KR102204439B1 - Pharmaceutical Composition comprising SGLT-2 inhibitor and DPP-IV inhibitor - Google Patents

Abstract

The present invention relates to dapagliflozin, a pharmaceutically acceptable salt, hydrate or solvate thereof; Linagliptin, a pharmaceutically acceptable salt, hydrate or solvate thereof; And a pharmaceutical composition comprising an excipient and a method for manufacturing the same, which improved the therapeutic effect of type 2 diabetes and alleviated side effects, and while securing the dissolution rate and nonclinical equivalence equivalent to the formulation containing each single component By minimizing the size of the product and improving the stability of the product quality, it shows the advantage that it can be usefully used as an effective type 2 diabetes prevention or treatment by improving patient convenience and medication compliance.

Description

Pharmaceutical composition comprising SGLT-2 inhibitor and DPP-IV inhibitor {Pharmaceutical Composition comprising SGLT-2 inhibitor and DPP-IV inhibitor}

The present invention relates to a pharmaceutical composition comprising an SGLT-2 inhibitor and a DPP-IV inhibitor, and a method for preparing the same. More specifically, as 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 size of the tablet is minimized and the stability of the drug is improved. The present invention relates to a pharmaceutical composition and a method of manufacturing the same, which improves patient convenience and medication compliance.

Non-insulin dependent diabetes mellitus (NIDDM) is an increasingly prevalent disease that results in a significant decrease in life expectancy due to a high frequency of complications. More than 171 million people around the world suffer from type 2 diabetes, which is characterized by excessive hepatic glucose production and hyperglycemia due to peripheral insulin resistance. Hyperglycemia is considered to be a major risk factor for the onset of diabetes complications, and may be a direct cause of impaired insulin secretion 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 2- to 5-fold increased risk of cardiovascular disease. Therefore, continuous control of plasma glucose levels in type 2 diabetic patients may offset the onset of diabetes complications and beta cell dysfunction in advanced disease.

Plasma glucose is typically filtered in the renal glomerulus and is actively reabsorbed in the proximal tubules. SGLT-2 (Sodium-glucose cotransporter 2) is considered to be growing major transportation involved in the reuptake of glucose at this site. Selective inhibitors of the sodium-dependent glucose transporter SGLT-2 in the kidney are expected to normalize plasma glucose levels by enhancing the excretion of glucose in the urine, thereby improving insulin sensitivity and delaying the onset of diabetic complications.

Orally active SGLT-2 inhibitors, compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof (hereinafter dapagliflozin), are disclosed in U.S. Patent No. 6,515,117 (the entirety of which is incorporated herein by reference). have.

Formula I

US 2008-0004336 A1 discloses dapagliflozin in the form of (S)-propylene glycol ((S)-PG) hydrate and (R)-propylene glycol ((R)-PG) hydrate.

(S)-Propylene glycol hydrate is referred to as form SC-3 and has the structure of formula Ia below.

Formula Ia

(R)-Propylene glycol hydrate is referred to as form SD-3 and has the structure of formula Ib below.

Formula Ib

Methods for the preparation of (S)-PG hydrate and (R)-PG hydrate of dapagliflozin are provided in US 2008-0004336 A1 (the entirety of which is incorporated herein by reference).

The 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 dipeptide from the N-terminus of a number of proteins having a proline or alanine residue at the N-terminus. Due to the above properties, the DPP-IV inhibitor interferes with the plasma concentration of bioactive peptides including the peptide GLP-1, and is considered to be a promising drug for the treatment of diabetes, especially type 2 diabetes. WO 2007/128724 describes a pharmaceutical composition comprising linagliptin as the sole active pharmaceutical ingredient.

On the other hand, when diabetes persists for a long time, most type 2 diabetic patients eventually fail in oral treatment and become insulin dependent, requiring daily injections and glucose measurements several times a day.

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

However, the treatment failure rate is high even when taken for a long period of time, and long-term hyperglycemia-related complications or chronic damage (e.g., microvascular and macrovascular disease such as diabetic nephropathy, retinopathy or neuropathy) in a high proportion of type 2 diabetic patients. Complications, or cardiovascular complications).

