KR20160111237A - An oral composite formulation containing metformin and sitagliptin - Google Patents

Abstract

Provided is a composite preparation which includes: a sustained-release layer including metformin or a pharmaceutically acceptable salt thereof and a sustained-release carrier; and an immediate release layer including sitagliptin or a pharmaceutically acceptable salt thereof. Also, provided is a production method thereof. According to the present invention, the composite preparation contains both metformin-containing sustained-release layer and the sitagliptin-containing immediate release layer in a single preparation, thereby reducing side effects and providing long-lasting effects of metformin owing to sustained-release properties of metformin.

Description

An oral composite formulation containing metformin and sitagliptin comprising metformin and < RTI ID = 0.0 >

The present invention relates to an oral combination preparation comprising metformin and citalogliptin as an active ingredient and more particularly to a composition for oral administration comprising metformin and citalogliptin, And a method for preparing the same.

Metformin is a drug for the treatment of biguanide type diabetes mellitus and is an oral drug and a blood sugar drug mainly used for the treatment of patients with type 2 diabetes. Metformin's glycemic control mechanism is independent of insulin secretion and is known to activate glucose transporters in the liver, for example. Metformin induces weight loss in diabetic patients, decreases blood triglyceride and low density lipoprotein and increases the effect of high density lipoprotein. Therefore, it can be used as a primary drug in non-insulin dependent diabetic patients showing insulin resistance.

Currently, metformin is commercially available as a tablet of GLUCOPHAGE (Bristol-Myers Squibb Company) as its hydrochloride salt. Commercially available glucophage tablets contain 500 mg, 850 mg, or 1000 mg of metformin hydrochloride and their administration is within a range that does not exceed the maximum required dose of 2550 mg per day in view of both efficacy and tolerance . The side effects associated with the use of metformin are anorexia, abdominal bloating, nausea and diarrhea in 20 to 30% of patients who are taking it, and most of them are temporarily lost and disappear after 2 to 3 weeks after taking them. If diarrhea or severe abdominal bloating is not gone, stop taking it. Rarely, skin rash and urticaria can occur. This side effect can be partially avoided by using a slow release formulation that can reduce the minimum and / or sustained dose or reduce the number of doses.

Dipeptidyl peptidase-IV (DPP-4) inhibitor is a new class of drugs developed for the treatment of type 2 diabetes patients or for the improvement of blood glucose control. DPP-4 inhibitors that have already been marketed or are being clinically tested for the treatment of type 2 diabetes include sitagliptin, birdagliptin, saxagliptin, and meloglyptin. For example, it has been known that oral administration of sitagliptin to patients with type 2 diabetes significantly reduces HbA1c levels and decreases fasting glucose and postprandial blood glucose secretion.

Citagliptin and metformin have been shown to have substantial and ad hoc glucose-lowering effects in patients with type 2 diabetes, and a combination composition for the treatment of diabetes comprising citagliptin and metformin has been reported (Patent Document 1). Also, adult patients with type 2 diabetes mellitus comprising 50 mg of cyproglitine and 500 or 10000 mg of metformin and all of which exhibit rapid response are not adequately controlled by metformin or cetagliptin alone, or adult patients with imitargillin and metformin For patients undergoing combined treatment, the product is marketed as JANUMET in several countries including the United States, Europe and Mexico.

Further studies have been made on metformin or citalogliptin-containing complex agents, and a complex agent containing metformin as a sustained core and citergliptin as an immediate-release coating layer has been reported (Patent Document 2). However, the combined preparation can sustain the sustained release of metformin and the immediate release of the citagliptin, but the stability of the active ingredient may be lowered and the uniformity of the content of the citagliptin may be lowered.

WO2007 / 078726 US 2010/0330177

It is an object of the present invention to provide an oral combination preparation of metformin and citagliptin, which is capable of achieving sustained release of metformin, immediate release of citagliptin, and high stability of active ingredient and uniformity of content of citagliptin.

It is another object of the present invention to provide a process for preparing the combined oral dosage form of metformin and citriptyline.

One aspect of the present invention is

Metformin or a pharmaceutically acceptable salt thereof, and a sustained release carrier; And

Or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

In another aspect of the present invention,

Metformin or a pharmaceutically acceptable salt thereof, and metformin granules containing a sustained release carrier;

Preparing a citagliptin granulate comprising sitagliptin or a pharmaceutically acceptable salt thereof; And

And tableting the metformin granule and the citagliptin granule by using a two-layer tablet machine. The present invention also provides a method for producing a combination preparation for oral use according to one aspect of the present invention.

