacologically active ingredients

The pharmacologically active ingredient of the delayed-release compartment includes amlodipine and pharmaceutically acceptable salts, wherein the active ingredient in the delayed-release compartment may comprise about 1-100 mg of amlodipine in the unit formulation, with 1-20 mg being preferred.

In the formulation of the present invention, amlodipine during oral administration is released in less than 20% of the total amount of amlodipine in the unit formulation within 2 hours after the start of ebesatan elution, preferably less than 10%, with a time difference from ibesatan Metabolized in the liver

(2-1) Release control substance

The delayed-release compartment in the pharmaceutical formulation of the present invention comprises at least one release controlling substance selected from the group consisting of enteric polymers, water insoluble polymers, hydrophobic compounds, and hydrophilic polymers. And at least one release controlling material selected from water insoluble polymers and enteric polymers.

In the delayed-release compartment of the present invention, the release control material may be used in an amount of 0.05 to 100 parts by weight based on 1 part by weight of amlodipine, and when the amount is less than the above range, sufficient delayed release property cannot be obtained. This delay results in no significant clinical effect.

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 specific pH conditions of pH 5 or higher. The enteric polymer that can be used in the present invention is at least one selected from the group consisting of an enteric cellulose derivative, an enteric acrylic acid copolymer, an enteric maleic acid copolymer and an enteric polyvinyl derivative, and the enteric cellulose derivative is hypromellose acetate succinate. , Hypromellose phthalate, hydroxymethylethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, cellulose propionate phthalate, methyl cellulose phthalate, carboxymethyl ethyl cellulose and ethyl At least one selected from hydroxyethyl cellulose phthalate and methyl hydroxyethyl cellulose; The enteric acrylic acid copolymers include styrene-acrylic acid copolymers, methyl acrylate-acrylic acid copolymers, methyl methacrylate acrylates (e.g., acrylics), butyl-styrene acrylate-acrylic acid copolymers, methacrylic acid-methacrylates Methyl acid copolymer (e.g. Eudragit L 100, Eudragit S, Evonik, Germany), methacrylic acid-ethyl acrylate copolymer (e.g. Eudragit L 100-55, Evonik, Germany), and At least one selected from methyl acrylate-methacrylic acid and octyl acrylate copolymer; The enteric maleic acid-based copolymer may be a vinyl acetate-maleic anhydride copolymer, a styrene-maleic anhydride copolymer, a styrene-maleic acid monoester copolymer, a vinyl methyl ether-maleic anhydride copolymer, an ethylene-maleic anhydride copolymer, or a vinyl butyl ether At least one selected from maleic anhydride copolymer, acrylonitrile-methyl methacrylate-maleic anhydride copolymer, and butyl styrene-maleic-maleic anhydride copolymer; The enteric polyvinyl derivative is at least one selected from polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butyrate phthalate and polyvinyl acetacetal phthalate. In the formulation of the present invention, the enteric polymer is preferably hypromellose acetate succinate.

The enteric polymer according to the present invention may be included in an amount of 0.1 to 20 parts by weight, preferably 0.5 to 10 parts by weight, and less than 0.1 parts by weight, when the enteric polymer according to the present invention is easily dissolved at a pH of less than 5 parts. There is a problem that the total weight of the formulation is unnecessarily large or excessively delayed dissolution.

The water insoluble polymer refers to a polymer that is not soluble in pharmaceutically acceptable water that controls the release of the drug. The water insoluble polymers usable in the present invention are polyvinylacetate, water insoluble polymethacrylate copolymers such as poly (ethylacrylate-methyl methacrylate) copolymers such as Eudragit NE30D, poly (ethylacrylate -Methyl methacrylate-trimethylaminoethyl methacrylate) copolymer (e.g. Eudragit RSPO), ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose And at least one member selected from the group consisting of acetate, cellulose diacetate, and cellulose triacetate.The water-insoluble polymer in the formulation of the present invention is preferably polyvinylacetate.

The water-insoluble polymer according to the present invention may be included in an amount of 0.1 to 30 parts by weight, preferably 0.5 to 20 parts by weight, and less than 0.1 parts by weight, and the release of the drug is not controlled. In this case, excessive elution is delayed.

The hydrophobic compound refers to a substance that does not dissolve in pharmaceutically acceptable water that controls the release of the drug. The hydrophobic compounds usable in the present invention are selected from the group consisting of fatty acids and fatty acid esters, fatty alcohols, waxes, inorganic substances, and mixtures thereof, and the fatty acids and fatty acid esters are glyceryl palmitostearate, glycerol. At least one selected from aryl stearate, glyceryl bihenate, cetyl palmitate, glyceryl mono oleate, and threaric acid; The fatty acid alcohols are at least one selected from cetostearyl alcohol, cetyl alcohol and stearyl alcohol; The wax is at least one selected from carnauba wax, beeswax, and microcrystalline wax; The inorganic substance is at least one selected from talc, precipitated calcium carbonate, calcium dihydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite and non-gum. In the formulation of the present invention, the hydrophobic compound is preferably carnauba wax.

The hydrophobic compound according to the present invention may be included in an amount of 0.1 to 20 parts by weight, preferably 0.5 to 10 parts by weight, and less than 0.1 parts by weight of the amlodipine. There is a problem in that elution is excessively delayed.

The hydrophilic polymer refers to a polymeric material that is dissolved in pharmaceutically acceptable water that controls the release of the drug. The hydrophilic polymer usable in the present invention is selected from the group consisting of sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, hydrophilic polymethacrylate copolymers, polyethylene derivatives, carboxyvinyl polymers, and mixtures thereof. The sugar is one selected from dextrin, polydextrin, dextran, pectin and pectin derivatives, alginates, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropylstarch, amylose, and amylopectin Above; The cellulose derivative is at least one selected from hypromellose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose and carboxymethyl cellulose sodium; 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 polymethacrylate copolymer may be poly (butyl methacrylate- (2-dimethylaminoethyl) methacrylate-methylmethacrylate) copolymer (e.g. Eudragit E100, Evonik, Germany), poly (meth At least one selected from acrylate-methylmethacrylate) copolymers (eg Eudragit L100), and poly (methacrylate-ethylacrylate) copolymers (eg Eudragit L100-55); The polyethylene derivative is at least one selected from polyethylene glycol, and polyethylene oxide; And the carboxyvinyl polymer is carbomer. The hydrophilic polymer in the formulation of the present invention is preferably at least one selected from hypromellose and hydroxypropyl cellulose.

The hydrophilic polymer according to the present invention may be included in 0.05 to 30 parts by weight, preferably 0.5 to 20 parts by weight with respect to 1 part by weight of amlodipine, when the release rate is less than 0.05 parts by weight, there is a problem that the release rate is not controlled, 30 parts by weight If it exceeds, there is a problem that the release rate is not controlled, if more than 30 parts by weight excessive dissolution is delayed.

