Pharmaceutical formulation with improved stability comprising dapagliflozin, linagliptin, and metformin

Abstract

The present invention relates to a pharmaceutical formulation containing three drugs: linagliptin, dapagliflozin, and metformin, and being prepared as a bilayered tablet comprising: an immediate-release layer comprising dapagliflozin and linagliptin as active ingredients; and a sustained-release layer comprising metformin as an active ingredient, wherein the immediate-release layer includes a lipophilic polyphenolic antioxidant as a stabilizer, and the sustained-release layer uses carboxymethylcellulose sodium and hypromellose 2208 together as sustained-release agents. In the pharmaceutical formulation according to the present invention, delamination of the formulation is suppressed, thus enabling the preparation of a high-quality formulation, and the formation of related substances of the active ingredients is suppressed, thus enabling long-term storage. Thus, the pharmaceutical formulation can increase medication compliance as a pharmaceutical composition for improving glycemic control in patients with insufficient glycemic control.

Description

Pharmaceutical formulations with improved stability, including dapagliflozin, linagliptin, and metformin

[0001] The present invention relates to a pharmaceutical formulation having improved stability of a pharmaceutical composition comprising an SGLT-2 inhibitor, a DPP-4 inhibitor and optionally an additional antidiabetic agent disclosed in WO 2010 / 092125.

[0002] With the advent of industrialization and civilized society, the number of diabetes patients has rapidly increased worldwide due to excessive food intake and lack of exercise. Consequently, advances in treatment technologies and pharmaceuticals have led to a decrease in mortality rates from acute diabetic complications and infections. However, despite the rapid increase in the number of diabetic patients regardless of age, the number of patients suffering from chronic diabetic complications has not decreased. This has led to significant interest in maintenance therapies that prevent and delay the onset of chronic diabetic complications.

[0003] Representative antidiabetic drugs include metformin, sulfonylureas (e.g., glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinediones (e.g., rosiglitazone, pioglitazone), PPAR-gamma-agonists (e.g., GI 262570) and antagonists, PPAR-gamma / alpha modulators (e.g., KRP 297), alpha-glucosidase inhibitors (e.g., acarbose, voglibose), DPP-4 inhibitors (e.g., linagliptin), SGLT-2 inhibitors (e.g., empagliflozin, dapagliflozin), alpha2-agonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g., exendin-4), or antidiabetic drugs such as amylin.

[0004] When selecting oral medications for typical diabetes patients, metformin, a non-glycemic agent that has been used for approximately 60 years and has a proven safety profile against hypoglycemic side effects, is often chosen as the first-line treatment. However, metformin monotherapy often fails to achieve target blood sugar levels in diabetic patients. Therefore, in most medical settings, blood sugar levels are controlled through combination therapy with two or three drugs. In particular, DPP-4 inhibitors and SGLT-2 inhibitors are currently the most preferred second-line agents and are widely used in medical settings. Research on combinations and complex formulations utilizing these agents is also actively underway.

[0005] DPP-4 inhibitors are drugs that lower blood sugar and improve glucose tolerance by inhibiting the decomposition of DPP-4, an enzyme that decomposes GLP-1, an incretin. Examples of DPP-4 inhibitors include saxagliptin, sitagliptin, vildagliptin, linagliptin, dutogliptin, and alogliptin.

[0006] SGLT-2 inhibitors are drugs that inhibit glucose reabsorption in the renal tubules, thereby causing glucose to be excreted through urine. Examples include dapagliflozin, canagliflozin, luceogliflozin, tofogliflozin, ipragliflozin, ertugliflozin, atigliflozin, remogliflozin, and empagliflozin.

[0007] When formulated as a single drug or multiple drugs, there are often no major issues with the quality stability of the formulation for a single drug, but when multiple drugs are formulated as a single tablet, it is often difficult to ensure long-term quality stability.

[0008] WO 2004 / 018468 and WO 2007 / 128761 disclose pharmaceutical compositions for treating diabetes comprising linagliptin and metformin, and WO 2008 / 116179 and WO 2009 / 100936 disclose that dapagliflozin or dapagliflozin propylene glycol hydrate can be used in combination with one or more other therapeutic agents including antidiabetic agents, antihyperglycemic agents, lipid-lowering agents / lipid-lowering agents, antiobesity agents, antihypertensive agents and appetite suppressants, either in the same dosage form (fixed dose) or in separate dosage forms.

[0009] And, in WO 2009 / 121945, in an attempt to prepare a pharmaceutical composition comprising a fixed dose combination of a DPP-4 inhibitor drug and a partner drug (metformin), it was observed that DPP-4 inhibitors having primary or secondary amino groups are very stable compounds, but show incompatibility, degradation problems or extraction problems with a number of common excipients such as microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, tartaric acid, citric acid, glucose, fructose, saccharose, lactose and maltodextrin, and it is suggested that protection against degradation and deterioration can be achieved by the use of nucleophilic substances and / or basic agents (e.g. buffers and / or pH adjusting agents) as stabilizers to solve these technical problems, the buffers used being basic amino acids having intramolecular amino groups and alkaline properties (isoelectric point, pI: 7.59 to 10.76), For example, it has been suggested that it could be L-arginine, L-lysine or L-histidine.

[0010] In addition, WO 2011 / 039367 discloses a pharmaceutical composition or combination of a DPP-4 inhibitor and metformin for improving glycemic control in patients with insufficient glycemic control despite monotherapy with metformin or combination therapy with two antidiabetic drugs, and WO 2010 / 092163 discloses a pharmaceutical composition comprising a DPP-4 inhibitor, metformin and a third antidiabetic agent selected from group G3 consisting of biguanides, thiazolidinediones, sulfonylureas, glinides, alpha-glucosidase inhibitors and GLP-1 analogs.

