KR102647472B1 - Solid composite formulation for oral administration comprising dipeptidyl peptidase-4 inhibitor and metformine, and a process for the preparation thereof - Google Patents

Abstract

The present invention relates to an oral solid combination preparation containing a dipeptidyl peptidase-4 inhibitor and metformin, and a method for producing the same. Specifically, the oral solid composite preparation is a wet formulation prepared by homogeneously mixing a granule forming composition containing a dipeptidyl peptidase-4 inhibitor or a pharmaceutically acceptable salt thereof, and metformin or a pharmaceutically acceptable salt thereof. Contains granules. The oral solid composite preparation according to the present invention has excellent effects in terms of productivity and stability.

Description

Oral solid composite preparation containing dipeptidyl peptidase-4 inhibitor and metformin and method for manufacturing same {SOLID COMPOSITE FORMULATION FOR ORAL ADMINISTRATION COMPRISING DIPEPTIDYL PEPTIDASE-4 INHIBITOR AND METFORMINE, AND A PROCESS FOR THE PREPARATION THEREOF}

The present invention relates to an oral solid combination preparation containing a dipeptidyl peptidase-4 inhibitor and metformin, and a method for producing the same.

Dipeptidyl peptidase-4 (DPP-4) inhibits glucagon like peptide-1 (GLP-1), one of the main stimulators of pancreatic insulin secretion, and GLP-1 It has a positive effect on glucose conversion. Accordingly, inhibition of DPP-4 is effective in treating diseases such as non-insulin dependent diabetes mellitus (NIDDM).

Linagliptin, Sitagliptin, Vildagliptin, etc. are widely known as DPP-4 inhibitors in the art. Here, the linagliptin is 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1- [(4-methyl-2-quinazolinyl)methyl-1H-purine-2,6-dione(8-[(3R)-3-Amino-1-piperidinyl]-7-(2-butyn-1-yl )-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl-1H-purine-2,6-dione), and the sitagliptin is (3R)-3 -Amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-5H[1,2,4]triazolo[4,3-a]pyrazin-7-yl]- 4-(2,4,5-trifluorophenyl)butan-1-one ((3R)-3-Amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-5H[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one). In addition, vildagliptin is a compound disclosed in International Publication No. 2000-034241 and the like, and is an N-substituted-2-cyanopyrrolidine-based compound.

These DPP-4 inhibitors are widely used as diabetes treatments along with certain partner drugs such as metformin hydrochloride (Metformin HCl). Since the DPP-4 inhibitor has a therapeutic effect by simultaneously administering the partner drug metformin, research is continuing in the technical field to develop a combination preparation containing both the DPP-4 inhibitor and the partner drug metformin.

However, DPP-4 inhibitors are unstable in water, which limits the preparation method. Unlike the use of DPP-4 inhibitors alone, there is a problem that the amount of related substances significantly increases when used together with metformin. Therefore, there is a need in the relevant technical field for a method to solve these problems and manufacture complex preparations with high stability and productivity.

Republic of Korea Patent No. 10-1111101

The inventor of the present invention confirmed that there is a problem of decreased productivity and stability when a dipeptidyl peptidase-4 inhibitor, which is effective in treating diabetes, is used together with the partner drug metformin, and after extensive research to solve this problem, The invention was completed.

The present invention seeks to provide an oral solid combination preparation with improved productivity and stability while using a dipeptidyl peptidase-4 inhibitor and metformin as active ingredients.

According to the first aspect of the present invention,

The present invention provides an oral solid comprising wet granules prepared by homogeneously mixing a dipeptidyl peptidase-4 inhibitor or a pharmaceutically acceptable salt thereof, and a composition for forming granules containing metformin or a pharmaceutically acceptable salt thereof. Provides combination preparations.

In one embodiment of the present invention, the dipeptidyl peptidase-4 inhibitor is linagliptin, sitagliptin, or vildagliptin.

In one embodiment of the present invention, the dipeptidyl peptidase-4 inhibitor is vildagliptin.

In one embodiment of the present invention, the wet granules are manufactured in a fluid bed granulator.

In one embodiment of the present invention, the composition for forming granules further includes a binder, and the binder is hydroxypropyl cellulose, povidone, hydroxypropyl methylcellulose, or a mixture thereof.

In one embodiment of the present invention, the oral solid composite preparation further includes one or more pharmaceutically acceptable additives selected from the group consisting of disintegrants, lubricants, stabilizers, and combinations thereof.

In one embodiment of the present invention, the oral solid combination preparation has a moisture content of 0.8% by weight or less based on the total weight of the combination preparation.

