KR102490653B1 - Pharmaceutical composition comprising dapagliflozin and glimepiride - Google Patents

Abstract

The present invention discloses a pharmaceutical composition comprising dapagliflozin and glimepiride with improved patient compliance when used as a single administration regimen. Treatment using the composition of the present invention can be used as an effective treatment strategy by ensuring high patient compliance and excellent treatment effect and durability compared to a method of combined administration of two drugs.

Description

Pharmaceutical composition comprising dapagliflozin and glimepiride

The present invention relates to a pharmaceutical composition comprising dapagliflozin and glimepiride.

Metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, and insulin have been used for a long time to treat diabetes, one of the representative chronic diseases. (glucagon like peptide-1) analogues, etc., are being used in a new class of drugs.

SGLT-2 inhibitors inhibit reabsorption of glucose in the renal tubules, thereby allowing glucose to be excreted in the urine, and act independently of insulin resistance or beta cell function.

Dapagliflozin, one of the SGLT-2 inhibitors, was approved in Europe in 2012 and approved by the US Food and Drug Administration in 2014, and has the most clinical data among SGLT2 inhibitors.

Currently, clinical study results of dapagliflozin monotherapy and combination therapy added to metformin, pioglitazone, sitagliptin, and insulin have been published. Based on these clinical study results, dapagliflozin is used as monotherapy by preparing a combination drug with metformin and/or sitagliptin.

One of the sulfonylurea drugs, glimepiride, is commonly used for the medical management of type 2 diabetes (T2DM) after diet and exercise fail, and has not yet been used as a monotherapy as it has been manufactured in the form of a combination drug. .

KR 10-2015-0038555A (2015.04.08) KR 10-2018-0078762A (2018.07.10)

In the present invention, a pharmaceutical composition capable of using dapagliflozin and glimepiride as monotherapy was prepared.

The pharmaceutical composition of the present invention is dapagliflozin or a pharmaceutically acceptable salt thereof; And glimepiride or a pharmaceutically acceptable salt thereof; discloses a pharmaceutical composition containing as an active ingredient.

The pharmaceutical composition is used for preventing or treating diabetes, diabetes-related diseases or diabetic complications.

The pharmaceutical composition may be administered orally; rectal administration; It is formulated into a preparation form selected from the group consisting of intraperitoneal administration, transdermal administration, subcutaneous administration, intramuscular administration, intravenous administration, ocular administration, intrapulmonary administration, and parenteral administration including intranasal administration.

The pharmaceutical composition includes dapagliflozin in an amount of 2.5 to 10 mg and glimepiride in an amount of 1 to 8 mg.

The pharmaceutical composition is a combination preparation for single administration, and is a combination preparation for oral administration.

Hereinafter, the present invention will be described in detail.

Dapagliflozin of the present invention has a basic structure represented by Formula 1 below.

[Formula 1]

The IUPAC chemical name of dapagliflozin is (1 S )-1,5-anhydro-1-C- 4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl-D-glucitol, CAS Number 461432-26 -8.

Dapagliflozin may be an amorphous form of dapagliflozin complex, dapagliflozin co-crystal, dapagliflozin solvate, dapagliflozin hydrate, or mixtures thereof.

In the present specification, 'hydrate' may be one in which dapagliflozin, or a pharmaceutically acceptable salt thereof, and water are bound by non-covalent intermolecular forces, and may contain a stoichiometric amount of water. Specifically, the hydrate may include water in an amount of about 0.25 to about 10 moles based on 1 mole of the active ingredient, and more specifically, about 0.5 moles, about 1 moles, about 1.5 moles, about 2 moles, or about 2.5 moles. moles, about 3 moles, about 5 moles, and the like.

According to one embodiment, dapagliflozin has a ( S )-propylene glycol (( S )-PG) hydrate form represented by Formula 2 below.

[Formula 2]

According to one embodiment, dapagliflozin is represented by Formula 3 ( R ) -propylene glycol (( R ) -PG) has a form of hydrate.

[Formula 3]

Glimepiride is a drug represented by Formula 4 below and is known as a drug for treating type 2 diabetes mellitus, which secretes normal insulin but is resistant to insulin.

