KR102622198B1 - Solid formulation for oral administration containing vildagliptin and a process for the preparation thereof - Google Patents

Abstract

Provided is an oral solid formulation comprising wet granules containing vildagliptin hydrochloride and a diluent with improved storage stability, compatibility, and dissolution rate, and a method for manufacturing the same.

Description

Solid formulation for oral administration containing vildagliptin and a process for the preparation thereof}

It relates to an oral solid formulation containing vildagliptin and a method for manufacturing the same, and more specifically, to a highly stable oral solid formulation of vildagliptin containing a novel salt of vildagliptin and a method for producing the same.

Vildagliptin is an N-substituted-2-cyanopyrrolidine compound that acts as an inhibitor of dipeptidyl peptidase-4 (DPP-IV). DPP-IV inhibits glucagon-like peptide-1 (GLP-1), one of the main stimulators of pancreatic insulin secretion, and GLP-1 has a positive effect on glucose conversion. Therefore, inhibition of DPP-IV is effective in treating diseases such as non-insulin dependent diabetes mellitus (NIDDM). Patent Document 1 discloses that the compound is useful in the treatment of non-insulin dependent diabetes, arthritis, obesity, osteoporosis, and other conditions of impaired glucose tolerance.

However, vildagliptin is known to be unstable in moisture, and Patent Document 2 discloses a direct compression tablet containing a high dose of a DPP-IV inhibitor to solve this problem. In order to manufacture vildagliptin tablets by direct compression, pharmaceutical excipients such as binders for direct compression must be added, but vildagliptin has poor compatibility with these pharmaceutical excipients and has poor stability over time. As it deteriorates, the drug may decompose or produce by-products that can be harmful when taking the drug. In addition, vildagliptin has a rapid time to reach peak blood concentration (Tmax) of 1.5 to 2.0 hours, so in order to obtain the desired therapeutic effect after being administered in tablet form, it needs to be rapidly disintegrated and dissolved and absorbed into the body at the beginning. . Nevertheless, it was difficult to improve both the stability and dissolution rate of vildagliptin using conventional methods.

Therefore, there is a need to develop a vildagliptin-containing formulation that does not decompose even after long-term storage, has good compatibility with pharmaceutical additives, and does not reduce the dissolution rate.

International Publication No. 2000-034241 Korean Registration Publication No. 10-1259645

Provided is an oral solid formulation containing vildagliptin that has excellent storage stability and mixing stability with excipients, is easy to control, and has a high initial dissolution rate.

A method for manufacturing an oral solid formulation containing vildagliptin that has excellent storage stability, compatibility, and dissolution rate and is easy to control is provided.

One aspect provides an oral solid dosage form comprising wet granules prepared from a mixture comprising vildagliptin hydrochloride and a diluent.

As used herein, the term "Vildagliptin" refers to an N-substituted-2-cyanophyte represented by the following formula (1), which acts as one of the inhibitors of dipeptidyl peptidase-4 (DPP-IV). Refers to a rolidine-based compound. The vildagliptin specifically refers to the compound (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine).

[Formula 1]

The vildagliptin may refer to both its active metabolites and prodrugs. The “metabolite” is an active derivative of vildagliptin that can be produced when vildagliptin is metabolized, and the “prodrug” is metabolite(s) that are metabolized to vildagliptin, or are the same as vildagliptin. refers to a compound that is metabolized into In addition, the vildagliptin may include all of its pharmaceutically acceptable salts, crystal forms, hydrates, solvates, diastereomers, or enantiomers.

The vildagliptin is prone to decomposition in the presence of moisture, generating related substances, and when mixed with pharmaceutical additives, the dissolution rate is likely to decrease or show undesirable interactions, thereby improving the stability and dissolution rate of the preparation and simultaneously improving the pharmaceutical additive. There is a need to develop a formulation that can improve compatibility with.

As used herein, the term "direct compression process" or "direct compression process" or "direct compression process" refers to a method of compressing powder directly into tablets without granulating, and has a relatively short disintegration time and active Ingredients can be released and absorbed quickly. However, vildagliptin has a problem of poor compatibility with excipients for direct compression, showing pharmaceutical incompatibility such as decomposition of the active ingredient or decreased dissolution rate.

As used herein, the term "dry granule" refers to granules manufactured in a dry state, specifically manufactured substantially without the use of externally applied granulating solvents such as water or ethanol, and used in the pharmaceutical field. It can be manufactured by any dry granulation process used in. The dry granules can be made by compressing the powder mixture into large pieces and crushing or granulating them to size granules, and can also be used as the term "compression granulation." This method can improve the moisture stability of vildagliptin by not using water, but there is still a need to further improve the uniformity of the active ingredient content, poor dispersibility, and a large loss rate of the active ingredient. There is.

As a result of research in this specification, this problem was solved by containing vildagliptin in the form of hydrochloride and formulating it into wet granules.

As used herein, the term “wet granule” refers to granules manufactured in a wet state, and may be manufactured by a wet granulation process. The wet granulation process has excellent fluidity and flowability compared to the direct compression process in which granules are directly compressed into tablets, resulting in excellent fillability and productivity. There is empty space between the granules, so they do not clump up when placed in water, increasing the surface area. Because it expands, it has the advantage of improved solubility. In addition, since all manufactured granules contain the same amount of drug, the drug content uniformity is good and there is an advantage in preventing separation of the drug from excipients, which can occur in the direct compression process or dry granulation process. In other words, wet granules have relatively increased powder cohesion and compressibility, and can maintain their shape even after drying, preventing separation of components. The wet granules can be manufactured by any wet granulation method, and can be manufactured using a general wet granule manufacturing machine used to manufacture wet granules in the pharmaceutical field, such as a fluidized bed granulator or a spray dryer. In one embodiment, the wet granules may be manufactured by a fluid bed granulator.

