WO2020040474A1 - Method for preparing preparation containing sitagliptin immediate release layer, preparation prepared by preparation method, method for coating sitagliptin immediate release layer, and composition for coating sitagliptin immediate release layer - Google Patents

Abstract

The present invention relates to a method for preparing a preparation containing a sitagliptin immediate release layer, a preparation prepared by the preparation method, a method for coating a sitagliptin immediate release layer, and a composition for coating a sitagliptin immediate release layer, the preparation method comprising the steps of: (a) preparing a coating solution by dissolving sitagliptin or a pharmaceutically acceptable salt in a highly volatile solvent; and (b) coating a sustained release layer with the coating solution.

Description

A method for preparing a formulation comprising a cytagliptin immediate release layer, a formulation prepared by the above method, a method for coating a cytagliptin immediate release layer, and a composition for coating a cytagliptin immediate release layer

The present invention provides a method for preparing a formulation comprising a cytagliptin immediate release layer,

It relates to a formulation prepared for, a method for coating cytagliptin immediate release layer, and a composition for coating a cytagliptin immediate release layer.

Sitagliptin is a type 2 diabetes treatment that is a dipeptidyl peptidase-4 (DPP-4) inhibitor. Citagliptin is marketed under the product names Januvia, Janumet, and Janumet X-R (MSD) in Korea, and the active ingredient is in the form of citagliptin phosphate monohydrate (dipeptidyl peptidase-IV inhibitor Phosphate, Korean Patent No. 10-1016569).

Among them, xanumetxal is composed of a sustained release layer of metformin and a cytagliptin immediate release layer, and in connection with the preparation method of the cytagliptin immediate release layer, an international patent pharmaceutical composition of a combination of Metformin and a Dipetidyl Peptidase-IV Inhibitor (WO 2009 -099734 A1) provides a rapid release layer of cytagliptin, but since this technique uses a low volatility solvent, there is a big problem that the rapid release layer of cytagliptin can be completed only after a long coating process.

Accordingly, the present inventors have studied to develop a method for preparing a formulation including a cytagliptin immediate release layer having a shorter coating time, and thus, the present invention has been completed to reduce the coating time without generating decomposition products.

An object of the present invention comprises (a) dissolving cytagliptin or a pharmaceutically acceptable salt thereof in a highly volatile solvent to prepare a coating solution, and (b) coating the sustained release layer with the coating solution. It is to provide a method for producing a formulation comprising a liptin immediate release layer.

Another object of the present invention comprises the steps of preparing a coating solution by dissolving cytagliptin or a pharmaceutically acceptable salt thereof in a high volatility solvent, and (b) coating the sustained release layer with the coating solution. It is to provide a method for coating the immediate release layer of gliptin.

Still another object of the present invention is to provide a composition for cytagliptin immediate release layer containing cytagliptin hydrochloride and a high volatility solvent.

Still another object of the present invention is to provide a preparation prepared by the preparation method of the preparation.

The method for preparing a formulation comprising a cytagliptin immediate release layer, a method for coating a cytagliptin immediate release layer, and a composition for coating a cytagliptin immediate release layer may reduce coating time and generate a flexible material by using a high volatility solvent. It is effective to avoid.

1 is a diagram showing the solubility of cytagliptin phosphate hydrate in water and ethanol.

2 is a diagram showing the solubility of cytagliptin hydrochloride hydrate in water and ethanol.

Figure 3 is a view showing the result of measuring the degree of generation of the flexible material of (a) cytagliptin phosphate hydrate and (b) cytagliptin hydrochloride hydrate exposed to room temperature or 60 ℃ for 48 hours.

Figure 4 shows one specific form of a formulation comprising a cytagliptin immediate release layer.

Detailed description for carrying out the present invention is as follows. Meanwhile, each of the descriptions and the embodiments disclosed herein may be applied to each of the other descriptions and the embodiments. That is, all combinations of the various elements disclosed herein are within the scope of the present invention. In addition, the scope of the present invention is not limited by the specific description described below.