[Formula 4]

The IUPAC name for glimepiride is 3-ethyl-4-methyl-N-(4-[N-((1r,4r)-4-methylcyclohexylcarbamoyl)sulfamoyl]phenethyl)-2-oxo-2,5-dihydro-1H-pyrrole -1-carboxamide, CAS Number is 93479-97-1.

Insulin secretion disorder and insulin resistance, which are the main pathophysiology of patients with type 2 diabetes, lead to hyperglycemia, which is an important cause of microvascular and macrovascular complications. Accordingly, concomitant administration of other drugs is required for better blood sugar control.

The dapagliflozin and glimepiride are more effective when used together than each single therapy.

Dapagliflozin and glimepiride of the present invention can be used in the form of pharmaceutically acceptable salts, and acid addition salts formed by pharmaceutically acceptable free acids are useful as salts. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanedios. It is obtained from non-toxic organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, and the like. Such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulphate, sulphite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, i. Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube rate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate , glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

The acid addition salt according to the present invention can be prepared by a conventional method. For example, it is prepared by dissolving dapagliflozin and glimepiride in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., and adding an organic or inorganic acid, filtering and drying the precipitate, or reducing the solvent and excess acid. It can be prepared by distillation, drying, and crystallization in an organic solvent.

In addition, pharmaceutically acceptable metal salts using bases are exemplified. An alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salts as metal salts. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg, silver nitrate).

Furthermore, a pharmaceutically acceptable salt can be prepared using an amino acid to which an amino group is attached to an organic acid. Examples of the amino acid salt include natural amino acids such as glycine, alanine, phenylalanine, valine, lysine, and glutamic acid. It is pharmaceutically suitable to prepare.

In addition, the present invention includes all of dapagliflozin and glimepiride and pharmaceutically acceptable salts thereof, as well as solvates, optical isomers, hydrates and the like that can be prepared therefrom.

A pharmaceutical composition according to the present invention is administered to a subject in a therapeutically effective amount.

The "therapeutically effective amount" means an amount sufficient for effective treatment when administered to a subject in need of treatment. In particular, an “effective” amount is an amount necessary to obtain a desired result, and a “therapeutically effective” amount is an amount necessary to obtain a desired therapeutic effect.

The "subject" includes living animals and humans.

The term "treating or treatment" means treating or treating a disease or condition in a subject, such as a mammal, particularly a human, including: (a) preventing the disease or condition from occurring, i.e. preventive treatment of the subject; (b) ameliorating the disease or condition, ie, causing or eliminating regression of the subject's disease or condition; (c) inhibiting the disease or condition, ie, slowing or stopping the progression of the subject's disease or condition; or (d) alleviating the symptoms of the disease or disorder in the subject. A "subject" is an animal, such as a human, currently being treated for the prevention or treatment of a particular disease or condition, and a test subject in which a composition of the present invention is evaluated or used in an assay, such as an animal model, in need of treatment or prophylaxis. is to include

The "disease or condition" may be diabetes, a diabetes-related disease or a diabetic complication.

Diabetes mellitus (DM, or diabetes) refers to a group of metabolic diseases in which high blood sugar levels persist for a long period of time. Diabetes can result from the pancreas not making enough insulin or the body's cells not responding properly to the insulin it makes. Diabetes of the present invention may include both type 1 diabetes and type 2 diabetes. Type 1 diabetes refers to a disease characterized by destruction of pancreatic beta cells and absolute deficiency of insulin caused by interactions of genetic, environmental, and immunological causes. Type 2 diabetes refers to a disease that begins with insulin resistance in which cells do not respond properly to insulin, and may develop due to overweight and low activity. In type 2 diabetes, insulin deficiency may occur as the disease progresses.