The salt of vildagliptin may be an acid addition salt such as a hydrochloride salt. In the vildagliptin acid addition salt, the stoichiometric ratio of acid and vildagliptin may be substantially 1:1. In one embodiment, vildagliptin may be included as vildagliptin hydrochloride. The vildagliptin hydrochloride salt may include corresponding solvates (e.g., hydrates) and polymorphic modifications, and amorphous forms, as appropriate and advantageous. The vildagliptin hydrochloride may be included in an amount of about 1% to about 50% by weight, about 10% by weight to about 40% by weight, or about 20% by weight to about 40% by weight based on the total amount of the solid preparation. In a range lower than the above range, the total amount of solid preparation compared to one dose increases, which may increase the size of the tablet, which may reduce the patient's convenience in taking it. In the higher range, the ratio of diluent to the main ingredient with high viscosity, low diluent ratio, relatively small tablet mass, etc. As a result, binding force increases, making it difficult to achieve rapid efficacy, and thus, the desired effect according to vildagliptin formulation may not be obtained.

As a result of the test, the vildagliptin hydrochloride shows less change in the content of the main ingredient and generates less related substances under harsh and accelerated conditions than the free form of vildagliptin (salt-free), and the vildagliptin hydrochloride is more stable than the free form of vildagliptin. was confirmed (see Test Example 1). In addition, vildagliptin hydrochloride showed a higher viscosity increase than the free form of vildagliptin when exposed to moisture. From this, vildagliptin hydrochloride showed a binding force similar to that of a binder when in contact with moisture due to its own properties alone. This was confirmed (see Test Example 2). In addition, it was confirmed that the vildagliptin hydrochloride generates less related substances and is more stable under harsh and accelerated conditions when manufactured as a wet granule tablet than the vildagliptin free type (unsalted) (see Test Examples 3 and 4).

As used herein, “diluent” refers to a substance used to increase the total weight of a solid formulation, such as microcrystalline cellulose, mannitol, pregelatinized starch, dibasic or tribasic calcium phosphate, hydroxypropyl cellulose, etc. It may be one or more selected from the group consisting of L-HPC, HPC-L, EXF, lactose, cellulose and its derivatives, sorbitol, xylitol, and any combination thereof, but is not limited thereto. In one embodiment, the diluent may be one or more selected from the group consisting of microcrystalline cellulose, D-mannitol, pregelatinized starch, anhydrous calcium phosphate, and any combination thereof. The content of the diluent may be about 1% by weight to about 70% by weight, about 20% by weight to about 60% by weight, or about 30% by weight to about 60% by weight based on the total amount of the solid preparation. Outside the above range, the desired effect due to the addition of the diluent may not be obtained.

As used herein, “binder” generally refers to a substance other than water, such as distilled water, that binds primary particles of a powdered material into secondary aggregates by imparting cohesive qualities to the powdered material. For example, the binder may be included in the granulation step of the active ingredient and added to the granulation mixture to stabilize the resulting granules. In this case, the binder is said to be present in the “internal phase”. Alternatively, the binder may be added after completion of the granulation step, in which case the binder is said to be present in the “external phase”. Accordingly, it should be understood that the term “internal phase” refers to the composition inside the granule and the term “external phase” refers to the composition outside the granule.

The binder can optionally be added to the mixture of powdered materials as a dry powder, or dissolved or suspended in water, or any other suitable solvent such as ethanol, isopropanol, or solvent mixtures (including aqueous solutions), and then added as a liquid. . A mixture containing hydrochloride and a diluent for preparing wet granules included in a solid preparation according to one embodiment may not contain a binder. The wet granules do not contain a binder and can be manufactured using water as a solvent. In one embodiment, the mixture containing hydrochloride and diluent for preparing the wet granules may include water as a solvent in the “internal phase of the granules.” In one embodiment, the water may be included in an amount of about 0.8% by weight to about 8% by weight, about 1% by weight to about 6% by weight, and preferably about 3% by weight based on the total amount of the solid preparation. In one embodiment, the solid formulation may not contain a binder inside the granules. In one embodiment, the solid formulation may be prepared using only water, for example, distilled water, instead of the binder.

In one embodiment, when the solid preparation is a tablet, the tablet may be manufactured using 2 to 8 mL of distilled water as a solvent for producing granules per tablet. As a result of the test, if water is contained in an amount less than the above range, granules cannot be formed, and if water is contained in a larger amount, the stability is reduced, the production of granules is not good, or the amount of related substances is increased. .

In one embodiment, to prepare the wet granules, the solvent is included in an amount of about 0.8% by weight to about 8% by weight, specifically about 1% by weight to about 6% by weight, and more specifically about 3% by weight based on the total amount of the solid preparation. When used, it can have a viscosity of about 2 mPas to 15 mPas, so the solvent alone can act as a binder.

In one embodiment, the mixture containing hydrochloride and diluent for preparing the wet granules may not contain hydroxypropyl cellulose (HPC) or povidone as a binder in the “internal phase of the granule.”

In one embodiment, the viscosity of vildagliptin hydrochloride present in the wet granules may be 2 mPas to 15 mPas at 25°C and 5% aqueous solution. For example, the viscosity of vildagliptin hydrochloride present in the wet granules may be 2 mPas to 15 mPas, 2 mPas to 10 mPas, and 3 mPas to 10 mPas in a 5% aqueous solution condition at 25°C. As the wet granules have a viscosity in the above range, wet granules with excellent granule properties and dissolution rate can be formed. If the wet granules have a viscosity lower than this range, granules are not produced, or even if they are produced, the granule strength is low and the granules are easily broken. Abrasion may occur, and if the viscosity is higher than this range, the binding force of the granules may increase, which may have the effect of delaying the initial drug release. In one embodiment, the solid formulation may further include one or more pharmaceutically acceptable additives selected from the group consisting of disintegrants, lubricants, binders, stabilizers, and any combinations thereof.