The combined oral preparation according to the present invention may include both a metformin-containing sustained-release layer and a citergliptin-containing immediate-release layer in one preparation to achieve a sustained effect and side effect improvement of metformin due to sustained release of metformin, Because the blood glucose level can be improved immediately by the quick action of the blood glucose level. In addition, compared with the conventional controlled-release combination preparation, the storage stability of the active ingredient is remarkably high, and the content uniformity of cyproglitine is improved, which is advantageous from a pharmaceutical point of view.

FIG. 1 shows the results of dissolution test at 75 rpm in a second solution of pH 6.8 using a sinker in a USP paddle for the preparation of Example 1 and Comparative Examples 1 and 2. As a result, the dissolution rate of citriptyltin was measured Fig.
FIG. 2 shows the dissolution rate of each metformin measured over time as a result of a dissolution test at 75 rpm in a second liquid at pH 6.8 using a sinker in a USP paddle for the preparation of Example 1 and Comparative Examples 1 and 2 Fig.
Fig. 3 shows the results of measuring the amounts of the individual maximum softening substances at 1, 2, and 4 weeks after storage in an HDPE bottle under the conditions of sealing at 60 DEG C for the preparations of Example 1 and Comparative Examples 1 and 2 Graph.
FIG. 4 is a graph showing the results of measurement of the total amount of the flexible substances in the first, second and fourth weeks after sealing the HDPE bottle under the conditions of sealing at 60 ° C for the preparation of Example 1 and Comparative Examples 1 and 2 to be.

All technical terms used in the present invention are used in the sense that they are generally understood by those of ordinary skill in the relevant field of the present invention unless otherwise defined. In addition, preferred methods or samples are described in this specification, but similar or equivalent ones are also included in the scope of the present invention. The contents of all publications referred to in this specification are incorporated herein by reference in their entirety.

One aspect of the present invention is

Metformin or a pharmaceutically acceptable salt thereof, and a sustained release carrier; And

Or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

The oral combination preparation may be in the form of a two-layer tablet comprising a sustained-release layer and a immediate-release layer. Hereinafter, the oral combination preparation is classified into a sustained-release layer, a immediate-release layer, do.

(i)

The sustained release layer may contain metformin or a pharmaceutically acceptable salt thereof, and a sustained release carrier.

Pharmaceutically acceptable salts of metformin include pharmaceutically acceptable acid addition salts, including, but not limited to, hydrochloride, succinate, or fumarate. In one embodiment, the pharmaceutically acceptable salt of metformin is metformin hydrochloride.

The combined preparation may contain about 500 to 1,000 mg of metformin hydrochloride per unit dosage form, for example, 500 mg, 750 mg, 850 mg, or 1,000 mg per unit dosage form.

The sustained release layer may be formed by tableting granules of a mixture comprising metformin or a pharmaceutically acceptable salt thereof and a sustained release carrier, wherein the granules comprise dry granules or wet granules. In one embodiment, the granulate is a wet granulate, which is preferred in terms of stability in tableting with wet granules. Dry granules may cause problems such as breakage of tablets when tableted.

The sustained release carrier may be any sustained release carrier as is known in the art. The sustained release carrier may be, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, polyethylene oxide, guar gum, locust bean gum, xanthan gum, glyceryl distearate, sodium Carboxymethylcellulose, polyvinylpyrrolidone, and any combination thereof. In one embodiment, the sustained release carrier is a combination of hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose 2910, and locust bean gum.

The sustained release carrier may be contained in an amount of 10 to 50 parts by weight, specifically about 20 to 40 parts by weight, based on 100 parts by weight of metformin or a pharmaceutically acceptable salt thereof.

The sustained release layer may further comprise a pharmaceutically acceptable additive selected from the group consisting of diluents, lubricants, and mixtures thereof.

The diluent may be selected from the group consisting of microcrystalline cellulose, anhydrous calcium phosphate, mannitol, sucrose, lactose, sorbitol, xylitol, glucose, and any combination thereof, but is not limited thereto. The diluent may be contained in an amount of 20 to 70 parts by weight based on 100 parts by weight of metformin or a pharmaceutically acceptable salt thereof.

