WO2019221473A1 - Pharmaceutical composition comprising sglt-2 inhibitor and dpp-iv inhibitor - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising dapagliflozin or a pharmaceutically acceptable salt, hydrate, or solvate thereof; linagliptin or a pharmaceutically acceptable salt, hydrate, or solvate thereof; and an excipient, and a preparation method therefor. The pharmaceutical composition enhances a therapeutic effect on non-insulin dependent diabetes mellitus, with reduced side effects, and secure equivalent dissolution rates and non-clinical equivalence to respective agents including individual ingredients. The composition allows the minimization of tablet sizes and enhances the stability of product quality, as well, thereby improving patient's convenience for drug intake, and drug compliance. Therefore, the composition can be advantageously used as an effective prophylatic or therapeutic agent for non-insulin dependent diabetes mellitus.

Description

Pharmaceutical composition comprising SGLT-2 inhibitor and DPP-IV inhibitor

Cross Citation with Related Applications

This application claims the benefit of priority based on Korean Patent Application No. 10-2018-0055146 dated May 14, 2018, and all content disclosed in the literature of that Korean patent application is incorporated as part of this specification.

Field of technology

The present invention relates to pharmaceutical compositions comprising SGLT-2 inhibitors and DPP-IV inhibitors and methods for their preparation. More specifically, a pharmaceutical composition comprising an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof, and a DPP-IV inhibitor or a pharmaceutically acceptable salt thereof, the method comprising minimizing the size of a tablet and improving the stability of the drug The present invention relates to a pharmaceutical composition and a method for preparing the same, which improve patient convenience and medication compliance.

Non-insulin dependent diabetes mellitus (NIDDM) is a health-threatening condition that is a prevalent disease that leads to a significant reduction in life expectancy due to high frequency of complications. Type 2 diabetes accounts for more than 85% of diabetes incidence worldwide, and more than 171 million people have type 2 diabetes, characterized by hyperglycemia due to excessive hepatic glucose production and peripheral insulin resistance do. Hyperglycemia is considered to be a major risk factor for the development of diabetic complications and is likely to be a direct cause of insulin secretion damage seen in advanced type 2 diabetes. Due to diabetes-related microvascular complications, type 2 diabetes is currently the most frequent cause of adult-onset vision loss, renal failure and amputation in developed countries. In addition, the presence of type 2 diabetes is associated with a two to five fold increase in the risk of cardiovascular disease. Therefore, continuous control of plasma glucose levels in type 2 diabetic patients can offset the development of diabetes complications and beta cell dysfunction in progressive disease.

Plasma glucose is usually filtered in the renal glomeruli and actively resorbed in the proximal tubule. Sodium-glucose cotransporter 2 (SGLT-2) is believed to be a major transporter involved in the resorption of glucose at this site. Selective inhibitors of sodium-dependent glucose transporter SGLT-2 in the kidney are expected to normalize plasma glucose levels by enhancing glucose excretion in urine, thereby improving insulin sensitivity and delaying the onset of diabetic complications.

Compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof (hereinafter dapagliflozin) that are orally active SGLT-2 inhibitors are disclosed in WO 01/27128 and WO 03 / 099836, the entirety of which is incorporated herein by reference.

US 2008-0004336 discloses dapagliflozin in the form of (S) -propylene glycol ((S) -PG) hydrate and (R) -propylene glycol ((R) -PG) hydrate. .

(S) -propylene glycol hydrate is called Form SC-3 and has a structure of formula (Ia).

Formula Ia

(R) -propylene glycol hydrate is called Form SD-3 and has a structure of formula (Ib).

Formula Ib

Methods for preparing (S) -PG hydrate and (R) -PG hydrate of dapagliflozin are provided in US Patent Publication No. 2008-0004336, which is incorporated herein by reference in its entirety.

Compound linagliptin is a DPP-IV inhibitor. The enzyme DPP-IV (Dipeptidyl Peptidase IV), also known as CD26, is a serine protease known to induce cleavage of dipeptides from the N-terminus of many proteins with proline or alanine residues at the N-terminus. Because of this property, DPP-IV inhibitors interfere with the plasma concentrations of bioactive peptides, including peptide GLP-1, and are thought to be promising drugs for the treatment of diabetes, particularly type 2 diabetes. WO 2007/128724 describes a pharmaceutical composition comprising linagliptin as the sole active pharmaceutical ingredient.

On the other hand, if diabetes lasts for a long time, most patients with type 2 diabetes eventually fail in oral treatment and become insulin dependent, requiring daily injections and several daily glucose measurements.

Oral antidiabetic drugs commonly used in conventional oral therapies (eg, primary or secondary, and / or single or (initial or additional) combination therapy) include metformin, sulfonylurea, thiazolidinedione, glinide and Glucosidase inhibitors are known.

However, these drugs have a high rate of treatment failure even after long-term use, and long-term hyperglycemia-related complications or chronic damage (e.g., microvascular and macrovascular diseases such as diabetic nephropathy, retinopathy or neuropathy) Complications, or cardiovascular complications).

Thus, there is an unmet medical need for methods, pharmaceuticals and pharmaceutical compositions that have good efficacy in glycemic control, disease-improvement properties, and cardiovascular incidence and mortality, while exhibiting improved stability profiles.