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

International Patent Publication No. WO 01/27128 International Patent Publication No. WO 03/099836 International Patent Publication No. WO 2005/092877 International Patent Publication No. WO 2006/034489 International Patent Publication WO 2006/064033 International Patent Publication No. WO 2006/117359 International Patent Publication No. WO 2006/117360 International Patent Publication No. WO 2007/025943 International Patent Publication No. WO 2007/028814 International Patent Publication No. WO 2007/031548 International Patent Publication No. WO 2007/093610 International Patent Publication No. WO 2007/128749 International Patent Publication No. WO 2008/049923 International Patent Publication No. WO 2008/055870 International Patent Publication No. WO 2008/055940 International Patent Publication No. WO 2010/092124 International Patent Publication No. WO 2015/011113 US Patent Publication No. US 2008-0004336

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 combination formulation that improves the stability of the formulation and minimizes the size of the tablet, thereby improving patient convenience and compliance with medication.

In order to solve the above problems, the present invention provides dapagliflozin, a pharmaceutically acceptable salt thereof, a hydrate thereof, a co-crystal form thereof, or a solvate thereof; Linagliptin, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof; And it provides a pharmaceutical composition comprising an excipient.

Compared to the single formulation of dapagliflozin and the single formulation of linagliptin, the pharmaceutical composition of the present invention can minimize the size and minimize the size of the drug while exhibiting sufficient efficacy when formulated into a combined formulation in an oral dosage form as a tablet. By improving it, it is possible to provide a combination formulation with improved patient convenience and medication compliance.

The excipients include mannitol, pregelatinized starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, calcium phosphate, calcium carbonate (CaCO ₃ ), silicified microcrystalline cellulose, or mixtures thereof.

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

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

In the embodiments of the present invention, the calcium phosphate hydrate may be calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate?㏈致?water, and specifically, calcium hydrogen phosphate?㎱? It can be a luggage.

For example, the calcium phosphate may be tricalcium phosphate anhydrous, 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 silicified microcrystalline cellulose. Specifically, it may contain three or more different excipients selected from mannitol, pregelatinized starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, calcium phosphate, calcium carbonate (CaCO ₃ ), and silicified microcrystalline cellulose, and more specifically May contain three different types of excipients selected from mannitol, pregelatinized starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, calcium phosphate, calcium carbonate (CaCO ₃ ), and silicified microcrystalline cellulose.

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

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

This unpredictable problem is exacerbated by the low dosage 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 active ingredients.

In addition, the pharmaceutical composition of the present invention can significantly improve the patient's medication convenience. Although the pharmaceutical composition of the present invention contains two different drugs, the size of the tablet is appropriate, exhibits excellent therapeutic effect, and is excellent in stability, so that the patient's medication convenience can be remarkably improved.

In addition, the composition is excellent in stability and the manufacturing process is simple, and as a result, it is suitable for mass production and is economical. In other words, the composition according to the present invention does not have a process such as dissolving an active ingredient and one or more polymers in a solvent and evaporating, and as a result, a separate manufacturing facility (e.g., FBG, spray dryer) is not required for this, so that Simple and economical. In the present invention, dapagliflozin means (1S)-1,5-anhydro-1-[4-chloro-3-(4-ethoxybenzyl)phenyl]-D-glucitol.

In the embodiments of the present invention, dapagliflozin, a pharmaceutically acceptable salt thereof, a hydrate thereof, a co-crystalline form thereof, or a solvate thereof is specifically dapagliflozin, a co-crystalline form of dapagliflozin, It may be a hydrate of dapagliflozin, a solvate of dapagliflozin, and more specifically, dapagliflozin, a co-crystalline form of proline of dapagliflozin (molar ratio = 1:2), dapagliflozin (S)-propanediol hydrate, dapagliflozin (R)-propanediol hydrate or a mixture thereof, or dapagliprolazine citrate co-crystalline form, more specifically dapagliflozin, dapagliflozin It may be rosin (S)-propanediol hydrate, dapagliflozin (R)-propanediol hydrate or a mixture thereof, or dapagliflozin citrate co-crystal, and more specifically, dapagliflozin Rosin or dapagliflozin citrate co-crystal.

