JP5671767B2 - Oral preparation containing metformin and α-glycosidase inhibitor, and method for producing the same - Google Patents

Description

The present invention relates to an oral preparation useful for the treatment of type 2 diabetes containing metformin and voglibose and a method for producing the same, and more specifically, equivalent to or more than when metformin and voglibose are administered separately as separate preparations. In addition, the present invention relates to an oral preparation that can be easily taken and can improve patient compliance, and a method for producing the same.

Type 2 diabetes, a non-insulin dependent diabetes mellitus, is one of the most common metabolic diseases with a prevalence of about 5% worldwide, and will tend to increase to 7% within 2010. The total number of diabetic patients worldwide is expected to increase approximately double over the next decade.

The pathophysiology of type 2 diabetes is characterized by impaired insulin secretion and insulin resistance, which can lead to hyperinsulinism from the beta cells of the pancreas, which again leads to hyperinsulinemia. Bloodemia already exists before it is diagnosed as diabetes and acts as an independent risk factor for various other diseases. In the course of this process, β-cell function declines and insulin deficiency occurs, and as a result, diabetes characterized by decreased glucose tolerance and fasting hyperglycemia after meals develops. Various chronic complications, such as microvascular complications such as retinopathy, neuropathy, or heart disease, and macrovascular complications such as cardiovascular, cerebrovascular, or peripheral arterial blood vessels after long-term diabetes Will occur. Such chronic complications reduce the quality of life of diabetics and greatly increase mortality. Therefore, management of type 2 diabetes is to prevent chronic complications, in other words, to delay the onset and progression of such chronic complications.

  Diabetics who may experience chronic complications from diabetes participate in a rigorous diabetes care process and have sufficient metabolism to maintain normal or at least near normal glycated hemoglobin (HbA1c). You have to make adjustments. The results of the Diabetes Control and Complication Trial and the United Kingdom Prospective Diabetes Study (UKPDS) show that strict glycemic control reduces the risk of developing chronic complications due to diabetes. It shows well. However, in practice, many patients with type 2 diabetes have failed to regulate blood glucose below the target value presented by the American Diabetes Association. In addition, the UKPDS analysis results show that the failure rate of oral antihyperglycemic monotherapy increases over time, so that combined use with other drugs is indispensable for effective blood glucose control. is there.

Selection of an appropriate drug in combination therapy varies depending on individual circumstances, but it is preferable to use drugs having different mechanisms in consideration of mutually complementary effects. From this aspect, the combination of α-glycosidase inhibitor and metformin is an ideal combination therapy that can simultaneously regulate postprandial blood glucose increase and insulin resistance, two pathological mechanisms of type 2 diabetes . In fact, many clinical trials have already proved that the combination therapy of α-glycosidase-inhibiting drugs and metformin is more effective in terms of glycemic control than each monotherapy (Clinical therapeutics vol.25 No .12 2003, Diabetes Care vol.24 No.6 June 2001).

However, the combination therapy of two or more oral hypoglycemic agents is that in practice it is difficult for patients to sustain an unspecified long period. Such low compliance is ultimately one of the important causes of failure of glycemic control in a significant number of type 2 diabetic patients who require combination therapy with oral hypoglycemic agents.

Thus, a combination of two oral hypoglycemic agents combined into a single dosage form is convenient for taking and can improve patient compliance with drugs and can be an alternative for long-term and effective blood glucose control. According to a study that compared patient compliance by dosage regimen in combination therapy with oral hypoglycemic agents, the compliance of the group of subjects who took each separately remained at 54%, while taking the combination The compliance of the selected group showed 77%, and the benefits of such a combination go beyond simple possibilities and provide substantial benefits to a significant number of patients with type 2 diabetes who require long-term combination therapy It was proved that

  Metformin, a therapeutic agent for biguanide diabetes, is in the form of hydrochloride and is sold under the registered trademark Glucophage. Metformin hydrochloride is a drug that increases insulin sensitivity by decreasing sugar production in the liver and increasing terminal absorption. It is also a hydrophilic drug with oral bioavailability of 50-60%, 500mg 3 times a day to maintain effective plasma concentration with various biological half-life of 1.5-4.5 hours It is a drug that must be administered repeatedly. Metformin hydrochloride is essentially absorbed in the upper gastrointestinal tract and poorly permeable in the lower gastrointestinal tract such as the small intestine, large intestine and colon. Therefore, if a formulation containing metformin does not release metformin rapidly and moves to the lower part of the gastrointestinal tract over time, the bioavailability of metformin will decrease.