In one embodiment of the present invention, the wet granules have 30% or less of particles with a particle diameter of less than 75㎛.

In one embodiment of the present invention, the wet granules have 25% or more of particles having a particle diameter of 150㎛ or more.

In one embodiment of the present invention, the oral solid composite preparation is a tablet or capsule.

According to the second aspect of the present invention,

The present invention is a method for producing the above-described oral solid composite preparation,

(a) preparing a composition for forming granules containing a dipeptidyl peptidase-4 inhibitor or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof, and (b) homogenizing the composition for forming granules. It includes the step of mixing thoroughly and then producing wet granules through a granulation process.

In one embodiment of the present invention, the granulation process is a fluid bed granulation process.

In one embodiment of the present invention, in step (a), the composition for forming granules further includes a binder, and in step (b), 5 to 10% by weight of binder is added together with the composition for forming granules in the fluidized bed granulation process. Inject a binding solution containing.

In one embodiment of the present invention, the weight ratio of the binder included in the composition for forming granules in step (a) and the binder included in the binder solution in step (b) is 3:1 to 9:1.

The oral solid composite preparation according to the present invention has good uniformity of content, almost no capping phenomenon occurs during tableting, and very low friability, resulting in high product productivity.

The oral solid composite preparation according to the present invention minimizes moisture contact with the dipeptidyl peptidase-4 inhibitor, which is vulnerable to moisture, and produces stable drug effects by suppressing the production of related substances even when wet granulation process is performed together with metformin, a partner drug. You can. Accordingly, the patient's medication compliance with the combination medication can also be increased.

Figure 1 is a graph showing the size distribution of granules according to Examples 1, 3, and 5 and Comparative Examples 3 to 5.
Figure 2 is a graph showing the ratio of the granules according to Examples 1, 3, and 5 and Comparative Examples 3 to 5 separated into 150 μm or more and less than 75 μm, respectively.

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

All technical terms used in the present invention, unless otherwise defined, are used with the same meaning as commonly understood by a person skilled in the art in the field related to the present invention. In addition, although preferred methods and samples are described in this specification, similar or equivalent methods are also included in the scope of the present invention. The contents of all publications incorporated by reference herein are hereby incorporated by reference in their entirety.

The present invention provides an oral solid combination preparation containing a dipeptidyl peptidase-4 inhibitor or a pharmaceutically acceptable salt thereof, and metformin or a pharmaceutically acceptable salt thereof. In this specification, although the active ingredient is described as dipeptidyl peptidase-4 inhibitor or metformin, it can be interpreted to also include pharmaceutically acceptable salt forms thereof. Because dipeptidyl peptidase-4 inhibits glucagon-like peptide-1 (GLP-1), one of the main stimulators of pancreatic insulin secretion, dipeptidyl peptidase-4 inhibitors promote insulin secretion, preventing diabetes. It is used as an effective active substance in the treatment of diseases such as. These dipeptidyl peptidase-4 inhibitors are widely used as diabetes treatments along with certain partner drugs such as metformin hydrochloride. However, when the dipeptidyl peptidase-4 inhibitor is used together with the partner drug metformin, problems such as decreased productivity and stability may occur. The present invention provides an oral solid combination preparation that can solve these problems.

