KR101750690B1 - Pharmaceutical composition comprising metformin and lobeglitazone - Google Patents

Abstract

The present invention provides a pharmaceutical composition comprising metformin or a pharmaceutically acceptable salt thereof and Lobeglitazone or a pharmaceutically acceptable salt thereof and a pharmaceutical preparation containing the same. The pharmaceutical composition of the present invention exhibits a synergistic effect of controlling blood sugar and inhibits the possibility of side effects, and the pharmaceutical preparation of the present invention provides a combination preparation which can be administered once a day to improve the compliance Effect.

Description

Metformin and < RTI ID = 0.0 > lobeglitazone < / RTI >

The present invention relates to a pharmaceutical composition comprising metformin and robeglitazone as an active ingredient.

Diabetes mellitus is a type of diabetes mellitus which can be divided into type 1 diabetes and type 2 diabetes. Of these, type 2 diabetes is a disease in which both insulin resistance (i.e., a state in which the responsiveness of a cell or tissue to insulin in a given insulin concentration is lower than normal) and an insulin secretion disorder due to a decrease in the? -Cell function of the pancreas, More than 85% of people with diabetes are adults with type 2 diabetes, and the number of people with type 2 diabetes is steadily increasing as lifestyle and obesity increase.

These type 2 diabetes develop hyperinsulinemia due to glucose intolerance and insulin resistance at the onset of illness, and then develop diseases such as hyperglycemia and hypothyroidism to be. Therefore, the selection of the appropriate drug to be effective in the stage of disease is very important for diabetes.

The oral hypoglycemic agents used for the treatment of diabetes include, but are not limited to, 1) insulin secretagogues (sulphonylating agent, non-sulphonylating agent), 2) biguanide drugs, 3) alpha-glucosidase inhibitors, 4) Drug, 5) DPP-IV inhibitor, and 6) SGLT-2 inhibitor.

Metformin, one of the biguanide-based drugs, is an oral drug used as a primary drug for the treatment of type 2 diabetes.

[Chemical Formula 1]

Metformin acts to increase the susceptibility to insulin in the peripheral tissues of the host and specifically includes inhibition of glucose uptake from the intestine, suppression of hepatic gluconeogenesis, It regulates blood sugar by being involved in inhibition of oxidation. Metformin's glycemic control mechanism is independent of insulin secretion, induces weight loss in diabetic patients, decreases blood triglyceride and low density lipoprotein, and increases high density lipoprotein. Therefore, it can be used as a primary drug for patients with type 2 diabetes with insulin resistance. Metformin, however, is known to have side effects such as anorexia, abdominal bloating, nausea and diarrhea in 20-30% of patients taking it. Most of them are temporary, and usually disappear after 2 to 3 weeks. However, if diarrhea or severe abdominal bloating are not lost, stop taking them. Rarely, skin rash and urticaria can occur. Such side effects can be improved by a method of using a slow release formulation that can reduce the minimum and / or sustained dose or reduce the number of doses.

On the other hand, the glitazone-based drug is a peroxisome proliferator activated receptor gamma agonist, which is expressed in adipocytes and promotes adipogenesis and glucose uptake. PPARgamma < / RTI > stimulates and enhances the susceptibility to insulin in the body. The glitazone drug is not a mechanism for promoting insulin secretion, so it is advantageous to protect the β-cells of the pancreas and improves insulin resistance, so that it is particularly effective for insulin resistant diabetics, maintains blood glucose for a long time, And is known to have a more potent therapeutic effect on early diabetes. These glitazone drugs are currently in the mainstream of drugs with thiazolidinedione (TZD) structures. However, it is known that glitazone-based drugs have a limitation in treatment with a single drug because the drug alone does not have a high anti-diabetic effect, and side effects such as edema and weight gain may occur depending on a person.

Among these glitazone drugs, Lobeglitazone is a drug developed by the present applicant, and its structural formula is shown in the following formula (2).