In addition, one of ordinary skill in the art can recognize or identify many equivalents to certain aspects of the invention described in this application using conventional experiments only. In addition, such equivalents are intended to be included in the present invention.

As one embodiment for achieving the above object, the present invention comprises the steps of (a) dissolving cytagliptin or a pharmaceutically acceptable salt thereof in a high-volatile solvent to prepare a coating solution and (b) to form a sustained release layer with the coating solution It provides a method for preparing a formulation comprising a cytagliptin immediate release layer comprising the step of coating.

Specifically, cytagliptin of the present invention is an orally active dipeptidyl peptidase-4 (DPP-4) inhibitor known to improve sugar control in patients with type 2 diabetes by slowing the inactivation of the incretin hormone. The chemical structure of cytagliptin may be represented by the following Chemical Formula 1, and the chemical name of cytagliptin is (R) -3-amino-1- (3- (trifluoromethyl) -5,6-dihydro- [ 1,2,4] triazolo [4,3-a] pyrazin-7 (8H) -yl) -4- (2,4,5-trifluorophenyl) butan-1-one. Cytagliptin is also included in the present invention without limitation, in which some functional groups are modified or protected with protecting groups as long as the dipeptidyl-peptidase-4 inhibitory effect is maintained.

In addition, in the present invention, cytagliptin is a concept including all of its pharmaceutically acceptable salts, hydrates, solvates, isomers, derivatives, and the like within the range having the same efficacy. Cytagliptin of the present invention may be obtained by using chemically synthesized or commercially available materials.

The pharmaceutically acceptable salt of cytagliptin may be prepared from an inorganic base, an organic base, an inorganic acid, or an organic acid, but is not limited thereto.

Pharmaceutically acceptable salts of cytagliptin derived from inorganic bases include, but are not limited to, aluminum, ammonium, calcium, copper, ferrous iron, ferric iron, lithium, magnesium, potassium, sodium, zinc and the like. Pharmaceutically acceptable salts of cytagliptin derived from organic bases include primary amines, secondary amines, tertiary amines, substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically arginine, Betaine, caffeine, choline, NN-dibenzylethylene diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, histidine, lysine, piperazine, Piperidine, polyamine resin, procaine, purine, triethylamine, trimethylamine, and the like, but are not limited thereto.

Pharmaceutically acceptable salts of cytagliptin derived from inorganic or organic acids include, but are not limited to, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, bromic acid, Hydrochloric acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like. Cytagliptin or a pharmaceutically acceptable salt of cytagliptin may be in the form of a hydrate, but is not limited thereto.

Specifically, the pharmaceutically acceptable salt of cytagliptin may be at least one selected from the group consisting of cytagliptin hydrochloride, cytagliptin phosphate, cytagliptin sulfate, cytagliptin acetate, and cytagliptin malate salt. have. More specifically, the pharmaceutically acceptable salt of cytagliptin is cytagliptin hydrochloride.

Pharmaceutically acceptable salts of cytagliptin may have different solubility and / or stability even in the same solvent depending on the kind thereof, and the degree of generation of the flexible substance may be different when the cytagliptin immediate release layer is coated using the same. have. Specifically, in one embodiment of the present invention, the cytagliptin phosphate has low solubility in a high volatility solvent such as ethanol (FIG. 1), and the cytagliptin immediate release layer may be coated using the cytagliptin phosphate in the solvent. In the case of the flexible material occurred (Fig. 3). On the other hand, cytagliptin hydrochloride has a relatively high solubility in a high volatility solvent such as ethanol (FIG. 2), and when a cytagliptin immediate release layer is coated using the cytagliptin hydrochloride in the solvent, no softening material is generated. (FIG. 3). From this, the inventors confirmed that when the preparation is prepared by coating with cytagliptin hydrochloride and a high volatile solvent, the coating time is shortened and the formation of the flexible material is inhibited, thereby increasing productivity.