[Preceding technical literature]

[Patent Documents]

(Patent Document 1) International Patent Publication WO 01/27128

(Patent Document 2) International Patent Publication WO 03/099836

(Patent Document 3) International Patent Publication WO 2005/092877

(Patent Document 4) International Patent Publication WO 2006/064033

(Patent Document 5) International Patent Publication WO 2006/034489

(Patent Document 6) International Patent Publication WO 2006/117359

(Patent Document 7) International Patent Publication WO 2006/117360

(Patent Document 8) International Patent Publication WO 2008/049923

(Patent Document 9) International Patent Publication WO 2007/028814

(Patent Document 10) International Patent Publication WO 2007/025943

(Patent Document 11) International Patent Publication WO 2007/031548

(Patent Document 12) International Patent Publication WO 2007/093610

(Patent Document 13) International Patent Publication WO 2007/128749

(Patent Document 14) International Patent Publication WO 2008/055870

(Patent Document 15) International Patent Publication WO 2008/055940

(Patent Document 16) International Patent Publication WO 2010/092124

(Patent Document 17) International Patent Publication WO 2015/011113

(Patent Document 18) US Publication No. US 2008-0004336

(Patent Document 19) International Patent Publication WO 2007/128724

It is an object of the present invention to provide a pharmaceutical composition comprising a SGLT-2 inhibitor and a DPP-IV inhibitor and a method for preparing the same.

In particular, it is an object of the present invention to provide a complex formulation that improves patient formulation convenience and medication compliance by minimizing the size of the tablet while improving the stability of the formulation.

In order to solve the above problems, the present invention not only reduces the size of the tablet, but also significantly reduces the size of the tablet while ensuring the same dissolution rate and non-clinical equivalence as the formulation containing a single component of dapagliflozin or linagliptin. By improving the stability of the patient was confirmed that it can provide a complex formulation with improved convenience and medication compliance.

Hereinafter, the present invention will be described in detail.

Pharmaceutical composition

The present invention relates to dapagliflozin, a pharmaceutically acceptable salt thereof, a hydrate thereof, a cocrystal form thereof, or a solvate thereof; Linagliptin, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof; And an excipient, wherein the excipient comprises mannitol, pregelatinized starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, calcium phosphate, calcium carbonate and microcrystalline cellulose. A pharmaceutical composition of the present invention can be minimized in size while exhibiting sufficient efficacy when formulated in a tablet oral dosage form as compared to a dapagliflozin single formulation and a linagliptin single formulation. It is possible to provide a combination formulation that improves the stability of the drug to improve patient convenience and medication compliance.

In the present invention, the term "dapagliflozin" refers to (1S) -1,5-anhydro-1- [4-chloro-3- (4-ethoxybenzyl) phenyl]- D-glucitol, which means an oral diabetes treatment. In the tubules of the kidney, sodium glucose co-receptor-2 (SGLT-2), a type of glucose transporter, is present, where more than 90% of the filtered glucose is reabsorbed and enters the bloodstream. Dapagliflozin inhibits glucose resorption and releases glucose into the urine, thereby inhibiting blood glucose elevation.

[Formula 1]

As used herein, the term "pharmaceutically acceptable" refers to a physiologically acceptable and, when administered to a human, usually does not cause an allergic reaction, such as gastrointestinal disorders, dizziness, or the like, the term "salt", As acid addition salts formed by pharmaceutically acceptable free acid, it is meant salts prepared according to conventional methods, and methods for preparing such pharmaceutically acceptable salts are known to those skilled in the art. Specifically, the pharmaceutically acceptable salts include, but are not limited to, salts derived from the following pharmacologically or physiologically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric acid, bromic acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfuric acid Phonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, salicylic acid, and the like may be included, but the salts used in the present invention are not limited by the salts listed. Salts derived from suitable bases may include, but are not limited to, alkali metals such as sodium or potassium, alkaline earth metals such as magnesium.

In the present invention, the term "hydrate" means that the dapagliflozin and water are bonded by a force between non-covalent molecules, and mean that they include stoichiometric or non-stoichiometric amounts of water. Specifically, the hydrate may include about 0.25 moles to about 10 moles of water 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, about 3 moles, about 5 moles, and the like.

In the present invention, the term "about" indicates a numerical value that is ± 10% of the preceding value.

As used herein, the term "cocrystal form" means a crystalline form that includes one or more compounds in the crystal lattice. Cocrystalline forms include crystalline molecular complexes of two or more non-volatile compounds bonded together in a crystal lattice through non-ionic interactions.

In the present invention, the term "solvate" is a combination of the dapagliflozin and the solvent by the force between the non-covalent molecules, it means to include a stoichiometric or non-stoichiometric amount of the solvent. Preferred solvents are volatile, non-toxic and can be administered in very small amounts to humans. Specifically, the solvate may include about 0.25 mol to about 10 mol of water based on 1 mol of the active ingredient, more specifically about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, About 3 moles, about 5 moles, and the like.

In embodiments of the present invention, dapagliflozin, a pharmaceutically acceptable salt thereof, a hydrate thereof, a cocrystalline form thereof or a solvate thereof is specifically dapagliflozin, a cocrystalline form of dapagliflozin, It may be a hydrate of dapagliflozin, a solvate of dapagliflozin, more specifically dapagliflozin, cocrystalline form of proline of dapagliflozin (molar ratio = 1: 2), dapagliflozin (S) -propanediol hydrate, dapagliflozin (R) -propanediol hydrate or mixtures thereof, or dapagliproline citrate co-crystalline, and more specifically dapagliflozin, dapaglifle Rosin (S) -propanediol hydrate, dapagliflozin (R) -propanediol hydrate or mixtures thereof, or dapagliflozin citrate cocrystal, and more particularly dapaglifle Rosin or dapagle It may be a reflowed citrate cocrystal.