(2)

Robeglitazone not only has a stable molecular energy structure but also has a structural characteristic that best matches the active site pocket of PPARγ and has a high active activity, It is a drug that weakens blood lipid lowering effect which was pointed out as a disadvantage of drug.

Diabetes mellitus is very complicated and each diabetic drug has distinct advantages and disadvantages. Therefore, it is necessary to use two or more antidiabetic agents with different mechanisms of action Therapy has been prescribed many times in clinical practice. Such combination therapies may have a significant improvement in glycemic control as compared to monotherapy and may reduce the likelihood of multiple side effects caused by the administration of high doses of a single active ingredient. However, when two or more kinds of medicines are coadministered, there is a problem that the patient's compliance with medicines is poor. Accordingly, there is a continuing need to develop a combination preparation in which two or more active ingredients can be administered as one medicament .

Glitazone-based drugs are known to be effective when used in combination with other drugs of action. In particular, when glycemic control is insufficient, it can be administered in combination with metformin. European Patent Publication No. 0749751 discloses a combination preparation of pioglitazone and metformin as a combined preparation of a glitazone drug and metformin, and International Patent Publication No. WO 98/57634 discloses a combination preparation of rosiglitazone and metformin And a combination preparation thereof.

However, the combination of metformin with rovetyltazone, a novel glitazone drug, has not yet been specifically investigated for its therapeutic effect or side effects, and further shows its optimal dissolution pattern and can reduce administration frequency No combination formulations have been studied. Therefore, it is urgent to develop a pharmaceutical composition comprising metformin and robeglitazone and a pharmaceutical preparation thereof.

European Patent Publication No. 0749751 International Patent Publication No. WO 98/57634

It is an object of the present invention to provide a pharmaceutical composition comprising metformin and robeglitazone which exhibits excellent therapeutic activity against type 2 diabetes and related diseases and which can reduce side effects of a single active ingredient.

Another object of the present invention is to provide a pharmaceutical composition which is capable of sustained release of metformin and immediate release of robeglitazone, and which has PK data equivalent to that of a single preparation, and which has excellent physical stability and stability stability To provide a formulation.

In order to accomplish the object of the present invention, the present invention provides a pharmaceutical composition comprising metformin and robeglitazone, and a pharmaceutical preparation containing the same. Hereinafter, this will be described in more detail.

Metformin and Robeglitazon  The pharmaceutical composition comprising

The present invention provides a pharmaceutical composition comprising (A1) metformin or a pharmaceutically acceptable salt thereof, and (A2) robeglitazone or a pharmaceutically acceptable salt thereof as an active ingredient.

In the pharmaceutical composition of the present invention, metformin or its pharmaceutically acceptable salt (A1) used as an active ingredient and (A2) robeglitazone or a pharmaceutically acceptable salt thereof both do not promote insulin secretion Drugs that improve insulin resistance. Accordingly, the pharmaceutical composition of the present invention exhibits an effect of regulating blood sugar while maintaining the function of the pancreatic? -Cell.

The pharmaceutically acceptable salt of metformin is most preferably a hydrochloride, and the pharmaceutically acceptable salt of robeglitazone is most preferably a sulfate.

In the pharmaceutical composition of the present invention, (A1) metformin or a pharmaceutically acceptable salt thereof may be contained in an amount of 250 to 2000 mg, preferably 500 to 1000 mg. Further, (A2) robeglitazone or a pharmaceutically acceptable salt thereof may be contained in an amount of 0.1 to 2.0 mg, preferably 0.2 to 1.0 mg.

The pharmaceutical composition of the present invention can be administered concomitantly with (A1) metformin or a pharmaceutically acceptable salt thereof and (A2) robeglitazone or a pharmaceutically acceptable salt thereof, which is an insulin resistance improving agent of different mechanism of action And exhibits a synergistic effect on blood glucose control rather than administration of a single active ingredient. In addition, since the pharmaceutical composition of the present invention exhibits a synergistic effect by the combined administration, each active ingredient can be contained at a lower content, and the possibility of potential side effects at the time of high dose administration can be prevented.