[0011] WO 2011 / 138421 describes a method for reducing and maintaining body weight and / or body fat in a patient in need thereof, for example, an overweight or obese patient with or without diabetes (in particular an obese or overweight patient with type 2 diabetes), comprising administering in combination (e.g., separately, simultaneously or sequentially) a GLP-1 receptor agonist (e.g., GLP-1 or a GLP-1 analogue) and a DPP-4 inhibitor.

[0012] Furthermore, WO 2012 / 031124 discloses a coated tablet comprising a first layer coating a tablet core comprising an antidiabetic agent, metformin, dapagliflozin, and a water-soluble antioxidant, a second layer coating the first layer comprising at least one water-soluble antioxidant and an active pharmaceutical ingredient, saxagliptin, sitagliptin, vildagliptin, linagliptin, dutogliptin, or alogliptin, and a third layer coating the second layer comprising at least one water-soluble antioxidant. The prior art suggests ascorbic acid, propyl gallate, sodium sulfite, sodium metabisulfite, sodium bisulfite, thioglycerol, and thioglycolic acid as water-soluble antioxidants.

[0013] Korean Patent No. 10-2204439 discloses an oral administration formulation comprising dapagliflozin and linagliptin, which, compared to a single dapagliflozin formulation and a single linagliptin formulation, can exhibit sufficient efficacy while minimizing the size when formulated as a combination oral administration form in the form of tablets, and improve the stability of the drug, thereby improving the convenience of taking the drug and the compliance of the patient, and comprises three or more excipients selected from the group consisting of mannitol, pregelatinized starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, calcium phosphate, calcium carbonate, and silicified microcrystalline cellulose as excipients.

[0014] Korean Patent Publication No. 2023-0055762 discloses a pharmaceutical formulation comprising metformin, linagliptin, and meglumine, comprising: a core portion comprising metformin, a pharmaceutically acceptable salt thereof, or a hydrate thereof; an endothelial coating layer formed on the core portion; and a drug coating layer formed on the endothelial coating layer and comprising linagliptin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and meglumine.

[0015] Korean Patent Publication No. 2021-0121599 discloses a composite tablet comprising a first layer comprising dry granules containing sitagliptin and dapagliflozin and a second layer comprising wet granules containing metformin and colloidal silicon dioxide. The prior art discloses a composite tablet in which sitagliptin and dapagliflozin are relatively more susceptible to moisture than metformin, thus having a bilayer tablet structure, and metformin has the form of wet granules, thereby ensuring excellent flowability, and the second layer contains colloidal silicon dioxide, thereby providing excellent stability.

[0016] Meanwhile, preparations containing metformin, SGLT-2 inhibitors, and DPP-4 inhibitors are known to undergo degradation factors such as acid hydrolysis, alkaline hydrolysis, thermal hydrolysis, photolysis, and oxidative degradation.

[0017] The present inventors sought to prepare a pharmaceutical preparation comprising three drugs, including dapagliflozin, an SGLT-2 inhibitor disclosed in WO 2010 / 092125, linagliptin, a DPP-4 inhibitor, and metformin, a type 3 diabetes treatment agent, as a preparation useful for treating diabetes to prevent, delay the progression of, or treat type 2 diabetes, particularly in patients requiring improved glycemic control or metabolic disorders.

[0018] However, it was confirmed that the pharmaceutical preparation containing metformin, dapagliflozin and linagliptin disclosed in WO 2010 / 092125 had a problem with stability due to a significant increase in the amount of flexible substances in the dosage form during the manufacturing process and / or storage during development, and also that the preparation containing metformin had problems with hardness and friability due to peeling during the manufacturing process and storage of the semi-finished product.

[0019] The present inventors attempted to solve the above problems by manufacturing a bilayer tablet comprising dapagliflozin and linagliptin in the immediate-release layer and metformin in the sustained-release layer. That is, WO 2009 / 121945 discloses a nucleophilic substance and / or a basic agent (e.g., a buffer and / or a pH adjusting agent) as a stabilizer to suppress the formation of related substances in a formulation comprising dapagliflozin and linagliptin, and attempted to apply these to the immediate-release layer of the present invention, and attempted to apply excipients disclosed in Republic of Korea Patent No. 10-2204439, but neither of them secured formulation stability.

[0020] In addition, the inventor of the present invention has confirmed through numerous studies that the main decomposition factor of the formulation of the present invention is oxidative decomposition, and has revealed that such oxidative decomposition is a phenomenon in which the main ingredient is oxidized by free radicals in the composition and manufacturing process of the formulation, and has applied a water-soluble antioxidant disclosed in the prior art WO 2012 / 031124 to conduct an effect evaluation study on antioxidants to suppress oxidative decomposition, but has not obtained satisfactory results.

[0021] These pharmaceutical preparations, which will be described in more detail herein, have now been found to possess surprising and particularly advantageous properties. Surprisingly, it has been found that the use of a lipid-soluble polyphenol antioxidant suitable for stabilization, such as an antioxidant suitable as a stabilizer, in these pharmaceutical preparations can overcome the problem of a significant increase in the amount of volatile substances in the dosage form during the manufacturing process and / or storage. Thus, the use of a lipid-soluble polyphenol antioxidant suitable for stabilization in these pharmaceutical preparations can provide protection for long-term quality stability.

[0022] In addition, Korean Patent Publication No. 2021-0121599 discloses that the layer separation problem occurring in a formulation containing metformin, sitagliptin, and dapagliflozin is solved by including colloidal silicon dioxide in the metformin-containing layer, and this was applied to the sustained-release layer of the present invention, but the separation phenomenon was not suppressed.

[0023] In response to these problems, the inventors of the present invention solved the problem of peeling of tablets by using sodium carboxymethylcellulose and hypromellose 2208 together as sustained-release agents in the sustained-release layer containing metformin.

[0024] The present invention aims to provide a pharmaceutical preparation for treating diabetes with improved stability by preventing or reducing the production of volatile substances during the manufacturing process and storage of a pharmaceutical preparation containing three drugs, linagliptin, dapagliflozin, and metformin, as active ingredients.

