KR101526825B1 - Pharmaceutical Compositions for The Treatment of Diabetes - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for treatment of diabetes, comprising metformin and a DPP-IV inhibitor. The pharmaceutical composition for treatment of diabetes is capable of blocking a contact between the DPP-IV inhibitor and the metformin, thereby increasing an effective life thereof and decreasing types and quantities of impurities existing in the composition. In addition, the pharmaceutical composition is capable of quickly discharging the DPP-IV inhibitor and controlling a sustained release of the metformin.

Description

[0001] The present invention relates to pharmaceutical compositions for the treatment of diabetes,

The present invention relates to a pharmaceutical composition for the treatment of diabetes mellitus, and more particularly, to a pharmaceutical composition for treating diabetes mellitus, which comprises metformin and dipeptidyl peptidase 4 (DPP-IV, hereinafter referred to as DPP-IV) And a pharmaceutical composition for the treatment of diabetes.

DPP-IV inhibitors and metformin are well known in the art for the treatment of diabetes.

Since the above-mentioned medicinal compounds exert an antidiabetic effect through different mechanisms, it is disclosed that the combination of the two drugs exerts a good effect in the treatment of diabetic patients. (Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2013 : 6 187-95)

Korean Patent Laid-Open Nos. 2014-0021049 and 2008-0056171 also disclose pharmaceutical compositions comprising DPP-IV inhibitors and metformin, and methods for their preparation.

However, there is no known effect of co-administration of two drugs on the stability and dissolution pattern of other drugs.

The inventors of the present invention have found that when developing a combination of DPP-IV inhibitor and metformin, the interaction of DPP-IV inhibitor and metformin on a single preparation affects the stability of DPP-IV inhibitor . In addition, it has been found that the amount, or ratio, of the sequestration layer that inhibits the contact of metformin with the DPP-IV inhibitor affects the stability of the DPP-IV inhibitor.

Medicines can also break down over time or create by-products that harm the patient. Therefore, the development of formulations capable of minimizing the generation of non-pharmaceutically acceptable substances that are not decomposed even in long-term storage is highly desired in the art, particularly in the field of manufacturing complex products.

In the development of a complex drug, it is necessary to exert an appropriate elution sufficient for the drug to be absorbed into the body. However, since the physical and chemical properties of each substance are different, development of a complex drug formulation is not easy. Even if a formulation that exhibits desirable dissolution is developed, it may be difficult to apply because of problems such as cost problems or residual solvents.

Accordingly, the inventors of the present invention completed the present invention after developing a dosage form which can improve the stability of a DPP-IV inhibitor in a pharmaceutical composition for the treatment of diabetes comprising both a DPP-IV inhibitor and metformin, .

Korean Patent Publication No. 2008-0056171 Korean Patent Publication No. 2014-0021049

Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2013: 6 187-95

It is an object of the present invention to provide a pharmaceutical composition for the treatment of diabetes which is highly stable, comprising metformin and a DPP-IV inhibitor.

It is still another object of the present invention to provide a pharmaceutical composition for the treatment of diabetes which can achieve a desired dissolution pattern.

In order to achieve the above object,

A pharmaceutical composition for the treatment of diabetes comprising a metformin and a DPP-IV inhibitor and an isolated layer for blocking contact between the metformin and the DPP-IV inhibitor.

The pharmaceutical composition for the treatment of diabetes according to the present invention can block the contact between the DPP-IV inhibitor and metformin, thereby increasing the shelf life of the composition and reducing the amount of the soft substance as well as the amount thereof. In addition, there is an advantage that rapid release of the DPP-IV inhibitor is possible, while the controlled release of metformin can be controlled.

FIG. 1 is a graph showing the dissolution test results of the DPP-IV inhibitor (tenerigliptin) of the positive control group, Example 2 and Comparative Example 1. FIG.

Hereinafter, the present invention will be described in detail.

The present invention relates to metformin and; A DPP-IV inhibitor, and an isolated layer for blocking contact between the metformin and the DPP-IV inhibitor.

Metformin is an agent for treating type 2 diabetes mellitus, which increases susceptibility to insulin in human peripheral tissues. It is also involved in inhibiting glucose uptake in the intestines, inhibiting gluconeogenesis, and inhibiting fatty acid oxidation. The typical dose administered to a diabetic patient is from 250 mg to 1000 mg.