According to an embodiment of the present invention, the dapagliflozin, a pharmaceutically acceptable salt thereof, a hydrate thereof, a co-crystalline form thereof, or a solvate thereof may be a crystalline form.

In the present invention, linagliptin is 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-[( 4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione.

In the present invention, the pharmaceutically acceptable salt refers to a salt prepared according to a conventional method, and such a method of preparation is known to those skilled in the art. Specifically, the pharmaceutically acceptable salt includes, but is not limited to, pharmacologically or physiologically acceptable salts derived from inorganic acids and organic acids and bases below. 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, methanesulfur Phonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. 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 embodiments of the present invention, the linagliptin, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof may be crystalline or amorphous, and specifically, may be a crystalline form.

In embodiments of the present invention, the composition may further include a pharmaceutically acceptable additive such as a binder, a disintegrant, a fluidizing agent, a lubricant, or a mixture thereof in addition to an excipient, 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 a mixture thereof, but is not limited thereto. Specifically, the binder may be povidone, copovidone, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium, pregelatinized starch, or a mixture thereof, and more specifically, copovidone, ethylcellulose or these It may be a mixture of.

In embodiments of the present invention, the disintegrant may be alginic acid, carboxymethylcellulose calcium, starch, crospovidone, croscarmellose sodium, croscarmellose calcium, sodium starch glycolate, or a mixture thereof, but is not limited thereto. Does not. Specifically, the disintegrant may be alginic acid, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, sodium starch glycolate, or a mixture thereof, and more specifically crospovidone.

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

In embodiments of the present invention, the lubricant may be magnesium stearate, calcium stearate, corn starch, talc and sodium stearyl fumarate, light magnesium oxide, or a mixture thereof, but is not limited thereto. It may be 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 linagliptin, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, in combination of about 1.5 to about 10% by weight, 10 to 85% by weight of at least one excipient, at least one binder, and at least one disintegrant drug. It may contain 0.2 to 10% by weight.

In the pharmaceutical composition of the present invention, the excipient may be specifically included in an amount of 10 to 85% by weight based on the total weight of the pharmaceutical composition.

In the pharmaceutical composition of the present invention, the binder may be specifically included in an amount of 0.2 to 15% by weight based on the total weight of the pharmaceutical composition.

In the pharmaceutical composition of the present invention, the disintegrant may be specifically contained in an amount of 0.2 to 10% by weight based on the total weight of the pharmaceutical composition.

In embodiments of the present invention, the pharmaceutical composition may be in the form of granules, capsules, or tablets, and specifically may be in the form of tablets.

The tablet includes a tablet without a coating layer and a tablet with one or more coating layers, and may be a single layer or multiple layers. Further, the tablets may include mini tablets, melt tablets, chewable tablets, effervescent tablets, and oral disintegrating tablets.

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

In the present invention, a single-layer tablet means that there are no separate layers having different compositions in the tablet except for the coating layer.

The two-layered tablet or the double-layered tablet refers to a tablet in which two different layers excluding the coating layer exist, and the two-layered tablet means that two layers each containing different main components except for the coating are stacked, and the double-layered tablet is It means 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 excluding the coating layer.

In addition, the coating layer does not contain an active ingredient and refers to a layer surrounding the outside of the tablet. The coating layer may be formed to be about 1% to 5% by weight based on the total weight of the tablet excluding the coating layer, and specifically may be formed to be about 2% to about 4% by weight.

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

Although the pharmaceutical composition contains both dapagliflozin and linagliptin as active ingredients, it can be prepared as a single-layer tablet, and it can maintain a size less than a certain level, thus significantly improving the patient's medication convenience. have.

According to a specific experimental example of the present invention, when the pharmaceutical composition of the present invention is stored for 4 weeks at 60° C. and 80% relative humidity, dapagliflozin, a pharmaceutically acceptable salt thereof, a hydrate thereof, Co-crystalline form or solvate thereof; And a decomposition product of linagliptin, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof,

Dapagliflozin, a pharmaceutically acceptable salt thereof, a hydrate thereof, a co-crystalline form thereof, or a solvate thereof; Linagliptin, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; And a decomposition product thereof (dapagliflozin, a pharmaceutically acceptable salt thereof, a hydrate thereof, a co-crystal form thereof, or a decomposition product thereof, and linagliptin, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof Decomposition products) can be maintained at less than 1% total based on the total amount.