The lubricant may be selected from the group consisting of calcium stearate, fumed silica (Aerosil), glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, But are not limited to, acids, hardened vegetable oils, polyethylene glycols, sodium benzoate, talc, and any combination thereof. In one embodiment, the lubricant is magnesium stearate and / or colloidal silica (fumed silica, Aerosil). The glidant may be contained in an amount of 0.1 to 10 parts by weight based on 100 parts by weight of metformin or a pharmaceutically acceptable salt thereof.

(ii)

The immediate-release layer contains cytarglytine or a pharmaceutically acceptable salt thereof as an active ingredient.

The pharmaceutically acceptable salts of the said gentagliptin include pharmaceutically acceptable acid addition salts. In one embodiment, the pharmaceutically acceptable salt of sitagliptin is citagliptin phosphate and the citagliptin phosphate is preferably citagliptin phosphate monohydrate as disclosed in US 7,326,708.

Methods for the preparation of the foregoing cytglyptin and pharmaceutically acceptable salts thereof are known in the art and are disclosed, for example, in US 6,699,871. Methods for making the citriptyline phosphate monohydrate are known in the art and are disclosed in US 7,326,708.

The combined preparation may contain about 25 to 100 mg of citraglitine free base anhydride per unit dosage form. In one embodiment, it contains 25 mg, 50 mg, or 100 mg per unit dosage, corresponding to 32.125, 64.25, or 128.5 mg of citraglitine phosphate monohydrate, respectively.

The immediate-release layer may be formed by tableting granules of a mixture comprising citagliptin or a pharmaceutically acceptable salt thereof, wherein the granules comprise dry granules or wet granules. In one embodiment, the granules are wet granules.

In addition to the active ingredient, the immediate-release layer may additionally comprise any pharmaceutically acceptable additive known in the art for the manufacture of the granules. The pharmaceutically acceptable excipient may be selected from the group consisting of plasticizers, dispersants, diluents, disintegrants, lubricants, and any combination thereof.

The plasticizer may be selected from the group consisting of polyethylene glycol, glycerin, stearic acid, silica, dimethicone, concentrated glycerin, propylene glycol, and any combination thereof, but is not limited thereto. In one embodiment, the plasticizer is PEG 6000. The plasticizer may be contained in an amount of 1 to 30 parts by weight based on 100 parts by weight of citriptyline or a pharmaceutically acceptable salt thereof.

The dispersing agent may be selected from the group consisting of kaolin, aluminum oxide, titanium oxide, sorbitan sesquiole, silicone resin, gum arabic, ethylcellulose, calcium carbonate, bentonite, carbomer and any combination thereof no. In one embodiment, the dispersing agent is kaolin. The dispersing agent may be contained in an amount of 5 to 30 parts by weight based on 100 parts by weight of citriptyline or a pharmaceutically acceptable salt thereof.

The diluent may be selected from the group consisting of microcrystalline cellulose, anhydrous calcium phosphate, mannitol, sucrose, lactose, sorbitol, xylitol, glucose, and mixtures thereof, but is not limited thereto. In one embodiment, the diluent is microcrystalline cellulose and / or anhydrous calcium hydrogen phosphate. The diluent may be contained in an amount of 20 to 70 parts by weight based on 100 parts by weight of citriptyline or a pharmaceutically acceptable salt thereof.

The disintegrant may be selected from the group consisting of alginic acid, sodium alginate, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, crospovidone, pregelatinized starch, starch glycolic acid sodium, starch and mixtures thereof However, the present invention is not limited thereto. In one embodiment, the disintegrant is croscarmellose sodium. The disintegrant may be contained in an amount of 1 to 10 parts by weight based on 100 parts by weight of sitagliptin or a pharmaceutically acceptable salt thereof.

The lubricant may be selected from the group consisting of calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulphate, sodium stearyl fumarate, zinc stearate, stearic acid, cured vegetable oil, polyethylene glycol, Sodium, talc, and mixtures thereof, but is not limited thereto. In one embodiment, the lubricant is magnesium stearate. The glidant may be contained in an amount of 1 to 10 parts by weight based on 100 parts by weight of citriptyline or a pharmaceutically acceptable salt thereof.

(iii)

Wherein the two-layer tablet comprises a granulate of the mixture comprising metformin or a pharmaceutically acceptable salt thereof and a sustained release carrier as a first layer (the sustained release layer), and comprising citriptyline or a pharmaceutically acceptable salt thereof And granulating the mixture into a second layer (the inner layer) and compressing it into a two-layered form.