The dipeptidyl peptidase-4 inhibitor included in the oral solid combination preparation according to the present invention may be linagliptin, sitagliptin, or vildagliptin, and preferably may be vildagliptin. Pharmaceutically acceptable salts of the dipeptidyl peptidase-4 inhibitor may be acid addition salts, such as 4-acetamidobenzoate, acetate, adipate, alginate, 4-aminosalicylate, and ascorbate. , aspartate, benzenesulfonate, benzoate, butyrate, camphorate, camphorsulfonate, carbonate, cinnamate, citrate, cyclamate, cyclopentanepropionate, decanoate, 2,2-dichloro. Acetate, digluconate, dodecyl sulfate, ethane-1,2-disulfonate, ethane sulfonate, formate, fumarate, galactarate, gentisate, glucoheptanoate, gluconate, glucuronate, Glutamate, glycerophosphate, glycolate, hemisulphate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane sulfonate, isobutyrate, lactate, lactose. Bionate, laurate, maleate, maleate, malonate, mandelate, methanesulfonate, naphthalene-1,5-disulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, octanoate, oleate ate, orotate, oxalate, 2-oxoglutarate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pidolate (L-pyroglutamate), pivalate , propionate, salicylate, sebacate, hydrogen sebacate, stearate, succinate, sulfate, tannate, tartrate, hydrogen tartrate, thiocyanate, tosylate and undecanoate. More preferably, it may be trisalt or fumaric acid. In one embodiment of the present invention, the dipeptidyl peptidase-4 inhibitor may be vildagliptin hydrochloride, fumaric acid salt, or free base. In the case of vildagliptin, it has greater moisture instability compared to other substances, so when applied to the oral solid composite preparation according to the present invention, the effect of improving productivity and stability may be greater. Instability to moisture limits the manufacturing methods of granules. When the moisture-sensitive dipeptidyl peptidase-4 inhibitor is granulated with its partner drug, metformin hydrochloride, conventionally, the dipeptidyl peptidase-4 is granulated by dry granulation, direct compression, or wet granulation of metformin hydrochloride. A method of granulating by adding an inhibitor was used. Here, the “dry granulation method” refers to a method of manufacturing granules without using an externally applied granulation solvent such as water or ethanol, and the “direct compression method” refers to direct purification without granulating the powder. It refers to the method of tableting. In addition, “wet granulation method” refers to a method of manufacturing granules in a wet state using a granulating solvent. However, the dry granulation method has problems such as poor dispersion of the active ingredient in the content and a large loss rate of the active ingredient, and the direct compression method has problems in that the dipeptidyl peptidase-4 inhibitor does not have good compatibility with excipients for direct compression, resulting in low activity. There is a problem of pharmaceutical incompatibility, such as decomposition of ingredients or decreased dissolution rate. In addition, the method of wet granulating metformin hydrochloride in advance has a problem in that content variation between preparations after manufacturing may increase due to differences in particle size and density between the metformin hydrochloride granule portion and the dipeptidyl peptidase-4 inhibitor.

In order to solve the above-mentioned problem, in the present invention, the active ingredients dipeptidyl peptidase-4 inhibitor and metformin were granulated using a mixed wet granulation method. Here, the “mixed wet granulation method” refers to a method of granulating metformin or dipeptidyl peptidase-4 inhibitor by mixing them together and then adding them to the wet granulation process without granulating them first. When wet granules containing a dipeptidyl peptidase-4 inhibitor and metformin are manufactured using the mixed wet granulation method and then formulated into various forms, the moisture content in the formulation can be basically kept low while the capping phenomenon is prevented during tableting. It does not occur and the attrition rate can be reduced, thereby increasing the productivity of the preparation. In addition, by minimizing the moisture contact of the dipeptidyl peptidase-4 inhibitor, which is vulnerable to moisture, even when wet granulation is performed, the generation of related substances is significantly reduced, thereby increasing stability.

The oral solid composite preparation according to the present invention is a wet formulation prepared by homogeneously mixing a granule-forming composition containing a dipeptidyl peptidase-4 inhibitor or a pharmaceutically acceptable salt thereof, and metformin or a pharmaceutically acceptable salt thereof. Contains granules. Here, “homogeneously” means that either the active ingredients dipeptidyl peptidase-4 inhibitor or metformin are supplied in a similar powder form and are evenly dispersed, without being granulated first. The wet granules may be manufactured by various wet granulators commonly used in the pharmaceutical field, but according to one embodiment of the present invention, the wet granules may be preferably manufactured in a fluidized bed granulator. When using the fluid bed granulator, the contact time between the active ingredient and moisture can be reduced compared to producing mixed wet granules using a conventional high shear granulator, etc., thereby minimizing the generation of related substances.

To produce the wet granules, a binder may be used. The binder generally has the functionality of agglomerating the powdered material, and may be added to the granulation mixture to stabilize the resulting granules during the granulation step of the active ingredient. The binder may be mixed with the active ingredients to form a granule forming composition before being added to the fluidized bed granulator, or it may be prepared in the form of a binder solution with a solvent such as purified water and added simultaneously to the fluidized bed granulator without prior mixing with the active ingredients. It could be. In the present invention, an excess amount of binder is mixed with the active ingredients without a solvent such as purified water to form a composition for granule formation, and a relatively small amount of binder is mixed with purified water and fed into a fluidized bed granulator together with the composition for granule formation. It is possible to produce stable wet granules with low moisture content. According to an embodiment of the present invention, the binder may be hydroxypropyl cellulose, povidone, hydroxypropyl methylcellulose, or a mixture thereof. The content of the binder may be 1 to 20% by weight, preferably 1 to 10% by weight, and more preferably 5 to 10% by weight, based on the total weight of the solid composite preparation. Outside the above range, the desired effect due to the addition of the binder may not be obtained.