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. In one embodiment, the disintegrant may be croscarmellose sodium or starch glycolate sodium. The content of the disintegrant may be about 1% by weight to about 20% by weight, about 1% by weight to about 10% by weight, or about 2% by weight to about 5% by weight based on the total amount of the solid 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. In one embodiment, the lubricant may be magnesium stearate. The content of the disintegrant may be about 1% by weight to about 20% by weight, about 1% by weight to about 10% by weight, or about 2% by weight to about 5% by weight based on the total amount of the solid preparation. Outside the above range, the desired effect due to the addition of the lubricant may not be obtained.

These binders refer to “external granule phase” binders that are added after completion of the wet granulation step. The granule external phase binder is, for example, hydroxypropyl cellulose (HPC), copovidone (copolymer of vinylpyrrolidone with other vinyl derivatives), and hydroxypropyl methylcellulose (HPMC). , polyvinyl pyrrolidone (povidone), macrogol, and any combination thereof, but is not limited thereto. The content of the binder may be about 1% by weight to about 20% by weight, about 1% by weight to about 10% by weight, or about 2% by weight to about 5% by weight based on the total amount of the solid preparation. Outside the above range, the desired effect due to the addition of the binder may not be obtained.

The stabilizer may be an antioxidant, acidifying agent, or alkalinizing agent, but is not limited thereto. The content of the stabilizer may be about 1% by weight to about 20% by weight, about 1% by weight to about 10% by weight, or about 2% by weight to about 5% by weight based on the total amount of the solid preparation. Outside the above range, the desired effect due to the addition of the stabilizer may not be obtained.

When formulating a drug, the dissolution or stability of the active ingredient may be reduced due to the characteristics of the additional excipients or interactions with the excipients. As used herein, the term "compatibility" or "pharmaceutical incompatibility" refers to the decomposition of the main ingredient or additive resulting in a decrease in concentration or softening due to inappropriate interaction between the raw drug substance and other excipients and additives. It refers to an element that evaluates whether there is an inappropriate change in the quality of a pharmaceutical product, such as the occurrence of substances or discoloration of the dosage form or packaging components. In this specification, the term may be used interchangeably with “mixing stability” as a term for evaluating the results of interaction with excipients.

As a result of testing the compatibility of excipients with the main ingredient in an oral solid dosage form according to one embodiment, vildagliptin or vildagliptin hydrochloride was relatively resistant to harsh and accelerated storage when mixed with lactose series such as anhydrous lactose used as a diluent. The amount of related substances generated increased and the mixing stability decreased (see Test Example 5). In addition, it was confirmed that microcrystalline cellulose, D-mannitol, pregelatinized starch, or anhydrous calcium phosphate as a diluent had better mixing stability with vildagliptin or vildagliptin hydrochloride (see Test Example 6).

Additionally, as a result of the test, vildagliptin or vildagliptin hydrochloride was subjected to severe and accelerated stress and acceleration when combined with hydroxypropyl cellulose (HPC) series such as HPC-L, L-HPC, etc., or povidone series such as povidone K30, which are used as binders. During storage, the amount of related substances generated increased and the mixing stability decreased (see Test Example 7).

When performing a dissolution test, the solid formulation may exhibit a dissolution rate of vildagliptin of 50% or more in 5 minutes and 85% or more in 10 minutes. When the solid preparation was tested for dissolution, the dissolution rate of vildagliptin was 50%, 55%, 60%, 65%, or 70% at 5 minutes, and 85%, 90%, 95%, or 99% at 10 minutes. You can.

The dissolution test can be performed by the paddle method according to the dissolution test method 2 of the Korean Pharmacopoeia. The dissolution test can be performed using pH 1.2 simulated gastric fluid (SGF) or 0.1 N hydrochloric acid solution. The dissolution test may be performed at 40 to 60 revolutions per minute (rpm), such as 50 rpm. The dissolution test may be performed at about 30°C to about 40°C, about 32°C to about 40°C, about 34°C to about 40°C, about 36°C to about 40°C, or about 37°C.

In this specification, “initial dissolution rate” means a dissolution rate within about 1.5 to 2.0 hours, for example, within 1 hour, specifically within about 30 minutes, and more specifically within about 10 minutes after oral administration. In one embodiment, the initial dissolution rate can be measured by performing a dissolution test in about 0.1 N hydrochloric acid solution at a paddle rotation speed of 50 rpm according to the dissolution test method 2 of the Korean Pharmacopoeia.

In one embodiment, the solid formulation has a dissolution test of more than 50% in 5 minutes and more than 85% in 10 minutes when dissolution is tested in a 0.1 N hydrochloric acid solution at a paddle rotation speed of 50 rpm according to the dissolution test method 2 of the Korean Pharmacopoeia. This may indicate the dissolution rate of liptin.

As a result of the test, the initial dissolution rate of vildagliptin hydrochloride decreased when mixed with hydroxypropyl cellulose (HPC) series such as HPC-L, L-HPC, etc., which are used as binders, or povidone series such as povidone K30 (test example) 8).

As used herein, “solid preparation” refers to a preparation made by molding or encapsulating a drug into a certain shape. The oral solid preparation may be made of wet granules or any oral solid preparation that may contain wet granules, for example, dry syrup, granules, tablets (including single-layer tablets, double-layer tablets, inner core tablets, etc.), It may be formulated as a pellet or capsule, but is not limited thereto. The solid 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, the solid preparation may be a tablet containing wet granules. In one embodiment, the oral solid dosage form is a tablet.

The solid preparation may be a solid preparation for preventing or treating diseases related to dipeptidyl peptidase IV (Dipeptidyl peptidase-4: DPP-IV). The solid preparation may be 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, retina. disease, nephropathy, neuropathy, syndrome It can be used for the treatment or prevention of diseases or conditions selected from osteoporosis. The solid formulation produces a sedative or anxiolytic effect, attenuates postoperative catabolic changes or hormonal responses to stress, reduces mortality and morbidity after myocardial infarction, hyperlipidemia or related symptoms. It can be used to control or lower VLDL, LDL, or Lp(a) levels. In one embodiment, 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 preparation may be for oral or parenteral administration depending on the purpose of treatment. The dosage of the solid preparation is, for example, about 0.001 mg/kg to about 100 mg/kg, about 0.01 mg/kg to about 10 mg/kg, or about 0.1 mg/kg to about 1 mg/kg based on adults. It may be within the range of 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, the solid preparation can be administered at 50 mg per day once a day in the morning or 100 mg per day divided into 50 mg twice a day in the morning and evening.