The two-layer tablet contains both a metformin-containing sustained-release layer and a cytargyline-containing sustained-release layer in one preparation, and the sustained effect of metformin and the adverse effects of metformin can be improved due to the sustained release of metformin. (See Experimental Example 1).

In one embodiment, the two-layered tablet has a dissolution rate of 90% or more of citagliptin over 60 minutes in a dissolution test at 75 rpm in an aqueous buffer at 37 ± 0.5 ° C, pH 6.8 according to the second-law paddle method according to USP (USP) , And metformin 5 - 15%.

The two-layer tablet minimizes the contact between the active ingredient of the slow-release layer and the active ingredient of the immediate-release layer, thereby improving the storage stability of the active ingredient. As a result of the test, the two-layer tablet according to one embodiment of the present invention had sustained release of metformin similar to that of the conventional controlled-release combination preparation including core and coating layer and quick release of citaloglitine (Experimental Example 1) (Experimental Example 2). ≪ tb > < TABLE > In addition, the bilayer tablet contains citagliptin as an independent layer, which is far superior to the conventional controlled-release combination formulation comprising citagliptin as a coating layer in terms of uniformity of content.

Accordingly, the oral combination preparation according to the present invention has a sustained release of metformin similar to that of the conventional controlled-release combination preparation and a rapid release of citagliptin, but the storage stability of the active ingredient is lower than that of the conventional controlled-release combination preparation And the content uniformity of cyproglitine is improved, which is advantageous in terms of pharmaceuticals.

In one embodiment, the binocular is less than or equal to about 0.3% by weight of the total content of the citagliptin flux when the combination formulation is stored for 4 weeks at about 60 ° C and about 75% relative humidity.

The two-layer tablet may further include a film coating layer on the outer surface. The film coating layer may comprise any film coating agent and colorant exhibiting a quick release. The film coating agent includes, but is not limited to, a mixture of HPC and HPMC, or a mixture of polyvinyl alcohol (PVA) and PEG (polyethylene glycol). Examples of the coloring agent include titanium dioxide, iron oxide, and the like, but are not limited thereto. Representative commercially available film coatings include Opadry. The film coating layer may play a role of shielding the taste and impart stability to the final composite preparation.

The two-layered tablet may be used for the treatment of adult patients with type 2 diabetes mellitus or those who are under the combined treatment of imitagliptin and metformin, which are not adequately controlled by metformin or citalogliptin alone. The two-layer tablet may be administered once a day, twice a day, three times a day, or four times a day.

In another aspect of the present invention,

Metformin or a pharmaceutically acceptable salt thereof, and metformin granules containing a sustained release carrier; And

Preparing a citagliptin granulate comprising sitagliptin or a pharmaceutically acceptable salt thereof; And

And tableting the metformin granule and the citagliptin granule using a two-layer tablet machine. The present invention also provides a method for producing the oral combination preparation according to the present invention.

The details of the method for preparing the combined preparation may be applied to the combined preparation according to one aspect of the present invention.

The step of each step involved in the method for producing the complex preparation can be carried out according to a conventional two-layered tablet manufacturing process performed in the art.

[Example]

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example 1: Preparation of two-layer tablets of metformin and cetagliptin

A two-layer tablet of metformin and citagliptin was prepared according to the composition of Example 1 of Table 1 below. Specifically, the metformin moiety and the cytogliptin moiety were mixed except for the magnesium stearate with a high-speed mixer (Sejong, Korea; Agitator 126 ± 10 rpm, Chopper 3000 ± 300 rpm, (S-Mg) was added as a lubricant, and then the mixture was subjected to post-mixing with a column blender, respectively, To obtain granules. Next, metformin granules obtained by using a two-layer tablet machine (Synthesis 700, Kilian, Germany) as the first layer and the second granules of the citagliptin granules as the second layer were tableted in a double layer tablet, and 1000 mg of metformin hydrochloride and citriptyl phosphate 0.0 > mg < / RTI > monohydrate.

Comparative Example 1: Preparation of single-layer tablets of a mixture of citagliptin and metformin

A single layer tablet of a mixture of metformin and citergliptin was prepared according to the composition of Comparative Example 1 in Table 1 below. Specifically, wet granulation was carried out using a high speed mixer (Sejong, Korea; Agitator 126 ± 10 rpm, Chopper 3000 ± 300 rpm, combined time 2 ± 1 min) , Magnesium stearate (S-Mg) was added as a lubricant, and the mixture was then mixed with a column blender to obtain granules. Then, the resulting granules were tableted using a tablet machine (SF-100, Bosch, Germany) to prepare tablet formulations.