[0025] In addition, the present invention aims to provide a pharmaceutical preparation in the form of a bilayer tablet containing dapagliflozin and linagliptin in the immediate-release layer and metformin in the sustained-release layer, wherein the pharmaceutical preparation has improved stability by suppressing the peeling phenomenon of the sustained-release layer containing metformin.

[0026] The present invention provides a pharmaceutical preparation comprising three drugs, linagliptin, dapagliflozin, and metformin, wherein the immediate-release layer comprises dapagliflozin and linagliptin as active ingredients, and the sustained-release layer comprises metformin as an active ingredient, and the immediate-release layer comprises a fat-soluble polyphenol antioxidant as a stabilizer, and the sustained-release layer uses carboxymethylcellulose sodium and hypromellose 2208 together as a sustained-release agent.

[0027] In another aspect, the present invention provides a method for producing a pharmaceutical preparation in tablet form that prevents or reduces the release of soluble substances of an active ingredient, which is metformin, an SGLT-2 inhibitor and a DPP-4 inhibitor, and suppresses the exfoliation phenomenon, comprising adding a fat-soluble polyphenol antioxidant as a stabilizer and using carboxymethylcellulose sodium and hypromellose 2208 together as a release agent.

[0028] In another aspect, the present invention provides a method for inhibiting or reducing the formation of soluble substances and inhibiting the exfoliation phenomenon in a pharmaceutical preparation in tablet form, which comprises adding a fat-soluble polyphenol antioxidant as a stabilizer to the pharmaceutical preparation containing metformin, an SGLT-2 inhibitor, and a DPP-4 inhibitor, and using carboxymethylcellulose sodium and hypromellose 2208 together as a release agent.

[0029] Hereinafter, the present invention will be described in detail.

[0030] The present invention relates to a pharmaceutical preparation containing three drugs, linagliptin, dapagliflozin, and metformin, which is manufactured as a two-layer tablet in which the immediate-release layer contains dapagliflozin and linagliptin as active ingredients and the sustained-release layer contains metformin as an active ingredient, wherein the immediate-release layer contains a fat-soluble polyphenol antioxidant as a stabilizer, and the sustained-release layer uses carboxymethylcellulose sodium and hypromellose 2208 together as a sustained-release agent.

[0031] The immediate-release layer according to the present invention comprises dapagliflozin or a dapagliflozin solvate, which is an SGLT-2 inhibitor, as an active ingredient. The dapagliflozin used in the present invention is a (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol compound, having a structure represented by the following chemical formula 1, and can be prepared using a procedure similar to that described in WO 2003 / 099836, and the dapagliflozin solvate is dapagliflozin propylene glycol hydrate, dapagliflozin propanediol hydrate, dapagliflozin citrate, dapagliflozin butanediol, dapagliflozin L-proline, etc., and is preferably dapagliflozin propanediol hydrate.

[0032] <Chemical Formula 1>

[0033]

[0034] The present invention includes linagliptin, a DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof as another active ingredient of the immediate-release layer. The linagliptin used in the present invention is a 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine compound, having a structure represented by the following chemical formula 2, and can be prepared by a method similar to the method described in WO 2004 / 018468. In addition, the "pharmaceutically acceptable salt" used in linagliptin in the present invention refers to a salt widely known in the art. Examples of pharmaceutically acceptable salts include acetic acid, aspartic acid, benzenesulfonic acid, benzoic acid, butyric acid, citric acid, fumaric acid, hydrochloric acid, hydrobromic acid, lactic acid, maleic acid, malonic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid, nicotinic acid, phosphoric acid, succinic acid, sulfuric acid, or tartaric acid, prepared using methods well known in the art. A preferred pharmaceutically acceptable salt of the active ingredient linagliptin for use in the method of the present invention is HCl.

[0035] <Chemical Formula 2>

[0036]

[0037] In addition, the present invention includes a fat-soluble polyphenol antioxidant having an aromatic alcohol group in its molecular structure as a stabilizer in the fast-release layer. The fat-soluble polyphenol antioxidant included in the fast-release layer is selected from the group consisting of butylated hydroxytoluene, butylated hydroxyanisole, and resveratrol.

[0038] The immediate-release layer according to the present invention is a pharmaceutical dosage form comprising the active ingredients of linagliptin and dapagliflozin and a fat-soluble polyphenol antioxidant. The immediate-release layer comprises 0.1 to 10 parts by weight of the fat-soluble polyphenol antioxidant per 100 parts by weight of linagliptin or a pharmaceutically acceptable salt thereof and dapagliflozin or dapagliflozin propanediol hydrate.

[0039] In one aspect, the immediate-release layer of the present invention comprises a diluent, a binder, a disintegrant, a lubricant, a fat-soluble polyphenol antioxidant, and linagliptin and dapagliflozin as active ingredients. In one specific embodiment of the present invention, the immediate-release layer is a granule mixture comprising dapagliflozin granules, linagliptin granules, a fat-soluble polyphenol antioxidant, and magnesium stearate. Specifically, the dapagliflozin granules comprise microcrystalline cellulose, copovidone, sodium starch glycolate, and dapagliflozin propanediol hydrate, and the linagliptin granules comprise microcrystalline cellulose, mannitol, copovidone, sodium starch glycolate, and linagliptin. In addition, the immediate-release layer comprises magnesium stearate as a lubricant and butylated hydroxyanisole, or resveratrol, which are fat-soluble polyphenol antioxidants, as stabilizers.