Diabetes-related diseases include glucose toxicity (or glucotoxicity) and insulin resistance (IR). The glycotoxicity refers to a phenomenon in which cells in the body that make and use insulin are damaged due to high blood sugar levels, and induces tissue-dependent insulin resistance to cause nephropathy, retinopathy, dyslipidemia, hypertension, hypertriglyceridemia, obesity, and metabolic syndrome (eg , Syndrome X), or may cause secondary complications of suffering from such a disease. The insulin resistance refers to the inability of cells to effectively burn glucose due to a decrease in the function of insulin to lower blood sugar. When insulin resistance is high, the body makes too much insulin, which can lead to high blood pressure, hyperlipidemia, or diabetes.

Diabetic complications include diabetic ketoacidosis, hyperglycemic hyperosmotic nonketotic coma, stroke, chronic renal failure, microalbuminuria or macroalbuminuria, proteinuria, retinopathy, cataracts, neuropathy, learning or memory disorders, neurodegenerative or cognitive disorders, cardiovascular or Cerebrovascular disease, tissue ischemia, diabetic foot or ulcer, atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, peripheral arterial occlusive disease, cardiomyopathy, heart rhythm disorder, vascular restenosis and/or stroke; and the like.

The pharmaceutical composition according to the present invention is used to treat a subject or individual suffering from diabetes, diabetes-related disease or diabetic complication and/or in need of prophylactic treatment.

In addition, the pharmaceutical composition according to the present invention may exhibit an effective amount in the dosage range of about 1 to about 1,000 mg. Depending on the weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of the disease, the dosage or dosage may be administered in various dosages and methods, such as dividing and administering once or several times a day. administration is possible

A pharmaceutical composition according to the present invention may be administered alone or in combination with at least one other therapeutic agent. Specifically, the therapeutic agent that can be used in combination may be used in combination with a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, a therapeutic agent for hypertension, etc. having the same or different action mechanisms.

Combinable therapies are used for the treatment of diabetes and diabetic complications, such as α-glucosidase inhibitors, biguanides, insulin secretagogues, and insulin sensitizers. ), cannabinoid receptor 1 antagonist, DPP-IV inhibitor, and SGLT-2 inhibitor.

As the therapeutic agents that can be used in combination, the following drugs can be used, but are not limited thereto.

Alpha-glucosidase inhibitors show the action of delaying the absorption of carbohydrates in the intestines and contain at least one of agarbose, voglibose, emiglitate and miglitol. can include

Metformin is a representative biguanide drug, and buformin and phenformin also belong to this category.

Insulin secretagogues can be divided into sulfonylurea drugs and non-sulfonylurea drugs. For example, sulfonylurea structured insulin secretagogues include glybenclamide (glyburide), glipizide, gliclazide, glimepiride, and tolazamide. , tolbutamide, acetohexamide, carbutamide, chlorpropamide, glibornuride, gliquidone, glisentide , Glysolamide, glisoxepide, glyclopyamide, glycylamide, and glipentide. The non-sulfonyl urea structure stimulator of insulin secretion may include at least one of repaglinide and nateglinide.

Insulin sensitizers are drugs that activate peroxisome proliferator-activated receptors (PPARs). PPAR agonists include, for example, troglitazone, ciglitazone, rosiglitazone, pioglitazone, englitazone, elafibranor, saroglitazar and at least one of lobeglitazone.

Cannabinoid receptor-1 antagonists are relatively recently developed drug targets that inhibit the excessive activity of endocannabinoids to control body weight and energy balance as well as sugar and lipid metabolism. Acts on cannabinoid receptor-1 (CB1 receptor).

DPP-IV inhibitors stimulate glucose-dependent insulin secretion from pancreatic β-cells and rapidly cleaves GLP-1, which increases the pancreatic β-cell population. For example, sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, tenelrigl At least one of teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin and dutogliptin can include

SGLT-2 inhibitors include canag liflozin, empagliflozin, ertugl iflozin, ipragliflozin, ruzeogliflozin ( lus eogliflozin), remogliflozin, sergl iflozin, sotagliflozin, and tofo gliflozin.

The pharmaceutical composition of the present invention may be administered by any suitable route, eg oral administration; rectal administration; Or formulated to be administered by parenteral administration including intraperitoneal administration, transdermal administration, subcutaneous administration, intramuscular administration, intravenous administration, ocular administration, intrapulmonary administration and intranasal administration, of which the oral route is preferred. Do. It will be appreciated that the preferred route will depend on the age and overall condition of the subject being treated, the nature of the condition being treated, and the active ingredient selected.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, the solid dosage form may be prepared with a coating. Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions, as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions before use.