Accordingly, the pharmaceutical composition of the present invention can be usefully used for the prevention or treatment of diabetes, particularly type 2 diabetes.

Metformin and Robeglitazon  Containing pharmaceutical preparations

The present invention also provides pharmaceutical preparations comprising (A1) metformin or a pharmaceutically acceptable salt thereof and (A2) robeglitazone or a pharmaceutically acceptable salt thereof.

Since metformin or its pharmaceutically acceptable salts are very well soluble in water, when they are formulated into general tablets, rapid release can cause excessive blood glucose lowering and can lead to gastrointestinal disorders. Also, because metformin or its pharmaceutically acceptable salt is administered in a high dose, a rapid change in blood concentration due to rapid release has a problem that adverse effects and tolerance to metformin are exacerbated. Furthermore, since the blood half-life of metformin is as short as 2 to 6 hours, it is necessary to release metformin or its pharmaceutically acceptable salt slowly.

On the other hand, robeglitazone or its pharmaceutically acceptable salt is poorly soluble, and when it is formulated in a conventional manner, the dissolution rate is lowered. Therefore, it is necessary to cause rapid release of robeglitazone or a pharmaceutically acceptable salt thereof.

In order to achieve such a pharmaceutical purpose, the pharmaceutical preparation of the present invention comprises a core layer comprising (L1) metformin or a pharmaceutically acceptable salt thereof as an active ingredient, and (L2) robeglitazone or a pharmaceutical composition thereof And an outer layer comprising an acceptable salt as an active ingredient.

In the present invention, metformin or its pharmaceutically acceptable salt as an active ingredient of the core layer may be contained in an amount of 250 to 2000 mg, preferably 500 to 1000 mg. Further, it is preferably present in an amount of 60 to 80% by weight based on the total weight of the core layer.

In addition, the core layer (L1) may contain a water-soluble polymer to release metformin or a pharmaceutically acceptable salt thereof in a sustained manner. The water-soluble polymer is selected from the group consisting of hydroxypropylmethylcellulose (e.g., hypromellose), hydroxypropylcellulose, ethylcellulose, methylcellulose, polyvinylpyrrolidone, polymethacrylate and mixtures thereof And it is most preferable to use hydroxypropyl methylcellulose. The water-soluble polymer is preferably present in an amount of 15 to 25% by weight based on the total weight of the core layer.

In the present invention, robeglitazone or its pharmaceutically acceptable salt, which is an active ingredient of the outer layer, may be contained in an amount of 0.1 to 2.0 mg, preferably 0.2 to 1.0 mg. Further, it is preferably present in an amount of 0.1 to 2.0% by weight based on the total weight of the outer layer.

In the present invention, since robeglitazone or a pharmaceutically acceptable salt thereof has a considerably low capacity, the outer layer (L2) containing it as an active ingredient may be a coating layer.

In addition, the outer layer (L2) may include a binder having a viscosity of 6 mPa.s or less to increase the coating yield of the outer layer. The binder may be one or more selected from the group consisting of hydroxypropylmethylcellulose, polyvinylpyrrolidone, lactose, and a mixture thereof, and hydroxypropylmethylcellulose or polyvinylpyrrolidone is preferable, It is not.

Further, according to a preferred embodiment of the present invention, the outer layer may include a plasticizer.

The plasticizer is most preferably triethyl citrate. The content of such a plasticizer is preferably about 2.5 to 15% by weight, preferably about 5 to 10% by weight based on the total weight of the outer layer.

According to one embodiment of the present invention, the inner layer and the outer layer may further include an inactive interlayer (L3) for separating them.

The intermediate layer may contain a binder and / or a plasticizer, and the binder and plasticizer used in the outer layer may be used as they are. However, the present invention is not limited thereto.

The pharmaceutical preparations of the present invention release metformin or a pharmaceutically acceptable salt thereof in a sustained-release manner, and can cause rapid release of robeglitazone or a pharmaceutically acceptable salt thereof, which is administered once a day for 24 hours , Maintain a constant blood concentration, and exhibit an excellent synergistic effect in the treatment of diabetes. In addition, the pharmaceutical preparation of the present invention is equivalent to the PK data when compared to the case where a single preparation of metformin or a pharmaceutically acceptable salt thereof is co-administered with a single preparation of robeglitazone or a pharmaceutically acceptable salt thereof.