[0040] The sustained-release layer according to the present invention is a pharmaceutical dosage form comprising as an active ingredient metformin, a non-glycemic agent for treating diabetes, or a pharmaceutically acceptable salt thereof, and as a sustained-release agent sodium carboxymethylcellulose and hypromellose 2208. Suitable forms of metformin, the active ingredient for use in the sustained-release layer of the present invention, include pharmaceutically acceptable salts thereof, such as hydrochloric acid, hydrobromic acid, fumaric acid, succinic acid, and p-chlorophenoxyacetic acid. Preferably, the fumaric acid and succinic acid salts are metformin (2:1) fumaric acid and metformin (2:1) succinic acid. Metformin hydrochloride is a preferred salt.

[0041] The release-storing agent included in the above-mentioned release layer comprises 18.0 to 35.0 wt% based on the total weight of the release layer, and the release-storing agent sodium carboxymethylcellulose and hypromellose 2208 comprise 1:1 to 2:1 wt%, and at least sodium carboxymethylcellulose must be included in an amount equal to or greater than that of hypromellose 2208 to suppress the peeling phenomenon.

[0042] In one aspect, the sustained-release layer of the present invention comprises a sustained-release agent, a binder, a flow promoter, a lubricant, and metformin as an active ingredient. In one specific embodiment of the present invention, the sustained-release layer is a metformin granule comprising metformin hydrochloride as an active ingredient, sodium carboxymethylcellulose and hypromellose 2910 as sustained-release agents, and hypromellose 2208 as a binder. In addition, the sustained-release layer comprises colloidal silicon dioxide as a flow promoter and magnesium stearate as a lubricant.

[0043] Linagliptin, a DPP-4 inhibitor mentioned herein, is contained in a dosage range of 0.1 to 100 mg, particularly 0.5 to 10 mg. Accordingly, specific dosages of linagliptin are 0.5 mg, 1 mg, 2.5 mg, 5 mg, and 10 mg.

[0044] At least one compound selected from dapagliflozin and dapagliflozin propanediol hydrate is administered at an equivalent dose of about 5 mg / day of dapagliflozin. In some embodiments, the SGLT2 inhibitor, e.g., dapagliflozin, and one compound selected from dapagliflozin propanediol hydrate, is administered at an equivalent dose of about 2.5 mg / day of dapagliflozin.

[0045] Metformin is administered in various dosage regimens, typically ranging from about 250 mg to 3,000 mg daily, typically from 500 mg to 2,000 mg, and up to a maximum of 2,500 mg. Metformin dosages typically range from 100 mg to 500 mg, or from 200 mg to 850 mg once to three times daily, or from 300 mg to 1,000 mg once or twice daily.

[0046] In one embodiment, the pharmaceutical formulation of the present invention comprises an amount of one of the following components, based on the total weight of each layer, of the immediate-release layer and the sustained-release layer, and may further comprise optional excipients.

[0047] The inner layer

[0048] 1.0 to 5.0 wt% of linagliptin

[0049] Dapagliflozin propanediol hydrate 2.0 to 5.0 wt%

[0050] 5.0 to 25.0 wt% mannitol as a diluent

[0051] 65.5 to 80.0 wt% of microcrystalline cellulose as a diluent

[0052] 7.5 to 10.0 wt% of sodium starch glycolate as a disintegrant

[0053] 1.0 to 5.0 wt% of copovidone as a binder

[0054] 0.1 to 1.0 wt% of a fat-soluble polyphenol antioxidant as a stabilizer

[0055] 1.0 to 2.0 wt% of magnesium stearate as a lubricant

[0056] including;

[0057] The western layer

[0058] Metformin hydrochloride 67.0 to 75.0 wt%

[0059] 10.0 to 20.0 wt% of sodium carboxymethylcellulose, a preservative

[0060] 8.0 to 15.0 wt% of hypromellose 2208 (100,000 cps), a western-style antiseptic

[0061] 0.8 to 1.2 wt% of hypromellose 2910 (50 cps) as a binder

[0062] 0.5 to 1.0 wt% of colloidal silicon dioxide as a lubricant (fluid promoter)

[0063] 0.5 to 1.0 wt% of magnesium stearate as a lubricant

[0064] Includes.

[0065] In addition, the present invention provides a pharmaceutical preparation in the form of a double-layer film-coated tablet by coating a double-layer tablet with a film coating, the double-layer tablet comprising linagliptin, a DPP-4 inhibitor, and dapagliflozin, an SGLT-2 inhibitor, as active ingredients in the immediate-release layer and a fat-soluble polyphenol antioxidant as a stabilizer, and metformin, a nonagulin-based antidiabetic agent, as active ingredients in the sustained-release layer and sodium carboxymethylcellulose and hypromellose 2208 as sustained-release agents.

[0066] Suitable film coatings for use in the formulations of the present invention may be Opadry White (20A28381), Opadry QX Yellow 321A620000 or Tabshield Pink (91P1070).

[0067] Opadry White (20A28381) used in the present invention is manufactured by mixing 33.75% hydroxypropyl cellulose as a coating agent, 33.75% hypromellose 2910 15mPa.s, 20% talc, and 12.5% ​​titanium oxide as a coloring agent.

[0068] In addition, the film coating, Opadry QX Yellow 321A620000, is manufactured by evenly mixing 40% of macrogol polyvinyl alcohol grafted copolymer, 27.5% of talc, 23.675% of titanium oxide, 4% of glycerol monocaprylocaprate, 3.5% of polyvinyl alcohol, and 1.328% of yellow iron oxide.

[0069] In addition, the film coating of the above-mentioned tab shield pink (91P1070) is manufactured by evenly mixing 35% hydroxypropyl cellulose, 34% hypromellose, 27% titanium oxide, 3% red iron oxide, and 1% Allura Red AC aluminum lake.

[0070] The present invention relates to a method for producing a pharmaceutical preparation in tablet form that prevents or reduces the release of soluble substances of active ingredients, which are metformin, SGLT-2 inhibitors and DPP-4 inhibitors, and suppresses the exfoliation phenomenon, by adding a fat-soluble polyphenol antioxidant as a stabilizer and sodium carboxymethylcellulose and hypromellose 2208 as release-promoting agents.