In addition, α-glycosidase inhibitors such as voglibose are non-insulin-dependent diabetes mellitus treatment agents, and inhibit α-glycosidase present in gastrointestinal cells by a binding method different from existing sulfonylurea-based drugs to glucose. By suppressing the conversion, an abrupt increase in blood glucose level immediately after a meal is significantly suppressed, and an excellent hypoglycemic effect is exhibited. In addition, it exhibits a sufficient blood glucose control effect without developing hypoglycemia and increases patient compliance. Similarly, such an α-glycosidase inhibitor must suppress a rapid increase in blood glucose level immediately after a meal, and therefore must be rapidly released from the preparation and absorbed in order to obtain a sufficient effect.

On the other hand, the dose of drug administered is very high at 250 to 1000 for metformin and voglibose corresponding to an α-glycosidase inhibitor is very low at 0.2 to 0.3 mg at a time. Therefore, when producing such two drug combinations, it is difficult to show uniform mixing and dissolution between the preparations due to the low volume of voglibose, and the respective pharmacokinetic properties and pharmacokinetics Depending on the physical properties, the absorption conditions of the required drugs may be affected.

Thus, each drug is administered in combination as a separate drug when manufacturing a combined preparation containing two or more oral hypoglycemic agents to effectively regulate blood glucose in diabetic patients and increase patient compliance There is a need to develop formulations that are as effective or better than the case.

Accordingly, an object of the present invention is to provide a metformin and α-glycosidase inhibitor that exhibits a uniform mixing degree and dissolution characteristics between preparations, and exhibits an effect equivalent to or higher than that when each drug is administered in combination as another drug. An oral formulation comprising:

Moreover, the objective of this invention is providing the method of manufacturing the oral formulation containing the said metformin and alpha-glycosidase inhibitor.

In order to achieve the above object, the present invention provides:
Secondary wet granules formed by coating primary wet granules produced by using a mixed solution of metformin and hydroxypropyl cellulose with an aqueous hydroxypropyl cellulose solution with an α-glycosidase inhibitor and an aqueous hydroxypropyl cellulose mixture. An oral formulation is provided.

The present invention also includes a step of putting a mixed powder of metformin and hydroxypropylcellulose into a fluidized bed granulator and spraying an aqueous hydroxypropylcellulose solution to form primary wet granules; and the primary wet granules in the fluidized bed granulator Spraying an α-glycosidase inhibitor and a hydroxypropylcellulose mixed aqueous solution to form secondary wet granules, and providing a method for producing the oral preparation according to the present invention.

Hereinafter, the present invention will be described in more detail.

The oral preparation according to the present invention is a preparation containing metformin and an α-glycosidase inhibitor, and the metformin and α-glycosidase inhibitor show uniform mixing and dissolution between the preparations, and each active ingredient is administered separately. It is a preparation for exhibiting an elution pattern that produces an effect equivalent to or better than that of the case.