According to one embodiment of the invention, the dapagliflozin, pharmaceutically acceptable salts thereof, hydrates thereof, co-crystal forms thereof or solvates thereof may be in crystalline form.

As used herein, the term "crystalline form" refers to a solid phase in which the substance has an internal structure arranged regularly at the molecular level and generates a unique X-ray diffraction pattern having a defined peak. These materials also exhibit liquid properties when heated sufficiently, but the change from solid to liquid is usually characterized by a primary ('melting point') phase change.

In the present invention, dapagliflozin is a concept including dapagliflozin itself, a pharmaceutically acceptable salt thereof, a hydrate thereof, a cocrystal form thereof, or a solvate thereof.

In the present invention, the term "linagliptin" refers to 8-[(3R) -3-amino-1-piperidinyl] -7- (2-butynyl) -3,7-dihydro having a structure of Formula 2 Oral antidiabetic agent of the class of dipeptidyl peptidase-4 (DPP-IV) inhibitor, which is -3-methyl-1-[(4-methyl-2-quinazolinyl) methyl] -1H-purin-2,6-dione Oral hypoglycemic agent). Incretin, a hormone secreted by the gastrointestinal tract during food intake, regulates blood sugar by controlling the secretion of insulin and glucagon depending on the level of blood sugar, that is, blood sugar.

[Formula 2]

In embodiments of the present invention, linagliptin, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof is specifically linagliptin, a co-crystalline form of linagliptin, a hydrate of linagliptin It may be a solvate of linagliptin, and more specifically, it may be linagliptin free base.

According to one embodiment of the present invention, the linagliptin, pharmaceutically acceptable salts thereof, hydrates thereof, co-crystal forms thereof or solvates thereof may be crystalline or amorphous, and specifically, may be crystalline.

Linagliptin as used herein is a concept including linagliptin itself, a pharmaceutically acceptable salt thereof, a hydrate thereof, a co-crystalline form thereof, or a solvate thereof.

In the present invention, the term "excipient" refers to an inert substance generally used as a diluent, vehicle, preservative, binder, or stabilizer, wherein the excipient is mannitol, pregelatinized starch, microcrystalline cellulose, low-substituted hydroxypropyl Cellulose, calcium phosphate, calcium carbonate (CaCO ₃ ), microcrystalline silica, or mixtures thereof.

In embodiments of the present invention, the calcium phosphate may be anhydrous calcium phosphate, calcium phosphate hydrate or a mixture thereof.

In embodiments of the present invention, the anhydrous calcium phosphate is anhydrous tricalcium phosphate (Ca ₃ (PO ₄ ) ₂ ), anhydrous calcium hydrogen phosphate (CaHPO ₄ ) or anhydrous calcium dihydrogen phosphate (Ca (HPO ₄ ) ₂ ) It may be, specifically, may be anhydrous tricalcium phosphate (Ca ₃ (PO ₄ ) ₂ ).

In embodiments of the present invention, the calcium phosphate hydrate may be calcium hydrogen phosphate hydrate or dihydrogen phosphate hydrate, specifically the calcium phosphate hydrate.

For example, the calcium phosphate may be anhydrous tricalcium phosphate, calcium hydrogen phosphate hydrate or a mixture thereof.

Specifically, the excipient may include two or more different excipients selected from mannitol, pregelatinized starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, calcium phosphate, calcium carbonate (CaCO ₃ ), and microcrystalline silicified cellulose, and more Specifically, it may include three or more different excipients selected from mannitol, pregelatinized starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, calcium phosphate, calcium carbonate (CaCO ₃ ) and microcrystalline silicified cellulose, and more specifically, May include three different excipients selected from mannitol, pregelatinized starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, calcium phosphate, calcium carbonate (CaCO ₃ ) and microcrystalline silicate cellulose.

In embodiments of the present invention, the excipient is a combination of mannitol, silicified microcrystalline cellulose and microcrystalline cellulose, pregelatinized starch, a combination of low-substituted hydroxypropyl cellulose and tricalcium phosphate, mannitol, calcium hydrogen phosphate hydrate and Combination of calcium carbonate, microcrystalline cellulose, microcrystalline cellulose and pregelatinized starch, low substituted hydroxypropyl cellulose, combination of anhydrous tricalcium phosphate and calcium hydrogen phosphate hydrate, combination of mannitol, microcrystalline cellulose and calcium carbonate, microcrystalline Combinations of cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, anhydrous tricalcium phosphate, calcium hydrogen phosphate hydrate, and calcium carbonate.

In embodiments of the present invention, the pharmaceutical composition comprises three different kinds of mannitol, pregelatinized starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, calcium phosphate, calcium carbonate (CaCO ₃ ) and microcrystalline silicified cellulose When including an excipient, the three excipients may be included in different weight ratios or in the same weight ratio. Specifically, the three different excipients may be included in different weight ratios, and more specifically, the weight ratio of the three different excipients may be 1: 1.5 to 2.5: 2 to 3.

In an attempt to prepare a pharmaceutical composition comprising linagliptin, linagliptin is used in a number of forms such as sodium starch glycolate, croscarmellose sodium, tartaric acid, sugars, fructose, saccharose, sucrose, lactose, maltodextrin. It has been observed to indicate incompatibility, degradation problems or extraction problems with conventional excipients. These conventional excipients are very stable in themselves, but react in contact with a large number of excipients and excipients used in solid dosage forms in the close contact and high excipient / drug ratios provided in formulations such as tablets and the like. Linagliptin appears to react with reducing sugars and other reactive carbonyl groups and carboxylic acid functional groups formed on the surface of the excipient by oxidation.