[0071] The rapid-release layer according to the present invention comprises the active ingredients of linagliptin and dapagliflozin and the fat-soluble polyphenol antioxidant in intimate contact with each other such that their respective chemical environments are substantially identical. Preferably, the active ingredients and the fat-soluble polyphenol antioxidant are homogeneously mixed. Of course, in certain embodiments, some degree of heterogeneity may exist (e.g., particles of the active ingredients and / or particles of the fat-soluble polyphenol antioxidant may be substantially part of the additionally mixed material). The rapid-release layer according to the present invention may be manufactured by a wet granulation process.

[0072] The sustained-release layer according to the present invention is a homogeneous mixture of the active ingredient of metformin and the sustained-release agent sodium carboxymethylcellulose and hypromellose 2208. The sustained-release layer according to the present invention can be manufactured using a wet granulation process.

[0073] To prepare a pharmaceutical formulation according to the present invention, granules may be prepared by a wet granulation process. Liquid granulation is another method for granulating the active ingredient and excipients, including fluidized bed granulation or one-pot granulation.

[0074] In the wet granulation process, the granulation liquid is a solvent such as water, ethanol, methanol, isopropanol, acetone, and preferably purified water, and contains a binder such as copovidone. The solvent is a volatile component that does not remain in the final product. Other excipients and active ingredients, excluding the lubricant, are premixed and granulated with the aqueous granulation liquid using a high-shear granulator. Following the wet granulation step, an optional wet sieving step, a drying step, and a sieving step of the granules are performed. For example, a fluidized bed dryer can be used for drying purposes.

[0075] The dried granules are sieved through a suitable sieve. After adding other excipients except the lubricant, the mixture is blended in a suitable conventional blender, such as a free fall blender, followed by adding a lubricant, such as magnesium stearate, and final blending in the blender.

[0076] In addition, the pharmaceutical preparation in tablet form of the present invention is manufactured in accordance with the manufacturing method set forth in the general provisions of the Korean Pharmacopoeia for preparations, but follows the following process. That is, the double-layer tablet of the present invention, including the immediate-release layer and the sustained-release layer, is produced by a high-shear wet granulation process and a double-layer tableting process using a multi-layer rotary press, and a double-layer tablet coated with a film-coating material is manufactured.

[0077] Therefore, an exemplary wet granulation process for the preparation of a pharmaceutical composition according to the present invention is

[0078] Method for preparing a mixture of dapagliflozin and linagliptin layers;

[0079] 1) A step of preparing a mixture by mixing dapagliflozin and an additive;

[0080] 2) a step of wet granulating the above mixture to produce granules; and

[0081] 3) A step of preparing a mixture by mixing linagliptin and an additive;

[0082] 4) A step of wet granulating the above mixture to produce granules; and

[0083] 5) A step of drying the above granules and passing them through a mesh screen;

[0084] 6) A step of lubricating the granules using a lubricant;

[0085] Method for preparing a mixture of metformin layers;

[0086] 7) A step of preparing a mixture by mixing metformin and an additive;

[0087] 8) A step of wet granulating the above mixture to produce granules; and

[0088] 9) A step of drying the above granules and passing them through a mesh screen;

[0089] 10) A step of lubricating the granules using a lubricant;

[0090] 11) A tablet forming step of forming a tablet using a double-stage tablet press using the active mixture of 6) and the active mixture of 10) can be manufactured, including;

[0091] The following examples describe in detail a method for manufacturing a pharmaceutical preparation in tablet form according to the present invention.

[0092] The present invention provides a pharmaceutical preparation manufactured as a bilayer tablet, wherein the immediate-release layer contains dapagliflozin and linagliptin as active ingredients and a fat-soluble polyphenol antioxidant as a stabilizer, and the sustained-release layer contains metformin as an active ingredient and uses sodium carboxymethylcellulose and hypromellose 2208 together as sustained-release agents, thereby suppressing the exfoliation phenomenon of the preparation, thereby enabling the manufacture of a preparation of superior quality, and suppressing the production of related substances of the active ingredient, thereby enabling long-term storage, thereby improving glycemic control in patients with insufficient glycemic control, thereby increasing drug compliance as a pharmaceutical composition.

[0093] Figure 1 is a photograph showing the peeling phenomenon of double tablets manufactured in Examples 1 and 4 and Comparative Examples 1 to 3 according to the present invention after being stored at room temperature for one week.

[0094] Hereinafter, the present invention will be described in detail by way of examples. However, these examples are intended to exemplify the present invention, and the scope of the present invention is not limited by these examples.

[0095] <Example 1> Preparation of a pharmaceutical preparation containing a fat-soluble polyphenol antioxidant

[0096] 1) Manufacture of fast-release granules

[0097] According to the composition described in Example 1 of Table 1 below, dapagliflozin propanediol hydrate and copovidone are dissolved in ethanol to prepare a binding solution containing dapagliflozin. Separately, microcrystalline cellulose and sodium starch glycolate are mixed using a high-shear granulator, and then wetted with the prepared binding solution to prepare a mixture. The mixture is wet granulated to prepare a granule, and then dried to prepare dapagliflozin granules.

[0098] Separately, copovidone is dissolved in purified water to prepare a binding solution. Separately, linagliptin, microcrystalline cellulose, mannitol, and sodium starch glycolate are mixed using a high-shear granulator, and then moistened with the prepared binding solution to prepare a mixture. The mixture is wet granulated to produce granules, which are then dried to prepare linagliptin granules.

[0099] The above-mentioned manufactured dapagliflozin granules and linagliptin granules are sieved using a 30-mesh sieve, and then mixed with butylated hydroxytoluene, a fat-soluble polyphenol antioxidant, as a stabilizer, and finally mixed with magnesium stearate to manufacture rapid-release granules containing dapagliflozin and linagliptin.