(2-2) Osmotic pressure regulator and semipermeable membrane coating base

The delayed-release compartment of the present invention includes an osmotic pressure control agent and may be a compartment coated with a semipermeable membrane coating base.

In the delayed-release compartment of the present invention, the osmotic pressure regulator is at least one selected from the group consisting of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, lithium sulfate, sodium sulfate, and mixtures thereof. Preferably sodium chloride and sodium sulfate are used.

Here, the osmotic pressure control agent may be included in 0.05 parts by weight to 30 parts by weight, preferably 0.1 to 20 parts by weight in 1 part by weight of amlodipine, and when less than 0.1 parts by weight, there is a problem in that the effect of generating osmotic pressure is more than 30 parts by weight. There is a problem that unnecessarily increase the total weight of the formulation or implement a suitable drug release rate.

In the delayed-release compartment of the present invention, the semi-permeable membrane coating base is a pharmaceutically usable coating base, which is formulated into the coating layer of the pharmaceutical formulation to be used to form a film which passes some components but does not pass other components. Say. In the present invention, the semipermeable membrane coating base includes, for example, polyvinyl acetate, polymethacrylate copolymer, ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose acetate, cellulose diacetate, And at least one selected from the group consisting of cellulose triacetate and mixtures thereof. In the preparation of the present invention, the semipermeable membrane coating base is preferably ethyl cellulose.

Here, the semi-permeable membrane coating base may be included in an amount of 0.05 parts by weight to 30 parts by weight, preferably 0.1 parts by weight to 20 parts by weight, and less than 0.05 parts by weight with respect to 1 part by weight of amlodipine. In case of more than 30 parts by weight, there is a problem in that the release of the drug does not occur or the delay time becomes over 9 hours or longer.

(3) pharmaceutically acceptable additives

The formulations of the present invention are diluents, binders, and borates other than those mentioned as pharmaceutically acceptable (2-1) release controlling substances and (2-2) osmotic pressure regulators and semipermeable membrane coating agents within the scope of not impairing the effects of the present invention. Commonly used additives such as releases, lubricants, pH adjusters, antifoams, dissolution aids and the like can be formulated further using within a range not departing from the nature of delayed release.

For example, starch, microcrystalline cellulose, lactose monohydrate, glucose, mannitol, di-mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol, anhydrous calcium hydrogen phosphate, or a mixture thereof may be used as a diluent; As a binder, starch, microcrystalline cellulose, highly dispersible silica, mannitol, sucrose, lactose monohydrate, polyethylene glycol, polyvinylpyrrolidone, hypromellose, hydroxypropyl cellulose, natural gum, synthetic gum, copovidone, povidone, gelatin, Or mixtures thereof.

As a disintegrant, starch or modified starches, such as sodium starch glycolate, corn starch, potato starch, or pregelatinized starch (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.

As lubricant, talc, stearic acid, magnesium stearate, calcium stearate, etc., sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, colloidal silicon dioxide, sodium stearyl fumarate, glyceryl behenate, glyceryl monolate, glyceryl monostea Latex, glyceryl palmitostearate, polyethylene glycol, magnesium aluminate silicate, and the like can be used.

As a pharmaceutically acceptable additive of the present invention, the pH adjusting agent may include acidifying agents such as acetic acid, adipic acid, ascorbic acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid, and basicizing agents such as precipitated calcium carbonate, aqueous ammonia, and meglumine. Can be used.

As the pharmaceutically acceptable additive of the present invention, the antifoaming agent may use dimethicone, oleyl alcohol, propylene glycol alginate, simethicone such as simethicone emulsion and the like.

In the pharmaceutically acceptable additives of the present invention, the dissolution aid may be polyoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate, polysorbate, docusate sodium and the like. It is also possible to add a plasticizer such as triethyl citrate and polyethylene glycol.

In addition to the various additives selected from colorants and flavorings, pharmaceutically acceptable additives may be selected and used to formulate the formulations of the present invention. 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.

In addition, in the delayed-release agent of the present invention, purified water, ethanol, methylene chloride, and the like may be used as a solvent of the binding solvent and the delayed-release additive, and more preferably purified water and ethanol.

In the pharmaceutically acceptable additives of the present invention, the range of usable additives is not limited to the use of such additives, and the above-mentioned additives may be formulated to contain a range of dosages by selection.

The formulations of the present invention can be prepared in a variety of formulations, for example, can be formulated in tablets, powders, granules, capsules and the like, such as uncoated tablets, coated tablets, multi-layered tablets, or nucleated tablets.

The preparation of the present invention is a tabletting by selectively mixing additives such as granules constituting the pre-release compartment and granules constituting the delayed-release compartment and the like to have a pre-release compartment and a delayed-release compartment in a single tablet, and thus the active ingredient of each compartment. This may be in the form of uncoated tablets will be eluted separately to show the respective effects.

The formulation of the present invention may be in the form of a biphasic matrix tablet consisting of the delayed-release compartment and the pre-release compartment surrounding it.

In addition, the formulation of the present invention may be in the form of a film coating tablet consisting of a tablet consisting of a delayed-release compartment and a film-coating layer consisting of a pre-release compartment surrounding the outside of the tablet, the film coating layer dissolves Ibesatan This will elute first.

In addition, the formulation 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 into double or triple wells using a multiple tableting machine, delayed-release compartment and pre-release The compartments may be in the form of multi-layered tablets forming a multi-layered structure. Each layer constituting the multilayer tablet may be in a parallel state. This formulation is a tablet for oral administration which is formulated to enable pre-release and delayed release in layers.

In addition, the 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 control agent inside the tablet for delayed release, followed by tableting, followed by coating the surface of the tablet with an osmotic semipermeable membrane to make it an inner core. In addition, the granules constituting the pre-release compartment are mixed with pharmaceutical additives and compressed into an outer layer to have a delayed-release inner core, and the surface of the inner core is surrounded by a pre-release layer.

The formulations of the present invention may be in the form of particles, granules, pellets, or capsules comprising tablets and particles, granules, pellets, or tablets, which consist of delayed-release compartments.

The tablet consisting of the delayed-release compartment of the capsule may include an osmotic pressure-controlling agent within the tablet and an osmotic coated tablet having a semipermeable membrane coating base on the surface of the tablet.

The material of the capsule may be one selected from gelatin, succinate gelatin, or hypromellose, or a mixture 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 particles, granules, pellets, or tablets, etc., which are composed of delayed-release compartments and / or pre-release compartments, may be coated for the purpose of delayed release or stabilization of the formulation.

The formulation according to the present invention may be provided in the form of uncoated tablets without additional coating, but may be in the form of a coated tablet further comprising a coating layer by forming a coating layer on the outside of the formulation, if necessary. 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 may be appropriately selected by 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 a fluidized bed coating method, a fan coating method may be applied, and preferably Fan coating can be applied.