This unforeseen problem is exacerbated by the low dose range of linagliptin.

The pharmaceutical composition of the present invention can solve the above problems related to the unexpected problem of linagliptin. For example, the pharmaceutical composition according to the present invention may exhibit sufficient stability even when both linagliptin and microcrystalline cellulose are included as an active ingredient.

In addition, the pharmaceutical compositions of the present invention can significantly improve patient convenience of medication. Although the pharmaceutical composition of the present invention contains two different drugs, the tablet is appropriate in size, has excellent therapeutic effect and excellent stability, and can significantly improve the convenience of medication for patients.

In addition, the composition is excellent in stability and the manufacturing process is simple. As a result, it is suitable for mass production and economical. That is, the composition according to the present invention does not have a process such as evaporating the active ingredient and one or more polymers in a solvent, and as a result, a separate manufacturing facility (for example, FBG, spray dryer) is not required for this process. Simple and economical

In embodiments of the present invention, the composition may further include, in addition to excipients, pharmaceutically acceptable additives such as binders, disintegrants, glidants, lubricants or mixtures thereof, but is not limited thereto.

In embodiments of the present invention, the binder may be povidone, copovidone, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, starch or mixtures thereof, but is not limited thereto. Specifically, the binder may be povidone, copovidone, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose sodium, pregelatinized starch or mixtures thereof, and more specifically copovidone, ethyl cellulose or these It may be a mixture of.

In embodiments of the present invention, the disintegrant may be alginic acid, calcium carboxymethyl cellulose, starch, crospovidone, croscarmellose sodium, croscarmellose calcium, sodium starch glycolate or mixtures thereof, but is not limited thereto. Do not. Specifically, the disintegrant may be alginic acid, carboxymethyl cellulose calcium, croscarmellose sodium, crospovidone, sodium starch glycolate or a mixture thereof, and more particularly crospovidone.

In embodiments of the present invention, the fluidizing agent may be, but is not limited to, colloidal silicon dioxide, light anhydrous silicic acid, magnesium aluminate silicate, silicon dioxide, polyvinyl alcohol, hydrous silicon dioxide, or a mixture thereof.

In embodiments of the present invention, the glidant may be, but is not limited to, magnesium stearate, calcium stearate, corn starch, talc, sodium stearyl fumarate, hard magnesium oxide, or a mixture thereof. Magnesium stearate.

In embodiments of the present invention, the pharmaceutical composition,

Based on the total weight of the pharmaceutical composition, the dapagliflozin, a pharmaceutically acceptable salt thereof, a hydrate thereof, a co-crystalline form thereof, or a solvate thereof; And from about 1.5 to about 10 weight percent of linagliptin, its pharmaceutically acceptable salts, its hydrates or solvates thereof, from 10 to 85 weight percent of one or more excipients, from about 0.2 to 15 weight percent of one or more binders, and One or more disintegrants may comprise about 0.2 to 10% by weight.

In the pharmaceutical composition of the present invention, the dapagliflozin, a pharmaceutically acceptable salt thereof, a hydrate thereof, a cocrystal form thereof or a solvate thereof; And linagliptin, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, may be included in an amount of 1.5 to about 10 wt% based on the total weight of the pharmaceutical composition, and the dapagliflo The weight ratio of gin, a pharmaceutically acceptable salt thereof, a hydrate thereof, a cocrystal form thereof, or a solvate thereof and linagliptin, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof may be 1.5 to 3: 1. .

In the pharmaceutical composition of the present invention, the excipient may specifically include 10 to 85% by weight based on the total weight of the pharmaceutical composition, but is not limited thereto.

In the pharmaceutical composition of the present invention, the binder may specifically include 0.2 to 15% by weight based on the total weight of the pharmaceutical composition, but is not limited thereto.

In the pharmaceutical composition of the present invention, the disintegrant may specifically include 0.2 to 10% by weight based on the total weight of the pharmaceutical composition, but is not limited thereto.

In embodiments of the present invention, the pharmaceutical composition may be in the form of granules, capsules or tablets, specifically, may be in the form of tablets, but is not limited thereto.

The tablets include tablets without a coating layer, and tablets with one or more coating layers, and can be single or multiple layers. In addition, the tablets may include, but are not limited to, mini tablets, melt tablets, chewable tablets, effervescent tablets and oral disintegrating tablets.

In embodiments of the present invention, the pharmaceutical composition may be a bilayer tablet or a double tablet or a single layer tablet, specifically, may be a single layer tablet, but is not limited thereto.

In the present invention, the term "single layer tablet", except for the coating layer means that there are no separate layers having different configurations in the tablet.

In the present invention, the term "two-layered tablet or double-crystal" refers to a tablet in which two different layers exist except for a coating layer, and the two-layered tablet refers to a layer in which two layers containing different main components except the coating layer are stacked. The double tablet refers to a tablet in which an additional layer is formed on the surface of the inner core tablet to cover the surface of the inner core tablet except for the coating layer.

In addition, in the present invention, the term "coating layer" refers to a layer surrounding the outside of the tablet without an active ingredient. The coating layer may be formed to about 1% by weight to 5% by weight based on the total weight of the tablet except the coating layer, specifically, may be formed to about 2% by weight to about 4% by weight.

The weight of the monolayer tablet of the present invention may be 100 to 300 mg, specifically 180 to 220 mg.

The pharmaceutical composition can be prepared as a single-layer tablet, despite containing both dapagliflozin and linagliptin as an active ingredient, and can maintain a certain size or less, thereby significantly improving the convenience of patient medication. have.