According to one embodiment of the present invention, the solid composite preparation for oral use consists of a binder in solid form and a binder contained in the liquid in a dry weight ratio of 3:1 to 9:1, preferably 4:1 to 9:1. may be included. When the binder is included in the above ratio, moisture contact of vildagliptin can be minimized and wet granulation can be performed to maintain stability, and when forming granules, the proportion of granules less than 75 μm is 30% or less, preferably 25% or less, more preferably is maintained below 20%, allowing for excellent tableting properties.

The oral solid composite preparation according to the present invention may further include one or more pharmaceutically acceptable additives selected from the group consisting of diluents, disintegrants, lubricants, stabilizers, and combinations thereof. The additives may be mixed with wet granules after production of wet granules and included in an oral solid composite preparation.

The diluent is, for example, selected from the group consisting of microcrystalline cellulose, mannitol, pregelatinized starch, di- or tri-basic calcium phosphate, hydroxypropyl cellulose, lactose, cellulose and its derivatives, sorbitol, xylitol, and any combinations thereof. There may be more than one species, but it is not limited thereto. The content of the diluent may be 1 to 30% by weight, preferably 1 to 20% by weight, based on the total weight of the solid composite preparation. Outside the above range, the desired effect due to the addition of the diluent may not be obtained.

The disintegrant is, for example, 1 selected from the group consisting of croscarmellose sodium, sodium starch glycolate, corn starch, crospovidone, low-substituted hydroxypropylcellulose, pregelatinized starch, and any combination thereof. There may be more than one species, but it is not limited thereto. The content of the disintegrant may be 0.1 to 10% by weight, preferably 0.5 to 5% by weight, and more preferably 0.5 to 2% by weight, based on the total weight of the solid composite preparation. Outside the above range, the desired effect due to the addition of the disintegrant may not be obtained.

The lubricants include, for example, stearic acid, stearic acid metal salts (e.g., calcium stearate, magnesium stearate, etc.), talc, colloidal silica, sucrose fatty acid ester, hydrogenated vegetable oil, wax, glyceryl fatty acid ester, glycerol It may be selected from the group consisting of behenate, and any combination thereof, but is not limited thereto. The content of the lubricant may be 0.1 to 10% by weight, preferably 0.5 to 5% by weight, and more preferably 0.7 to 2% by weight, based on the total weight of the solid preparation. Outside the above range, the desired effect may not be achieved by adding a lubricant.

The stabilizer may be an antioxidant, acidifying agent, or alkalinizing agent, but is not limited thereto. The content of the stabilizer may be 0.1 to 10% by weight, preferably 0.3 to 5% by weight, and more preferably 0.3 to 2% by weight, based on the total weight of the solid preparation. Outside the above range, the desired effect due to the addition of the stabilizer may not be obtained.

Wet granules according to one embodiment of the present invention may have 25% or more of particles with a particle diameter of 150 ㎛ or more. In the wet granules, the number of particles having a particle diameter of less than 75㎛ may be 30% or less, preferably 25% or less, and more preferably 20% or less. When the wet granules have a particle distribution within the above-mentioned range, the attrition rate can be improved and the incidence of problems that may occur during tableting, such as capping, can be reduced.

The oral solid composite preparation according to the present invention has a low moisture content by containing the above-described wet granules. According to one embodiment of the present invention, the oral solid composite preparation is 1% by weight or less, specifically 0.8% by weight or less, more specifically 0.3 to 0.8% by weight, more preferably, based on the total weight of the combination preparation. Typically, it may have a moisture content of 0.3 to 0.6% by weight. In this way, oral solid combination preparations of a DPP-4 inhibitor and metformin hydrochloride with a low moisture content of 0.8 or 1% by weight or less are excellent in stability as there is little generation of related substances even when stored for a long time.

As used herein, “solid composite preparation” refers to a preparation made by molding or encapsulating a drug containing two or more active ingredients into a certain shape. The oral solid composite preparation may be made of wet granules or any oral solid complex preparation that may contain wet granules, for example, dry syrup, granules, tablets (including single-layer tablets, double-layer tablets, inner core tablets, etc.) , pellets, or capsules, etc., specifically tablets (including single-layer tablets, double-layer tablets, inner core tablets, etc.) or capsules, but are not limited thereto. The solid composite preparation may be one filled with wet granules in the form of tablets, pellets, or capsules. The tablets, pellets, and capsules may be those commonly used in the art. The capsule may be a hard capsule or a soft capsule. When the oral solid composite preparation is a capsule, the capsule may be in a form containing granules or tablets therein. In one embodiment of the present invention, the solid composite preparation may be a tablet containing wet granules. In one embodiment of the present invention, the oral solid composite preparation may be a tablet.