Comparative Example 2: Preparation of Tablets with Metformin Core and Citergliptin-Containing Drug Coating Layer

After the metformin core was prepared according to the composition shown in Table 1, the tablets were coated with the citagliptin drug on the core to prepare tablets. Specifically, the metformin portion was wet granulated with a high speed mixer (Sejong, Korea; Agitator 126 ± 10 rpm, Chopper 3000 ± 300 rpm, combined time 2 ± 1 min) 10 ° C), magnesium stearate (S-Mg) was added as a lubricant, and the mixture was post-mixed with a column blender to obtain granules. The obtained metformin granules were then tableted using a tablet machine (SF-100, Bosch, Germany) to prepare a core tablet. The citriptyline coating solution prepared by dissolving the components of the citagliptin moiety in Table 1 in purified water was coated on the metformin core.

[Table 1]

Experimental Example 1: Elution test

The tablets of Example 1 and Comparative Examples 1 and 2 were subjected to a dissolution test using a sinker in a USP paddle at 900 rpm in a second liquid (pH 6.8) at 75 rpm. The results are shown in Table 4 and FIG. 1 and FIG. 2.

<Preparation of Standard Solution>

Approximately 36 mg of Citiglitine Phosphate Monohydrate Standard is precisely weighed and dissolved in the mobile phase, and the mobile phase is added to make exactly 25 mL. Take exactly 5 mL of this solution, add mobile phase to make 50 mL, and filter through a 0.45 ㎛ membrane filter to give a standard solution.

Approximately 28 mg of metformin hydrochloride standard is precisely weighed and dissolved in the mobile phase, and the mobile phase is added to make exactly 25 mL. The solution is filtered through a 0.45 ㎛ membrane filter to prepare a standard solution.

&Lt; HPLC Measurement Condition >

(1) Citigliptine Phosphate Monohydrate

10 μL of the standard solution and the test solution are subjected to the liquid chromatographic method under the conditions shown in Table 2 below.

[Table 2]

(2) Metformin hydrochloride

5 μL of the standard solution and the test solution are subjected to the liquid chromatographic method under the conditions shown in Table 3 below.

[Table 3]

[Table 4]

As shown in Table 4, FIG. 1 and FIG. 2, when the citriptyline portion and the metformin portion are present in a mixed state without being separated into separate layers as in Comparative Example 1, release of sitagliptin is accelerated .

Experimental Example 2: Evaluation of stability

The formulations of Example 1 and Comparative Examples 1 and 2 were sealed in HDPE (High-Density PolyEthylene) bottles and stored under the conditions of 60 ° C and 75% relative humidity, respectively, and after 1, 2 and 4 weeks, The amount of cyproglitin was determined by analytical method.

(One) Preparation of test solution

Take 5 tablets of each of the formulations of Example 1 and Comparative Examples 1 and 2, put them in a 1000-mL volumetric flask, align with the dilution to the marking, and use an automatic stirrer to stir well until the sample is completely dissolved. Take 4 mL of this solution, place it in a 25 mL volumetric flask, adjust to the mark with a diluted solution, and filter it through a 0.45 ㎛ membrane filter to prepare a sample solution.

(2) Preparation of standard solution

Approximately 13 mg of citriptylphosphate phosphate hydrate standard product is taken in a 100-mL volumetric flask and dissolved in diluted solution. The solution is adjusted to the indicated line with a dilution solution and filtered through a 0.45 ㎛ membrane filter to prepare a standard solution.

Diluent: 0.1% v / v phosphoric acid: acetonitrile = 19: 1 v / v

(3) Operation and calculation

20 μL of the standard solution and the test solution are subjected to the liquid chromatographic method under the conditions shown in Table 5 below.

[Table 5]

(4) Result of flexible material measurement

The amounts of the flexible substances produced from the formulations of Example 1 and Comparative Examples 1 and 2 were classified into the flexible substance I (the flexible substance having the largest area among the flexible substance peaks) and the total flexible substance, 4 (unit: wt%).