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

The present invention provides a pharmaceutical oral combination formulation comprising the pharmaceutical composition of the present invention.

The pharmaceutical oral combination formulation may be in the form of granules, capsules, or tablets, preferably in the form of tablets.

In addition, the present invention

1) Dapagliflozin, a pharmaceutically acceptable salt thereof, a hydrate thereof, a co-crystalline form thereof, or a solvate thereof; Linagliptin, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; And mixing an excipient to prepare a mixture.

2) preparing granules by wet granulating the mixture; And

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

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

In the above preparation method, the excipients include mannitol, pregelatinized starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, anhydrous calcium phosphate, calcium phosphate hydrate, calcium carbonate, silicified microcrystalline cellulose, or mixtures thereof.

The dapagliflozin, a pharmaceutically acceptable salt thereof, a hydrate thereof, a co-crystalline form thereof, or a solvate thereof; Linagliptin, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; And excipients and their contents are as described in detail above.

The manufacturing method of the present invention is a method of manufacturing a pharmaceutical composition having excellent quality with a simple facility generally used by pharmaceutical companies. In particular, since a separate manufacturing facility is not required and the process is simple, there is an effect of reducing manufacturing production cost, and by remarkably reducing the size of the dosage form, it is possible to improve the convenience of taking and increase medication compliance.

In embodiments of the present invention, the manufacturing method may further include a step of further mixing a binder, a disintegrant, a fluidizing agent, a lubricant, or a mixture thereof, which are pharmaceutically acceptable additives in step 1). Specifically, the step of adding a binder, a disintegrant, or a mixture thereof among pharmaceutically acceptable additives may be further included in step 1).

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

The binder, disintegrant, fluidizing agent, and lubricant 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, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; Excipients; And the preparation and granulation of a mixture of pharmaceutically acceptable additives may be performed simultaneously or separately, and specifically, each step may be performed separately.

In embodiments of the present invention, the preparation method may include dapagliflozin, a pharmaceutically acceptable salt thereof, a hydrate thereof, a co-crystalline form thereof, or a solvate thereof before step 1); Linagliptin, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; It may further comprise the step of weighing the excipient and the pharmaceutically acceptable salt.

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

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

In embodiments of the present invention, it may further include the step of tableting the granules passed through the mesh screen after step 3). The tableting may be prepared as a single-layer tablet or a double-layer tablet, but is not limited thereto.

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

Dapagliflozin of the present invention, a pharmaceutically acceptable salt thereof, a hydrate thereof, a co-crystalline form thereof, or a solvate thereof; And linagliptin, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof as an active ingredient, while securing the dissolution rate and nonclinical equivalence equivalent to the formulations containing each single component, stability of product quality It not only improves, but also minimizes the size of the tablet, thereby improving the patient's ease of use and medication compliance, thereby showing the advantage of being useful as an effective type 2 diabetes prevention or treatment.

The pharmaceutical composition of the present invention improves the therapeutic effect of type 2 diabetes and alleviates side effects, and while securing the dissolution rate and nonclinical equivalence equivalent to a formulation containing a single component of dapagliflozin or linagliptin, tablets In addition to dramatically reducing the size of the product, it is possible to provide a combination formulation that improves patient convenience and compliance with medication by improving the stability of product quality.

In addition, the manufacturing method of the present invention does not require a separate manufacturing facility and the process is simple, thereby reducing manufacturing production cost, and significantly reducing the size of the formulation to improve ease of use, thereby increasing medication compliance.

1 is a graph showing the results of a nonclinical test of a dapagliflozin component for the combination 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 a nonclinical test of linagliptin components for the combination administration of Comparative Example 1 and Comparative Example 2 and administration of the pharmaceutical composition of the present invention.
3 is a comparison chart of weights and sizes of Comparative Examples 1, 2, and Examples of the present invention.