Inhibitors of dipeptidyl peptidase-IV (DPP-IV) are known to be useful in the treatment of type 2 diabetes, especially in diabetes, and the usual dosage is 25 to 100 mg.

The mechanism of the DPP-IV inhibitor is as follows.

Glucagon-like peptide-1 (hereinafter, referred to as GLP-1) and gastric inhibitory peptide (hereinafter referred to as GIP) are representative examples of human hormone secreted when human is ingested. Incretin acts to enhance insulin secretion in dependence on blood glucose levels. DPP-IV inactivates incretins in vivo. Therefore, the inhibitor of DPP-IV prevents the decrease of serum insulin and exhibits an anti-diabetic effect.

As used herein, the term "metformin" includes metformin or a pharmaceutically acceptable salt thereof, a crystalline form, a hydrate, a solvate, a diastereomer or an enantiomer thereof.

As used herein, the term " DPP-IV inhibitor " includes both a DPP-IV inhibitor or a pharmaceutically acceptable salt thereof, a crystalline form, a hydrate, a solvate, a diastereomer or an enantiomer thereof.

Also, as used herein, the term "DPP-IV inhibitor" also refers to both its active metabolites and prodrugs, such as active metabolites and prodrugs of DPP-IV inhibitors. IV " is an active derivative of a DPP-IV inhibitor produced when a DPP-IV inhibitor is metabolized and said "prodrug" is metabolized to a DPP-IV inhibitor, or a metabolite ). ≪ / RTI >

DPP-IV inhibitors are known in the art. For example, it may be used in combination with other drugs such as Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin, Anagliptin, Teneligliptin, Alogliptin, Gemigliptin, Dutogliptin, etc. The most preferred DPP-IV inhibitor of the present invention is tenerigliptin.

Tenerigliptin has the advantage of achieving a desirable blood glucose lowering effect only once a day.

Whether DPP-IV inhibitors and metformin directly mediate pharmacological interactions is not known until now. It has been discovered for the first time by the present inventors that the difference in physical and chemical properties between the two drugs can affect the stability of some drugs.

Specifically, the inventors of the present invention have found that when DPP-IV inhibitors and metformin physically interact with each other, the stability of the DPP-IV inhibitor is significantly reduced compared to otherwise.

In one embodiment of the present invention, a pharmaceutical composition comprising both a DPP-IV inhibitor and metformin was prepared and then the stability of the two active ingredients was measured. As a result, when the two active ingredients were physically isolated by the isolation layer, The amount of the flexible material was measured at a remarkably low level. In addition, the lifetime was predicted to increase by more than 300% compared to the control group (see Experimental Example 1).

Therefore, when a DPP-IV inhibitor and metformin are prepared in a single formulation, an isolation layer capable of physically blocking the contact between the DPP-IV inhibitor and metformin must be present in order to ensure stability thereof.

The term " isolated layer " means a means capable of blocking the contact of the DPP-IV inhibitor with metformin, and the embodiments encompass any means that can be used in oral formulations in the art such as membranes, walls, coatings, and the like.

When the pharmaceutical composition for the treatment of diabetes according to the present invention is formulated into an oral formulation, the oral formulation includes metformin as an inner layer, a DPP-IV inhibitor as an outer layer, and an intermediate layer between the inner layer and the outer layer, ≪ / RTI >

In the case of the above formulations, there is a desirable advantage in terms of dissolution pattern as well as an effect of physically blocking the contact between both metformin and DPP-IV inhibitor to improve the stability of the DPP-IV inhibitor.

Metformin, for example, is slowly and incompletely absorbed in the gastrointestinal tract and is mainly absorbed from the upper part of the intestinal tract. Its plasma half-life is known to be 2 to 6 hours, and its solubility is very high, its absorption is very low and its drug half-life is short. Therefore, it is necessary to formulate the sustained-release drug slowly. For this purpose, it is advantageous for drug elution to be disposed on the inner side rather than on the outer side of the oral formulation.