The pharmaceutical preparation of the present invention may further comprise a pharmaceutically acceptable additive. The additive may be included in an amount of 5 to 90% by weight based on the total weight of the pharmaceutical preparation of the present invention. Examples of the additives include any of those commonly used in various formulations such as binders, disintegrants, lubricants, and the like, which are pharmaceutically acceptable.

The binder may be selected from the group consisting of polyvinylpyrrolidone (povidone), copolymers of vinylpyrrolidone and other vinyl derivatives (copovidone), microcrystalline cellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose and pregelatinized Starch, and hydroxypropylmethylcellulose or povidone are preferable.

The disintegrant can be selected from the group consisting of sodium croscarmellose (crosslinked carboxymethylcellulose sodium), sodium starch glycolate, crospovidone (crosslinked polyvinylpyrrolidone), corn starch, pregelatinized starch, low substituted hydroxypropyl Cellulose, and microcrystalline cellulose, with sodium glycolate and crospovidone being preferred.

The lubricant may be colloidal silicon dioxide, sodium stearyl fumarate or magnesium stearate, with magnesium stearate being preferred.

The pharmaceutical preparations of the present invention can be prepared by known techniques well known to those of ordinary skill in the art. First, a metformin composition which is sustained to provide a core layer (L1) comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient is prepared according to a wet granulation method and is tableted by an automatic tableting machine to form a tablet layer. Roveglitazone or a pharmaceutically acceptable salt thereof is dissolved in an appropriate solvent and stirred with a binder and a plasticizer to spray-dry the tablet. The coating can be carried out according to a conventional coating method, but it is preferable to coat the coating by water-based coating by a pan coating method used for tablet coating. That is, it is preferable to perform the coating while spraying the aqueous suspension of the binder. In this case, since the coating is carried out using an aqueous suspension without using an organic solvent, it may not cause problems such as environmental pollution due to the use of an organic solvent.

The pharmaceutical composition of the present invention exhibits a synergistic effect on diabetic therapeutic activity and can reduce side effects of a single active ingredient.

In addition, the pharmaceutical preparation of the present invention is capable of sustained release of metformin and immediate release of robeglitazone, and is equivalent to PK data when administered in combination with a single preparation, and has excellent physical stability and chemical stability.

1 is a graph showing the dissolution test results of paddle method (50 rpm, 37 캜) in pH 1.2 eluates of Examples 1, 5, 6 and 9.
FIG. 2 is a graph comparing blood concentrations of metformin in the case of administration of the combination composition of the present invention and the combination administration of the single agent of Comparative Examples 7 and 8. FIG.
FIG. 3 is a graph comparing the blood concentrations of robeglitazone in the case of administration of the combination composition of the present invention and the combination administration of the single preparations of Comparative Examples 7 and 8.

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples in order to facilitate understanding of the present invention. It should be understood, however, that the following examples and experimental examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The embodiments and experimental examples of the present invention are provided to enable those skilled in the art to more fully understand the present invention.

Example  1: Preparation of pharmaceutical preparations according to the invention

Step 1: A pharmaceutical composition comprising metformin or a pharmaceutically acceptable salt thereof nose Manufacture of fish layer

A granular mixture of metformin or a pharmaceutically acceptable salt thereof was prepared by the following preparation method with the composition of the following [Table 1].

[Table 1]

1) Preparation of granules

Metformin hydrochloride, Hypromellose 2208 and croscarmellose sodium were added and mixed. Purified water was added thereto and granulated, dried and fixed.

2) final mixing

The sized product of 1) was put into a mixer, and colloidal silicon dioxide and magnesium stearate were sieved and mixed, followed by mixing to prepare a final mixture.