The solid combination preparation may be a solid combination preparation for preventing or treating diseases related to dipeptidyl peptidase IV (Dipeptidyl peptidase-4: DPP-IV). The solid combination preparation is used for non-insulin-dependent diabetes, arthritis, obesity, allograft rejection, calcitonin-osteoporosis, heart failure, impaired glucose metabolism or impaired glucose tolerance, neurodegenerative diseases, cardiovascular or renal diseases, and neurodegenerative or cognitive disorders, hyperglycemia. , insulin resistance, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL level, high LDL level, atherosclerosis, vascular restenosis, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, Retinopathy, nephropathy, neuropathy, and osteoporosis. The solid combination preparation may produce a sedative or anxiolytic effect, attenuate postoperative catabolic changes or hormonal responses to stress, reduce mortality and morbidity after myocardial infarction, hyperlipidemia or related It can be used to control symptoms or lower VLDL, LDL, or Lp(a) levels. In one embodiment of the present invention, the solid preparation can be used for the prevention or treatment of non-insulin-dependent diabetes, arthritis, obesity, osteoporosis, and other symptoms of impaired glucose tolerance. The term “prevention” refers to all actions that suppress or delay the onset of the disease by administering the pharmaceutical composition. The term “treatment” refers to any action that improves or beneficially changes the symptoms of the disease by administering the pharmaceutical composition.

The solid combination preparation may be for oral administration depending on the purpose of treatment. The dosage of the solid combination preparation is, for example, in the case of a DPP-4 inhibitor/metformin combination preparation, more specifically, a vildagliptin/metformin hydrochloride combination preparation, about 0.001 mg/kg to about 100 mg/kg based on adults, It may range from about 0.01 mg/kg to about 10 mg/kg, or from about 0.1 mg/kg to about 1 mg/kg. The administration may be administered once a day, multiple times a day, or once a week, once every two weeks, once every three weeks, or once every four weeks to once a year. In one embodiment of the present invention, the solid preparation can be administered at 50/1000 mg per day once a day in the morning, or 100 mg per day at 50/1000 mg twice a day in divided doses in the morning and evening, 100 mg per day can be administered in divided doses of 50/500 mg twice a day in the morning and evening. In one embodiment of the present invention, the solid combination preparation of the present invention may contain 50 mg/500 to 1000 mg of DPP-4 inhibitor/metformin in each preparation, but is not limited thereto.

One embodiment of the present invention provides an oral solid composite preparation containing wet granules prepared by homogeneously mixing a granule-forming composition containing vildagliptin or its hydrochloride and metformin hydrochloride.

According to another aspect of the present invention, the present invention provides a method for producing the above-described oral solid composite preparation. The manufacturing method includes (a) preparing a composition for forming granules containing a dipeptidyl peptidase-4 inhibitor or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof, and (b) forming the granules. It includes the step of mixing the composition homogeneously and then producing wet granules through a granulation process. Here, the granulation process may be a fluid bed granulation process.

In the manufacturing method, in step (a), the composition for granule formation further includes a binder, and in step (b), the binder solution includes 5 to 10% by weight of a binder together with the composition for granule formation in the fluidized bed granulation process. can be input. The remaining component in the binding solution, excluding the binder, is a solvent capable of dissolving the binder, and this solvent may be water, or any other suitable solvent such as ethanol, isopropanol, or solvent mixtures (including aqueous solutions). The solvent may preferably be water. According to one embodiment of the present invention, the weight ratio of the binder included in the composition for forming granules in step (a) and the binder included in the binder solution in step (b) may be 4:1 to 9:1. By dispersing the binder in this way, stable wet granules can be manufactured while minimizing the moisture content in the wet granules containing the moisture-sensitive dipeptidyl peptidase-4 inhibitor. Parts not specifically disclosed in the above manufacturing method follow the above description.

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are only for illustrating the present invention and the scope of the present invention is not limited thereto.

Example

Example 1 to 5: metformin and vildagliptin Manufacturing of mixed wet granules

Since metformin has the property of hardening during storage, it was prepared by decompaction using Erweka all-purpose (AR-402) equipped with a 0.85 mm screen, and other raw materials were also prepared by sieving using a 0.6 mm screen. Excipients used as binders such as HPC-L, HPC-EXF, PVP K-30, and HPMC P-645 were weighed by dividing them into the granule input amount (X/-) and the binder input amount (-/Y), and purified water A binding solution was prepared using. At this time, purified water and binder were prepared in a ratio of 5 to 10% (w/w). Metformin hydrochloride, vildagliptin or its hydrochloride, and binder were added to a fluidized bed granulator (GR, XP-70) and mixed homogeneously for 3 minutes, and then the binder was added using a top spray method to form granules. After the binder was added, the granules were dried until they reached the drying temperature of the FBG (Fluidized Bed Granulator) process conditions and then sized using a cored mill equipped with a 0.6 mm sieve. Afterwards, the disintegrant was added using a V-mixer and mixed for 5 minutes at 50 rpm, and the lubricant was added and mixed for an additional 3 minutes. The mixed granules were compressed into tablets using a rotary tablet press (GRC-18) at a compression pressure of 7 to 9 kgf, and a coating weight of about 3 mg/cm ² was applied to the compressed core tablets using a coating machine (SFC-30).