In one embodiment of the present invention, the pharmaceutical compositions comprising both a DPP-IV inhibitor and metformin were prepared, and then the dissolution rate of the DPP-IV inhibitor, which should exhibit rapid efficacy, was measured. As a result, The dissolution rate was much higher than that in the case of no treatment (see Experimental Example 2).

Therefore, when a DPP-IV inhibitor and metformin are prepared in a single formulation, it is necessary to provide an isolation layer capable of blocking the contact between them in order to obtain a desired dissolution pattern.

In the case of the inner layer containing metformin, a swelling polymer may be further included for sustained release.

The swelling polymer may be at least one selected from the group consisting of high viscosity hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose sodium, crosslinked carboxymethylcellulose and derivatives thereof, methylcellulose, ethylcellulose and salts or derivatives thereof, carboxyvinylpolymers, polyvinyl And may be at least one selected from the group consisting of alcohol, polyethylene oxide (PEO), polymethacrylate polymer, and pharmaceutically acceptable biodegradable cellulose derivatives.

The swelling polymer is effective for achieving the desired dissolution pattern of metformin contained in the inner layer.

The swelling polymer preferably has a viscosity of 1,000 to 200,000 centipoise (cps), preferably 4,000 to 200,000 centipoise (cps), in order to realize excellent dissolution characteristics.

If the viscosity of the swelling polymer is lower than 1000 centipoise or higher than 200,000 centipoise, it may be difficult to achieve a desirable elution pattern according to the pharmacokinetic behavior of metformin.

The high viscosity cellulose derivative is preferably 20 to 50% by weight based on the total weight of the pharmaceutical composition of the present invention to achieve the desired dissolution pattern. The weight of the composition means dry weight.

If the swelling polymer is lower than 20 wt% or higher than 50 wt% based on the total weight of the pharmaceutical composition of the present invention, it may be difficult to achieve the desired dissolution pattern according to the pharmacokinetic behavior of metformin.

The inner layer may further comprise pharmaceutically acceptable excipients well known in the art.

DPP-IV inhibitor drugs should exhibit rapid efficacy. Therefore, when the pharmaceutical composition of the present invention is prepared for oral administration, it is advantageous to be placed outside.

The outer layer comprising the DPP-IV inhibitor is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), microcrystalline cellulose (MCC), polyvinyl alcohol, methylcellulose (MC), hydroxypropylcellulose (HPC) , At least one release modifier selected from the group consisting of cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), and polymethacrylate polymers can do.

The intermediate layer which blocks contact between the DPP-IV inhibitor and metformin is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), polyvinyl alcohol, polyethylene glycol and hydroxypropylcellulose (HPC) Or more of the water-soluble polymer.

The intermediate layer is preferably about 2 to 5% by weight based on the total weight of the pharmaceutical composition for treating diabetes of the present invention. The weight of the composition means dry weight.

According to one embodiment of the present invention, when the capacity of the intermediate layer is less than 2% by weight based on the total weight of the pharmaceutical composition of the present invention, the isolation of the DPP-IV inhibitor and metformin is not properly performed and the stability of the DPP- And the stability of the DPP-IV inhibitor is lowered even when it is higher than 5% by weight.

The pharmaceutical composition for treating diabetes of the present invention can be administered orally or parenterally, but it is more preferably prepared for oral use. Oral formulations have the advantage of being easy to administer, improving patient compliance, and reducing manufacturing and management costs.

The pharmaceutical compositions which can be orally administered include tablets, granules, pellets, pills, powders, suspensions, and capsules, including tablets, film-coated tablets, dragees, , Troches, powders, and the like, and all oral forms recognized by those skilled in the art.

Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings. However, the present invention is not limited to the examples.

Example

Examples 1 to 3 - Preparation of the pharmaceutical composition for treating diabetes (oral coated tablets) of the present invention

a. Preparation of metformin inner layer

The inner layers of Examples 1 to 3 were prepared according to the compositions and the capacities shown in Table 1.