According to one specific experimental example of the present invention, the pharmaceutical composition of the present invention, when stored for 4 weeks at 60 ℃ and 80% relative humidity, dapagliflozin, pharmaceutically acceptable salts thereof, hydrates thereof, Cocrystal form or solvate thereof; And degradation products of linagliptin, pharmaceutically acceptable salts thereof, hydrates thereof or solvates thereof,

Dapagliflozin, its pharmaceutically acceptable salts, hydrates thereof, co-crystal forms thereof, or solvates thereof; Linagliptin, pharmaceutically acceptable salts thereof, hydrates thereof or solvates thereof; And degradation products thereof (dapagliflozin, pharmaceutically acceptable salts thereof, hydrates thereof, lysates thereof or solvates thereof and linagliptin, pharmaceutically acceptable salts thereof, hydrates or solvates thereof Based on the total amount of decomposition products).

Specifically, the pharmaceutical composition of the present invention, when stored for 4 weeks at 60 ℃ and 80% relative humidity, dapagliflozin, pharmaceutically acceptable salts thereof, hydrates thereof, co-crystal form thereof or solvate thereof ; And degradation products of linagliptin, pharmaceutically acceptable salts thereof, hydrates thereof or solvates thereof,

Dapagliflozin, its pharmaceutically acceptable salts, hydrates thereof, co-crystal forms thereof, or solvates thereof; Linagliptin, pharmaceutically acceptable salts thereof, hydrates thereof or solvates thereof; And degradation products thereof (dapagliflozin, pharmaceutically acceptable salts thereof, hydrates thereof, lysates thereof or solvates thereof and linagliptin, pharmaceutically acceptable salts thereof, hydrates or solvates thereof Total of 0.01% to 0.99% based on the total amount of decomposition products).

Therefore, it can be seen that the stability of the pharmaceutical composition of the present invention is excellent.

In embodiments of the present invention, the pharmaceutical composition may be for the prevention or treatment of diabetes mellitus, diabetes-related diseases or diabetic complications.

In the present invention, "diabetes" means a metabolic disease such as lack of insulin secretion or normal function, and specifically diabetes refers to type 2 diabetes.

In the present invention, "diabetes-related disease" is hyperglycemia, hyperinsulinemia, hyperlipidemia, insulin resistance, impaired glucose metabolism, obesity, diabetic retinopathy, macular degeneration, cataracts, diabetic nephropathy, glomerulosclerosis, diabetic neuropathy, erection Impotence, premenstrual syndrome, vascular restenosis and ulcerative colitis.

In the present invention, "diabetic complication" means a disease associated with damage to blood vessels, and specifically includes, but is not limited to, coronary artery disease, stroke, peripheral artery disease, cardiomyopathy and heart failure. Postprandial hyperglycemia is known to have a higher risk factor for cardiovascular disease than fasting blood glucose, leading to complications of cardiovascular disease.

In the present invention, the term "prevention" means a delay in the onset of a disease, disorder or disease. Prevention can be considered complete if the onset of the disease, disorder or disease is delayed for a predetermined period of time.

As used herein, the term “treatment” partially or completely alleviates, ameliorates, alleviates, inhibits or delays the development of a particular disease, disorder and / or disease, reduces severity or reduces the occurrence of one or more symptoms or features. It means to let.

Complex formulation

The present invention provides a pharmaceutical oral dosage form complex preparation comprising the pharmaceutical composition of the present invention.

As used herein, the term "oral administration" means that the active substance is administered to a substance prepared for digestion, that is, to the gastrointestinal tract for absorption.

The pharmaceutical oral dosage form complex preparation may be in the form of granules, capsules or tablets, preferably in tablet form.

The weight of the pharmaceutical oral dosage form complex preparation may be 100 to 300 mg, specifically 180 to 220 mg.

Method of Preparation of Pharmaceutical Composition

In addition, the present invention

1) dapagliflozin, a pharmaceutically acceptable salt thereof, a hydrate thereof, a cocrystal form thereof, or a solvate thereof; Linagliptin, pharmaceutically acceptable salts thereof, hydrates thereof or solvates thereof; And mixing the excipients to produce a mixture;

2) wet granulating the mixture to prepare granules; And

3) drying the granules and passing them through a mesh screen

It provides a method for producing a pharmaceutical composition comprising a.

In the preparation method, the excipient includes mannitol, pregelatinized starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, anhydrous calcium phosphate, calcium phosphate hydrate, calcium carbonate, microcrystalline cellulose or a mixture thereof.

The dapagliflozin, pharmaceutically acceptable salts thereof, hydrates thereof, co-crystal forms thereof, or solvates thereof; Linagliptin, pharmaceutically acceptable salts thereof, hydrates thereof or solvates thereof; And excipients and their contents are as described in detail above.

The preparation method of the present invention is a method for preparing a pharmaceutical composition having excellent quality with a simple facility that is commonly used in pharmaceutical companies. In particular, there is no need for a separate manufacturing facility and the process is simple, thereby reducing the manufacturing and production costs, and dramatically reducing the size of the formulation, thereby improving the convenience of taking medications, thereby increasing drug compliance.

In embodiments of the present invention, the preparation method may further comprise the step of additionally mixing in step 1) a binder, disintegrant, glidant, lubricant or a mixture thereof which is a pharmaceutically acceptable additive. Specifically, the step 1) may further comprise the step of adding a binder, disintegrant or a mixture thereof in the pharmaceutically acceptable additives.