The coating layer may be formed using a coating agent, a coating aid, or a mixture thereof. For example, the coating agent may be a cellulose derivative such as hypromellose, hydroxypropyl cellulose, sugar derivatives, polyvinyl derivatives, waxes, fats, Gelatin, mixtures thereof, and the like; Coating aids may be polyethylene glycol, ethyl cellulose, glycerides, titanium oxide, talc, diethyl phthalate, or mixtures thereof.

The coating layer may include 0.5 to 15% by weight based on the total weight of the tablet.

The pharmaceutical formulation of the present invention may be formulated using a time-dose dosing principle as disclosed in Chrontherpeutics (2003, Peter Redfern, PhP) by any suitable method in the art, and specifically in a method comprising the following steps Can be prepared by

The first step is to mix, associate, dry, granulate, or coat amlodipine by administering one or two of the release controlling substances selected from an enteric polymer, a water insoluble polymer, a hydrophobic compound, and a hydrophilic polymer with a conventional additive used in pharmaceuticals, And obtaining delayed-release granules or tablets through tableting, or mixing, association, drying, sizing, or tableting amlodipine with an osmotic pressure-controlling agent and a conventional additive used in pharmaceuticals, and then coating with a semi-permeable membrane coating base to delay-release Obtaining granules or tablets.

The second step is a prior-release granule or tablet obtained through a conventional procedure for producing oral solids by mixing, coalescing, drying, granulating or coating, and tableting by administering ibesatan and pharmaceutically acceptable conventional additives. To get it.

In the third step, 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 composite 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.

[A] Preparation of two-phase matrix tablet

After further coating the particles or granules obtained in the first step as it is or with a release control material, the mixture is 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.

[B] Preparation of Film-Coated Tablets Containing Active Ingredients

The coated tablets or granules obtained in the first step are further 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 separately dissolve and disperse ivesartan in an aqueous film coating solution. By coating the outer layer of the tablet obtained in the first step can be prepared orally administered film coating tablet containing the active ingredient in the film coating.

Preparation of multi-layered tablets

The granules obtained in the first step as they are or are additionally coated and dried with a release controlling substance and the granules obtained in the second step can be prepared in double tablets using a tablet press. Coated multi-layered tablets can be prepared by formulating or coating triple or more multi-layered tablets by adding a release aid layer as needed, or by formulation design.

[D] Preparation of Nucleated Tablets

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.

[E] Preparation of Capsules (Granules or Tablets)

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. Can be prepared.

[Bar] Preparation of capsules (pellets)

(1) Dissolve or suspend amlodipine and the release control material and, if necessary, pharmaceutically acceptable additives in water, an organic solvent, or a mixed solvent and coat the spherical granules with sugar, and release the release control material alone or as necessary. Capsules may be prepared by dissolving in water, an organic solvent or a mixed solvent using more than one species, coating, drying, granulating obtained in the second step or tablets obtained in the third step, and then mixing the capsules and filling the capsule with a capsule filler. have.

(2) Dissolve or suspend ivesatan and a pharmaceutically acceptable additive in water, an organic solvent or a mixed solvent, coat the spherical granules with sugar, dry them, mix them with the release control pellet containing amlodipine, and then capsule Capsules may be prepared by filling the capsules with a filler.

[Product] Kit Preparation

The amlodipine-containing preparation obtained in the first step and the ibesatan-containing preparation obtained in the second step may be prepared together with a foil, blister, bottle, or the like to be used as a kit.

The pharmaceutical preparation of the present invention as described above is a time-diffusion preparation containing amlodipine and ibesatan as active ingredients, which is administered only once at an evening time (17 o'clock to 23 o'clock) to separately formulate each active ingredient and take it simultaneously. It is easier to take medications than other cases, and the antagonism between drugs does not occur, thereby reducing side effects due to antagonism, and the blood pressure control and lipid control effects of each drug are improved than their own effects. .

Looking at the specific effect of the pharmaceutical formulation of the present invention.

1) Maximum expression of two drugs

The risk from hypertension is highest in the morning, as a sharp rise in blood pressure is induced when it occurs in the morning. William et al., The American Journal of Cardiology. vol.100 (3) (2007) ps10-s16] However, the pharmaceutical formulation for evening administration of the present invention effectively releases Ibesatan, effectively lowering blood pressure until dawn, and after a certain release delay time, i. The release of amlodipine from two hours later, effectively lowering blood pressure after dawn, prevents even 24 hours of antihypertensive action and complications.

2) patient compliance and medication convenience

The pharmaceutical formulation of the present invention applies the so-called Chronotheraphy principle, which is administered at a time difference in the time of expression of pharmacological action in the body, thereby releasing each drug at a specific rate, thereby optimizing drug delivery time as well as easily once. By taking this drug, the patient's compliance with the increased convenience of taking it is also high.

3) Minimizing Side Effects by Drug Interactions

Absorption of different drugs into the body at the same time results in drug-to-drug interactions that affect the excretion of the drug's absorption metabolic distribution due to the nature of each drug. [Michael et al., Current Problems in Cardiology. vol. 33 (12) (2008). p703-768]

The pharmaceutical preparation, which is a time release releasing agent of the present invention, is controlled to release amlodipine after the release of ibesatan, thereby absorbing amlodipine which is delayed for 2 to 10 hours after Ibesatan is sufficiently released and sufficiently metabolized in the liver. It does not affect the metabolism of Ibesatan, thereby enabling the avoidance of drug interactions. This reduces the drug interactions and side effects that can occur with simple combinations.

In addition, all drugs have a dual appearance of disease treatment and side effects, so that the presence of drugs in the blood plays an important role in the therapeutic effect but also in the side effects. Therefore, if the concentration of drug in the blood is too high in a short time, the possibility of the occurrence of side effects increases. That is, if the maximum blood concentration (Cmax) of the two drugs are expressed at the same time, too many drugs are distributed in the blood in a short time there is a possibility that unexpected side effects occur.

However, in the pharmaceutical formulation of the present invention, the ibesatan in the pre-release compartment reaches Tmax after 2 hours and the amlodipine in the delayed-release compartment begins to be released after having a release delay of 1 hour to 2 hours and then the Tmax of the ibesatan. Since the Tmax is reached after a lapse of time, since the Cmax of each drug does not overlap in a short period of time, side effects due to the interaction of the two drugs can be minimized.

Accordingly, the present invention provides a pharmaceutical formulation for administration between 5 pm and 11 pm (17 to 23 pm) containing the pharmaceutical formulation of the present invention.

The human dosage of the formulation of the present invention is appropriately selected according to the absorption rate, inactivation rate and excretion rate of the active ingredient in the body, the age, sex and condition of the patient, but in general, the total amount of ibesatan and amlodipine in adults, 1 day 2 to 1400 mg is administered, and preferably 4 to 700 mg per day to exert anti-pressing effect, hypolipidemic effect and complication prevention effect.