3) Tablets

2) was tableted using an automated tablet machine (XP1, Korsch, Germany) to give a total weight of 1404 mg tablets (core layer).

Step 2: Intermediate layer coating

An intermediate layer was formed on the surface of the tablet (core layer) prepared in Step 1 through the following production method with the composition shown in Table 2 below.

[Table 2]

1) Preparation of spray liquid

The purified water, hypromellose 2910 and triethyl citrate were completely dissolved in a stirrer and used as a spray solution.

2) Coating of intermediate layer

The tablet (core layer) prepared in step 1 was placed in a coater (HC-LABO, FREUND, Germany), sprayed with 1), and dried to obtain a coating having a total weight of 1432 mg.

Step 3: Coating of outer layer comprising robeglitazone or a pharmaceutically acceptable salt thereof

The outer layer comprising robeglitazone or a pharmaceutically acceptable salt thereof was prepared by the following method with the composition shown in Table 3 below.

[Table 3]

1) Preparation of spray liquid

Purified water and robeglitazone sulfate, Hypromellose 2910 and triethyl citrate were added to a stirrer and completely dissolved and used as a spray solution.

2) coating of outer layer

The tablets prepared in Step 2 were placed in a coater (HC-LABO, FREUND, Germany), sprayed with 1), and dried to obtain tablets having a total weight of 1532 mg.

Examples 2 to 4, Comparative Example 1: Preparation of pharmaceutical preparations in which the viscosity of the binder contained in the outer layer was varied

To change the viscosity of the binder in the outer layer and to see the effect on yield loss or property, a pharmaceutical preparation was prepared by changing the viscosity of the binder used in Step 3 of Example 1 as shown in Table 4 below.

[Table 4]

Example  5 to 7: Preparation of pharmaceutical preparations having different types of binders contained in the outer layer

To determine the type and content of the binder for the preferred dissolution profile of the drug, the pharmaceutical formulation was prepared by varying the type of binder used in step 3 of Example 1, as shown in Table 5 below.

[Table 5]

Comparative Example  2 and 3: Preparation of Pharmaceutical Preparations Having Different Types of Plasticizers Contained in the Outer Layer

To examine the effect of drug stability on the type of plasticizer in the outer layer, a pharmaceutical preparation was prepared by varying the type of plasticizer used in step 3 of Example 1, as shown in Table 6 below.

[Table 6]

Example  8 and 9, Comparative Example  4 to 6: Preparation of pharmaceutical preparations in which the content of plasticizer contained in the outer layer was varied

To examine the influence of the plasticizer content of the outer layer, the pharmaceutical preparation was prepared by varying the amount of the plasticizer used in Step 3 of Example 1 as shown in Table 7 below.

[Table 7]

Comparative Example  7 and 8: metformin or Robeglitazon  A single composition comprising as active ingredient

As a composition containing metformin hydrochloride, 1000 mg of Glucophage xerosan manufactured and sold by Merck was used (Comparative Example 7). In addition, as a composition containing robeglitazone sulfate, 0.5 mg of DUBIEA manufactured and sold by the present applicant (Chong Kun Dang) was used (Comparative Example 8).

Experimental Example 1: Measurement of content of the composite composition according to the present invention

1) Experimental method

The content of metformin and robeglitazone in Example 1, which is a pharmaceutical preparation according to the present invention, was measured. The measurement method is as follows.

end. Metformin content test

- Detector: Ultraviolet absorptiometer (measuring wavelength: 255 nm)

- Column: C18 (4.6 mm x 250 mm, 5 m)

- Mobile phase: Phosphoric acid was added to a mixed solution of 10 mM ammonium phosphate solution and acetonitrile (700: 300) and adjusted to pH 3.0

- Flow rate: 1.0 mL / min

- Column temperature: 30 ° C

- Sample temperature: 25 ° C

I. Robeglitazone content test method

- Detector: Ultraviolet absorptiometer (measuring wavelength: 250 nm)

- Column: C18 (4.6 mm x 250 mm, 5 m)

- mobile phase: 50 mM ammonium acetate (pH 5.0) buffer / acetonitrile = 50/40

- Flow rate: 1.5 mL / min

- Column temperature: 40 ° C

- Sample temperature: 25 ° C

2) Experimental results

When the contents of metformin and robeglitazone in Example 1 were measured, metformin and robeglitazone were found to be about 98% and 99%, respectively, as shown in Table 8 below. This is an appropriate value for the content of the composite composition of 90 to 110%, indicating that the tablet preparation and coating process were properly performed.