In embodiments of the present invention, the binder may be added in a dissolved form in a solvent.

The binders, disintegrants, glidants and glidants and their contents are as described in detail above.

In embodiments of the present invention, the preparation method comprises dapagliflozin or a pharmaceutically acceptable salt thereof, a hydrate thereof, a co-crystalline form thereof or a solvate thereof in step 1), step 2) and step 3); Linagliptin, pharmaceutically acceptable salts thereof, hydrates thereof or solvates thereof; Excipients; And the preparation and granulation of the mixture of pharmaceutically acceptable additives can be carried out simultaneously or separately, specifically each step can be carried out separately.

In the embodiments of the present invention, the preparation method comprises before the step 1) dapagliflozin, a pharmaceutically acceptable salt thereof, a hydrate thereof, a co-crystalline form thereof or a solvate thereof; Linagliptin, pharmaceutically acceptable salts thereof, hydrates thereof or solvates thereof; Weighing excipients and pharmaceutically acceptable salts may be further included.

In the embodiments of the present invention, the step of preparing the granules may be performed by adding a binder solution in which a binder is dissolved in a solvent to the mixture prepared in step 1).

In embodiments of the present invention, the method may further include preparing a mixture containing granules by adding a fluidizing agent, a lubricant, or a mixture thereof to the granules prepared in step 3).

In embodiments of the present invention, after the step 3) may further comprise the step of tableting the granules passed through the mesh screen. The tableting may be prepared as a monolayer tablet or a bilayer tablet, but is not limited thereto.

In embodiments of the present invention, the manufacturing method may further comprise the step of coating after selectively tableting.

Dapagliflozin, pharmaceutically acceptable salts thereof, hydrates thereof, co-crystal forms thereof, or solvates thereof; And a composite formulation comprising linagliptin, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient, while maintaining the stability of product quality while ensuring the same dissolution rate and nonclinical equivalence as the formulation containing each single component. In addition to improving the size of the tablet to minimize the patient taking convenience and medication compliance shows that it can be useful as an effective type 2 diabetes prevention or treatment.

Use of a pharmaceutical composition for use in the preparation of a diabetes, diabetes related disease or diabetic complication disease formulation

The present invention provides the use of the pharmaceutical composition for use in the preparation of a diabetes, diabetes related disease or diabetic complication disease formulation.

The pharmaceutical composition of the present invention for the preparation of the formulation may be mixed with an acceptable carrier and the like, and may further include other agents.

The diabetes, diabetes-related diseases or diabetic complications are the same as described above unless there is a special situation.

Use of pharmaceutical compositions for the treatment of diabetes mellitus, diabetes related diseases or diabetic complications

The present invention provides the use of said pharmaceutical composition for the treatment of diabetes mellitus, diabetes related disease or diabetic complication disease.

The diabetes, diabetes-related diseases or diabetic complications are the same as described above unless there is a special situation.

How to prevent or treat diabetes, diabetes-related or diabetic complications

The present invention provides a method for preventing or treating an allergic disease comprising administering the pharmaceutical composition to a mammal, including a human, in a therapeutically effective amount.

As used herein, the term "therapeutically effective amount" refers to an amount effective for treating diabetes mellitus, diabetes related disease or diabetic complications, such as an amount administered to a subject to be treated, diabetes, diabetes related disease or diabetes. To prevent the occurrence or recurrence of sexual complications, to relieve symptoms, to inhibit direct or indirect pathological consequences, to prevent metastasis, to slow the progression, to reduce or temporarily relieve a condition, It can include all amounts of compositions that improve prognosis. That is, the therapeutically effective amount may be interpreted to encompass all doses in which the symptoms of allergic disease are improved or cured by the pharmaceutical composition.

The prophylactic or therapeutic method of the present invention includes not only addressing the disease itself prior to the onset of the indication, but also inhibiting or avoiding the indication thereof by administering the pharmaceutical composition of the present invention. In the management of a disease, the prophylactic or therapeutic dose of a particular active ingredient will vary depending on the nature and severity of the disease or condition and the route by which the active ingredient is administered. Dosage and frequency of dose will vary depending on the age, weight and response of the individual patient. Appropriate dosage regimens can be readily selected by those of ordinary skill in the art that naturally consider such factors. In addition, the method of treatment of the present invention may further comprise the administration of a therapeutically effective amount of an additional active agent in combination with the pharmaceutical composition to assist in the treatment of the disease, wherein the additional active agent is synergistic or additive with the pharmaceutical composition. Can have an enemy effect.

In the present invention, the term "mammal including a human" includes mammals such as humans, monkeys, cattle, horses, dogs, cats, rabbits, rats, and mice.

The diabetes, diabetes-related diseases or diabetic complications are the same as described above unless there is a special situation.

As used herein, the term “administering” refers to any method of providing a pharmaceutical composition of the invention to a subject. Such methods are well known to those skilled in the art and include oral, transdermal, inhaled, nasal, topical, as well as injectable, such as intravenous, intraarterial, intramuscular, and subcutaneous administration. Administration, intravaginal administration, ophthalmic administration, intramuscular administration, intracranial administration, rectal administration, and parenteral administration. Administration can be continuous or intermittent. In various aspects, the pharmaceutical compositions of the present invention can be administered therapeutically. In other words, it may be administered to treat an existing disease. In further various aspects, the pharmaceutical compositions of the present invention may be administered prophylactically. In other words, it may be administered for the prevention of the disease.

The matters mentioned in the pharmaceutical compositions of the present invention, methods for their preparation, combination preparations, uses, and methods of treatment apply equally unless they contradict each other.