[0100] 2) Manufacture of western layer granules

[0101] A binding solution is prepared by dissolving the binding agent, hypromellose 2910, in purified water. Separately, sodium carboxymethylcellulose, hypromellose 2208, and metformin hydrochloride are mixed using a high-shear granulator, and then moistened with the prepared binding solution to prepare a mixture. The mixture is wet granulated to produce granules, which are then dried to produce metformin granules.

[0102] The above-mentioned metformin granules are sieved using a 30-mesh sieve, and then finally mixed with colloidal silicon dioxide as a fluidizing agent and magnesium stearate as a lubricant to produce sustained-release granules containing metformin.

[0103] 3) Manufacture of two-layer tablets

[0104] The immediate-release granules containing dapagliflozin and linagliptin manufactured in the above 1) and the sustained-release granules containing metformin manufactured in 2) are each manufactured into a double-layer tablet using a double-layer tablet press. A coating suspension is separately manufactured, and the manufactured double-layer tablets are coated with the coating suspension to manufacture film-coated tablets, thereby manufacturing a pharmaceutical preparation in the form of a double-layer tablet comprising an immediate-release layer containing dapagliflozin and linagliptin and a sustained-release layer containing metformin according to the present invention.

[0105] <Examples 2 and 3> Preparation of pharmaceutical preparations containing fat-soluble polyphenol antioxidants

[0106] Pharmaceutical preparations in the form of two-layer tablets with a rapid-release layer and a sustained-release layer according to the present invention were prepared using the same method as Example 1 using the compositions described in Examples 2 and 3 of Table 1 below, and are designated as Examples 2 and 3, respectively.

[0107] Examples 2 and 3 according to the present invention are pharmaceutical preparations containing butylated hydroxyanisole and resveratrol, respectively, as lipid-soluble polyphenol antioxidants as stabilizers in the fast-release layer.

[0108] <Example 4> Preparation of a pharmaceutical preparation containing a 1:1 weight ratio of a preservative

[0109] A pharmaceutical preparation in the form of a two-layer tablet having a rapid-release layer and a sustained-release layer according to the present invention was prepared using the same method as Example 1 using the composition described in Example 4 of Table 1 below, and is referred to as Example 4.

[0110] Example 4 according to the present invention is a pharmaceutical formulation in which the immediate-release layer comprises butylated hydroxyanisole, a fat-soluble polyphenol antioxidant, as a stabilizer, similar to Example 1, and the sustained-release layer comprises sodium carboxymethylcellulose, a sustained-release agent, and hypromellose 2208, a sustained-release agent, in a 1:1 weight ratio. Meanwhile, the immediate-release layer of Example 1 is a pharmaceutical formulation in which the sustained-release agent sodium carboxymethylcellulose and the sustained-release agent hypromellose 2208 are in a 2:1 weight ratio.

[0111]

[0112] <Comparative Examples 1 to 3> Preparation of pharmaceutical preparations with different ratios of the release agent in the western layer

[0113] Pharmaceutical preparations in the form of two-layer tablets with an immediate-release layer and a sustained-release layer were prepared in the same manner as Example 1 using the compositions described in Comparative Examples 1 to 3 of Table 2 below, and are designated as Comparative Examples 1 to 3, respectively.

[0114] In Comparative Examples 1 to 3, the rapid-release layer is the same as in Example 1, and the sustained-release layer is a pharmaceutical preparation containing sustained-release agents, sodium carboxymethylcellulose and hypromellose 2208, in weight ratios of 0:100, 1:7.8, and 1:5.6, respectively, and does not contain a binder.

[0115]

[0116] <Comparative Example 4> Manufacture of a pharmaceutical preparation not containing a stabilizer

[0117] A pharmaceutical preparation in the form of a two-layer tablet with an immediate-release layer and a sustained-release layer is prepared using the same method as Example 1 using the composition described in Comparative Example 4 of Table 3 below.

[0118] Comparative Example 4 does not include a stabilizer in the fast-release layer, and the slow-release layer is the same formulation as Example 1.

[0119] <Comparative Example 5> Preparation of a pharmaceutical preparation containing a basic amino acid

[0120] A pharmaceutical preparation in the form of a two-layer tablet with a rapid-release layer and a sustained-release layer is prepared using the same method as Example 1 using the composition described in Comparative Example 5 of Table 3 below.

[0121] Comparative Example 5 comprises a basic amino acid (e.g., L-arginine, L-lysine, L-histidine) described in WO 2009-121945 as a stabilizer in the fast-release layer, and the sustained-release layer is the same pharmaceutical preparation as in Example 1.

[0122] <Comparative Examples 6 to 11> Preparation of pharmaceutical preparations containing water-soluble antioxidants

[0123] A pharmaceutical preparation in the form of a two-layer tablet with an immediate-release layer and a sustained-release layer is prepared using the same method as Example 1 using the compositions described in Comparative Examples 6 to 11 in Table 3 below.

[0124] Comparative Examples 6 to 11 include a water-soluble antioxidant described in WO 2012-031124 as a stabilizer in the fast-release layer, and the sustained-release layer is the same pharmaceutical formulation as Example 1.

[0125]

[0126] <Experimental Example 1> Comparison of the rate of change in tablet weight and tablet properties

[0127] In order to confirm the weight change rate, completeness of appearance, and presence of peeling phenomenon of the double-layer tablet according to the present invention, the double-layer tablets manufactured in Examples 1 and 4 and Comparative Examples 1 to 3 were stored at room temperature for about one week and then evaluated, and the results are shown in Table 4 and Figure 1.

[0128] As can be seen in Table 4 below, Examples 1 and 4 and Comparative Examples 2 and 3, which contain sodium carboxymethylcellulose and hypromellose 2208 as a release agent, show better weight change rate and hardness of tablets than Comparative Example 1, which does not contain sodium carboxymethylcellulose as a release agent.