In order for the preparation according to the present invention to exhibit such an elution pattern, the α-glycosidase is mixed with primary wet granules formed by using a hydroxypropylcellulose aqueous solution as a binding solution with respect to a mixed powder of metformin and hydroxypropylcellulose. It comprises secondary wet granules formed by coating with an inhibitor and a hydroxypropylcellulose mixed aqueous solution. In the preparation, metformin and hydroxypropylcellulose are homogeneously mixed in primary wet granules, and each granule is coated with an α-glycosidase inhibitor and hydroxypropylcellulose, and metformin and α-glycosidase are included in the preparation. Although the inhibitor is not in a homogeneous form, it has a form in which the α-glycosidase inhibitor is uniformly distributed in metformin. Therefore, it is expected that there is little variation in the mixing degree of the active ingredient between formulations. In addition, due to the characteristics of the drug, α-glycosidase inhibitor, which must be administered before meals to produce a rapid effect, is coated on the outside of the granule and dispersed together with the hydrophilic polymer hydroxypropylcellulose. Can be rapidly disintegrated and released, so that the above effects can be exhibited when an α-glycosidase inhibitor alone is administered as a combined preparation. The primary granule containing metformin can also be rapidly disintegrated and eluted with hydroxypropylcellulose after disintegration of the coating layer containing the α-glycosidase inhibitor. Therefore, the oral preparation according to the present invention releases each component more rapidly and is rapidly absorbed into the blood than the single preparations of metformin and α-glycosidase inhibitor currently on the market. it can.

The preparation of the primary wet granule and the preparation of the secondary wet granule in the oral preparation of the present invention may use a granule production method usually used in the pharmacology field, preferably a mixture of metformin and hydroxypropylcellulose. The primary granule is formed by spraying the hydroxypropylcellulose aqueous solution with the fluidized bed granulator, and then the primary granule is mixed with the α-glycosidase inhibitor and hydroxypropylcellulose in the fluidized bed granulator. Secondary granules can be produced by spraying an aqueous solution as a binding solution.

In the oral preparation according to the present invention, the primary wet granule contains 1 to 50 parts by weight of hydroxypropylcellulose with respect to 100 parts by weight of metformin, and the α-glycosidase inhibitor and the hydroxypropylcellulose mixed aqueous solution have an α-glycosidase inhibitor 100. It contains 500 to 5000 parts by weight of hydroxypropylcellulose with respect to parts by weight. The amount of hydroxypropyl cellulose relative to the active ingredient varies depending on the size and strength of the granule to be produced, the specific surface area of the granule, the content of the active ingredient and the dissolution rate of the desired active ingredient.

The oral preparation of the present invention is a granule in the form of the secondary granule, or is a form further formulated in a capsule or tablet containing the granule. Capsules are produced by filling capsules with the above-mentioned secondary granules alone or with excipients such as starches, lactose, celluloses, etc., according to a method for producing capsules usually used in the field of pharmacology. The oral preparation of the present invention is preferably a tablet, and the tablet is produced by tableting the secondary granule with a lubricant. The lubricant can be selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, talc, calcium stearate, carnauba wax, and combinations thereof.

Metformin contained as an active ingredient in the preparation for oral administration according to the present invention is metformin or a pharmaceutically acceptable salt of metformin, preferably metformin hydrochloride. The α-glycosidase inhibitor which is still another active ingredient is acarbose, miglitol, or voglibose, but is not limited thereto, and is preferably voglibose.

The preparation for oral administration according to the present invention may contain 250-1000 mg of metformin hydrochloride and 0.1-0.4 mg of voglibose per dose, and may be appropriately increased or decreased depending on the strength of the drug to be produced. it can. The oral formulation can be administered during or after a meal for the effective action of each component.

According to the following experimental example, the oral dosage form according to the present invention shows that metformin is released more rapidly in a medium having a pH of 1.2 to 7, compared with glucophage which is a conventional metformin single dosage form. It was confirmed that voglibose was released to the same level or more as the basin formulation. Also, a bioavailability test using beagle dogs showed that the oral administration preparation according to the present invention has a bioavailability for metformin that is equal to or greater than that of glucophage. Therefore, the preparation for oral administration according to the present invention is a complex preparation for regulating blood glucose that exhibits an effect equivalent to or higher than that when each active ingredient is administered in combination as another drug.

According to another aspect of the present invention, a mixed powder of metformin and hydroxypropylcellulose is placed in a fluidized bed granulator, and a primary wet granule is produced by spraying a hydroxypropylcellulose aqueous solution. Spraying a wet granule with an α-glycosidase inhibitor and an aqueous solution of hydroxypropylcellulose to form a secondary wet granule, to provide a method for producing an oral preparation according to the present invention.