The contents of the raw materials used in the production of wet granules in Examples 1 to 5 are shown in Table 1 below.

Ingredients (unit: mg) Example 1 Example 2 Example 3 Example 4 Example 5 metformin hydrochloride 1000 1000 1000 1000 1000 vildagliptin 50 - 50 50 50 Vildagliptin hydrochloride - 56 - - - HPC-L 85/15 90/10 - - - HPC-EXF - - 80/20 - - HPMC P-645 - - - 80/20 - PVP K-30 - - - - 80/20 microcrystalline cellulose - - - 100 - Lactose Anhydrous - - - - 100 Croscarmellose Sodium 12 - 12 15 10 Crospovidone - 12 - - 5 magnesium stearate 10 10 10 10 10

Additionally, the FBG process conditions in Examples 1 to 5 are shown in Table 2 below.

Examples 1 to 2 Example 3 Examples 4 to 5 Supply air temperature (℃) 28 35 32 Product temperature (℃) 27 31 29 Spray speed (g/min) 3.5 2.5 3.5 Drying temperature (℃) 32 32 32

Comparative example 1: Control drug ( Galvusmet Tab 50/1000mg, WV382)

Galvusmet Tab 50/1000mg (manufacturer: Novartis Korea), a commercial product containing metformin hydrochloride and vildagliptin as active ingredients, was used as Comparative Example 1.

Comparative example 2: After manufacturing metformin wet granules through fluid bed granulation process vildagliptin mix

Metformin hydrochloride and binder were added to the fluidized bed granulator and mixed homogeneously for 3 minutes, then the binder was added using a top spray method to form granules. After adding the binder, additional drying was performed at 27°C for about 3 minutes, and then sizing was performed using a cored mill incorporating a 0.6mm sieve. Afterwards, vildagliptin and disintegrant were added using a V-mixer and mixed at 50 rpm for 5 minutes, and a lubricant was added and mixed for an additional 3 minutes. Here, the content of the raw materials used is the same as Table 3 below, the process conditions are the same as Table 4 below, and other conditions, including tabletting and coating processes, except for the above-described details, were carried out in the same manner as in Example 1.

Comparative example 3: Metformin and vildagliptin Manufacturing of mixed wet granules

Except that the content of the raw materials used was adjusted as shown in Table 3 below, and the process conditions were adjusted as shown in Table 4 below, the remaining conditions were carried out in the same manner as in Example 1.

Comparative example 4: high shear Metformin through granulation process and vildagliptin Manufacturing of mixed wet granules

Add metformin hydrochloride, vildagliptin hydrochloride, and binder to a high shear granulator (SF-15L) and mix for 3 minutes to ensure homogeneity. Then, add the prepared binder solution at a constant rate (approximately 37 g/min) for 3 minutes to form granules. formed. After adding the binder, additional granulation is performed for 2 minutes, and the granules are placed in a fluidized bed dryer (GR, XP-70) and dried until the granule moisture is below 1% LoD. Using a cored mill equipped with a 0.6mm sieve, Establish it. Afterwards, the disintegrant was added using a V-mixer and mixed for 5 minutes at 50 rpm, and the lubricant was added and mixed for an additional 3 minutes. The content of the raw materials used here is the same as Table 3 below, and the remaining conditions, including tabletting and coating processes, except for the details described above, were carried out in the same manner as in Example 1.

Comparative example 5: direct hit metformin through process and vildagliptin Manufacturing of mixed wet granules

Metformin hydrochloride, vildagliptin or a pharmaceutically acceptable salt thereof, a binder, and a disintegrant were added and mixed for 5 minutes using a V-mixer. Magnesium stearate was additionally added as a lubricant, mixed for an additional 2 minutes, and then compressed into tablets using a rotary tablet press (GRC-18) at a tableting pressure of 7 to 9 kgf. The content of the raw materials used here was the same as Table 3 below.