[Table 8]

Experimental Example  2: Confirmation of the pharmacological effect of the composite composition of the present invention

1) Experimental method

In order to confirm the pharmacological effect of the composite composition of the present invention, a clinical trial was conducted on a rogiglitazone composition as a test drug, a pioglitazone composition as a comparator, a metformin composition as a concomitant drug, and a placebo of robeglitazone and pioglitazone composition as a placebo . This study was designed as a multicenter, randomized, double-blind, parallel, active control group and 253 subjects were evaluated for efficacy and safety when combined with metformin in combination with robeglitazone or pioglitazone for approximately 2 years.

2) Experimental results

- Results on effectiveness

The primary objective of this study was to compare the changes in HbA1c after 24 weeks from the baseline in HbA1c to HbA1c compared to the administration of pioglitazone and metformin in the doses of robeglitazone and metformin, It is to prove that the reduction effect is non-thermal.

As a result, the difference in the amount of change between the two treatment groups was found to be inferior, indicating that the lower limit of the confidence interval was -0.16, which is greater than the non-inferiority tolerance limit of -0.4. Secondary efficacy was assessed by glycemic parameters and lipid parameters. The results of the Glycemic parameters showed that administration of the robeglitazone composition improves effective blood glucose control and insulin function. These results are similar to those of the pioglitazone composition administration group. In the lipid paramerters, total cholesterol and LDL-C showed a tendency to increase significantly in both the rovagitazone composition administration group and the pioglitazone composition administration group. Triglycerides were significantly decreased in both treatment groups, and HDL-C, LDL-C, and FFA were significantly improved.

- Safety results

Overall adverse events occurred in 51.38% of the subjects, with 5.53% of abnormal drug reactions and 5.14% of serious adverse events. Most adverse events occurred in the same drug and no other adverse events were reported. All major adverse events were not associated with clinical drugs. There was no statistically significant difference in the overall incidence of adverse reactions, adverse reactions, and overall incidence in each of the two treatment groups in most of the overall adverse events, adverse drug reactions, and serious adverse events. There were no significant differences between the baseline and the treatment groups, especially regarding the risk factors such as liver failure, fat accumulation, blood sedimentation and congestive heart failure, which are known to occur in thiazolidinediones.

Experimental Example 3: Confirmation of influence of viscosity of binder contained in outer layer

The viscosity of the coating solution varies depending on the viscosity of the binder used in the outer layer coating, which affects the coating yield and the properties of the coating. In order to confirm this, an experiment was carried out to investigate the effect of binder viscosity.

1) Experimental method

The viscosity of the binder contained in the coating liquid for the outer layer was varied from 3 mPa.s to 15 mPa.s to obtain the preparations of Examples 1 to 4 and Comparative Example 1. [ After coating, the coating yield and properties were determined. Appearance was observed with a microscope (Digital microscope KH-7700, HIROX, Japan).

2) Experimental results

The preparations of Examples 1 to 4 were uniformly coated, and the preparations of Comparative Example 1 were observed to be partially clumped or adhered to tablets. The yield results shown in Table 9 below were also affected thereby, and the yield of Comparative Example 1 was as low as 88% at the lowest. On the other hand, Examples 1 to 4 show a remarkably better yield than Comparative Example 1, but the lower the viscosity of the hyphromellose, the higher the yield.

[Table 9]

Experimental Example  4: Confirm the influence of the type of binder contained in the outer layer

1) Experimental method

In order to examine the influence of the dissolution rate on the type of binder contained in the outer layer of the pharmaceutical preparation according to the present invention, the dissolution rate of robeglitazone in the pH 1.2 eluate of the preparations of Examples 1, 5, 6 and 7 Respectively. The dissolution test method is as follows.