Another aspect includes a granulation step of preparing wet granules comprising vildagliptin hydrochloride and pharmaceutically acceptable excipients; and

A method for producing an oral solid dosage form according to the above aspect is provided, including a post-mixing step of preparing a mixture containing the granulated wet granules and pharmaceutically acceptable additives.

The vildagliptin hydrochloride, pharmaceutically acceptable additives, diluents, binders, disintegrants, lubricants, stabilizers, and wet granule manufacturing processes are as described above. The mixing of vildagliptin hydrochloride with a pharmaceutically acceptable additive selected from the group consisting of diluents, binders, disintegrants, lubricants, stabilizers, and any combinations thereof may be performed simultaneously or sequentially. The granulation step of producing wet granules containing vildagliptin hydrochloride can be performed using methods known in the art. The step of postmixing wet granules containing vildagliptin hydrochloride and pharmaceutically acceptable additives may be performed simultaneously or sequentially.

The manufacturing method may further include the step of drying the wet granules. The drying process may be performed through air drying, fluidized bed drying, oven drying, or microwave drying at a temperature not exceeding about 60°C, preferably not exceeding about 50°C, considering the stability of the active ingredient. . In the post-mixing step of mixing the wet granules with a pharmaceutically acceptable additive, the additive may be a disintegrant and/or a lubricant. In one embodiment, the disintegrant may be croscarmellose sodium. In one embodiment, the lubricant may be magnesium stearate.

Another aspect provides a method of preventing or treating non-insulin dependent diabetes, arthritis, obesity, osteoporosis, and other symptoms of impaired glucose tolerance, comprising administering to a subject an oral solid formulation according to one aspect.

According to one aspect, an oral solid formulation comprising wet granules containing vildagliptin hydrochloride and pharmaceutically acceptable additives, and a method for manufacturing the same, have excellent storage stability and compatibility, are easy to control, and , it is possible to provide an oral solid formulation containing vildagliptin with improved dissolution rate. The oral solid dosage form has excellent mixing stability with excipients, generates little decomposition products even when stored for a long period of time, and can have a high initial dissolution rate.

Figure 1 shows the content change (%) of vildagliptin free form and hydrochloride-containing wet granule tablets measured under severe conditions.
Figure 2 shows the content change (%) of vildagliptin free form and hydrochloride-containing wet granule tablets measured under accelerated conditions.
Figure 3 shows the amount of related substances generated (%) in vildagliptin free type and hydrochloride-containing wet granule tablets measured under severe conditions.
Figure 4 shows the amount of related substances generated (%) in vildagliptin free type and hydrochloride-containing wet granule tablets measured under accelerated conditions.
Figure 5 shows the content change (%) of wet granule tablets containing vildagliptin hydrochloride, fumarate, malonate, or tartrate measured under severe conditions.
Figure 6 shows the content change (%) of wet granule tablets containing vildagliptin hydrochloride, fumarate, malonate, or tartrate measured under accelerated conditions.
Figure 7 shows the amount of related substances generated (%) in wet granule tablets containing vildagliptin hydrochloride, fumarate, malonate, or tartrate measured under severe conditions.
Figure 8 shows the amount of related substances generated (%) in wet granule tablets containing vildagliptin hydrochloride, fumarate, malonate, or tartrate measured under accelerated conditions.
Figure 9(a) shows the properties of vildagliptin free form when exposed to moisture. Figure 9(b) shows the properties of vildagliptin hydrochloride when exposed to moisture.
Figure 10 shows the amount of related substances generated (%) in Comparative Examples 1 to 3 measured under severe conditions.
Figure 11 shows the amount of related substances generated (%) in Comparative Examples 1 to 3 measured under accelerated conditions.
Figure 12 shows the mixing stability of excipients for vildagliptin free form measured under severe conditions.
Figure 13 shows the mixing stability of excipients for vildagliptin hydrochloride measured under severe conditions.
Figure 14 shows the mixing stability of excipients for vildagliptin free form measured under accelerated conditions.
Figure 15 shows the mixing stability of excipients for vildagliptin hydrochloride measured under accelerated conditions.
Figure 16 shows the amount of related substances generated (%) in Comparative Example 3 and Examples 1 to 5 measured under severe conditions.
Figure 17 shows the amount of related substances generated (%) in Comparative Example 3 and Examples 1 to 5 measured under accelerated conditions.
Figure 18 shows the amount of related substances generated (%) in Comparative Examples 4 to 5 and Example 1 measured under severe conditions.
Figure 19 shows the amount of related substances generated (%) in Comparative Examples 4 to 5 and Example 1 measured under accelerated conditions.
Figure 20 shows the dissolution rate (%) measured for Comparative Examples 4 to 5 and Example 1.
Figure 21 shows the amount of related substances generated (%) in Examples 5 to 8 measured under severe conditions.
Figure 22 shows the amount of related substances generated (%) in Examples 5 to 8 measured under accelerated conditions.

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. Hereinafter, the present invention will be described in more detail through the following examples and comparative examples. However, the following examples and comparative examples are only for illustrating the present invention and do not limit the scope of the present invention.

Examples 1 to 9: Preparation of wet granule tablets containing (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine hydrochloride

Vildagliptin hydrochloride is mixed with a diluent selected from microcrystalline cellulose, D-mannitol, pregelatinized starch, and anhydrous dicalcium phosphate, according to the ingredients and contents (unit: mg) of the preparation shown in Table 1 (but mL for D.W.) Then, it was put into a fluidized bed granulator and went through the process of kneading, granulating, and drying with distilled water, and then sizing to produce granules. Then, the prepared granules were postmixed with croscarmellose sodium and magnesium stearate. The granules were compressed into tablets to prepare wet granule tablets. The granules were compressed into tablets to prepare wet granule tablets.