Furtherance Volume
(mg) Metformin hydrochloride 1000 Hydroxypropylmethylcellulose
(100,000 cps) 313 Carboxymethylcellulose sodium 50 Polyvinyl pyrrolidone K-30 40 Magnesium stearate 15

Specifically, metformin hydrochloride, hydroxypropylmethylcellulose 100,000 centipoise (cps), carboxymethylcellulose sodium and polyvinylpyrrolidone K-30 were homogeneously mixed in a mixer, water was added in a certain amount to obtain wet granules, The granules were passed through a 14 mesh sieve and dried in a fluidized bed dryer. Magnesium stearate was added to the dried granules and mixed to obtain granules having excellent fluidity and compressibility. The metformin inner layer (bottom) was then obtained according to conventional tableting methods.

b. Preparation of intermediate layer

A coating solution was prepared to prepare an intermediate layer for interrupting the contact between metformin and DPP-IV inhibitor according to the composition and capacity shown in Table 2 below.

Furtherance Volume
(mg) Example 1 Example 2 Example 3 Hydroxypropylmethylcellulose 4.5 cps 35.7 47.6 59.6 Polyethylene glycol 6.8 9.1 11.3 Purified water 297.8 397.0 496.3

Specifically, polyethylene glycol and purified water were mixed and hydroxypropylmethylcellulose (4.5 cps) was added to the aqueous polyethylene glycol solution prepared above and mixed until a homogeneous drug coating solution was obtained. The coating solution prepared above was sprayed onto the inner layer containing metformin prepared in 1-a to form an intermediate layer.

c. DPP-IV inhibitor outer layer and completion of the pharmaceutical composition of the present invention

A coating solution for preparing the outer layers of Examples 1 to 3 was prepared according to the composition and the capacity shown in Table 3 below.

Furtherance Volume
(mg) Hydroxypropylmethylcellulose
(4.5 cps) 50 Polyethylene glycol 10 Tenerigliptin 31 Purified water 630

Specifically, tenerigliptin, polyethylene glycol, and hydroxypropylmethylcellulose (4.5 cps) were homogeneously dispersed in purified water and mixed until a homogeneous drug coating solution was obtained. The tablets having the inner layer and the intermediate layer were sprayed with the prepared coating solution in a coater and dried to prepare the pharmaceutical composition of the present invention.

Comparative Example  One

The tablets were prepared by the same composition and method as in Examples 1 to 3 except that the intermediate layer was not formed (the intermediate layer was not present).

Comparative Example  2 and 3

Preparations were prepared by the same composition and method as in Examples 1 to 3 except that the amount of interlayer coating was adjusted as shown in Table 4 below.

Furtherance Volume
(mg) Comparative Example 2 Comparative Example 3 Hydroxypropylmethylcellulose 4.5 cps 23.8 71.5 Polyethylene glycol 4.8 13.6 Purified water 198.5 595.6

Experimental Example  One. Stability test (severe test)

Among the stability test methods specified by the International Harmonization Organization (ICH), stability tests were conducted under the condition of severe test. The temperature was measured at 60 ° C and 75% relative humidity for 3 days. The results are shown in Table 5 below.

object Middle layer coating amount
(weight%) days unknown impurity-6 impurity C Forecast lifetime (months) Comparative Example 1 0 0 0 0 0.052 6 3 1.222 0.588 0.368 Comparative Example 2 1.8 0 0 0 0.052 18 3 0.522 0.195 0.29 Example 1 2.7 0 0 0 0.052 24 3 0.458 0.183 0.252 Example 2 3.6 0 0 0 0.052 28 3 0.385 0.155 0.226 Example 3 4.4 0 0 0 0.052 24 3 0.358 0.201 0.253 Comparative Example 3 5.3 0 0 0 0.052 18 3 0.388 0.2 0.291

As shown in Table 5, when the intermediate layer is not present (Comparative Example 1), the concentration of the flexible substance is higher than that in the case where the intermediate layer is present (Examples 1 to 3 and Comparative Examples 1 and 2) And the predicted validity period according to the results is remarkably short. In addition, it was found that the concentration of the suppositories of Comparative Examples 2 and 3 was higher than that of Examples 1 to 3 and the predicted lifetime was shorter than 24 months, indicating that the amount of the intermediate layer greatly affects the stability of the DPP-IV inhibitor I could.

Experimental Example  2. DPP - IV  Dissolution test of inhibitor

For pharmaceutical compositions comprising both a DPP-IV inhibitor and metformin, the effect of the presence of the quencher on the release characteristics of DPP-IV was determined.