The pharmaceutically acceptable salt of cytagliptin may be included in an amount of 0.6 to 60 parts by weight based on 100 parts by weight of the solvent. Specifically, the solvent may be included in an amount of 0.6 to 40, more specifically 0.6 to 20, more specifically 0.6 to 10, 1 to 10, 2 to 10, 3 to 9, or 4 to 8 parts by weight.

The coating solution of the present invention is a fluid for coating the sustained release layer of the bilayer tablet, and includes the cytagliptin or a pharmaceutically acceptable salt thereof, and may form an immediate release layer simultaneously with the coating of the sustained release layer. In addition, the present invention may be in the form of dissolving cytagliptin or a pharmaceutically acceptable salt thereof in the high volatile solvent. For the purpose of the present invention, the coating liquid may further include one or more selected from the group consisting of hypromellose, polyvinyl alcohol, hydroxypropyl cellulose, povidone, polyethylene glycol, kaolin, propyl gallate, However, any ingredient that does not affect the pharmacological activity and is beneficial to the coating performance may be included without limitation.

The high volatile solvent means a high volatility solvent, it is preferable that the biotoxicity is low. In the present invention, the high volatile solvent contributes to shortening the coating time, and enables the rapid release of the immediate release layer including the biologically active ingredient having high solubility in the solvent while having a high content of the active ingredient. The high volatile solvent may include one or more selected from the group consisting of anisole, ethanol, acetone, butyl methyl ether, methyl ethyl ketone, methyl isobutyl ketone, pentane, heptane. Specifically, the high volatile solvent may include ethanol at 5%, 10%, 15%, or 20% or more of the total solvent weight. In addition, the high volatile solvent may be a mixed solvent of ethanol and water or ethanol. Due to the high volatility of the solvent, the time for coating the sustained release layer with the cytagliptin immediate release layer can be shortened. Specifically, the coating time was 8 hours when using water as a solvent was shortened to 2 hours when using 80% ethanol.

The dissolution means that the solute is diffused into the solvent and mixed, and the dissolution in the present invention includes not only the solute being uniformly mixed in the solvent but also the solute is unevenly mixed in the solvent to form a suspension, a colloid, and the like.

The coating means coating all or part of the outer surface of the sustained release layer with a thin film using the coating liquid. The method of coating is not limited, and may be performed by one or more methods selected from the group consisting of a fan coating method and a fluidized bed coating method. The coating may be performed at or above room temperature, specifically, 50 to 90 ° C., 52 to 88 ° C., 56 to 84 ° C., 58 to 82 ° C., or 60 to 80 ° C., but is not limited thereto.

The formulations of the present invention comprise a sustained release layer comprising a biologically active substance, filler, disintegrant, diluent, additive, glidant, excipient, etc. and cytagliptin or a pharmaceutically acceptable salt, filler, disintegrant, diluent, additive, It may be a two-layered tablet or a multilayered tablet including an immediate release layer including a lubricant, an excipient, and the like, but is not limited thereto. In addition, the formulation of the present invention may further include a pharmaceutically acceptable carrier.

Examples of the pharmaceutically acceptable carrier include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, undetermined. Vaginal cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil and the like can be used. In addition, excipients, fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers and preservatives may be further included.

Disintegrants are used to absorb moisture and promote disintegration of the formulation to enhance cytagliptin or salt dissolution thereof. Non-limiting examples of disintegrants used in the immediate release layer and the sustained release layer in the present invention are each independently croscamellose sodium, sodium starch glycolate, microcrystalline cellulose, Crospovidone (cross-linked povidone) and other commercially available polyvinylpyrrolidone (PVP, Povidone), low-substituted hydroxypropylcellulose (low substituted), alginic acid, powdered cellulose Starch, sodium alginate, and mixtures thereof. Disintegrant may use 2 to 15% by weight, more specifically 5 to 10% by weight based on the total weight of the formulation, but is not limited thereto.

Non-limiting examples of excipients used in the immediate release layer and the sustained release layer in the present invention may each independently be lactose, mannitol, glucose, sorbitol, dextrin, sucrose, or mixtures thereof.