[0129] However, as can be seen in Fig. 1, it was confirmed that a peeling phenomenon occurred unexpectedly when the weight % of sodium carboxymethyl cellulose, which is a release agent, was less than the weight % of hypromellose, which is a release agent.

[0130] Therefore, the present invention comprises a release-controlling agent included in the release layer in an amount of 18.0 to 35.0 wt% based on the total weight of the release layer, and the release-controlling agent sodium carboxymethylcellulose and hypromellose 2208 are included in a weight ratio of 1:1 to 2:1, and at least sodium carboxymethylcellulose must be included in an amount equal to or greater than that of hypromellose 2208 to suppress the peeling phenomenon.

[0131]

[0132] <Experimental Example 2> Harsh stability test (45℃, RH75%)

[0133] To confirm the purity and stability of the pharmaceutical preparations according to the present invention, stability tests were conducted. The pharmaceutical preparations prepared in Examples 1 to 3 and Comparative Examples 4 to 11 were stored under harsh conditions (45°C, RH75%) for 4 weeks, and the amount of volatile substances produced was confirmed, as shown in Table 5.

[0134] [Test Conditions]:

[0135] - Storage conditions: 45±2℃, relative humidity 75±5% RH

[0136] - Testing time: Initial, 2 weeks, 4 weeks

[0137] - Analysis target: Total amount of flexible substances produced

[0138] [Liquid chromatography conditions]:

[0139] Use 25ul of the test solution and perform a test under the following conditions according to the liquid chromatography method of the Korean Pharmacopoeia to obtain the peak areas of dapagliflozin and linagliptin.

[0140] - Column: Octadecylsilyl silica gel column

[0141] - Mobile phase: Buffer:acetonitrile:methanol = 50:25:25

[0142] - Flow rate: 1.5ml / min

[0143] - Detector: UV spectrophotometer (measurement wavelength 225 nm)

[0144] - Buffer solution: Dissolve 6.8g of potassium dihydrogen phosphate in 1L of purified water and adjust the pH to 4.0 with phosphoric acid.

[0145]

[0146] As can be seen in Table 5 above, the pharmaceutical preparations of Examples 1 to 3 according to the present invention are pharmaceutical preparations that use butylated hydroxy toluene, butylated hydroxy anisole, and resveratrol, which are fat-soluble polyphenol antioxidants, as stabilizers. It was confirmed that the total flexible substances produced were butylated hydroxy toluene 0.69% (Example 1), butylated hydroxy anisole 1.70% (Example 2), and resveratrol 1.49% (Example 3) after 4 weeks under harsh conditions (45°C, RH75%).

[0147] In this regard, Comparative Example 4 is a pharmaceutical preparation without adding a stabilizer or antioxidant, and 2.39% of total flexible substances were generated in 4 weeks under harsh conditions (45°C, RH75%), and Comparative Example 5 is a pharmaceutical preparation containing L-arginine, a basic amino acid, as a stabilizer described in WO 2009-121945, and 2.09% of total flexible substances were generated in 4 weeks under harsh conditions (45°C, RH75%).

[0148] In addition, Comparative Examples 6 to 11 are pharmaceutical preparations that applied water-soluble antioxidants as stabilizers, such as ascorbic acid (Comparative Example 6), citric acid (Comparative Example 7), fumaric acid (Comparative Example 8), malic acid (Comparative Example 9), tocopherol acetate (Comparative Example 10), and vitamin B (Comparative Example 11), and it was confirmed that under harsh conditions (45°C, RH75%) for 4 weeks, the total flexible substances were ascorbic acid 7.66% (Comparative Example 6), citric acid 3.16% (Comparative Example 7), fumaric acid 3.30% (Comparative Example 8), malic acid 2.86% (Comparative Example 9), tocopherol acetate 2.82% (Comparative Example 10), and vitamin B 3.32% (Comparative Example 11).

[0149] From the above results, it was confirmed that the pharmaceutical formulations of Examples 1 to 3 according to the present invention, which applied a fat-soluble polyphenol antioxidant as a stabilizer, significantly reduced the amount of total reactive substances produced, thereby improving the stability of the formulations, compared to the pharmaceutical formulations of Comparative Example 4 which did not include a stabilizer or antioxidant, Comparative Example 5 which included a basic amino acid as a stabilizer, and Comparative Examples 6 to 11 which applied a water-soluble antioxidant as a stabilizer. Specifically, it was confirmed that the pharmaceutical formulations of Comparative Examples 6 to 11 which applied a water-soluble antioxidant as a stabilizer had a higher amount of total reactive substances produced, compared to the pharmaceutical formulations of Comparative Example 4 which did not include a stabilizer or antioxidant, and Comparative Example 5 which included a basic amino acid as a stabilizer.

[0150] Therefore, the pharmaceutical preparation containing a fat-soluble polyphenol antioxidant as a stabilizer according to the present invention has an unexpectedly excellent stabilizing effect.

[0151] <Experimental Example 3> Severe stability test (60℃)

[0152] To confirm the purity stability of pharmaceutical preparations containing fat-soluble polyphenol antioxidants as stabilizers according to the present invention, stability tests were conducted. The pharmaceutical preparations of Examples 1 to 3 and Comparative Examples 4 to 11 according to the present invention were stored under harsh conditions (60°C) for 4 weeks, and then subjected to purity test evaluations, which are shown in Table 6 below.

[0153] [Test Conditions]:

[0154] - Storage conditions: 60±2℃

[0155] - Testing time: Initial, 2 weeks, 4 weeks

[0156] - Analysis target: Total amount of flexible substances produced

[0157] [Liquid chromatography conditions]:

[0158] Measurement is performed under the same conditions as the liquid chromatography conditions described in Experimental Example 2.