Ingredients (unit: mg) Example 1 Example
2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 process wet granulation Vildagliptin hydrochloride 56.0 56.0 56.0 56.0 56.0 56.0 56.0 56.0 56.0 microcrystalline cellulose 40.0 40.0 40.0 - - - - - - D-mannitol 40.0 - - - 40.0 40.0 40.0 40.0 40.0 luxury starch - 40.0 - 40.0 40.0 40.0 40.0 40.0 40.0 Anhydrous Calcium Diphosphate - - 40.0 40.0 - - - - - (D.W.) (5mL) (5mL) (5mL) (5mL) (5mL) (2mL) (8mL) (12mL) (1mL) Croscarmellose Sodium 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 magnesium stearate 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 Sum 143.0 143.0 143.0 143.0 143.0 143.0 143.0 143.0 143.0

Comparative Example 1: Preparation of direct compressed tablets containing (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine free form

According to the ingredients and contents of the formulation shown in Table 2, vildagliptin free form was mixed with microcrystalline cellulose, anhydrous lactose, sodium starch glycolate, and sodium stearate. The mixture was compressed into tablets to prepare compressed tablets.

Comparative Example 2: Preparation of wet granule tablets containing (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine free form

According to the ingredients and contents of the preparation shown in Table 2, the vildagliptin free form is mixed with microcrystalline cellulose and anhydrous lactose, then placed in a fluidized bed granulator, kneaded with distilled water, granulated, and dried, and then sized to form granules. Manufactured. Then, the prepared granules were postmixed with croscarmellose magnesium and sodium stearate. The granules were compressed into tablets to prepare wet granule tablets. The granules were compressed into tablets to prepare wet granule tablets.

Comparative Example 3: Preparation of wet granule tablets containing (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine hydrochloride

According to the ingredients and contents of the preparation shown in Table 2, vildagliptin hydrochloride is mixed with microcrystalline cellulose and anhydrous lactose, then placed in a fluidized bed granulator, kneaded with distilled water, granulated, and dried, and then sized to produce granules. did. Then, the prepared granules were postmixed with croscarmellose magnesium and sodium stearate. The granules were compressed into tablets to prepare wet granule tablets. The granules were compressed into tablets to prepare wet granule tablets.

Comparative Examples 4 to 5: Preparation of wet granule tablets containing (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyanorolidine hydrochloride

According to the ingredients and contents of the preparation shown in Table 2, prepare hydroxypropylcellulose L-type (HPC-L) or Povidone K30 as a binding solution, and mix vildagliptin hydrochloride with microcrystalline cellulose and D-mannitol. Then, it was put into a fluidized bed granulator, a binder was added, and the mixture was sifted through the processes of kneading, granulation, and drying to produce granules. Then, the prepared granules were postmixed with croscarmellose magnesium and sodium stearate. The granules were compressed into tablets to prepare wet granule tablets. The granules were compressed into tablets to prepare wet granule tablets.

Ingredients (unit: mg) Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 process direct compression wet granulation Vildagliptin glass type 50.0 50.0 - - - Vildagliptin hydrochloride - - 56.0 56.0 56.0 microcrystalline cellulose 40.0 40.0 40.0 40.0 40.0 Lactose Anhydrous 40.0 40.0 40.0 - - D-mannitol - - - 40.0 40.0 HPC-L - - - 3.0 - Povidone K30 - - - - 3.0 (D.W.) - (5mL) (5mL) (5mL) (5mL) Croscarmellose Sodium - 4.0 4.0 4.0 4.0 Sodium Starch Glycolate 4.0 magnesium stearate 3.0 3.0 3.0 3.0 3.0 Sum 137.0 137.0 143.0 143.0 143.0

Comparative Examples 6 to 8: (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine fumaric acid salt, malonic acid salt, and L-tartrate salt Preparation of wet granular tablets comprising

Compared to the prescriptions of Comparative Examples 2 or 3 shown in Table 2, in Comparative Examples 6 to 8, wet granule tablets containing fumarate, malonate, or tartrate of vildagliptin were prepared by varying only the type of vildagliptin salt. . Fumarate, malonic acid, or tartrate of vildagliptin in an amount equivalent to 50 mg each of vildagliptin is mixed with microcrystalline cellulose and anhydrous lactose and then placed in a fluidized bed granulator for kneading, granulation, and drying with distilled water. After going through the process, the granules were manufactured by sizing. Then, the prepared granules were postmixed with croscarmellose magnesium and sodium stearate. The granules were compressed into tablets to prepare wet granule tablets. The granules were compressed into tablets to prepare wet granule tablets.

Test Example 1: Content analysis test and related substance analysis test of wet granule tablets under harsh and accelerated conditions depending on the type of main ingredient salt

In order to confirm the stability of wet granule tablets containing vildagliptin free form or vildagliptin hydrochloride as the main ingredient under harsh and accelerated conditions, tests were conducted to analyze the content of the main ingredient and related substances under the following conditions. Severe conditions were stored at 60℃±2℃ and 80% relative humidity for 2 and 4 weeks. Additionally, the acceleration conditions were stored at 40°C ± 2°C and 75% relative humidity for 2 and 4 weeks. Subsequently, the content and degree of production of related substances were analyzed under the following conditions, and the results are shown in Figures 1 to 4.

(1) Content analysis

For the comparative example and example samples, 10T tablets were placed in three 100mL flasks, and an appropriate dilution solution capable of extracting the main ingredient, for example, a solution of 0.01M hydrochloric acid aqueous solution and acetonitrile mixed in an appropriate ratio, was added. Stirring was performed and a content test was conducted. Results represent the average of the same sample group in each test. As shown in Figures 1 and 2, vildagliptin hydrochloride showed no significant change in content under both harsh and accelerated conditions. In comparison, as shown in Figures 1 and 2, the content of vildagliptin free form was confirmed to decrease under both harsh and accelerated conditions.