The present invention also provides a method for treating a cardiovascular disease comprising administering a pharmaceutical agent of the present invention to a mammal. Preferably, the present invention provides a method for treating hypertension and hyperlipidemia or consequent cardiovascular disease or metabolic syndrome, comprising administering a pharmaceutical preparation of the present invention to a mammal at 5 pm to 11 pm once a day.

The cardiovascular disease is a very broad disease that refers to both cardiovascular and other vascular diseases including cerebrovascular disease. Types of heart diseases include hypertension, heart failure, arrhythmia, cardiomyopathy, and endocarditis, representing ischemic heart disease (myocardial infarction, angina pectoris, etc.) due to the progression of arteriosclerosis. Vascular diseases include stroke (stroke) and peripheral vascular disease. . In addition, it includes hypertension and complications of those with metabolic syndrome, in which hypertension, diabetes, obesity, hyperlipidemia, and coronary artery disease are combined.

The pharmaceutical preparations of the present invention are very effective in treating hypertension and hyperlipidemia and preventing complications, and have an effect of improving patient compliance, optimizing drug delivery time, avoiding drug interactions and reducing side effects.

Examples are provided to help understand the present invention. The following examples are merely provided to more easily understand the present invention, but are not limited to the contents of the present invention by the production examples and examples.

Preparation Example 1 Preparation of Jivesatan Pre-Release Granules

Ibesatan (Irbesartan USP, Ranbaxy), croscarmellose sodium (Vivasol, JRS) were mixed with the ingredients and contents shown in Table 1 to prepare a mixture, and hydroxypropyl cellulose (HPC-L, Hercules) and polox as binders. Sammer 188 (Lutrol F68, Basf) was mixed with purified water (30 mg per composition ratio), combined with the above mixture, and dried. After granulating the dried granules, magnesium stearate (Nof) was added thereto, followed by mixing to prepare ibessatan pre-release granules.

Preparation Example 2 Preparation of Jybe Satan Pre-Release Granules

Ibesatan, lactose monohydrate (Lactose 200, DMV), pregelatinized starch (Starch 1500, Colorcon) and croscarmellose sodium were mixed with the ingredients and contents shown in Table 1. As a binding solution, poloxamer 188 was mixed in purified water (38 mg per composition ratio), combined with the above mixture, and dried. After the granules were dried, microcrystalline cellulose (Vivapur102, JRS, colloidal silicon oxide (Aerosil200VV, Degussa) and magnesium stearate) were added and mixed to prepare an ivesartan linear-release granule.

Preparation Example 3 Preparation of Jybe Satan Pre-Release Granules

It was prepared using purified water (43mg per composition ratio) in the same manner as in Preparation Example 2 with the ingredients and contents shown in Table 1.

Table 1 Ibesatan pre-release granule composition

Preparation Example 4 Preparation of Ie Satan Pre-Release Pellets

Ibesatan, poloxamer 188, hydroxypropyl cellulose, croscarmellose were added methylene chloride (600 mg per composition ratio) and ethanol (600 mg per composition ratio) in sugar beads (Non-pareil-101, Freund) according to the ingredients and contents shown in Table 2. The liquid dispersed and dissolved in was sprayed and coated using a fluidized bed granulator, followed by drying to prepare an ivesatan pre-release pellet.

[Table 2] Ibesatan pre-release pellet composition

Preparation Example 5 Preparation of Amlodipine Delayed-Release Granules Using Enteric Polymers

The mixture was prepared by mixing amlodipine besylate (Cipla), anhydrous calcium hydrogen phosphate (DCP A / T, Rhodia), microcrystalline cellulose, and sodium starch glycolate (Explotab, JRS) in the ingredients and contents shown in Table 3. Separately, hydroxypropyl cellulose was dissolved in purified water, and this solution was sprayed onto the mixture using a fluidized bed granulator to form granules. Separately, hypromellose acetate succinate (HPMC-AS LF, Shinetsu) was dissolved in 80% (v / v) ethanol (825 mg per composition ratio) and then sprayed on the granules formed above to coat the granules and then dry. Magnesium stearate was added to the granules and mixed to prepare amlodipine delayed-release granules.

Preparation Example 6 Preparation of Amlodipine Delayed-Release Tablet Using Enteric Polymer

The ammonia dipine besylate, anhydrous calcium hydrogen phosphate, microcrystalline cellulose, sodium starch glycolate and magnesium metasilicate (Neusilin UFL2, Fujichemical) and finally magnesium stearate were mixed with the ingredients and contents shown in Table 3. Tableting was carried out in a mounted rotary tablet press. The tablets on which tableting was completed were coated with a coating solution prepared by dissolving hypromellose acetate succinate in 80% (v / v) ethanol (150 mg per composition) to prepare amlodipine delayed-release tablets.

Preparation Example 7 Preparation of Amlodipine Delayed-Release Tablet Using Enteric Polymer as Dry Coating

Tableting in a rotary tablet press equipped with a 5.0 mm diameter punch by mixing amlodipine besylate, anhydrous calcium hydrogen phosphate, microcrystalline cellulose, sodium starch glycolate and magnesium metasilicate and finally magnesium stearate with the ingredients and contents shown in Table 3 It was. The tablets that had been tableted were used as inner cores, and compressed with a mixture of hypromellose acetate succinate, microcrystalline cellulose, and magnesium stearate in a nucleus tablet press equipped with a 10 mm punch to prepare dry-coated amlodipine delayed-release nucleated tablets. .

[Table 3] Amlodipine delayed-release granules and tablet composition using enteric polymer

Preparation Example 8 Preparation of Amlodipine Delayed-Release Granules Using Water Insoluble Polymers

A mixture was prepared by mixing amlodipine besylate, anhydrous calcium hydrogen phosphate, microcrystalline cellulose, and sodium starch glycolate as ingredients and contents shown in Table 4. Separately, hydroxypropyl cellulose was dissolved in purified water (48 mg per composition ratio), and then the solution was sprayed onto the mixture using a fluidized bed granulator to form granules. Separately, the Kollicoat SR 30D (Kollicoat SR 30D, Basf) was sprayed on purified granules (300 mg per composition ratio), and then sprayed on the granules formed above to coat the granules and then dry. Magnesium stearate was added to the granules and mixed to prepare amlodipine delayed-release granules.

Preparation Example 9 Preparation of Amlodipine Delayed-Release Tablet Using Water Insoluble Polymer

In a rotary tablet press equipped with a 5.0 mm punch, a mixture of amlodipine besylate, anhydrous calcium hydrogen phosphate, microcrystalline cellulose, sodium starch glycolate, magnesium metaalutate and finally magnesium stearate was mixed with the ingredients and contents shown in Table 4. Tableting. Amalodipine besylate delayed-release tablets were prepared by coating with a coating solution prepared by dispersing Colicoat SR 30D (Kollicoat SR 30D, Basf) in purified water (51 mg per composition ratio) in a tablet in which tableting was completed.