Hereinafter, the configuration and effects of the present invention will be described in more detail through examples. These examples are for illustrative purposes only, and the scope of the present invention is not limited by these examples. Each of the components used in the above Examples and Comparative Examples were purchased and used as known components.

[Example]

Examples 1 to 8: Preparation of pharmaceutical compositions according to the invention

Tablets were prepared according to the ingredients and contents in Table 1 below. The content in Table 1 represents the content per tablet (not including the coating layer). At this time, the coating layer was formed to be 4.0% by weight of the uncoated tablet weight.

[Table 1] Examples 1 to 8 components and contents

In the method for preparing a composite formulation of the present invention, after weighing according to Table 1 above, a binder was added to purified water to prepare a binder solution, and then mixed with the main ingredient, excipient, fluidizing agent, and disintegrant, and then combined to form granules. Thereafter, the granules were dried, passed through a mesh screen, and sized, and a lubricant was added to prepare a final mixture. And the final mixture was tableted to prepare a single layer tablet.

Comparative Example 1: Preparation of SGLT-2 inhibitor single agent

As a single formulation of dapagliflozin, Posiga® tablet (AstraZeneca Korea) containing 10mg as dapagliflozin was used, and the weight per tablet is 260mg.

Comparative Example 2: Preparation of DPP-IV inhibitor single agent

As a single formulation of linagliptin, Tragenta® tablet (Boehringer Ingelheim Korea) containing 5 mg of linagliptin was used, and the weight per tablet is 185 mg.

Experimental Example 1: Stability test

A stability test was conducted to confirm the stability of the pharmaceutical composition of the present invention. Specifically, as shown in Table 2, the composite formulation Example 1 and Comparative Examples 1 and 2 were stored for 4 weeks under severe conditions (60° C., 80% relative humidity), and then evaluated.

[Table 2] Comparison of total related substances in combination formulation and comparative example

In the above results, Comparative Examples 1 and 2 showed 3.5% of total related substances in 4 weeks of severe severity, but 0.7% of total related materials in 4 weeks of harshness of the present invention. It was shown that the quality was improved in the present invention than in Comparative Examples 1 and 2, which are commercially available products.

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

Comparative dissolution of dapagliflozin was performed in the first solution (pH 1.2) of the dissolution test using the combined formulation of Examples 1 to 8 and the single formulation of Comparative Example 1, USP II method.

The dissolution test results are shown in Table 3 below.

[Table 3] Differences in dissolution rates between Comparative Example 1 and Examples 1 to 8

As in the dissolution test results of Comparative Example 1 and Examples 1 to 8 above, excipients were used as mannitol, silicified microcrystalline cellulose, pregelatinized starch, low-substituted hydroxypropyl cellulose, anhydrous calcium phosphate, calcium hydrogen phosphate hydrate, calcium carbonate, etc. When prepared, comparative dissolution equivalence can be secured.

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

Comparative dissolution was performed for linagliptin in the first solution (pH 1.2) of the dissolution test by the combined formulation of Examples 1 to 8 and the single formulation of Comparative Example 2, USP II method.

The dissolution test results are shown in Table 4 below.

[Table 4] Differences in dissolution rates between Comparative Example 2 and Examples 1 to 8

As in the dissolution test results of Comparative Example 2 and Examples 1 to 8 above, additives were used as mannitol, silicified microcrystalline cellulose, pregelatinized starch, low-substituted hydroxypropyl cellulose, anhydrous calcium phosphate, calcium hydrogen phosphate hydrate, calcium carbonate, etc. When prepared, comparative dissolution equivalence can be secured.

Experimental Example 4: Non-clinical test

Using a male beagle dog, the combination administration of Comparative Example 1 and Comparative Example 2 and the in vivo kinetics of the drug of Example 1 were compared and evaluated. The following test was orally administered to a fasted beagle dog (male), and administered over two periods with a two-week withdrawal period by applying a cross-over design.

The non-clinical test results are shown in Table 5 below and FIGS. 1 and 2.

[Table 5] Non-clinical results of the present invention and comparative examples

(a) SGLT-2 (dapagliflozin)

(b) DPP-IV (linagliptin)

As shown in Comparative Examples 1 and 2 and the nonclinical test results of the present invention, nonclinical equivalence was secured.