(2) Analysis of related substances

For the comparative examples and example samples, 5T tablets were placed in three 50 mL flasks, and an appropriate diluent capable of extracting the main ingredient, for example, a solution of 0.01 M hydrochloric acid aqueous solution and acetonitrile mixed in an appropriate ratio, was added. Stirring was performed and a content test was conducted. Results represent the average of the same sample group in each test. As shown in Figures 3 and 4, vildagliptin hydrochloride did not show a significant increase in related substances (%) under both harsh and accelerated conditions. In comparison, as shown in Figures 3 and 4, the free form of vildagliptin increased in related substances (%) under both severe and accelerated conditions. From the above results, it was confirmed that the decrease in content and increase in related substances in vildagliptin under harsh conditions and accelerated exposure conditions were relatively lower when it was in hydrochloride form than when it was in free form.

Test Example 2: Content analysis test and related substance analysis test of wet granule tablets under harsh and accelerated conditions depending on the type of main ingredient salt

In order to confirm the stability under harsh and accelerated conditions for wet granule tablets of different types of vildagliptin salts, vildagliptin fumarate, vildagliptin malonate, or vildagliptin tartaric acid were used as main ingredients obtained in Comparative Examples 6 to 8. Wet granule tablets containing each salt were subjected to content and related substance analysis tests under the same conditions as Test Example 1. The results are shown in Figures 5 to 8 along with the results for Comparative Example 2.

As shown in Figures 5 to 8, compared to the wet granule tablet containing vildagliptin hydrochloride obtained in Comparative Example 2, vildagliptin fumarate, vildagliptin malonate, or vildagliptin obtained in Comparative Examples 6 to 8 It was confirmed that wet granule tablets containing gliptin L-tartrate showed a relative decrease in content and an increase in related substances under harsh or accelerated conditions. In particular, the wet granule tablet containing vildagliptin fumarate obtained in Comparative Example 6 was sensitive to heat and an increase in related substances was observed under harsh conditions, and the wet granule tablet containing vildagliptin malonate obtained in Comparative Example 7 was It is sensitive to moisture, so when stored under accelerated conditions, it melts easily and shows a decrease in content and an increase in related substances. In addition, the wet granule tablet containing vildagliptin L-tartrate obtained in Comparative Example 8 showed the worst results under both severe and accelerated conditions. From the above results, it was confirmed that the stability was the best when vildagliptin hydrochloride was included, and research continued on vildagliptin hydrochloride.

Test Example 3: Observation of properties and viscosity measurement test when exposed to moisture for the main ingredient

In order to confirm the effect of moisture on vildagliptin free form and vildagliptin hydrochloride as the main ingredients, changes in the properties and viscosity of the main ingredient were measured upon exposure to moisture under the following conditions.

(1) Observation of properties

10 g each of vildagliptin free form and vildagliptin hydrochloride were taken and exposed to 100 mL of purified water for 10 minutes at room temperature, and then their properties were compared. The results are shown in Figure 9.

As shown in Figure 9(a), the vildagliptin free form did not clump together like water-soaked sand even after exposure to moisture. In comparison, as shown in Figure 9(b), vildagliptin hydrochloride showed a property in which viscosity increased when exposed to moisture, became sticky, and was combined into lumps.

(2) Viscosity measurement

In order to accurately compare the change in viscosity of the main ingredient depending on moisture, 5 g each of vildagliptin free form and vildagliptin hydrochloride were added to 100 mL of purified water at 25°C and the viscosity was measured. The results are shown in Table 3.

25℃, 5% aqueous solution Purified water vildagliptin
glass type vildagliptin
hydrochloride HPC-L PVP-K30 Viscosity (mPas) 1.05 1.15 6.78 13.47 3.89

As shown in Table 3, in the case of vildagliptin free form, there was no significant change in viscosity of purified water, but vildagliptin hydrochloride showed a viscosity increase of about 3 times or more. In addition, the viscosity of vildagliptin hydrochloride increased by the addition of moisture is within the viscosity range of HPC series and PVP series, especially L-grade HPC and PVP K-30, which are frequently used as binders, so the properties of vildagliptin hydrochloride itself It can be confirmed that when in contact with moisture, it shows a bonding strength similar to that of using a binder. Based on the viscosity of the commonly used binder, the upper and lower viscosity ranges are set according to the addition ratio of vildagliptin hydrochloride and water to sufficiently function as a binder, preferably 2 mPas to 15 mPas in a 5% aqueous solution at 25°C. Specifically, when it has a viscosity of 3 mPas to 10 mPas, it can act as a binder. Generally, if the viscosity is lower than this range, granules are not produced, or even if they are produced, the granule strength is low and the granules can easily wear out. If the viscosity is higher than this range, the binding force of the granules increases, preventing initial drug release. It may have a delaying effect.

Test Example 4: Severe stability test

To evaluate the effect of vildagliptin hydrochloride on the stability, a comparative stability test was conducted under the conditions of stress testing among the stability test methods specified by the International Organization for Harmonization (ICH). The tablets obtained in Comparative Examples 1 to 3 were stored under harsh conditions of 60°C ± 2°C and 80% relative humidity for 1 week and 2 weeks, and then a test was performed to measure related substances under the following conditions. Liquid chromatography using an appropriate diluted solution capable of extracting the main component, for example, a solution of 0.01M hydrochloric acid aqueous solution and acetonitrile mixed in an appropriate ratio, and adjusting the final concentration of vildagliptin to 2000㎍/mL as the sample solution. The graph was performed, the degree of production of related substances was analyzed, and the results are shown in Table 4 and Figure 10.