Other suitable dosage forms include suppositories, sprays, ointments, creams, gels, inhalants, dermal patches, implants, and the like.

In one embodiment, the pharmaceutical composition of the present invention is formulated into a form suitable for oral administration, for example, a solid complex preparation.

For formulation as a combination preparation, the composition may include pharmaceutically acceptable carriers and/or additives in addition to active ingredients.

The selection of a particular carrier or excipient or combination of carriers or additives may depend on the type of disease or disease condition or dosage form being used to treat a particular subject. In this regard, the preparation of suitable compositions for a particular form of administration is within the scope of the pharmaceutical arts. Additionally, carriers or additives used in these compositions are commercially available. Alternatively, conventional formulation techniques are described in Remington: The Science and Practice of Pharmacy, 20th Edition, Lippincott Williams & White, Baltimore, Md. (2000); and HC Ansel et al ., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition, Lippincott Williams & White, Baltimore, Md. (1999).

Excipients are cellulose derivatives such as microcrystalline cellulose or lignocellulosic cellulose, lactose, sucrose, starch, pregelatinized starch, dextrose, mannitol, fructose, xylitol, sorbitol, corn starch, modified corn starch, inorganic salts such as carbonic acid calcium, calcium phosphate, dicalcium phosphate, calcium sulfate, dextrin/dextrates, maltodextrins, compressible sugars, and other known bulking or fillers, and/or mixtures of two or more thereof. Several types of microcrystalline cellulose, such as Avicel® types: PH101, PH102, PH103, PH105, PH112, PH113, PH200, PH301, and other types of microcrystalline cellulose, such as microcrystalline selected from the group consisting of silicified microcrystalline cellulose. Cellulose is suitable for use in the formulations described herein. Several types of lactose are possible, for example lactose selected from the group consisting of anhydrous lactose, lactose monohydrate, lactose fastflo, direct compressible lactose anhydrous and modified lactose monohydrate.

Binder is Povidone, Copovidone, Methylcellulose, Ethylcellulose, Hydroxypropyl Methylcellulose (HPMC), Sodium Carboxymethylcellulose, Corn Starch, Pregelatinized Starch, Modified Corn Starch, Polyvinylpyrrolidone, Lactose, Acacia Gum , cellulose acetate, as well as wax binders such as carnauba wax, paraffin, spermaceti, polyethylene or microcrystalline wax, as well as other conventional binders and/or mixtures of two or more thereof.

Disintegrants are crospovidone, pregelatinized starch, corn starch, methylcellulose, hydroxypropylmethylcellulose, sodium starch glycolate, croscarmellose sodium, low-substituted hydroxypropylcellulose, starch, potato starch, pregelatinized starch , alginic acid or its sodium salt, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and other known disintegrants. Several specific types of disintegrants are suitable for use in the formulations described herein. Any grade of crospovidone can be used, including crospovidone XL-10, Kollidon CL®, Polyplasdone XL®, Kollidon CL-M®, Polyplasdone XL-10® and a member selected from the group consisting of polyplasdone INF-10®.

Lubricants include magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, palmitic acid, sodium stearyl fumarate, sodium lauryl sulfate, glyceryl palmitostearate, palmitic acid , myristic acid and hydrogenated vegetable oils and fats, as well as other known lubricants, and/or mixtures of two or more thereof.

In addition, the complex preparation of the present invention may further include a pH adjusting agent, a suspending agent, a preservative, a flavoring agent, a coloring agent, a sweetening agent, an adsorbent, and the like, if necessary. The content of these additives is not particularly limited in the present invention and may be appropriately adjusted as needed.

As an example, an aluminum magnesium silicate compound may be used. The aluminum magnesium silicate compound is a compound in which silica, aluminum oxide, and magnesium oxide are mixed, and includes all of various types of compounds that exist according to the arrangement structure between each component and the content ratio between each component. Representatively, there are magnesium aluminosilicate, magnesium aluminometasilicate, magnesium aluminum silicate, and the like.