- eluent: pH 1.2

- Elution: paddle method (50 rpm)

- Leaching temperature: 37 ℃

The method of measuring the test solution of the above method is as follows.

- Detector: Ultraviolet absorptiometer (measuring wavelength: 250 nm)

- Column: C18 (4.6 mm x 250 mm, 5 m)

- mobile phase: 50 mM ammonium acetate (pH 5.0) buffer / acetonitrile = 50/40

- Flow rate: 1.5 mL / min

- Column temperature: 40 ° C

- Sample temperature: 25 ° C

2) Experimental results

The dissolution rates in the pH 1.2 eluates of Examples 1, 5, 6 and 7 are shown in Table 10 below and Fig. In Example 1 in which heptamelose alone was used as a coupling agent, elution of 5 minutes hardly occurred. In Examples 5 and 6 in which the content of hypromellose was reduced and lactose hydrate or povidone was used, the initial dissolution rate was improved. It was confirmed that the initial dissolution rate was significantly improved in Example 7 including both hypromellose, lactose hydrate and povidone.

[Table 10]

Experimental Example  5: Composite composition of the present invention Comparative Example  Pharmacokinetic studies of single preparations of 7 and 8

1) Experimental method

Pharmacokinetic tests (PK tests) were performed upon single doses of the combination compositions of the present invention and the single preparations of Comparative Examples 7 and 8 to assess bioequivalence with co-administration. That is, oral administration of the composite composition to healthy male volunteers, or oral administration of a single preparation of Comparative Examples 7 and 8 was performed. Blood samples were collected at the same time after single administration, and blood concentrations of robeglitazone and metformin were quantified using LC-MS / MS, respectively. After quantification, the AUC and Cmax values of roveglitazone and metformin in the combination composition and the oral administration of Comparative Examples 6 and 7 were log-transformed and then the geometric mean was calculated and a 90% confidence interval for the ratio of the geometric mean was calculated. If the 90% confidence interval is between 0.8 and 1.25, both agents are considered to be biologically equivalent.

- Test drug: Roveglitazone and metformin combination composition 0.5 / 1000 mg (Example 7)

- Control drug (1): 1000 mg of Glucophage xeroside (Comparative Example 7)

- Control drug (2): 0.5 mg tablets (Comparative Example 8)

2) Experimental results

The results of the bioequivalence evaluation as described above are shown in Table 11 and Table 12 below. The geometric mean of the RVEGA and metformin AUC and Cmax values was in the range of 0.8 to 1.25 with a 90% confidence interval in the range of 0.8 to 1.25 to ensure PK equivalency in the combined composition and the oral administration of Comparative Examples 6 and 7 (Figures 2 and 7) 3).

[Table 11]

[Table 12]

Experimental Example  6: Confirm the effect of the type of plasticizer contained in the outer layer

1) Experimental method

In order to examine the stability effects of the plasticizers contained in the outer layer of the pharmaceutical preparation according to the present invention, the formulations of Example 1, Comparative Examples 2 and 3 were subjected to an accelerated condition (40 DEG C, 75% RH) The decomposition products of robeglitazone were measured after being kept sealed in a bottle and kept in a sealed state in an HDPE bottle for 2 weeks under severe conditions (60 ° C). The measurement method is as follows.

- Detector: Ultraviolet absorptiometer (measuring wavelength: 250 nm)

- Column: C18 (4.6 mm x 250 mm, 5 m)

- Mobile phase: A-50 mM ammonium acetate (pH 5.0) buffer, B-acetonitrile

The concentration gradient is as follows

- Flow rate: 0.8 mL / min

- Column temperature: 40 ° C

- Sample temperature: 25 ° C

2) Experimental results

(%) Of roveglitazone were measured under the conditions of accelerated and harsh conditions, and the acceleration conditions were the results of [Table 13], [Table 14] and [Table 15] ], Respectively.