The pharmaceutical composition of the present invention improves the therapeutic effect of Type 2 diabetes and alleviates side effects, and provides tablets with dissolution rate and non-clinical equivalence equivalent to those containing a single component of dapagliflozin or linagliptin. In addition to significantly reducing the size of the product, by improving the stability of product quality, it is possible to provide a complex formulation that improves patient convenience and medication compliance.

In addition, the manufacturing method of the present invention does not require a separate manufacturing equipment and the process is simple, thereby reducing the manufacturing production cost, and can significantly increase the compliance with medication by reducing the dosage size significantly.

1 is a graph showing the results of the non-clinical test of the dapagliflozin component for the combined administration of Comparative Example 1 and Comparative Example 2 and administration of the pharmaceutical composition of the present invention.

Fig. 2 is a graph showing the results of nonclinical testing of linagliptin components for combination administration of Comparative Example 1 and Comparative Example 2 and administration of the pharmaceutical composition of the present invention.

3 is a comparative chart of the weight and size of Comparative Example 1, Comparative Example 2 and the embodiment of the present invention.

Hereinafter, the configuration and effects of the present invention through the embodiments will be described in more detail. These examples are only for illustrating the present invention, but the scope of the present invention is not limited by these examples.

Each component used in the above Examples and Comparative Examples were all purchased and used as known components.

EXAMPLE

Examples 1-8: Preparation of Pharmaceutical Compositions According to the Present Invention

Tablets were prepared according to the ingredients and contents in Table 1 below. The content in Table 1 represents the content per tablet (without coating layer). At this time, the coating layer was formed to be 4.0% by weight of the uncoated tablet weight.

Table 1 Components and Contents of Examples 1 to 8

In the composite formulation preparation method of the present invention, after weighing according to Table 1, a binder was added to purified water to prepare a binder solution, and then mixed with a main component, an excipient, a fluidizing agent, and a disintegrating agent to form granules. The granules were then dried and passed through a mesh screen to establish the final mixture by the addition of a lubricant. The final mixture was compressed into tablets to prepare a single layer.

Comparative Example 1: Preparation of SGLT-2 Inhibitor Single Formulation

Dapagliflozin As a single formulation, Posigar® tablets (AstraZeneca Korea) containing 10 mg as dapagliflozin were used, with a weight of 260 mg per tablet.

Comparative Example 2: Preparation of DPP-IV Inhibitor Single Formulation

As a single formulation of linagliptin, Tragenta® tablets (Beringer Ingelheim, Inc.) containing 5 mg of linagliptin were used, and the weight per tablet was 185 mg.

Experimental Example

Experimental Example 1: Stability Test

Stability tests were conducted to confirm the stability of the pharmaceutical compositions of the present invention. Specifically, as shown in Table 2, the composite formulation Example 1 and the single formulation Comparative Examples 1 and 2 were stored for 4 weeks in harsh conditions (60 ° C., 80% relative humidity), and then the amount of the flexible substance was evaluated.

Table 2 Comparison of Total Formulations

In the above results, Comparative Examples 1 and 2 exhibited 3.5% total analogues in harsh 4 weeks, but the composite formulation of Example 1 showed 0.7% total analogues in severe 4 weeks. That is, the composite formulation of Example 1 is very stable even in harsh conditions, and by securing more than equivalent stability in terms of stability than the single formulation of Comparative Examples 1 and 2, which is more effective in the present invention than the single formulation of Comparative Examples 1 and 2, It has been improved in quality and has excellent stability, which makes it easy to handle and store, and is very useful for mass production.

Experimental Example 2: Dissolution test of Examples 1 to 8 and Comparative Example 1

The composite formulations of Examples 1 to 8 and the single formulation of Comparative Example 1, USP method II method (paddle method) dissolution test 1 solution (pH 1.2, 900 mL) at 50 rpm at 37.0 ± 0.5 ℃ Comparative elution was performed for dapagliflozin.

The dissolution test results are shown in Table 3 below.

TABLE 3 Dissolution rate difference between Comparative Example 1 and Examples 1 to 8

As the comparative example 1 and the dissolution test results of Examples 1 to 8, the excipient was mannitol, microcrystalline cellulose, pregelatinized starch, low-substituted hydroxypropyl cellulose, anhydrous calcium phosphate, calcium hydrogen phosphate hydrate, calcium carbonate and the like. When prepared, the dissolution rate difference is equivalent to that of a single formulation of Comparative Example 1, so that the comparative dissolution equivalence of the composite formulations of Examples 1 to 8 with respect to the single formulation of Comparative Example 1 may be ensured.

Experimental Example 3: Dissolution test of Examples 1 to 8 and Comparative Example 2

The composite formulations of Examples 1 to 8 and the single formulation of Comparative Example 2, USP Pharmacopeia (USP) method II method (paddle method) dissolution test 1 solution (pH 1.2, 900 mL) at 50 rpm at 37.0 ± 0.5 ℃ Comparative elution was performed for linagliptin.

The dissolution test results are shown in Table 4 below.

TABLE 4 Dissolution rate difference between Comparative Example 2 and Examples 1 to 8

As in Comparative Example 2 and the dissolution test results of Examples 1 to 8, the additive is mannitol, microcrystalline cellulose, pregelatinized starch, low-substituted hydroxypropyl cellulose, anhydrous calcium phosphate, calcium hydrogen phosphate hydrate, calcium carbonate and the like. When prepared, the dissolution rate difference is equivalent to that of the single formulation of Comparative Example 2, so that the comparative dissolution equivalence of the composite formulations of Examples 1 to 8 with respect to the single formulation of Comparative Example 2 can be ensured.