[Table 4] Amlodipine delayed-release granules and tablet composition using water-insoluble polymer

Preparation Example 10 Preparation of Amlodipine Delayed-Release Granules Using Hydrophobic Compounds and Hydrophilic Polymers

A mixture was prepared by mixing amlodipine besylate, anhydrous calcium hydrogen phosphate, microcrystalline cellulose, and sodium starch glycolate with the ingredients and contents shown in Table 5. Separately, hydroxypropyl cellulose was dissolved in purified water (60 mg per composition ratio), and then the liquid was sprayed onto the mixture using a fluidized bed granulator to form granules. Separately, carnauba wax (Cavawax W6, ISP), hypromellose (Methocel, Colorcon), and polyethylene glycol 6000 (PEG6000, Duksan) were dispersed in water and sprayed on the granules formed above to coat the granules, and then dried. . Magnesium stearate was added to the granules and mixed to prepare amlodipine delayed-release granules.

Preparation Example 11 Preparation of Amlodipine Delayed-Release Tablet Using Hydrophobic Compound and Hydrophilic Polymer

Tablets were prepared in a rotary tablet press equipped with a 5.0 mm diameter punch by mixing amlodipine besylate, calcium hydrogen phosphate anhydrous, microcrystalline cellulose, sodium starch glycolate and magnesium metasilicate and finally magnesium stearate with the ingredients and contents shown in Table 5. It was. Carnauba wax, hypromellose, and polyethylene glycol 6000 was coated in a tablet solution prepared by dispersing the tablet in a tablet solution, and thus, amlodipine delayed-release tablets were prepared.

[Table 5] Amlodipine delayed-release granules and tablet composition using hydrophobic compounds and hydrophilic polymers

Preparation Example 12 Preparation of Amlodipine Delayed-Release Granules Manufactured Granules Using Hydrophilic Polymers

A mixture was prepared by mixing amlodipine besylate, anhydrous calcium hydrogen phosphate, microcrystalline cellulose, and sodium starch glycolate with the ingredients and contents shown in Table 6. Separately, hydroxypropyl cellulose was dissolved in purified water (60 mg per composition ratio), and then the liquid was sprayed onto the mixture using a fluidized bed granulator to form granules. Separately, hydroxypropyl cellulose and polyethylene glycol 6000 were dissolved in purified water (3000 mg per composition ratio), and then sprayed on the granules formed above to coat the granules and then dry. Magnesium stearate was added to the granules and mixed to prepare amlodipine delayed-release granules.

Preparation Example 13 Preparation of Amlodipine Delayed-Release Tablet Using Hydrophilic Polymer

Tablets were prepared in a rotary tablet press equipped with a 5.0 mm diameter punch by mixing amlodipine besylate, anhydrous calcium phosphate, microcrystalline cellulose, sodium starch glycolate and magnesium metasilicate and finally magnesium stearate with the ingredients and contents shown in Table 6. It was. Hydroxypropyl cellulose and polyethylene glycol 6000 were dissolved in purified water (300 mg per composition ratio) and then coated with a coating solution to prepare an amlodipine delayed-release tablet.

[Table 6] Amlodipine delayed-release granules and tablet composition using hydrophilic polymer

Preparation 14 Preparation of Amlodipine Delayed-Release Granules Using Semipermeable Membrane Coating Base and Osmotic Pressure Regulator

A mixture was prepared by mixing amlodipine besylate, anhydrous calcium hydrogen phosphate, microcrystalline cellulose, sodium starch glycolate, and sodium chloride (NaCl, Duksan) with the ingredients and contents shown in Table 7. Separately, hydroxypropyl cellulose was dissolved in purified water (60 mg per composition ratio), and then the solution was sprayed onto the mixture using a fluidized bed granulator to form granules. Separately, ethyl cellulose (Ethocel, Colorcon) was dissolved in a mixed solution of methylene chloride (360 mg per composition ratio) and ethanol (360 mg per composition ratio), and then sprayed on the granules formed above to coat the granules and then dry. Magnesium stearate was added to the granules and mixed to prepare amlodipine delayed-release granules.

Preparation Example 15 Preparation of Amlodipine Delayed-Release Tablet Using Semipermeable Membrane Coating Base and Osmotic Pressure Regulator

Rotary tablet press equipped with a 5.0 mm diameter punch by mixing amlodipine besylate, anhydrous calcium hydrogen phosphate, microcrystalline cellulose, sodium starch glycolate, magnesium aluminate silicate and sodium chloride and finally magnesium stearate with the ingredients and contents shown in Table 7. It was tableted at. The tablets on which tableting was completed were coated with a coating solution prepared by dissolving ethyl cellulose in a mixed solution of methylene chloride (65 mg per composition) and ethanol (65 mg per composition) to prepare amlodipine delayed-release tablets.

[Table 7] Amlodipine delayed-release granules and tablets composition using semipermeable membrane coating agent and osmotic pressure regulator

Preparation Example 16 Preparation of Delayed-Release Pellets of Amlodipine Using Enteric Polymers

A liquid obtained by dispersing and dissolving amlodipine besylate, anhydrous calcium phosphate, microcrystalline cellulose hydroxypropyl cellulose, and sodium starch glycolate in purified water (60 mg per composition ratio) in sugar beads using a fluidized bed granulator Sprayed and coated. Separately, a solution prepared by dissolving hypromellose acetate succinate in 80% (v / v) ethanol (750 mg per composition ratio) was sprayed on the above beads again, coated, and dried to prepare a delayed-release pellet of amlodipine.

[Table 8] Amlodipine delayed-release pellet composition using enteric polymer

Example 1 Preparation of Matrix Tablets on Ibesartan-Amlodipine Two Phase

The Ibesatan pre-release granules of Preparation Example 2 and the amlodipine delayed-release granules using the enteric polymers of Preparation Example 5 were mixed, and then compressed into a rotary tablet press equipped with a 11 mm diameter punch. The two-phase matrix tablet having the tableting completed was coated with a coating solution dissolved in purified water (300 mg per composition ratio) using the ingredients and contents shown in Table 9.

Table 9 Composition of Film Coating Layer

Example 2 Preparation of Amlodipine Film-Coated Tablets Containing Ibesatan in Coating Layer

Amlodipine delayed-release tablet using the water-insoluble polymer of Preparation Example 9 as a coating solution containing Ibesatan prepared by dissolving methylene chloride (1400 mg per composition ratio) and ethanol (1400 mg per composition ratio) in the ingredients and contents shown in Table 10. Coating was performed to prepare a film-coated tablet.

Example 3 Preparation of Amlodipine Nucleated Film Coated Tablets Containing Ivesartan in Coating Layer

In the amlodipine delayed-release nucleated tablet using the enteric polymer of Preparation Example 7 as a dry coating, the ingredients and contents shown in Table 10 were dissolved in methylene chloride (1400 mg per composition) and ethanol (1400 mg per composition). Coating with a coating solution to prepare a film-coated tablets.