As shown in Table 15 below, in Example 1, the amount of the flexible material did not significantly increase until 8 weeks of acceleration, and the results were appropriate. On the other hand, in Comparative Examples 2 and 3, as shown in [Table 14] and [Table 15], the increase in individual unknown values was significant from the beginning to the 8th week of acceleration, . The results of the severe storage 1 week shown in Table 16 below also showed that the Example 1 had a very low value of the flexural value as compared with Comparative Examples 2 and 3. Therefore, it is confirmed that triethyl citrate is preferable as a plasticizer for drug stability of the outer layer.

[Table 13]

[Table 14]

[Table 15]

[Table 16]

Experimental Example 7: Determination of Effect of Amount of Plasticizer Contained in Outer Layer

Experiments were conducted to investigate the effect of the amount of plasticizer used in outer layer coating.

1) Experimental method

(10.00 wt%), Example 8 (5.00 wt%), Example 9 (7.501 wt%) and Comparative Example 4 (2.50 wt%) were controlled by adjusting the amount of triethyl citrate as a plasticizer contained in the outer layer coating solution. ), Comparative Example 5 (12.50 wt%), and Comparative Example 6 (15.00 wt%). After coating, the coating yield, properties, hardness and stability were selected. The properties were observed with a microscope (Digital microscope KH-7700, HIROX, Japan) and ten tablets were measured with a hardness tester (PTP-411, Pharma-Test, Germany) in each example or comparative example.

In the stability test, degradation products of robeglitazone were measured in sealed state in HDPE bottles for 8 weeks under accelerated conditions (40 ° C., 75% RH) and in sealed state in HDPE bottles for 2 weeks in harsh conditions (60 ° C.). The measurement method is the same as in Experimental Example 4.

2) Experimental results

The stability test results showed no significant difference as shown in [Table 17] and [Table 18] below.

However, observation of the properties of the final tablet of Comparative Example 4 through a microscope revealed that the surface of the tablets was wrinkled, and the surface of the final tablets of Comparative Example 5 and Comparative Example 6 was not smooth. In addition, the average hardness measurement results shown in Table 19 below also showed a significant difference in hardness. Therefore, it is preferable that triethyl citrate is contained in an amount of 5 to 10% by weight based on the total weight of the outer layer in consideration of the property and hardness.

[Table 17]

[Table 18]

[Table 19]

Claims (15)

delete delete delete A core layer comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient; And
An outer layer comprising robeglitazone or a pharmaceutically acceptable salt thereof as an active ingredient;
≪ RTI ID = 0.0 >
Wherein the outer layer comprises a binder having a viscosity of 6 mPa.s or less and comprises triethyl citrate as a plasticizer. 5. The pharmaceutical preparation according to claim 4, wherein metformin or a pharmaceutically acceptable salt thereof is present in an amount of 60 to 80% by weight based on the total weight of the core layer. 5. The pharmaceutical preparation according to claim 4, wherein the core layer comprises a water-soluble polymer. The pharmaceutical composition according to claim 6, wherein the water-soluble polymer is selected from the group consisting of hydroxypropylmethylcellulose, ethylcellulose, methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polymethacrylate, Formulation. The pharmaceutical preparation according to claim 6, wherein the water-soluble polymer is present in an amount of 15 to 25% by weight based on the total weight of the core layer. 5. The pharmaceutical preparation according to claim 4, wherein the robeglitazone or a pharmaceutically acceptable salt thereof is present in an amount of 0.1 to 2.0% by weight based on the total weight of the outer layer. delete 5. The pharmaceutical formulation according to claim 4, wherein the binder is selected from the group consisting of hydroxypropylmethylcellulose, polyvinylpyrrolidone, lactose, and mixtures thereof. delete delete 5. The pharmaceutical preparation according to claim 4, wherein the triethyl citrate is present in an amount of 5 to 10% by weight based on the total weight of the outer layer. 5. The pharmaceutical preparation according to claim 4, further comprising an inert intermediate layer between the core layer and the outer layer.

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