The production of granules using a fluidized bed granulator used for producing the primary wet granules and the secondary wet granules can be performed under a temperature condition of 50 to 70 ° C.

After the production of the primary wet granule and the secondary wet granule, it is preferable to use a granule having a size of 75 to 500 m in a subsequent stage by sieving with a sieve.

In the method for producing the oral preparation, a tablet can be produced by further adding a step of producing the tablet by compressing the produced secondary wet granule together with a lubricant.

  The lubricant may be selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, talc, calcium stearate, carnauba wax, and combinations thereof, but is not limited thereto.

According to the present invention, not only has a uniform mixing degree and dissolution rate between preparations, but also provides a combined preparation for regulating blood glucose that exhibits an effect equivalent to or higher than that when metformin and an α-glycosidase inhibitor are administered together as separate drugs. can do. These combined preparations can effectively regulate blood glucose in diabetic patients and increase patient compliance by combining two drugs, which is very effective for blood glucose management in diabetes requiring long-term blood glucose regulation Is.

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

Example 1: Production of a combined preparation of metformin and voglibose (1)
Metformin hydrochloride (300 g) and hydroxypropyl cellulose (36 g) were uniformly mixed, then sieved using a 20 mesh sieve, placed in a fluid bed granulator and preheated at 60 ° C. for 10 minutes. A binder solution was prepared by dissolving 6 g of hydroxypropylcellulose in 120 mL of water, and then the prepared binder solution was sprayed at a rate of 7 mL per minute to produce primary granules, which were sieved with a 20 mesh sieve.

 0.18 g of voglibose and 6 g of hydroxypropylcellulose were dissolved in 120 mL of water with sufficient stirring, and then sprayed onto the prepared granules to produce secondary granules. After sieving with a 20 mesh sieve, it was dried and completed.

Example 2: Production of a combined preparation of metformin and voglibose (2)
Metformin hydrochloride (300 g) and hydroxypropyl cellulose (36 g) were uniformly mixed, then sieved using a 20 mesh sieve, placed in a fluid bed granulator and preheated at 60 ° C. for 10 minutes. A binder solution was prepared by dissolving 6 g of hydroxypropylcellulose in 120 mL of water, and then the prepared binder solution was sprayed at a rate of 7 mL per minute to produce primary granules, which were sieved with a 20 mesh sieve.

  After 0.1 g of voglibose and 6 g of hydroxypropylcellulose were dissolved in 120 mL of water with sufficient stirring, this was sprayed onto the produced granules to produce secondary granules. After sieving with a 20 mesh sieve, it was dried and completed.

Example 3: Production of a combined preparation of metformin and voglibose (3)
Metformin hydrochloride (300 g) and hydroxypropyl cellulose (36 g) were uniformly mixed, then sieved using a 20 mesh sieve, placed in a fluid bed granulator and preheated at 60 ° C. for 10 minutes. A binder solution was prepared by dissolving 6 g of hydroxypropylcellulose in 120 mL of water, and then the prepared binder solution was sprayed at a rate of 7 mL per minute to produce primary granules, which were sieved with a 20 mesh sieve.

 0.36 g of voglibose and 6 g of hydroxypropylcellulose were dissolved in 120 mL of water with sufficient stirring, and then sprayed onto the produced granules to produce secondary granules. After sieving with a 20 mesh sieve, it was dried and completed.

Example 4: Production of a combined preparation of metformin and voglibose (4)
Metformin hydrochloride (300 g) and hydroxypropyl cellulose (36 g) were uniformly mixed, then sieved using a 20 mesh sieve, placed in a fluid bed granulator and preheated at 60 ° C. for 10 minutes. A binder solution was prepared by dissolving 6 g of hydroxypropylcellulose in 120 mL of water, and then the prepared binder solution was sprayed at a rate of 7 mL per minute to produce primary granules, which were sieved with a 20 mesh sieve.

 0.24 g of voglibose and 6 g of hydroxypropylcellulose were dissolved in 120 mL of water with sufficient stirring and then sprayed onto the prepared granules to produce secondary granules. After sieving with a 20 mesh sieve, it was dried and completed.