[0159]

[0160] As can be seen in Table 6 above, the pharmaceutical preparations of Examples 1 to 3 according to the present invention are pharmaceutical preparations that use butylated hydroxy toluene, butylated hydroxy anisole, and resveratrol, which are fat-soluble polyphenol antioxidants, as stabilizers. It was confirmed that, under harsh conditions (60°C) for 4 weeks, the total flexible substances were generated at 2.48% for Example 1 (butylated hydroxy toluene), 4.09% for Example 2 (butylated hydroxy anisole), and 3.48% for Example 3 (resveratrol).

[0161] In this regard, Comparative Example 4 is a pharmaceutical preparation without adding a stabilizer or antioxidant, and it was confirmed that 8.16% of total flexible substances were generated after 4 weeks under harsh conditions (60°C), and Comparative Example 5 is a pharmaceutical preparation containing L-arginine, a basic amino acid, as a stabilizer described in WO 2009-121945, and it was confirmed that 3.33% of total flexible substances were generated after 4 weeks under harsh conditions (60°C). In addition, Comparative Examples 6 to 11 are pharmaceutical preparations that use water-soluble antioxidants as stabilizers, such as ascorbic acid (Comparative Example 6), citric acid (Comparative Example 7), fumaric acid (Comparative Example 8), malic acid (Comparative Example 9), tocopherol acetate (Comparative Example 10), and vitamin B (Comparative Example 11). It was confirmed that under harsh conditions (60°C) for 4 weeks, the total flexible substances were ascorbic acid 6.99% (Comparative Example 6), citric acid 7.13% (Comparative Example 7), fumaric acid 6.91% (Comparative Example 8), malic acid 7.41% (Comparative Example 9), tocopherol acetate 6.78% (Comparative Example 10), and vitamin B 6.74% (Comparative Example 11).

[0162] From the above results, it was confirmed that the pharmaceutical formulations of Examples 1 to 3 according to the present invention, which applied a fat-soluble polyphenol antioxidant as a stabilizer, showed a significantly reduced amount of total reactive substances compared to the pharmaceutical formulations of Comparative Example 4 which did not include a stabilizer or antioxidant, Comparative Example 5 which included a basic amino acid as a stabilizer, and Comparative Examples 6 to 11 which applied a water-soluble antioxidant as a stabilizer, thereby improving the stability of the formulations. In particular, it was confirmed that the pharmaceutical formulation of Comparative Example 4 which did not include a stabilizer or antioxidant showed a significantly increased amount of total reactive substances compared to the pharmaceutical formulations of Comparative Example 5 which included a basic amino acid as a stabilizer, and Comparative Examples 6 to 11 which applied a water-soluble antioxidant as a stabilizer.

[0163] Therefore, a pharmaceutical preparation containing a fat-soluble polyphenol antioxidant as a stabilizer according to the present invention has an excellent stabilizing effect by significantly suppressing the production of total flexible substances.

Claims

1. An immediate-release layer comprising linagliptin or a pharmaceutically acceptable salt thereof as a DPP-4 inhibitor, dapagliflozin or a dapagliflozin solvate as an SGLT-2 inhibitor, and a fat-soluble polyphenol antioxidant as a stabilizer; and A type 3 diabetes treatment agent, which is metformin or a pharmaceutically acceptable salt thereof, and a sustained-release layer comprising carboxymethylcellulose sodium and hypromellose 2208 as sustained-release agents in a weight ratio of 1:1 to 2:1, in an amount of 18.0 to 35.0 wt% based on the total weight of the sustained-release layer; A pharmaceutical preparation for the treatment of diabetes in the form of a double-layer tablet comprising:

2. A pharmaceutical preparation according to claim 1, wherein the dapagliflozin solvate is selected from dapagliflozin propylene glycol hydrate, dapagliflozin propanediol hydrate, dapagliflozin citrate, dapagliflozin butanediol, and dapagliflozin L-proline.

3. A pharmaceutical preparation according to claim 2, wherein the dapagliflozin solvate is dapagliflozin propanediol hydrate.

4. A pharmaceutical preparation according to claim 1, wherein the third antidiabetic agent is metformin hydrochloride.

5. A pharmaceutical preparation according to claim 1, wherein the stabilizer is a fat-soluble polyphenol antioxidant selected from butylated hydroxytoluene, butylated hydroxyanisole, and resveratrol.

6. A pharmaceutical preparation according to any one of claims 1 to 5, wherein the bilayer tablet is in the form of a bilayer film-coated tablet coated with a film coating.

7. The quick-release layer 1.0 to 5.0 wt% of linagliptin Dapagliflozin propanediol hydrate 2.0 to 5.0 wt% 5.0 to 25.0 wt% mannitol as a diluent 65.5 to 80.0 wt% of microcrystalline cellulose as a diluent 7.5 to 10.0 wt% of sodium starch glycolate as a disintegrant 1.0 to 5.0 wt% of copovidone as a binder 0.1 to 1.0 wt% of a fat-soluble polyphenol antioxidant as a stabilizer 1.0 to 2.0 wt% of magnesium stearate as a lubricant including; The western layer Metformin hydrochloride 67.0 to 75.0 wt% 10.0 to 20.0 wt% of sodium carboxymethylcellulose, a preservative 8.0 to 15.0 wt% of hypromellose 2208 (100,000 cps), a western-style antiseptic 0.8 to 1.2 wt% of hypromellose 2910 (50 cps) as a binder 0.5 to 1.0 wt% of colloidal silicon dioxide as a lubricant (fluid promoter) 0.5 to 1.0 wt% of magnesium stearate as a lubricant A pharmaceutical preparation for the treatment of diabetes in the form of a double-layer tablet comprising:

8. A pharmaceutical preparation according to claim 7, wherein the stabilizer is a fat-soluble polyphenol antioxidant selected from the group consisting of butylated hydroxytoluene, butylated hydroxyanisole, and resveratrol.

9. A pharmaceutical preparation in the form of a double-layer film-coated tablet in which the double-layer tablet is coated with a film coating in accordance with paragraph 6.

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