[Table 10] Composition of film coating layer containing ibesatan

Example 4 Preparation of Ibesatan-Amlodipine Double Tablet

The double ammonium tablets were prepared by putting the ibesartan pre-release granules of Preparation Example 2 and the amlodipine delayed-release granules using the water-insoluble polymer of Preparation Example 8 into different granule inlets of a rotary triple tablet press machine equipped with a 11 mm diameter punch. It was. Once the tablet is completed, it was coated with a coating solution prepared by dissolving in purified water (300 mg per composition ratio) to the ingredients and contents shown in Table 9.

Example 5 Preparation of Ivesartan-Amlodipine Multi-Layered Tablets

The Ibesatan pre-release granules of Preparation Example 2 were divided into one layer and three layers, and 11 mm diameter punches were equipped with the amlodipine delayed-release granules using the hydrophobic compound and the hydrophilic polymer of Preparation Example 10 as the intermediate layer (the second layer). The multi-layered tablets were prepared by putting them into different granule inlets of the rotary triple tablet press tableting machine. The tablets having been tableted were coated with a coating solution prepared by dissolving the ingredients and contents shown in Table 9 in purified water (300 mg per composition ratio).

Example 6 Preparation of Ibesatan-Amlodipine Nucleus Tablets

Nucleated tablets were prepared by tableting in a nucleus tableting machine equipped with an 11 mm punch together with the ibesartan prior-release granules of Preparation Example 3 using the amlodipine delayed-release tablet using the enteric polymer of Preparation Example 6 as the inner core. The tablets having been tableted were coated with a coating solution prepared by dissolving the ingredients and contents shown in Table 9 in purified water (300 mg per composition ratio).

Example 7 Preparation of Ivesartan-Amlodipine Nucleus Double Tablet

When tableting amlodipine delayed-release nucleated tablets using the enteric polymer of Preparation Example 7 as dry coating, Ibesatan pre-release granules of Preparation Example 1 were added to another inlet, and then compressed into one nucleus tablet to form a nucleated tablet. A courtyard was prepared. The tablets having been tableted were coated with a coating solution prepared by dissolving the ingredients and contents shown in Table 9 in purified water (300 mg per composition ratio).

Example 8 ibesatan-amlodipine capsules (tablets + tablets) preparation

Ibesatan pre-release granules of Preparation Example 1 were compressed in a No. 0 capsule together with amlodipine delayed-release tablets using hydrophilic polymer of Preparation Example 13 by tableting in a rotary tablet press equipped with a 6 mm punch. The agent was prepared.

Example 9 Ibesatan-Amlodipine Capsule Preparation (Granule + Tablet)

Ibesatan pre-release granules of Preparation Example 1 were filled into No. 0 capsules with amlodipine delayed-release tablets using hydrophobic compounds and hydrophilic polymers of Preparation Example 11 to prepare capsules containing granules and tablets.

<Example 10> Ibesatan-amlodipine capsules (tablets + granules) preparation

Ibesatan pre-release granules of Preparation Example 1 were compressed in a No. 0 capsule together with amlodipine delayed-release granules using hydrophilic polymer of Preparation Example 12 by tableting in a rotary tablet press equipped with a 6 mm punch to contain tablets and granules. Capsules were prepared.

Example 11 Ibesatan-Amlodipine Capsule Preparation (Granule + Granule)

The capsules containing granules and granules were prepared by filling 0 capsules with the ivesatan pre-release granules of Preparation Example 1 and the amlodipine delayed-release granules using the semipermeable membrane coating agent of Preparation Example 14 and the osmotic pressure regulator.

<Example 12> Ibesatan-Amlodipine capsules (pellets + tablets) preparation

The capsules containing pellets and tablets were prepared by filling the capsule No. 0 together with the ivesatan pre-release pellet of Preparation Example 4 and the amlodipine delayed-release tablet using the semipermeable membrane coating agent of Preparation Example 15 and the osmotic pressure regulator.

Example 13 Preparation of Ibesatan-Amlodipine Capsule (Pellets + Granules)

Capsules containing pellets and granules were prepared by filling into capsule No. 0 together with the albodipine delayed-release granules using the ivesatan pre-release pellet of Preparation Example 4 and the enteric polymer of Preparation Example 5.

<Example 14> Ibesatan-amlodipine capsules (tablets + pellets) preparation

Ibesatan pre-release granules of Preparation Example 1 were compressed in a No. 0 capsule together with amlodipine delayed-release pellets using enteric polymer of Preparation Example 16 by tableting in a rotary tablet press equipped with a 6 mm punch to contain tablets and pellets. Capsules were prepared.

<Example 15> Ibesatan-amlodipine capsule (granules + pellets) preparation

A capsule containing granules and pellets was prepared by filling into capsule No. 0 together with the albodipine delayed-release pellet using the ivesatan prerelease of Preparation Example 1 and the enteric polymer of Preparation Example 16.

<Example 16> Ibesatan-amlodipine capsules (granules + capsules) preparation

The amlodipine delayed-release granules using the enteric polymer of Preparation Example 5 were filled into No. 2 capsules, and the capsules containing granules and capsules were prepared by filling into No. 0 capsules with the Ibesatan prior-release granules of Preparation Example 1. .

Example 17 Preparation of Ivesartan-Amlodipine Capsule (Granule + Delayed-Release Capsule)

Fill the No. 2 capsule with amlodipine besylate, anhydrous calcium hydrogen phosphate, microcrystalline cellulose, sodium starch glycolate, sodium metasilicate silicate and magnesium stearate to the ingredients and contents shown in Table 11, and then hypromellose acetate succinate. Capsules were coated using a coating solution prepared by dissolving in 80% (v / v) ethanol (300 mg per composition ratio). Capsules coated with enteric polymers were filled into capsule 0 together with the immediate release granules of Preparation Example 1 to prepare capsules containing granules and delayed-release capsules.

TABLE 11 Delayed-Release Capsule Compositions with Amlodipine

Example 18 Preparation of Ivesartan-Amlodipine Blister Packaging Kit

Ibesatan pre-release granules of Preparation Example 1 was compressed in a rotary tablet press equipped with a 6 mm punch and packed in one PTP (Press Through Pack) packaging container together with amlodipine delayed-release tablets using enteric polymer of Preparation Example 6 A packaging kit was prepared for simultaneous use.

Experimental Example 1 Dissolution profile test 1 (dissolution profile test)

Tablets obtained in Example 2 (the film-coated tablets of the main ingredient), and Example 4 (double tablets) and capsules obtained in Example 8 (the capsules containing the tablets plus the tablets in the capsule) were used as control agents. A comparative dissolution test was conducted using (Pfizer: Ivesartan monolith) and Novask tablet (Pfizer: amlodipine besylate monolith) according to the following conditions.