In one embodiment, the combined formulation contains dapagliflozin in an amount of 2.5 to 10 mg and glimepiride in an amount of 1 to 8 mg. At this time, when the salt form of dapagliflozin and glimepiride may exceed the above range, the actual content of dapagliflozin and glimepiride is within the above range.

Specifically, the combination formulation of the present invention exhibits the following ranges for each drug concentration in the body in clinical trials.

AUClast
(hr.ng/mL) Cmax
(ng/mL) dapagliflozin 455 (348~596) 146 (109-~95) glimepiride 1152 (752-1764) 197 (142~274)

In the case of combined administration of two or more existing preparations, the patient's compliance is low because the weight increases to about 400 to 500 mg, but in the present invention, single administration in the form of a single dosage form is possible.

The combination preparation may be in the form of a tablet, capsule, or caplet. The combination preparation is a tablet, and in this case, the tablet may be in the form of a single-layer tablet, a two-layer tablet, a three-layer tablet, or a press-coated tablet.

The combination preparation of the present invention may vary in shape when prepared in tablet form, for example, ovoid, triangular, almond, peanut, parallelogram, round, pentagonal, hexagonal and trapezoidal. Preferred shapes are round, oval and parallelogram shapes.

In particular, when the combination preparation of the present invention is a tablet, it can be manufactured into a small tablet, so the size can also be reduced.

As used herein, "small size" is a concept compared to the weight (or size) of existing tablets combining dapagliflozin and glimepiride, respectively, and means that the weight is smaller than conventionally known drugs. Reducing the weight in the present invention means that the size can also be reduced.

AstraZeneca Korea Co., Ltd.’s Posigajeong 10mg (dapagliflozin) weighs about 260mg per tablet, and Handok’s Amaryl Tab. 4mg (glimepiride) weighs about 170mg per tablet. have weight In addition, Posi family is 5mg, 10mg unit, Amaryl tablet is used in units of 1mg, 4mg, 8mg, in the case of 1mg, the weight per tablet is 85mg, the sum of these two is about 345mg.

Previously, when taking dapagliflozin and glimepiride together, the weight of the tablet increases, which may cause dysphagia or vomiting, especially when the elderly or children take the pharmaceutical tablet.

However, the combined formulation of the present invention has a weight of a small tablet of about 400 mg or less, 340 mg or less, 300 mg or less, or 250 mg or less. Preferably it has a weight of 300 mg or less and 250 mg or less.

According to an embodiment of the present invention, when containing 10mg of dapagliflozin and 4mg of glimepiride together, a small tablet of 230mg or less was prepared, and when the content of glimepiride is reduced, its weight can be further reduced. In addition, as a tablet containing 2.5 to 10 mg of dapagliflozin and 1 to 8 mg of glimepiride, a small tablet having a weight of 300 mg or less may be prepared.

These combination formulations are mini-tablets and improve patient compliance with ease of administration. In addition, despite the reduced size of the tablet, the stability of the active ingredient can be ensured, and the bioavailability is equal compared to the combination therapy of existing commercially available medicines, thereby providing substantial benefits to the patient.

In addition, the combined formulation of the present invention containing dapagliflozin and glimepiride of the present invention showed a content change of 90 to 110% as a result of storage for 3 weeks at 40 ° C / 75% and open conditions. This was found to be at an equivalent level compared to the commercially available Forshigajeong and Amaryl tablets, and through this, it can be seen that the combination between dapagliflozin and glimepiride two drugs is suitable.

The following various forms of purification are possible. At this time, although not separately described, dapagliflozin and glimepiride may be included in a pharmaceutically acceptable salt form.

In one embodiment, when the combined formulation is a single-layer tablet, it is prepared by mixing dapagliflozin and glimepiride with a carrier and pharmaceutical additives and then tableting.

In one embodiment, when the composite formulation is a single-layer tablet, a first mixing unit and a second mixing unit are prepared in which two types of drugs are mixed with separate carriers and pharmaceutical additives, respectively, and then mixed again and then tableted. In this case, the first mixing unit may be dapagliflozin or glimepiride, and the second mixing unit may be glimepiride or dapagliflozin.