The present invention can use a binder that serves to increase the binding strength of the formulation to the immediate release layer and the sustained release layer. Non-limiting examples of binders that can be used include polyvinylpyrrolidone (common name: povidone), but may be added in 3 to 10% by weight of the total weight of the formulation, but is not limited thereto.

Non-limiting examples of glidants usable in the immediate release layer and the sustained release layer in the present invention may each independently be light silicic anhydride, silicon dioxide, talc, stearic acid, magnesium stearate or mixtures thereof. Glidants facilitate the compression and release of tablets, and may add 0.5 to 5% by weight relative to the weight of the formulation, but is not limited thereto.

The sustained release layer means a slower release of biologically active material than the immediate release layer. The sustained release layer may be spherical or plate-like. In the present invention, the biologically active substance included in the sustained release layer may be metformin or a pharmaceutically acceptable salt thereof, but is not limited thereto. Pharmaceutically acceptable salts of metformin include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trichloroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, Acid addition salts formed by organic carbon acids such as maleic acid, salicylic acid and the like, sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. In addition, pharmaceutically acceptable salts of metformin include metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium and the like, amino acid salts such as lysine, arginine, guanidine, dicyclohexylamine, N-methyl-D Organic salts such as -glucamine, tris (hydroxymethyl) methylamine, diethanolamine, choline and triethylamine and the like.

The immediate release layer is a layer formed by coating the sustained release layer with the coating solution, and refers to a layer that releases the biologically active substance in vivo enough to achieve a desired effect in a patient within a limited time. In the present invention, the biologically active substance included in the immediate release layer is cytagliptin or a pharmaceutically acceptable salt thereof. The immediate release layer may be spherical or plate-shaped, but is not limited thereto.

The immediate release layer and the sustained release layer of the present invention may be formed by tableting granules of a mixture comprising a biologically active substance, the granules comprising dry granules or wet granules, and may be prepared by any method known in the art. Can be.

The formulation of the present invention has a total weight of 2000 mg or less, specifically 500 mg to 2000 mg, 600 to 2000 mg, 700 to 2000 mg, 800 to 2000 mg, 900 to 2000 mg, 1000 mg to 2000 mg, 1100 to 2000 mg , 1400 to 2000 mg, or 1500 to 2000 mg, but the total weight of the formulation may be appropriately selected and implemented by those skilled in the art to satisfy the required efficacy.

Cytagliptin or a salt thereof, which is a biologically active substance, may be included in an amount of 2 to 10 wt%, specifically 3 to 7 wt%, based on the weight of the preparation, but is not limited thereto.

The formulations may be prepared in various formulations using the pharmaceutically acceptable carrier, and may be tablets, powders, granules or capsules such as uncoated tablets, film coated tablets, bilayer tablets, multi-layer tablets or nucleated tablets, and the like.

The preparation method of the formulation of the present invention may be to shorten the coating time without generating decomposition products. Specifically, the formulation can be prepared with high coating performance by coating the sustained release layer with a coating solution in which cytagliptin hydrochloride is dissolved in a high volatile solvent (eg, ethanol). The formulation prepared by the method of the present invention is expected to have excellent industrial value by including cytagliptin hydrochloride as an immediate release layer and exhibiting high productivity while having the same efficacy as a conventional known cytagliptin formulation.

In another aspect, the present invention comprises the steps of (a) dissolving cytagliptin or a pharmaceutically acceptable salt thereof in a high volatile solvent to prepare a coating solution, and (b) coating the sustained release layer with the coating solution. To provide a cytagliptin immediate release layer coating method. The coating method of the present invention is expected to increase the quality and productivity of the formulation including the cytagliptin immediate release layer coating because it shortens the coating time without generating decomposition products.

As another aspect, the present invention provides a composition for coating a cytagliptin immediate release layer comprising a cytagliptin hydrochloride and a high volatile solvent. The cytagliptin hydrochloride may be present in a dissolved state in a solvent. In one embodiment of the present invention, it was confirmed that the coating composition including cytagliptin hydrochloride and a high volatile solvent shortens the coating time and generates little decomposition products. From this, the inventors confirmed that when the composition for coating containing cytagliptin hydrochloride and a high volatile solvent is used, coating time of the preparation is shortened and the formation of a flexible material is inhibited, thereby improving coating performance.