Example 5: Preparation of a combined preparation of metformin and voglibose (5)
The granule produced in Example 1 was mixed with 3 g of lubricant magnesium stearate for an appropriate time, and then compressed into an oval tablet with a weight of 585.3 ± 30 mg. Each tablet contains, on average, 500 mg metformin hydrochloride and 0.3 mg voglibose.

Example 6: Preparation of a combined preparation of metformin and voglibose (6)
The granule produced in Example 2 was mixed with 3 g of lubricant magnesium stearate for an appropriate time, and then compressed into an oval tablet with a weight of 585.3 ± 30 mg. Each tablet contains, on average, 500 mg metformin hydrochloride and 0.2 mg voglibose.

Example 7: Production of a combined preparation of metformin and voglibose (7)
The granule produced in Example 3 was mixed with 3 g of lubricant magnesium stearate for an appropriate time, and then compressed into an oval tablet with a weight of 292.8 ± 15 mg. Each tablet contains, on average, 250 mg metformin hydrochloride and 0.3 mg voglibose.

Example 8: Production of a combined preparation of metformin and voglibose (8)
The granule produced in Example 1 was mixed with 3 g of lubricant magnesium stearate for an appropriate time, and then compressed into an oval tablet with a weight of 292.8 ± 15 mg. Each tablet contains, on average, metformin hydrochloride 292.8 ± 15 mg and voglibose 0.2 mg.

Example 1
The tablets prepared in Example 7 were subjected to a dissolution test on glucophage. The conditions of the dissolution test are as follows.

-Eluent: purified water, pH 6.8 phosphate buffer, pH 4.0 acetate buffer, pH 1.2 buffer
The pH 1.2 buffer (disintegration test method 1st solution) is made by dissolving 7.0 mL of c-HCl and water in 2.0 g of NaCl to make 1 L. This solution is colorless and odorless and has a pH of about 1.2. The pH 4.0 acetate buffer solution (acetate buffer solution) is prepared by preparing a mixed solution (41: 9) of 0.05 mol / L acetic acid solution and 0.05 mol / L sodium acetate solution and adjusting the pH to 4.0.
-Dissolution equipment: Hanson Dissolution Tester (USA)
-Elution rate: 50rpm
-Elution time: 60 minutes-Preparation of test solution: Take 30 mL of the eluate 30 minutes after the start of the dissolution test and filter through a 0.45 μm membrane filter. Discard the first 5 mL of filtrate and take the remaining 5 mL into a 100 mL volumetric flask. Use the eluate as a test solution according to the marked line.
-Preparation of standard solution: 50 mg of metformin standard product is accurately taken into a 20 mL volumetric flask and adjusted to the marked line with the eluate. Take exactly 1mL of this solution and place it in a 20mL volumetric flask. Again, 5 mL of this solution is accurately taken and placed in a 50-mL volumetric flask.
-Operation: The absorbance of each of the test solution and the standard solution is measured at 233 nm by ultraviolet-visible absorbance measurement.

The results of the dissolution test under the above conditions are shown in FIGS.

According to the results shown in FIGS. 1 to 4, it was found that the complex preparation according to the present invention releases metformin more rapidly in a medium having a pH of 1.2-7 than glucophage which is a conventional commercial preparation.

Experimental Example 2: Bioavailability Test The tablets produced in Example 5 were orally administered to beagle dogs by the following method using glucophage as a control drug and tested for bioavailability.

-Test equipment:
Vortex Mixer (Thermolyne, USA; Type 37600 Mixer)
Freezer (LASSELE; DY-110F)
Micro Centrifuge (Hanil Co., Korea; Micro 17TR)
HPLC (SHISEIDO; NANOSPACE)
MS / MS (Applied Biosystems; API 5000)

-Test equipment
Dispenser (Eppendorf)
Micro Pipette (Gilson Co., France; P-20, P-100, P-200, P-1000)

-Test method Stock solution production: Metformin and IS (phenformin) used as standard substances were weighed in a glass vial (5mL vial wiped with water and ACN) and weighed more than 3mg, then micropipette Is used in the experiment by dissolving in methanol to a concentration of 1 mg / ml. Store at 4 ° C until use. 1 mg / ml metformin stock solution is diluted 10-fold with 50% ACN to produce 100 μg / ml stock solution, then diluted 2-fold to 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39 μg / ml stock solution is prepared and used for the calibration curve, among which high, medium and low concentrations and LLOQ concentration are used as validation samples.