Ingredients (unit: mg) Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 metformin hydrochloride 1000 1000 1000 1000 vildagliptin 50 50 - 50 Vildagliptin hydrochloride - - 56 - HPC-EXF 80/20 100/- 80/20 100 Croscarmellose Sodium 12 12 - - magnesium stearate 10 10 10 10

Comparative Examples 2 to 3 Supply air temperature (℃) 28 Product temperature (℃) 27 Spray speed (g/min) 3.5 Drying temperature (℃) 27

Experiment example

Experiment example 1: Particle size distribution and tabletting evaluation

The particle size distribution and tableting properties of tablets according to Examples and Comparative Examples were measured, and the results are shown in Table 5 and Figures 1 and 2 below.

Example 1 Example 3 Example 5 Comparative Example 3 Comparative Example 4 Comparative Example 5 Granule particle size distribution (%) 500μm or more 0.6 0 0.2 0.1 18.6 0.1 More than 250 μm ~ Less than 500 μm 20.9 2.6 16.1 1.6 33.2 0.1 More than 150μm ~ Less than 250μm 42.1 26.4 35.5 18 31.6 8.1 More than 75μm ~ Less than 150μm 25.8 51.5 30.3 35.6 10.8 39.6 Less than 75μm 10.6 19.5 17.9 44.7 5.8 52.1 Tablet performance (frequency of capping occurrence (%)) 0.5 or less 0.5 or less 0.5 or less over 65 0.5 or less over 90

According to Table 5 and Figures 1 and 2, when the number of particles with a particle size of 150 μm or more is 25% or more and the number of particles with a particle size of less than 75 μm is 30% or less, problems that may occur during tableting, such as capping, rarely occur. didn't When granules were manufactured through the fluidized bed granulation process (Examples 1, 3, and 5), the proportion of particles in the range of 75 to 250 μm was high, resulting in low particle size variation.

Experiment example 2: granular powder Tablet hardness and moisture content Masondo evaluation

The moisture content of the granules and the hardness and friability of the tablets according to the examples and comparative examples were measured, and the results are shown in Table 6 below. Specifically, the moisture of each granule was measured using a Karl fischer (metrohm, 870 KF titrino plus), and after measuring the moisture, tablets were obtained by finally tableting according to each manufacturing method. Afterwards, the hardness of each tablet was measured using a durometer (ERWEKA, TB310 MD), and the friability was measured (25 rpm 4 minutes) according to USP General Chapters: <1216> TABLET FRIABILITY using a friability meter (ERWEKA, TAR 220). The degree was measured.

Example 1 Example 3 Example 5 Comparative Example 3 Comparative Example 4 Comparative Example 5 Granule moisture (K/F)(%) 0.50 0.43 0.59 1.56 0.85 0.32 Hardness (kp) 23 18 20 8 30 4 Friability (%) 0.36 0.44 0.31 1.49 0.28 over 10

According to Table 6, when producing granules through the fluidized bed granulation process (Examples 1, 3, and 5), tablets with the desired hardness (12-24 kp) can be obtained even when the granule moisture is less than 1%. Friability was also good, within 0.5%.

Experiment example 3: Evaluation of content uniformity of tablets

The content uniformity of metformin hydrochloride and vildagliptin was measured according to the content test method of the Korean Pharmacopoeia General Test Method for Preparation Uniformity, and the results are shown in Table 7 below.

Example 1 Example 3 Comparative Example 2 Content uniformity of metformin hydrochloride (%) 2.1 2.4 4.8 Content uniformity of vildagliptin (%) 6.9 5.0 12.6

According to Table 7, metformin hydrochloride had relatively good content uniformity compared to vildagliptin. In Examples 1 and 3, in which both metformin hydrochloride and vildagliptin were mixed and granulated, the content uniformity was improved by about two times compared to Comparative Example 2, in which vildagliptin was separately mixed and granulated after metformin hydrochloride granulation. In particular, the content uniformity of vildagliptin was improved to about 5.7-7.6%, which is expected to be due to a separation phenomenon due to the difference in particle size between the metformin hydrochloride granule and the main component of vildagliptin.

Experiment example 4: Evaluation of moisture content and stability of tablets

The moisture content and amount of related substances of the tablets according to Examples and Comparative Examples were measured, and the results are shown in Table 8 below. Specifically, the moisture of the tablets according to Examples and Comparative Examples was measured using Karl fischer (metrohm, 870 KF titrino plus). In addition, the tablets prepared according to Examples and Comparative Examples were packaged in Al-Al blister, and Comparative Example 1, which used a commercially available control drug, was packaged in commercially available (Al-Al) blister packaging, respectively, in a 60°C chamber. After storing for 7 days (Labfine, FLT-600S), a test was conducted to measure flexible substances. Liquid chromatography using an appropriate diluted solution capable of extracting the main component, for example, a solution of 0.01 M hydrochloric acid aqueous solution and acetonitrile mixed in an appropriate ratio, and adjusting the final concentration of vildagliptin to 2000 μg/mL as the sample solution. was performed, and the degree of production of related substances was analyzed.