Experimental Example 4: Non-Clinical Test

The male beagle dog was used to compare and evaluate the co-administration of Comparative Example 1 and Comparative Example 2 with the in vivo kinetics of the drug of Example 1. The following tests were administered orally in fasted beagle dogs (males) and administered over two phases with a 2-week washout period using a cross-over design.

The nonclinical test results are shown in Table 5 and FIGS. 1 and 2.

Table 5 Nonclinical Results of the Invention and Comparative Examples

In the case of the combination formulation of Example 1, AUC was also equivalent while maintaining blood levels at the same level as the single formulation of Comparative Examples 1 and 2, which are commercially available formulations. Therefore, when comparing the composite formulation of Example 1 and the single formulation of Comparative Examples 1 and 2, which are commercially available formulations, it was confirmed that the medicinal effect was maintained for a long time without decreasing the bioavailability.

Therefore, the nonclinical equivalence was secured similarly to the comparative examples 1 and 2 and the nonclinical test results of the present invention.

Experimental Example 5: Observation of Appearance

Photographs of the appearances of Comparative Examples 1 and 2 and Example 1 of the present invention were taken to observe the shape, and the major axis, the short axis and the thickness thereof were checked using vernier calipers, and Comparative Examples 1 and 2 and Example 1 of the present invention The weight was measured with an electronic balance.

The results are shown in Figure 3, it was confirmed that the composite formulation of Example 1 of the present invention is reduced by about 46.7% (445mg (260mg + 185mg) → 208mg) compared to the combination of Comparative Examples 1 and 2.

In addition, it was confirmed that the composite preparation of Example 1 of the present invention and the single preparation of Comparative Examples 1 and 2 were equivalent in length, short axis, and thickness.

The pharmaceutical composition of the present invention improves the therapeutic effect and reduces the side effects of type 2 diabetes mellitus, while minimizing the size of the tablet while ensuring the same dissolution rate and nonclinical equivalence as the formulation containing each single component, It improves the stability and patient convenience and medication compliance, which can be useful as an effective prevention or treatment of type 2 diabetes mellitus.

Claims (15)

Dapagliflozin, its pharmaceutically acceptable salts, hydrates thereof, co-crystal forms thereof, or solvates thereof; Linagliptin, pharmaceutically acceptable salts thereof, hydrates thereof or solvates thereof; And Includes excipients, The excipient is mannitol, pregelatinized starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, calcium phosphate, calcium carbonate and microcrystalline microcrystalline cellulose comprising one or more selected from the group consisting of. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition further comprises one or more selected from the group consisting of a binder, a disintegrant, a glidant, and a lubricant. The pharmaceutical composition of claim 2, based on the total weight of the pharmaceutical composition Dapagliflozin, its pharmaceutically acceptable salts, hydrates thereof, co-crystal forms thereof, or solvates thereof; And linagliptin, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, in total from 1.5 to 10.0% by weight, 10 to 85 weight percent of one or more excipients, 0.2-15 weight% of one or more binders, and 0.2 to 10% by weight of one or more disintegrants Pharmaceutical composition comprising a. The pharmaceutical composition of claim 2, wherein the binder is at least one selected from the group consisting of povidone, copovidone, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and pregelatinized starch. The pharmaceutical composition of claim 2, wherein the disintegrant is at least one selected from the group consisting of alginic acid, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, and sodium starch glycolate. The pharmaceutical composition according to any one of claims 1 to 5, in the form of granules, capsules or tablets. The method of claim 1, wherein when stored for 4 weeks at 60 ° C. and 80% relative humidity, dapagliflozin, a pharmaceutically acceptable salt thereof, a hydrate thereof, a co-crystalline form thereof, or a solvate thereof; And the amount of degradation products of linagliptin, pharmaceutically acceptable salts thereof, hydrates thereof, or solvates thereof, Dapagliflozin, its pharmaceutically acceptable salts, hydrates thereof, co-crystal forms thereof, or solvates thereof; And linagliptin, pharmaceutically acceptable salts thereof, hydrates thereof or solvates thereof; And based on the total amount of their decomposition products Pharmaceutical compositions maintained at less than 1%. A pharmaceutical oral dosage form complex formulation comprising a pharmaceutical composition according to any one of claims 1 to 7. The pharmaceutical oral dosage form complex formulation according to claim 8, comprising the pharmaceutical composition in tablet form. 10. The combination formulation of claim 9, wherein the tablet has a weight of 100 to 300 mg. 1) dapagliflozin, a pharmaceutically acceptable salt thereof, a hydrate thereof, a cocrystal form thereof, or a solvate thereof; Linagliptin, pharmaceutically acceptable salts thereof, hydrates thereof or solvates thereof; And mixing the excipients to produce a mixture; 2) wet granulating the mixture to produce granules; And 3) drying the granules and passing them through a mesh screen Method for producing a pharmaceutical composition of claim 1 comprising a. The method of claim 11, wherein preparing the mixture comprises: The method of manufacturing, further comprising the step of adding and mixing at least one selected from the group consisting of a binder and a disintegrant. Use of said pharmaceutical composition for use in the preparation of a diabetes, diabetes related disease or diabetic complication disease formulation. Use of said pharmaceutical composition for the treatment of diabetes mellitus, diabetes related disease or diabetic complication disease. A method of preventing or treating an allergic disease comprising administering a pharmaceutical composition to a mammal, including a human, in a therapeutically effective amount.

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