Similar to the absorption path of the drug of the living body, the acidic condition was set to 0.1N hydrochloric acid solution and the intestinal condition to pH 6.8 (Korean Pharmacopoeia) solution. After elution, sodium phosphate solution and sodium hydroxide EH were adjusted to pH 6.8 by adding hydrochloric acid solution, and then the dissolution test was conducted by proceeding with the test.

[Amlodipine Besylate Test Method]

Dissolution test basis: Dissolution test method of General Test Method

Test method: Paddle method, 50 revolutions / minute

Test solution: 750 mL of 0.1 N hydrochloric acid solution for 0 ~ 2 hours, 250 mL of 0.2 mol / L sodium phosphate solution, 1 mol / L sodium hydroxide solution and 2 mol / L hydrochloric acid solution in 750 mL of 0.1 N hydrochloric acid solution after 2 hours Dissolution test was conducted with a solution adjusted to pH6.8.

Assay: HPLC-UV (detection wavelength = maximum 237 nm)

Ibesatan Test Method

Dissolution test basis: 'Irbesartan tablet' in USP 31

Test method: Paddle method, 50 revolutions / minute

Test solution: 0.1 N-hydrochloric acid solution (acid environment), 1000 mL

Analytical method: HPLC-UV (detection wavelength = 220 nm)

As a result of the dissolution test, the following results were obtained as shown in Table 12 and FIG.

In contrast, amlodipine besylate in the formulation of the present invention, unlike Novask tablets (control formulation) in which about 85% of the total amount of amlodipine besylate of the formulation was eluted within 15 minutes after the dissolution test, up to 120 minutes to 180 minutes after the dissolution test. Within about 20% of the total amount of amlodipine besylate eluted, it was confirmed that the release of amlodipine was delayed by about 2 hours compared to Ibesatan.

Table 12 Dissolution Test Results Table of Experimental Example 1

Average Dissolution Rate (%) Ibersatan Amlodipine besylate Minutes Control agent Example 2 Example 4 Example 8 Control agent Example 2 Example 4 Example 8 15 41.7 60.8 45.5 32.7 84.0 0.0 0.0 0.0 30 90.8 89.5 88.7 90.1 97.8 0.0 0.0 0.0 60 97.0 94.3 94.8 95.5 99.8 0.0 1.1 1.2 90 98.0 97.5 96.9 97.8 100.1 3.5 2.6 2.9 120 98.4 99.4 97.2 98.8 100.1 9.4 8.8 11.4 150 - - - - - 22.5 20.7 26.8 180 - - - - - 58.8 42.2 68.7 210 - - - - - 76.6 61.5 85.5 240 - - - - - 82.5 74.8 88.7 270 - - - - - 85.8 83.4 89.5 300 - - - - - 89.2 85.5 90.1 360 - - - - - 90.1 86.7 90.2 Latency (20% emission) Less than 15 minutes About 150 minutes About 150 minutes About 120 minutes

Experimental Example 2 Dissolution profile test 2 (dissolution profile test)

Dissolution test of the tablets obtained in Example 6 (nucleated tablets) and Example 15 (capsules filled with granules + pellets), and Example 17 (capsules filled with granules + delayed-release capsules) Was carried out.

Similar to the absorption path of the drug in the living body, the acidic condition was set to 0.1N HCl and the intestinal condition was set to pH 6.8 (Korean Pharmacopoeia) solution. After the elution test was carried out by proceeding the test at pH 6.8.

[Amlodipine Besylate Test Method]

Dissolution test basis: Dissolution test method of General Test Method

Test method: Paddle method, 50 revolutions / minute

Test solution: The elution test was performed in 1,000 mL of 0.1 N hydrochloric acid solution from 0 mL to 2 hours after 2 hours in pH 6.8 phosphate buffer solution.

Assay: HPLC-UV (detection wavelength = maximum 237 nm)

Ibesatan Test Method

Dissolution test basis: 'Irbesartan tablet' in USP 31

Test method: Paddle method, 50 revolutions / minute

Test solution: 0.1 N-hydrochloric acid solution (acid environment), 1000 mL

Analytical method: HPLC-UV (detection wavelength = 220 nm)

As a result of the dissolution test, the results shown in Table 13 and FIG. 2 were obtained, and the Ibesatan components of Examples 6, 15, and 17 exhibited the same dissolution properties as compared to the control formulation of Aprobel tablet.

In contrast, amlodipine besylate in the formulations of the present invention, unlike Novask tablets (control), in which about 85% of the total amount of amlodipine besylate of the formulation was eluted within 15 minutes after the dissolution test, the amlodipine besylate until 120 minutes after the dissolution test. Was not eluted at all, the formulation of the present invention was confirmed that the release of amlodipine delayed by about 2 hours compared to the Ibesatan.

Table 13 Dissolution Test Results Table of Experimental Example 2

Average Dissolution Rate (%) Ibersatan Amlodipine besylate Minutes Control Agent (Experimental Example 1) Example 6 Example 15 Example 17 Control Agent (Experimental Example 1) Example 6 Example 15 Example 17 15 41.7 54.8 43.3 55.2 84.0 0.0 0.0 0.0 30 90.8 89.0 87.8 92.1 97.8 0.0 0.0 0.0 60 97.0 94.3 95.6 95.7 99.8 0.0 0.0 0.0 90 98.0 98.3 98.8 97.8 100.1 0.0 0.0 0.0 120 98.4 99.7 99.4 98.9 100.1 0.0 0.0 0.0 135 - - - - - 0.0 10.2 20.8 150 - - - - - 27.9 33.6 48.9 180 - - - - - 68.3 70.6 77.6 210 - - - - - 80.0 83.2 85.6 240 - - - - - 83.4 84.8 88.2 300 - - - - - 84.5 86.5 90.4 360 - - - - - 85.1 89.2 92.5

1 is a graph showing the dissolution rate of amlodipine besylate in Ibesatan and Novask tablets in Aprobel tablets, which are the timed release formulations and control agents of Examples 2, 4 and 8.

Figure 2 is a graph showing the dissolution rate of amlodipine besylate in Ibesatan and Novasque tablets in Aprobel tablets, which are the timed release formulations and control agents of Examples 6, 15 and 17.