<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℃

Total related substances (%) exposure period Early 60℃, 80%
1 week exposure 60℃, 80%
1 week exposure Comparative Example 1 0.01 0.16 0.35 Comparative Example 2 0.02 0.37 0.64 Comparative Example 3 0.01 0.17 0.34

As shown in Table 4 and Figure 10, in the case of the conventional vildagliptin free form, Comparative Example 2 was manufactured by a wet granulation process due to the instability of the vildagliptin drug to moisture. Comparative Example 2 was manufactured by a direct compression process. It was confirmed that the amount of related substances generated from vildagliptin increased under harsher storage conditions than 1. In comparison, in Comparative Example 3 using vildagliptin hydrochloride, it was confirmed that the amount of related substances generated was reduced under harsh storage conditions compared to Comparative Example 2 even if it was manufactured by a wet granulation process. From this, it was confirmed that vildagliptin hydrochloride was relatively stable even in the wet granulation process.

Test Example 5: Accelerated stability test

To evaluate the effect of vildagliptin hydrochloride on the stability, a comparative stability test was conducted under accelerated test conditions among the stability test methods specified by the International Organization for Harmonization (ICH). The tablets obtained in Comparative Examples 1 to 3 were stored under accelerated conditions of 40°C ± 2°C and 75% relative humidity for 1 week and 2 weeks, and then a test was performed to measure related substances. An appropriate diluent capable of extracting the main ingredient, e.g. For example, liquid chromatography was performed in the same manner as Test Example 3, using a solution of 0.01 M aqueous hydrochloric acid and acetonitrile mixed in an appropriate ratio and adjusting the final concentration of vildagliptin to 2000 ㎍/mL as the sample solution. The degree of production of related substances was analyzed, and the results are shown in Table 5 and Figure 11.

Total related substances (%) exposure period Early 40℃, 75%
1 week exposure 40℃, 75%
1 week exposure Comparative Example 1 0.01 0.23 0.51 Comparative Example 2 0.02 0.48 0.86 Comparative Example 3 0.01 0.21 0.47

As shown in Table 5 and Figure 11, in the case of the conventional vildagliptin free form, Comparative Example 2 was manufactured by a wet granulation process due to the instability of the vildagliptin drug to moisture. Comparative Example 2 was manufactured by a direct compression process. It was confirmed that the amount of related substances generated from vildagliptin increased under accelerated storage conditions compared to 1. In comparison, in Comparative Example 3 using vildagliptin hydrochloride, it was confirmed that the amount of related substances generated was reduced under accelerated storage conditions compared to Comparative Example 2 even if it was manufactured by a wet granulation process. From this, it was confirmed that vildagliptin hydrochloride was relatively stable even in the wet granulation process.

Test Example 6: Mixing Stability Test (1)

In order to evaluate the effect of excipients on vildagliptin on the stability, a comparative stability test was conducted on a mixture of excipients and vildagliptin under severe and accelerated test conditions among the stability test methods specified by the International Organization for Harmonization (ICH). A test to measure related substances under harsh or accelerated storage conditions in the same manner as Test Example 3 or Test Example 4 after uniformly mixing 5g of vildagliptin free form or vildagliptin hydrochloride with 5g of excipients selected from Table 6 below. was carried out. In addition, the degree of production of related substances was analyzed and the results are shown in Figures 12 to 15.

excipient Microcrystalline cellulose Lactose Anhydrous Pre-gelatinized starch Anhydrous dicalcium phosphate D-mannitol L-HPC HPC-L Povidone K30 Sodium Starch Glycolate Croscarmellose Na Magnesium stearate

As shown in Figures 12 to 15, vildagliptin or vildagliptin hydrochloride is a hydroxypropyl cellulose (HPC) series such as HPC-L, L-HPC, etc., or a povidone series such as povidone K30 used as a binder. It was confirmed that the mixing stability was not good as the amount of related substances increased during harsh and accelerated storage when mixing. In addition, it was confirmed that vildagliptin or vildagliptin hydrochloride had poor mixing stability due to an increase in the amount of related substances generated during harsh and accelerated storage when mixed with lactose series such as anhydrous lactose used as a diluent.

Test Example 7: Mixing stability test (2)

In order to evaluate the effect of vildagliptin excipients on the stability, a comparative stability test was conducted on wet granule tablets manufactured with different types of diluents under the conditions of severe and accelerated tests among the stability test methods specified by the International Organization for Harmonization (ICH). It was carried out. The wet granule tablets prepared in Comparative Example 3 and Examples 1 to 5 were tested to measure related substances under harsh or accelerated storage conditions in the same manner as Test Example 3 or Test Example 4. The degree of production of related substances was analyzed and the results are shown in Figures 16 and 17.

As shown in Figures 16 and 17, it was confirmed that Comparative Example 3 containing anhydrous lactose and Examples 1 to 5 containing different types of diluent decreased the related substances of vildagliptin under harsh and accelerated storage conditions. Specifically, Examples 1 to 5, which included a combination selected from microcrystalline cellulose, D-mannitol, pregelatinized starch, and anhydrous dicalcium phosphate as a diluent instead of anhydrous lactose, significantly reduced the amount of related substances generated. As a diluent, it was confirmed that anhydrous lactose had poor mixing stability with vildagliptin or vildagliptin hydrochloride, and that microcrystalline cellulose, D-mannitol, pregelatinized starch, or anhydrous calcium diphosphate had better mixing stability with vildagliptin.

Test Example 8: Mixing stability test (3)

In order to evaluate the effect of vildagliptin excipients on the stability, the stability of wet granule tablets manufactured with different types or types of binders was compared under the conditions of severe and accelerated tests among the stability test methods specified by the International Organization for Harmonization (ICH). A test was conducted. The wet granule tablets prepared in Example 1 and Comparative Examples 4 to 5 were tested to measure related substances under harsh or accelerated storage conditions in the same manner as Test Example 3 or Test Example 4. The degree of production of related substances was analyzed and the results are shown in Figures 18 and 19.