Sample pretreatment: Add 10 μl IS (phenformin, 25 μg / ml) to 100 μl blank plasma, vortex for 5 seconds, then add 500 μl ACN and vortex for 2 minutes. After centrifuging at 13,000 rpm and 4 ° C. for 5 minutes in a centrifuge, transfer 50 μl of the upper layer solution to a new tube, put 500 μl of the mobile phase therein, and vortex for 1 minute. After centrifugation (13,000 rpm, 4 ° C., 2 minutes) and filtration (0.2 μm), analysis is performed by LC / MS / MS.

HPLC conditions:
Column-CAPCELL PAK CR 5μ (50 x 2.00 mm)
Column temperature -40 ° C
Eluent-ACN (0.1% formic acid): 10 mM ammonium acetate (0.1% formic acid) = 250: 50
Flow rate: 0.3 ml / min
Injection volume: 2μl
Running time -3.0 minutes

MS / MS conditions:
Polarity -ES +
Injection potential-10V
Declustering potential-81V (metformin), 86V (phenformin)
Collision energy-35V (metformin), 25V (phenformin)
Collision Cell Exit Potential-14V (metformin), 10V (phenformin)
Collision gas-10
Curtain Gas-20
Ion Source Gas 1−50
Ion Source Gas 2-50
Ion spray voltage-5500
Temperature -450 ° C

The results of the bioavailability test under the test conditions are shown in FIG.

According to the results of FIG. 2, it can be seen that the composite preparation according to the present invention has a bioavailability equal to or higher than that of basin, which is a conventional commercial preparation.

Experimental Example 3: Stability Test A stability test was performed on the tablets produced in Example 5 together with glucophage and basin under the following conditions.

-Test conditions: Accelerated stability test (45 ° C, 75%)
-Test period: 6 months

-Test method:
Preparation of test solution Take 10 tablets of this medicine, add exactly 200 mL of mobile phase, mix thoroughly by shaking and centrifuge. Filter the supernatant through a 0.45 μm membrane filter. Discard the first 1 mL of filtrate and use the next solution as the sample solution.

Preparation of standard solution Take approximately 10 mg of quantifying voglibose accurately and dissolve in the mobile phase to make exactly 20 mL, then take 2 mL into each 100 mL volumetric flask and align the mark with the mobile phase.

Liquid chromatographic operating condition detector-Fluorometer (excitation wavelength: 350nm, fluorescence wavelength: 430nm)
Column-YMC-Pack polyamine (4.6 mm ID x 250 mm L, 5 μm)
Column temperature -25 ° C
Mobile phase-acetonitrile: sodium phosphate buffer (pH 6.5) mixture = 1: 1
Sodium phosphate buffer (pH 6.5) is dissolved in 1.38 g of sodium dihydrogen phosphate monohydrate by adding water to 500 mL, and dissolved in 1.42 g of sodium monohydrogen phosphate by adding water to 500 mL. And adjusted to pH 6.5.
Flow rate-Adjust so that the retention time of voglibose is about 15 minutes.
Fluorescence reagent-Taurine 6.25g and sodium periodate 2.56g are dissolved in water to make 1L.
Temperature of thermostat for reaction coil: 100 ℃
Temperature of thermostat for cooling coil: 25 ℃

The results are shown in Table 1 below.

According to the results of Table 1 above, it was confirmed that the preparation according to the present invention has the stability equal to or higher than the single preparation of each component in terms of storage stability.