In one embodiment, the composite preparation may be a single-layered tablet (eg, peanut shape) in which one side is connected to the first mixing part and the second mixing part on the left and right. At this time, the first mixture part on the left contains dapagliflozin or glimepiride, and the second mixture part on the right contains glimepiride or dapagliflozin.

In one embodiment, when the combined formulation is a bilayer tablet, the first layer contains dapagliflozin or glimepiride, and the second layer contains glimepiride or dapagliflozin.

In one embodiment, when the combination formulation is a trilayer tablet, a buffer layer (intermediate layer or inactive layer) may be included between the first layer and the second layer. The first layer contains dapagliflozin or glimepiride, and the second layer contains glimepiride or dapagliflozin. The buffer layer contains only carriers and pharmaceutical additives other than the active ingredient, that is, dapagliflozin or glimepiride.

In one embodiment, when the combined preparation is a press-coated tablet separated into an inner core layer and an outer layer, the inner core layer contains dapagliflozin or glimepiride, and the outer layer contains glimepiride or dapagliflozin.

Pharmaceutically acceptable carriers and/or excipients of particular composition may be used to prepare mini-tablets.

The manufacture of small tablets can be prepared by wet granulating glimepiride with suitable excipients and then mixing them with dapagliflozin, carriers and additives into tablets. In particular, when the dapagliprozin is used in the form of propanediol hydrate, it is suitable for direct mixing and tableting due to the problem of tableting at a low temperature due to its physicochemical properties, but selection of carriers and additives because problems with non-uniform content often occur due to aggregation of raw materials This is important.

The wet granulation of glimepiride is referred to as the 'first mixing part', and the addition of dapagliflozin and the carrier is referred to as the 'second mixing part', and the contents of each mixing part are limited as follows.

The first mixing unit may be granulated by mixing glimepiride, mannitol (excipient), sodium starch glycolate (disintegrant), povidone (binder), and water, and then using a dryer such as a fluidized bed dryer to determine the granulation.

The second mixing part contains dapagliflozin propanediol hydrate, mannitol (excipient), anhydrous lactose (excipient), microcrystalline cellulose (disintegrant), crospovidone (disintegrant), magnesium metasilicate aluminate, and magnesium stearate as a lubricant. and sodium stearyl fumarate.

Magnesium metasilicate aluminate acts as an adsorbent to suppress agglomeration of dapagliflozin propanediol hydrate, thereby solving the problem of non-uniform content in small tablets. At this time, the magnesium metasilicate aluminate is used in an amount of 5 to 20% by weight in 100% by weight of the total second mixing unit and 2 to 10% by weight based on the total tablet content. If the content is less than the above range, the agglomeration phenomenon cannot be sufficiently resolved, and on the contrary, excessive use may cause a decrease in dissolution rate or increase the size of the tablet, causing inconvenience during intake.

Magnesium stearate and sodium stearyl fumarate are mixed and used as a lubricant, but used in an amount of 5 to 20% by weight within 100% by weight of the total second mixing part. Preferably, magnesium stearate:sodium stearyl fumarate is used in a content ratio of 1:1.5 to 1:3, reducing dissolution of the drug, improving tableting properties, reducing mass variation, and improving content uniformity when sodium stearyl fumarate is used in an excessive amount. can be raised

After adding each composition of the second mixing part to the first mixing part, it is possible to obtain a small tablet through tableting by uniformly mixing.

In one embodiment, the combined formulation of the present invention has a coating layer. Suitable examples of the polymer for the coating layer include polyvinyl alcohol, ethyl cellulose, methacrylic acid polymer, starch, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, methacrylic acid-methacrylic acid ester copolymer, and those used for enteric coating, such as cellulose acetate trimellitate, carboxymethyl ethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, and the like.

In one embodiment, the coating layer may further include a plasticizer. Suitable plasticizers include, but are not limited to, triacetin, diethylphthalate, tributyl sebacate, polyethylene glycol, glycerin, triacetin and triacetyl citrate, for example.