Example 2 and Comparative Example 1 were each tested at 37 ° C in 900 ml Tris buffer eluate at 50 rpm according to the elution method described in USP (Method II), and the eluate was taken at each time period and analyzed by high pressure liquid chromatography The content of tenerigliptin was measured according to the following formula. As a positive control group, 20 mg of teneliori was used.

The results are shown in Table 6 below, and the same contents are shown in detail in FIG.

Elution time (min) Dissolution rate of tenerigliptin Positive control group
(%) Example 2
(%) Comparative Example 1
(%) 10 71.6 81.1 68.7 15 92.2 88.7 78.2 30 103.3 94.2 86.8 45 103.8 95.6 88.9

As shown in the above table, in Example 2 in which an intermediate layer separating the active ingredients of tenerigliptin and metformin was present, the dissolution pattern was almost similar to that in the positive control whereas in Comparative Example 1 in which no intermediate layer was present, And showed a different pattern from the control group. Based on the results of Table 6 above, the similarity factor (f2) was calculated according to the equivalence test standard of the food safety status of drug substance (more than 50 if the similarity factor is more than 50) for more objective judgment. 7.

Example  2 Comparative Example  One Similarity factor (f2) 54.9 43.9 result equal Asynchronous

As shown in the above table, it can be seen that Example 2 is equivalent to a positive control, whereas Comparative Example 1 is not.

Claims (15)

Metformin and;
Teneragliptin, < / RTI >
And an isolation layer for blocking contact between the metformin and tenerigliptin, wherein the isolation layer is 2-5 wt% based on the total weight of the pharmaceutical composition.
delete The method according to claim 1,
The metformin is included in the inner layer,
Wherein the tenerigliptin is included in the outer layer,
Wherein the isolation layer forms an intermediate layer disposed between the inner layer and the outer layer.
The method of claim 3,
Wherein the inner layer is a swellable polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose sodium, crosslinked carboxymethylcellulose and derivatives thereof, methylcellulose, ethylcellulose and salts or derivatives thereof, carboxyvinylpolymers, poly A pharmaceutical composition for the treatment of diabetes, which further comprises at least one member selected from the group consisting of vinyl alcohol, polyethylene oxide (PEO), polymethacrylate polymer, and pharmaceutically acceptable biodegradable cellulose derivatives.
delete 5. The method of claim 4,
Wherein the swelling polymer is a polymer having a viscosity of 1,000 to 200,000 centipoise (cps).
The method according to claim 6,
Wherein the swelling polymer is a polymer having a viscosity of 4,000 to 200,000 centipoise (cps).
5. The method of claim 4,
Wherein the swelling polymer is present in an amount of 20 to 50% by weight based on the total weight of the pharmaceutical composition.
The method of claim 3,
Wherein the outer layer comprises at least one of hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), microcrystalline cellulose (MCC), polyvinyl alcohol, methylcellulose (MC), hydroxypropylcellulose (HPC), cellulose acetate phthalate (CAP) , Hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), and polymethacrylate polymers. The pharmaceutical composition according to claim 1, A pharmaceutical composition for therapeutic use.
The method of claim 3,
Characterized in that the intermediate layer is at least one water-soluble polymer selected from the group consisting of hydroxypropylmethylcellulose (HPMC) carboxymethylcellulose (CMC), polyvinylalcohol, polyethylene glycol and hydroxypropylcellulose (HPC) ≪ / RTI >
delete The method according to claim 1,
The pharmaceutical composition for the treatment of diabetes, wherein the pharmaceutical composition for treating diabetes is orally administered.
The method according to claim 1,
A pharmaceutical composition for the treatment of diabetes, which comprises 250 mg to 1000 mg of metformin.
The method according to claim 1,
A pharmaceutical composition for the treatment of diabetes, which comprises 25 mg to 100 mg of said tenerigliptin.
i) preparing an inner layer comprising metformin,
ii) coating the inner layer surface with at least one water-soluble polymer selected from the group consisting of hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), polyethylene glycol and hydroxypropylcellulose (HPC) ,
iii) preparing an outer layer containing tenerigliptin on the surface of the intermediate layer
≪ RTI ID = 0.0 > 1. ≪ / RTI >

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