As shown in Figures 18 and 19, the wet granule tablets of Comparative Examples 4 and 5 manufactured using HPC-L or povidone K30 as a binder are better than the wet granule tablets of Example 1 manufactured without using such binder. The amount of vodka related substances generated significantly increased under harsh and accelerated conditions. It was confirmed that HPC-L or povidone K30 as a binder had poor mixing stability with vildagliptin or vildagliptin hydrochloride.

Test Example 9: Dissolution test

In order to evaluate the effect of vildagliptin hydrochloride on the dissolution rate, a dissolution test was performed on the tablets obtained in Example 1 and Comparative Examples 4 to 5 under the following conditions. The results are shown in Figure 20.

<Dissolution test conditions>

1) Dissolution method: Dissolution test method 2 (paddle method) of the Korean Pharmacopoeia

2) Eluate: 0.1N hydrochloric acid (HCl) solution

3) Eluent volume: 900 mL

4) Elutriator temperature: 37.5℃

5) Paddle speed: 50 rpm

6) Number of test groups: 6

7) Sample collection time: 5, 10, 15, 30, 45, 60 minutes

<Sample analysis conditions>

Detector: Ultraviolet absorptiometry (measurement wavelength: 200 nm)

Column: 150mm C18 column

Mobile phase: mixture of pH 3.0 buffer and acetonitrile in a 7:3 ratio

Flow rate: 0.8ml/min

Column temperature: 40℃

As shown in Figure 20, Comparative Examples 4 and 5, which additionally contain a binder, showed lower dissolution rates than Example 1 due to the high viscosity properties of vildagliptin hydrochloride when in contact with moisture. Specifically, the wet granule tablets of Comparative Examples 4 and 5 prepared using HPC-L or povidone K30 as a binder showed a dissolution rate of less than 30% after 5 minutes from the start of dissolution and less than 50% after 10 minutes. In comparison, Example 1, manufactured by a wet granulation process without the use of an additional binder, showed a dissolution rate of more than 50% after 5 minutes from the start of dissolution and more than 85% after 10 minutes. As the viscosity of vildagliptin hydrochloride increases when in contact with moisture, the binding force of the granules increases, so Comparative Examples 4 and 5, which additionally used a binder, showed relatively slower initial dissolution than Example 1, which did not use a binder.

Test Example 10: Granule productivity and severe and accelerated stability tests

In order to evaluate the effect of the binder content on the properties of the granules and the stability of the wet granule tablets, the productivity of the wet granules and wet granule tablets obtained in Examples 5 to 9 was observed, and the same as Test Example 3 or Test Example 4 was observed. A test was conducted to measure related substances under harsh or accelerated storage conditions. Specifically, in Examples 5 to 9, distilled water was used as a binding solution in amounts of 5 mL, 2 mL, 8 mL, 12 mL, and 1 mL per tablet, respectively.

(1) Observation of granule formation

In Examples 5 to 7, in which 2 mL to 8 mL of distilled water was used as a binding solution per tablet, granules of an appropriate size were produced in a fluidized bed granulator. However, in Example 9, where less than 2 mL of distilled water was used as a binder per tablet, granules were not formed and existed in fine powder form, resulting in a high loss rate of the main ingredient. In addition, Example 8, which used 12 mL of distilled water as a binding solution per tablet, formed granules, but stability was reduced due to contact with excessive water.

(2) Analysis of related substances

The degree of production of related substances was analyzed and the results are shown in Figures 21 and 22. As shown in Figures 21 and 22, compared to Examples 5 to 7 in which 2 mL to 8 mL of distilled water was used as a binding solution per tablet, in Example 8 in which 12 ml of distilled water was used, both harsh and accelerated storage conditions were observed. It was confirmed that the amount of related substances generated increased.

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 (11)

Contains wet granules containing vildagliptin hydrochloride and a diluent,
The diluent is at least one selected from the group consisting of microcrystalline cellulose, D-mannitol, pregelatinized starch, anhydrous dicalcium phosphate, and any combination thereof, wherein the wet granules do not contain anhydrous lactose,
The wet granules are manufactured using water as a solvent without using a binder,
The vildagliptin hydrochloride is included in an amount of 20% to 40% by weight based on the total amount of the solid preparation,
The diluent is included in an amount of 30% to 60% by weight based on the total amount of the solid preparation,
An oral solid preparation containing 1% to 6% by weight of water based on the total amount of the solid preparation. delete delete The solid formulation according to claim 1, wherein the wet granules do not contain hydroxypropyl cellulose (HPC) or povidone as an internal phase binder of the granules. The solid formulation according to claim 1, wherein the vildagliptin hydrochloride present in the wet granules has a viscosity of 2 mPas to 15 mPas at 25°C in a 5% aqueous solution condition. The solid formulation of claim 1, further comprising at least one pharmaceutically acceptable additive selected from the group consisting of a disintegrant, a lubricant, a stabilizer, and any combination thereof. delete delete The solid preparation according to claim 1, wherein the solid preparation is granules, dry syrup, tablets, pellets, or capsules. The method of claim 1, wherein when the solid preparation is tested for dissolution in a 0.1 N hydrochloric acid solution at a paddle rotation speed of 50 rpm according to the dissolution test method 2 of the Korean Pharmacopoeia, the dissolution rate of vildagliptin is more than 50% for 5 minutes, and 10 A solid dosage form that is 85% or more for minutes. preparing wet granules from a mixture comprising vildagliptin hydrochloride and a diluent; and
Postmixing the wet granules and pharmaceutically acceptable additives,
The diluent is at least one selected from the group consisting of microcrystalline cellulose, D-mannitol, pregelatinized starch, anhydrous dicalcium phosphate, and any combination thereof, wherein the wet granules do not contain anhydrous lactose,
The wet granules are manufactured using water as a solvent without using a binder,
The vildagliptin hydrochloride is included in an amount of 20% to 40% by weight based on the total amount of the solid preparation,
The diluent is included in an amount of 30% to 60% by weight based on the total amount of the solid preparation,
The method for producing an oral solid formulation according to claim 1, wherein the water is contained in an amount of 1% to 6% by weight based on the total amount of the solid formulation.