Claims (36)

A prior release compartment comprising Irbesartan or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient, and a delayed release compartment comprising amlodipine, an isomer thereof or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient Pharmaceutical formulations comprising a. The pharmaceutical formulation of claim 1, wherein at least 80% of the total amount of ibesatan is released within 30 minutes after the start of dissolution of the ibesatan. The pharmaceutical formulation of claim 1, wherein the amlodipine is released 1 hour and 30 minutes after the start of Ibesatan elution upon oral administration. The pharmaceutical formulation of claim 1, wherein the amlodipine is released at 20% or less of the total amount of amlodipine in the unit dosage form within 2 hours after the start of ebesatan elution upon oral administration. The pharmaceutical formulation of claim 1, wherein the ibesatan is 50-400 mg in the formulation. The pharmaceutical formulation of claim 1, wherein the amlodipine is 1-20 mg in the formulation. The pharmaceutical formulation of claim 1, wherein the delayed-release compartment comprises one or more release controlling substances selected from the group consisting of enteric polymers, water insoluble polymers, hydrophobic compounds, and hydrophilic polymers. 8. A pharmaceutical formulation according to claim 7, wherein said release controlling substance is at least one selected from an enteric polymer and a water insoluble polymer. 8. The pharmaceutical formulation of claim 7, wherein the release controlling substance is contained in an amount of 0.05 parts by weight to 100 parts by weight with respect to 1 part by weight of amlodipine. 8. The pharmaceutical formulation of claim 7, wherein the enteric polymer is at least one selected from an enteric cellulose derivative, an enteric acrylic acid copolymer, an enteric maleic acid copolymer and an enteric polyvinyl derivative. The method of claim 10, wherein the enteric cellulose derivative is hypromellose acetate succinate, hypomellose phthalate, hydroxymethylethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, At least one selected from cellulose propionate phthalate, methyl cellulose phthalate, carboxymethylethyl cellulose, ethyl hydroxy ethyl cellulose phthalate and methyl hydroxyethyl cellulose; The enteric acrylic acid copolymer may be a styrene-acrylic acid copolymer, a methyl acrylate-acrylic acid copolymer, a methyl methacrylate acrylic acid copolymer, a butyl styrene-acrylate-acrylic acid copolymer, a methacrylic acid-methyl methacrylate copolymer, or methacrylic acid. At least one selected from an acid ethyl acrylate copolymer and a methyl acrylate-methacrylic acid-octyl acrylate copolymer; The enteric maleic acid-based copolymer may be a vinyl acetate-maleic anhydride copolymer, a styrene-maleic anhydride copolymer, a styrene-maleic acid monoester copolymer, a vinyl methyl ether-maleic anhydride copolymer, an ethylene-maleic anhydride copolymer, or a vinyl butyl ether At least one selected from maleic anhydride copolymer, acrylonitrile-methyl methacrylate maleic anhydride copolymer and butyl styrene-maleic anhydride copolymer; Or the enteric polyvinyl derivative is at least one selected from polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butyrate phthalate, and polyvinyl acetal phthalate. The pharmaceutical formulation of claim 11 wherein the enteric polymer is hypromellose acetate succinate. The pharmaceutical formulation of claim 10, wherein the enteric polymer is 0.1 part by weight to 20 parts by weight based on 1 part by weight of amlodipine. The method according to claim 7, wherein the water-insoluble polymer is polyvinylacetate, water-insoluble polymethacrylate copolymer, ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose acetate, A pharmaceutical formulation which is at least one selected from cellulose diacetate, and cellulose triacetate. The pharmaceutical formulation of claim 14, wherein the water insoluble polymer is polyvinylacetate. The pharmaceutical formulation according to claim 14, wherein the water-insoluble polymer is 0.1 parts by weight to 30 parts by weight with respect to 1 part by weight of amlodipine. The pharmaceutical formulation of claim 7, wherein the hydrophobic compound is at least one selected from fatty acids and fatty acid esters, fatty alcohols, waxes and inorganic substances. 18. The method of claim 17, wherein the fatty acid and fatty acid esters are at least one selected from glyceryl palmitostearate, glyceryl stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate and stearic acid; The fatty acid alcohol is at least one selected from cetostearyl alcohol, cetyl alcohol and stearyl alcohol, and the wax is at least one selected from carnauba wax, beeswax and microcrystalline wax; The inorganic substance is at least one selected from talc, precipitated calcium carbonate, calcium dihydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite and non-gum. 18. The pharmaceutical formulation of claim 17, wherein the hydrophobic compound is 0.1 to 20 parts by weight based on 1 part by weight of amlodipine. The pharmaceutical formulation of claim 7, wherein the hydrophilic polymer is at least one selected from sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, hydrophilic polymethacrylate copolymers, polyethylene derivatives, and carboxyvinyl polymers. The method of claim 20, wherein the saccharide is dextrin, polydextrin, dextran, pectin and pectin derivatives, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropylstarch, amylose And amylopectin; The cellulose derivative is one selected from hypromellose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl methyl cellulose acetate succinate and hydroxyethyl methyl cellulose. Above; 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) copolymer, poly (methacrylate-methylmethacrylate) copolymer and poly (Methacrylate-ethylacrylate) at least one member selected from copolymers; The polyethylene derivative is at least one selected from polyethylene glycol and polyethylene oxide; The carboxyvinyl polymer is a carbomer. The pharmaceutical formulation according to claim 20, wherein the hydrophilic polymer is 0.05 parts by weight to 30 parts by weight with respect to 1 part by weight of amlodipine. The pharmaceutical formulation of claim 1, wherein the delayed-release compartment comprises an osmotic pressure regulator and is coated with a semipermeable membrane coating base. The pharmaceutical preparation according to claim 23, wherein the osmotic pressure regulator is at least one selected from the group consisting of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, lithium sulfate, sodium sulfate, and mixtures thereof. 25. The method of claim 23, wherein the semipermeable membrane coating base is polyvinyl acetate, poly methacrylate copolymer, ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose acetate, cellulose A pharmaceutical formulation of at least one selected from the group consisting of diacetate, cellulose triacetate, and mixtures thereof. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is in the form of a biphasic matrix tablet consisting of the delayed-release compartment and a pre-release compartment surrounding it. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is 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 prior-release compartment surrounding the outside of the tablet. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is in the form of a multi-layered tablet in which the delayed-release compartment and the prior-release compartment are layered. The pharmaceutical formulation according to claim 1, wherein the formulation is in the form of a nucleus tablet consisting of an inner core consisting of a delayed-release compartment and an outer layer consisting of a prior-release compartment surrounding an outer surface of the inner core. 30. The pharmaceutical formulation of claim 29, wherein the nucleated tablet is an osmotic nucleated tablet. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is in the form of a capsule comprising granules, granules, pellets, or tablets consisting of delayed-release compartments and particles, granules, pellets, or tablets consisting of prior-release compartments. . The pharmaceutical formulation of claim 1, further comprising a coating layer on the exterior of at least one of the delayed-release compartment or the prior-release compartment. The pharmaceutical formulation according to claim 1, which is in the form of a coated tablet further comprising a coating layer on the outside. The pharmaceutical formulation of claim 1, wherein the formulation is in the form of a kit comprising a delayed release compartment and a prior release compartment. The pharmaceutical formulation of claim 1, wherein the formulation is for administration between 5 pm and 11 pm. 36. A method for treating cardiovascular disease comprising administering to a mammal the pharmaceutical formulation of any one of claims 1 to 35.

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