6 is a graph showing the results of a dissolution test over time with water using glucophage as a control drug for a tablet according to an embodiment of the present invention. 6 is a graph showing the results of conducting a dissolution test over time with a phosphate buffer solution at pH 6.8 using glucophage as a control drug for tablets according to an embodiment of the present invention. 6 is a graph showing the results of conducting a dissolution test over time with a pH 4.0 acetate buffer solution using glucophage as a control drug for a tablet according to an embodiment of the present invention. 6 is a graph showing the results of performing a dissolution test over time with a buffer solution of pH 1.2 using glucophage as a control drug for a tablet according to an embodiment of the present invention. 3 is a graph showing the results of measuring the plasma concentration of metformin over time after a tablet according to an embodiment of the present invention was orally administered to a beagle dog using glucophage as a control drug.

FO801: Tablet manufactured in Example 7

Claims (17)

Metformin or a pharmaceutically acceptable salt thereof 250-1000 mg and voglibose 0.1-0.4 mg as an oral combined preparation for the treatment of diabetes, the oral combined preparation for the treatment of diabetes is metformin or a pharmaceutically acceptable salt thereof. And a first granule layer in which a pharmaceutically acceptable carrier is bound, and a second granule layer in which a mixture of voglibose and a pharmaceutically acceptable carrier is coated on the outside of the first granule layer It characterized the this antidiabetic oral complex formulation. The oral combined preparation for treating diabetes according to claim 1, wherein the pharmaceutically acceptable salt of metformin is metformin hydrochloride. The oral composite preparation for treating diabetes according to claim 1, wherein the pharmaceutically acceptable carrier is hydroxypropylcellulose. The diabetes mellitus treatment according to claim 1, wherein the first granule layer is formed by bonding a mixed powder of metformin or a pharmaceutically acceptable salt thereof and hydroxypropylcellulose using a hydroxypropylcellulose aqueous solution as a binding solution. Oral combined preparation. The oral composite preparation for treating diabetes according to claim 1, wherein the first granule layer contains 1 to 50 parts by weight of hydroxypropylcellulose with respect to 100 parts by weight of metformin. The oral combination preparation for diabetes treatment according to claim 1, wherein the mixture of voglibose and a pharmaceutically acceptable carrier contains 500 to 5000 parts by weight of hydroxypropylcellulose with respect to 100 parts by weight of voglibose. The oral combined preparation for treating diabetes according to claim 1, wherein the single dose of the combined preparation is 3 times. Diabetes oral therapeutic combination preparation according to claim 1, characterized in that the form of the oral combination formulation is a capsule or tablet dosage. Forming a primary granule in which metformin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier are combined, and voglibose and a pharmaceutically acceptable carrier outside the primary granule. characterized that you and a step of spraying the mixed solution of forming secondary granules manufacturing method of treating diabetes oral complex formulation. The method for producing an oral combined preparation for treating diabetes according to claim 9, wherein the pharmaceutically acceptable salt of metformin is metformin hydrochloride. The method for producing an oral combined preparation for treating diabetes according to claim 9, wherein the pharmaceutically acceptable carrier is hydroxypropylcellulose. The step of forming the primary granule includes a step of mixing metformin or a pharmaceutically acceptable salt thereof with hydroxypropylcellulose to form a mixed powder, and spraying an aqueous hydroxypropylcellulose solution onto the mixed powder. The method for producing an oral combined preparation for treating diabetes according to claim 9, comprising the step of forming a next granule. The method for producing an oral combined preparation for diabetes treatment according to claim 12, wherein the primary granule contains 1 to 50 parts by weight of hydroxypropylcellulose with respect to 100 parts by weight of metformin. The oral combination preparation for treating diabetes according to claim 9, wherein the mixture of voglibose and a pharmaceutically acceptable carrier contains 500 to 5000 parts by weight of hydroxypropylcellulose with respect to 100 parts by weight of voglibose. Production method . The method for producing an oral combined preparation for treating diabetes according to claim 9, further comprising the step of mixing the secondary granule with a lubricant and then compressing it with an oval tablet. The method according to claim 15, wherein the combined preparation comprises metformin 250-1000 mg and voglibose 0.1-0.4 m. The method for producing an oral composite preparation for treating diabetes according to claim 9, further comprising a step of sieving with a sieve and drying after the production of the primary granules and the secondary granules.

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