In one embodiment, the coating layer is an anti-adherent or glidant such as talc, fumed silica, magnesium stearate; opacifiers such as titanium dioxide; iron oxide based colorants; etc. may be further included.

Examples of commercially available coating materials for coating layers include Opadry®HP and Opadry®II White.

The preparation of the combined preparation of the present invention can be prepared by adding various excipients and their order. The usefulness of these formulations is not limited to a particular dosage form or manufacturing method. For example, it may be prepared by wet granulation, dry granulation, direct blending, or other methods known in the art.

The combined preparation of the present invention may be packaged in a unit dosage form for oral administration. "Unit dosage form" means a physically discrete unit suitable for administration by a subject, i.e., containing a predetermined amount of an active agent calculated to produce the desired therapeutic effect, either alone or in combination with one or more additional units. refers to each unit. For example, a sealed high-density polyethylene (HDPE) bottle containing a silica gel desiccant or an aluminum blister lined with PVC may be used. The use of such a package helps control unwanted oxidation of the product at room temperature.

In the pharmaceutical composition of the present invention, dapagliflozin and glimepiride may be used as monotherapy.

As a result, treatment using the composition of the present invention can be used as an effective treatment strategy by securing high patient compliance and excellent therapeutic effect and durability compared to the method of combined administration of the two drugs.

1 is a photograph of a tablet prepared in Example 1.

Hereinafter, the present invention will be described in more detail through examples. These examples are intended to explain the present invention in more detail, and the scope of the present invention is not limited by these examples.

Example 1: Preparation of complex formulations

Composite formulations of single-layer tablets (small tablets) were prepared according to the composition shown in the table below.

First, a binding solution was prepared by dissolving povidone K30 in purified water. The remaining ingredients were put into a high-speed kneader and kneaded by adding the binder solution while mixing. The kneaded material was dried and meshed to obtain wet granulated granules. After mixing the granules and the components of the mixed layer of dapagliflozin, tableting was prepared by tableting in a tableting machine, and then film-coated.

The obtained tablets were manufactured into small tablets as shown in FIG. 1 with a weight of 230 mg per tablet.

glimepiride granular part Dapagliflozin mixture part Additive name amount
(mg/T) Additive name amount
(mg/T) glimepiride 4.0 dapagliflozin
Propanediol Hydrate 12.3
(Based on dapagliflozin 10mg) D-mannitol 93.5 D-mannitol 29.0 Sodium starch glycolate 9.7 anhydrous lactose 24.7 Povidone K30 1.8 microcrystalline cellulose 25.0 Purified water 0.028 mL crospovidone 6.0 Magnesium Metasilicate Aluminate 9.0 Magnesium Stearate 5.0 Sodium stearyl fumarate 10.0 Sum 109.0 Sum 121.0

Test Example 1: Simple stability test

The single-layer tablet prepared according to Example 1, and the control drug, 10 mg of Forshiga tab (dapagliflozin propanediol hydrate (12.3 mg), AstraZeneca Korea Co., Ltd.), 4 mg of Amaryl tablet (glimepiride 4 mg, Handok Co., Ltd.) A simple stability test was conducted. In the simple stability test, after storage at 40 ° C / 75% and open conditions for 3 weeks, the content change was measured and shown in the table below.

content(%) dapagliflozin glimepiride Comparative drug (Foshigajeong 10mg) Example 1 Control drug (Amaryl Tab. 4mg) Example 1 Early 98.25 99.69 98.6 99.84 7 days 98.6 99.84 97.16 100.35 21st 100.95 101.91 100.63 96.4

Looking at the table, as time cured, the tablet of Example 1 was observed to change the content of dapagliflozin, which was shown at an equivalent level compared to the control drug Posi family.

This tendency was also found in glimepiride. That is, it was confirmed that the content of glimepiride in the tablet of Example 1 was also changed to the same level as the control drug, Amaryl tablet.

As a result, in the above table, the combination formulation of the present invention containing both dapagliflozin and glimepiride showed no significant change in drug content, and the content stability showed a tendency similar to that of commercially available single tablets. From these results, it can be seen that the combination between the two drugs presented in the present invention, dapagliflozin and glimepiride, is suitable.