<Analysis conditions>

Detector: Ultraviolet absorptiometry (measurement wavelength: 210nm)

Column: 250mm C18 column

Mobile phase: pH 8.2 buffer, pH 4.2 buffer, methanol gradient solvent transport analysis

Flow rate: 1.0 ml/min

Column temperature: 30℃

Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 Comparative Example 4 Purified moisture (K/F) (%) 0.52 0.66 0.43 0.77 0.60 1.32 1.55 0.91 Amide related substances (Imp.7) ¹⁾ (%) 0.12 0.16 0.13 0.20 0.18 0.43 0.36 1.59 Imine related substances (RRT 0.88) ²⁾ (%) 0.10 0.12 0.06 0.19 0.13 0.40 0.34 0.87 Total related substances (%) 0.27 0.38 0.22 0.60 0.39 1.41 1.09 2.79 1) It is a compound having the following exemplary structure.

2) It is a compound having the following exemplary structure.

According to Table 8, it was confirmed that the amount of related substances increased by about 1.8 to 3 times in Comparative Examples 1 and 2 where the moisture content was 1% by weight or more. In the case of Comparative Example 4, although the moisture content was lower than that of Comparative Example 2 during storage, it was confirmed that the amount of related substances increased significantly. This is because the main component of Vildagliptin was in contact with a large amount of moisture for a long time in the high shear granulator, resulting in a change in physical properties. is expected to have occurred.

So far, the present invention has been examined focusing on its preferred embodiments. A person skilled in the art to which the present invention pertains will understand that the present invention may be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered from an illustrative rather than a restrictive perspective. The scope of the present invention is indicated in the claims rather than the foregoing description, and all differences within the equivalent scope should be construed as being included in the present invention.

Claims (15)

A method for producing a 50 mg/500 to 1000 mg dipeptidyl peptidase-4 inhibitor/metformin oral solid combination formulation,
The manufacturing method includes (a) preparing a composition for granule formation comprising a dipeptidyl peptidase-4 inhibitor or a pharmaceutically acceptable salt thereof, metformin or a pharmaceutically acceptable salt thereof, a binder, a disintegrant, and a lubricant. ; and
(b) mixing the granule forming composition homogeneously and then producing wet granules through a fluidization granulation process using a binding liquid containing a binder,
In the oral solid combination preparation,
The binder includes hydroxypropyl cellulose, povidone, hydroxypropyl methylcellulose, or a mixture thereof, and the content of the binder is 1 to 20% by weight based on the total weight of the solid composite preparation,
The content of the disintegrant is 0.1 to 10% by weight based on the total weight of the solid composite preparation,
The content of the lubricant is 0.1 to 10% by weight based on the total weight of the solid preparation,
The content of the active ingredients of the dipeptidyl peptidase-4 inhibitor and metformin is 98.8% by weight or less,
The weight ratio of the binder contained in the composition for forming granules in step (a) and the binder contained in the binder solution in step (b) is 3:1 to 9:1,
The dipeptidyl peptidase-4 inhibitor or a pharmaceutically acceptable salt thereof is vildagliptin or a pharmaceutically acceptable salt thereof,
A method for producing an oral solid composite preparation wherein the weight ratio of vildagliptin or a pharmaceutically acceptable salt thereof and the binder contained in the binder solution in step (b) is 56:10 to 50:20. delete delete delete delete In claim 1,
A method for producing an oral solid combination preparation, characterized in that the oral solid combination preparation further comprises one or more pharmaceutically acceptable additives selected from the group consisting of diluents, stabilizers, and combinations thereof. In claim 1,
A method for producing an oral solid composite formulation, characterized in that the oral solid composite formulation has a moisture content of 0.8% by weight or less based on the total weight of the composite formulation. In claim 1,
A method for producing an oral solid composite preparation, characterized in that the wet granules contain 30% or less of particles with a particle diameter of less than 75㎛. In claim 1,
A method for producing an oral solid composite preparation, characterized in that the wet granules contain 25% or more of particles with a particle diameter of 150㎛ or more. In claim 1,
A method for producing an oral solid composite preparation, characterized in that the oral solid combination preparation is a tablet or capsule. delete delete delete delete delete