[Table 6]

As shown in Table 6, FIG. 3 and FIG. 4, peaks of the individual flexible substances versus the main component peak area and the total flexible substances were observed in the order of the first, first, second and fourth weeks, And the preparation of Comparative Example 1 were significantly less in amount of the flexible substance than the preparation of Comparative Example 2 wherein the core was coated with the citagliptin coating solution prepared by dissolving citagliptin in purified water.

These results show that the stability of sitagliptin can be improved when granulated, rather than used as a coating solution, by dissolving citagliptin in a solvent for the preparation of a combination of metformin and citagliptin.

The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the above-described embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

Claims (14)

Metformin or a pharmaceutically acceptable salt thereof, and a sustained release carrier; And
Or a pharmaceutically acceptable salt thereof, or a salt thereof. The combination preparation for oral administration according to claim 1, wherein the sustained-release layer and the immediate-release layer are each formed by tableting granules. 3. The oral combined preparation according to claim 2, wherein the granule is a wet granule. 2. The combination preparation for oral administration according to claim 1, wherein the oral combination preparation is a two-layered formulation comprising a sustained-release layer and an immediate-release layer. The composition of claim 1, wherein the sustained release carrier is selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, polyethylene oxide, guar gum, locust bean gum, xanthan gum, glyceryl distearate , Sodium carboxymethyl cellulose, polyvinyl pyrrolidone, and any combination thereof. The combination formulation of claim 1, wherein said sustained release layer further comprises a pharmaceutically acceptable additive selected from the group consisting of diluents, lubricants, and any combination thereof. The method according to claim 6,
Wherein the diluent is selected from the group consisting of microcrystalline cellulose, mannitol, sucrose, lactose, sorbitol, xylitol, glucose and any combination thereof,
The lubricant may be selected from the group consisting of calcium stearate, fumed silica (Aerosil), glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, An acid, a hardened vegetable oil, polyethylene glycol, sodium benzoate, talc, and any combination thereof. The combination formulation of claim 1, wherein the immediate-release layer further comprises a pharmaceutically-acceptable additive selected from the group consisting of plasticizers, dispersants, diluents, disintegrants, lubricants, and any combination thereof. 9. The method of claim 8,
Wherein the plasticizer is selected from the group consisting of polyethylene glycol, glycerin, stearic acid, silica, dimethicone, concentrated glycerin, propylene glycol, and any combination thereof,
Wherein the dispersing agent is selected from the group consisting of kaolin, aluminum oxide, titanium oxide, sorbitan sesquiole, silicone resin, gum arabic, ethylcellulose, calcium carbonate, bentonite, carbomer and any combination thereof,
Wherein the diluent is selected from the group consisting of microcrystalline cellulose, anhydrous calcium phosphate, mannitol, sucrose, lactose, sorbitol, xylitol, glucose and any combination thereof,
The disintegrant may be selected from the group consisting of alginic acid, sodium alginate, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, crospovidone, pregelatinized starch, starch glycolic acid sodium, starch, Lt; / RTI &gt;
The lubricant may be selected from the group consisting of calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulphate, sodium stearyl fumarate, zinc stearate, stearic acid, cured vegetable oil, polyethylene glycol, &Lt; / RTI &gt; sodium, talc, and any combination thereof. The method according to claim 1, wherein, in the elution test at 75 rpm in an aqueous buffer solution at 37 占 0.5 占 폚, pH 6.8 according to the second law paddle method according to USP, a dissolution rate of 90% or more of citagliptin over 60 minutes, And a dissolution rate of 5 - 15%. 2. The oral combination preparation according to claim 1, wherein when the combination preparation is stored at 60 DEG C and 75% relative humidity for 4 weeks, the total content of the citagliptin softener is 0.3% by weight or less. 2. The oral combined preparation according to claim 1, wherein the metformin is contained as metformin hydrochloride in an amount of 500-1000 mg per unit dosage form. 2. The combination preparation for oral administration according to claim 1, wherein the cyctagliptin is contained as a cyglglyptin free base in an amount of 25-100 mg per unit dosage form. Metformin or a pharmaceutically acceptable salt thereof, and metformin granules containing a sustained release carrier;
Preparing a citagliptin granulate comprising sitagliptin or a pharmaceutically acceptable salt thereof; And
The method according to any one of claims 1 to 13, comprising the step of tableting the metformin granules as a first layer and the citalogliptin granules as a second layer using a two-layer tablet machine Gt;

Images