Test Example 2: Preliminary clinical test

In this experiment, the single-layered tablet of Example 1 (dapagliflozin propanediol hydrate 12.3mg, glimepiride 4mg) alone administered group, and the commercially available focigajeong 10mg (dapagliflozinpropanediol hydrate (12.3mg) Korea Astra Clinical trials were conducted with a combination administration group of Zeneca Co., Ltd.) and Amaryl Tab. 4mg (Glimepiride 4mg, Handok Co., Ltd.).

(1) Test purpose

The safety and pharmacokinetic properties of the single-layered tablet of Example 1 administered to healthy adult males and the combined administration of Parsiga and Amaryl tablets were compared to explore whether the properties were similar.

(2) Trial design

- Total number of subjects: 40 (Healthy adult males between the ages of 19 and 55)

- Administration schedule by order group

Am Target number Period 1 drug holiday Period 2 A 20 Dapagliflozin 10mg + Glimepiride 4mg more than 5 days Example 1 Single layer tablet B 20 Example 1 Single layer tablet Dapagliflozin 10mg + Glimepiride 4mg

- Dosage, route of administration, and method of administration

The subject is orally administered with 150mL of water with 30g of sugar added at around 9:00 am while maintaining an empty stomach for at least 10 hours.

- Pharmacokinetic blood collection time and setting considerations

1) Blood sampling time

Immediately before administration (0hr) and after administration 0.17, 0.25, 0.6, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36, 48h (total number of blood sampling: 18 times * 2period = 36 times)

2) Grounds for blood collection time setting

The Tmax of dapagliflozin is reported to be about 1 hour and the half-life is about 12.9 hours, and the Tmax of glimepiride is reported to be about 2.5 hours and the half-life is about 5.7 hours. Set the blood sampling time to secure concentration data up to 3 half-lives or more.

(3) Pharmacokinetic evaluation

After drug administration, the concentrations of dapagliflozin and glimepiride were measured in plasma. The pharmacokinetic parameters of Cmax (maximum observed plasma concentration) and AUClast (area under the plasma concentration versus time curve from dosing to the last quantifiable concentration) were obtained for each subject and then Average, standard deviation, coefficient of variation, etc. were analyzed descriptively.

dapagliflozin comparative evaluation items AUClast
(hr.ng/mL) Cmax
(ng/mL) reference drug Forshi Gajeong 10mg 443.8 133.2 test drug Single layer tablet of Example 1 455.7 146.1 90% confidence interval
(Standard: log0.8-log1.25) 1.01-1.05 0.99-1.21

glimepiride comparative evaluation items AUClast
(hr.ng/mL) Cmax
(ng/mL) reference drug Amaryl Tab. 4mg 1151.7 218.3 test drug Single layer tablet of Example 1 1152.5 197.5 90% confidence interval
(Standard: log0.8-log1.25) 0.94-1.07 0.83-0.98

Looking at the results of the above table, it can be seen that the Cmax and AUClast results of dapagliflozin (Poshigajeong) and glimepiride (Amaryl tablet) were almost similar to those of Example 1 when the monolayer tablet was administered alone.

From these results, it can be seen that instead of the combined administration of dapagliflozin and glimepiride, the combination preparation of the present invention, for example, single administration of a monolayer tablet can be substituted.

Claims (7)

Dapagliflozin or a pharmaceutically acceptable salt thereof: and
A pharmaceutical composition for preventing or treating diabetes comprising as an active ingredient; glimepiride or a pharmaceutically acceptable salt thereof;
The pharmaceutical composition has a tablet form for oral administration and has a weight of 400 mg or less, contains dapagliflozin in an amount of 2.5 to 10 mg and glimepiride in an amount of 1 to 8 mg, and contains 2 to 10% by weight of the total content of the tablet. A pharmaceutical composition comprising magnesium aluminometasilicate. delete delete delete delete delete According to claim 1,
The tablet, after wet granulation of glimepiride, the pharmaceutical composition by mixing dapagliflozin into tablets.

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