Experimental Example 5: Observation of appearance

Pictures 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, minor axis, thickness and weight were measured.

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

Claims (14)

Dapagliflozin, a pharmaceutically acceptable salt thereof, a hydrate thereof, a co-crystalline form thereof, or a solvate thereof;
Linagliptin, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; And
Contains excipients,
The excipients include three or more selected from the group consisting of mannitol, pregelatinized starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, calcium phosphate, calcium carbonate, and silicified microcrystalline cellulose, and the three or more excipients are different from each other. The formulation for oral administration. The formulation for oral administration according to claim 1, wherein the formulation for oral administration further comprises at least one selected from the group consisting of a binder, a disintegrant, a fluidizing agent, and a lubricant. The method of claim 2, based on the total weight of the pharmaceutical composition
Dapagliflozin, a pharmaceutically acceptable salt thereof, a hydrate thereof, a co-crystalline form thereof, or a solvate thereof; And linagliptin, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof in 1.5 to 10.0% by weight,
10 to 85% by weight of three or more excipients,
0.2 to 15% by weight of at least one binder, and
0.2 to 10% by weight of one or more disintegrants
Formulation for oral administration comprising a. The preparation for oral administration according to 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 formulation for oral administration according to 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 formulation for oral administration according to any one of claims 1 to 5, which is in the form of granules, capsules or tablets. delete The preparation for oral administration according to claim 6, wherein the preparation for oral administration is in the form of a tablet. According to claim 1, When stored for 4 weeks at 60 ℃ and 80% relative humidity, dapagliflozin, a pharmaceutically acceptable salt thereof, a hydrate thereof, a co-crystal form or a solvate thereof; And the amount of the decomposition product of linagliptin, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof,
Dapagliflozin, a pharmaceutically acceptable salt thereof, a hydrate thereof, a co-crystalline form thereof, or a solvate thereof; And linagliptin, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof; And based on the total amount of their decomposition products
Formulations for oral administration that remain below 1%. The formulation for oral administration according to claim 8, wherein the weight of the tablet is 100 to 300 mg. 1) Dapagliflozin, a pharmaceutically acceptable salt thereof, a hydrate thereof, a co-crystalline form thereof, or a solvate thereof; Linagliptin, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; And mixing an excipient to prepare a mixture.
2) preparing granules by wet granulating the mixture; And
3) drying the granules and passing them through a mesh screen
A method for producing a formulation for oral administration of claim 1 comprising a. The method of claim 11, wherein preparing the mixture,
The manufacturing method further comprises the step of adding and mixing at least one selected from the group consisting of a binder and a disintegrant.
The method of claim 1, wherein the excipient is a mixture of mannitol, silicified microcrystalline cellulose and microcrystalline cellulose, pregelatinized starch, a mixture of low-substituted hydroxypropyl cellulose and anhydrous tricalcium phosphate, mannitol, a mixture of calcium hydrogen phosphate hydrate and calcium carbonate. , Silicified microcrystalline cellulose, mixture of microcrystalline cellulose and pregelatinized starch, low-substituted hydroxypropyl cellulose, mixture of anhydrous tricalcium phosphate and calcium hydrogen phosphate hydrate, mannitol, mixture of silicified microcrystalline cellulose and calcium carbonate, microcrystalline cellulose, pregelatinized A formulation for oral administration that is a mixture of starch and low-substituted hydroxypropyl cellulose or a mixture of anhydrous tricalcium phosphate, calcium hydrogen phosphate hydrate and calcium carbonate. The method of claim 1, wherein the calcium phosphate is anhydrous calcium phosphate, calcium phosphate hydrate or a mixture thereof,
The anhydrous calcium phosphate is at least one selected from the group consisting of anhydrous tricalcium phosphate (Ca3(PO4)2), anhydrous calcium hydrogen phosphate (CaHPO4), and anhydrous calcium dihydrogen phosphate (Ca(HPO4)2),
The calcium phosphate hydrate is at least one selected from the group consisting of calcium hydrogen phosphate hydrate and calcium dihydrogen phosphate hydrate, a formulation for oral administration.

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