In another embodiment, the present invention provides a method of preparing a coating solution by dissolving cytagliptin or a pharmaceutically acceptable salt thereof in a high volatile solvent, and (b) coating the sustained release layer with the coating solution. It provides a formulation prepared by a manufacturing method comprising. Specifically, the formulation may be one having a dissolution rate of more than 80% of cytagliptin within 60 minutes when the dissolution test in purified water according to the Korean Pharmacopoeia dissolution test method 2 (paddle method), rotation speed 100 rpm. Such formulations contain low amounts of softeners and are of good quality.

Such a method for preparing a formulation comprising a cytagliptin immediate release layer, a method for coating a cytagliptin immediate release layer, and a composition for coating a cytagliptin immediate release layer can shorten a coating time without generating a flexible material. Has a beneficial effect.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are intended to illustrate the present invention in more detail, and the scope of the present invention is not limited by these examples.

Experimental Example 1: Analysis of Solubility in Water and Ethanol According to Cytagliptin Salts

The present inventors analyzed solubility in water and ethanol of cytagliptin phosphate and cytagliptin hydrochloride to analyze the difference in solubility according to the type of cytagliptin salt.

Experimental Example 1-1: Solubility of Cytagliptin Phosphate in Water and Ethanol

0.6 g of cytagliptin phosphate hydrate was placed in a vial, and 8.8 g of a mixed solvent of purified water and ethanol having different ratios of purified water and ethanol was added thereto, followed by shaking for 1 hour. The results are shown in FIG. 1, and the results of visual evaluation of solubility are shown in Table 1. It was observed that the higher the ratio of ethanol, the more dissolves the cytagliptin phosphate hydrate without melting.

Solubility of Citagliptin Phosphate Hydrates According to the Solvent Composition

number	One	2	3	4	5
Citagliptin Phosphate Heptahydrate	0.6 g	0.6 g	0.6 g	0.6 g	0.6 g
Purified water	100%	80%	60%	20%	-
ethanol	-	20%	40%	80%	100%
Solubility	Almost clear solution	Translucent suspension	Opaque suspension	Opaque suspension	Opaque suspension

Experimental Example 1-2: Solubility of Cytagliptin Hydrochloride in Water and Ethanol

0.6 g of cytagliptin hydrochloride hydrate was placed in a vial, and 8.8 g of a mixed solvent having a different weight ratio of purified water and ethanol was added thereto, and the solution was shaken for 1 hour. The results are shown in FIG. 2, and the results of visual evaluation of solubility are shown in Table 2. As the ratio of ethanol was higher, it was observed that the citagliptin hydrochloride hydrate was not dissolved but suspended.

Solubility of Citagliptin Hydrochloride Hydrate According to Solvent Composition

number	6	7	8	9	10
Citagliptin Hydrochloride Hydrate	0.6 g	0.6 g	0.6 g	0.6 g	0.6 g
Purified water	100%	80%	60%	20%	-
ethanol	-	20%	40%	80%	100%
Solubility	Clear solution	Clear solution	Clear solution	Clear solution	Opaque suspension

Experimental Example 2: Coating performance analysis of cytagliptin hydrochloride hydrate and cytagliptin phosphate hydrate

The coating time, content, and degree of formation of the flexible material according to the cytagliptin salt and the type of the solvent were analyzed as follows.

1) Content analysis method

1-1) Preparation of Test Solution and Standard Solution

Take 100 mg of cytagliptin, place it in a 100 mL flask, add diluent to completely dissolve it, and mark it. 10 mL of this solution was taken into a 50 mL flask, diluted with water, and used as a sample solution. The standard solution was prepared at the same concentration as the sample solution.

1-2) Analysis Method

10 μL of the sample solution and the standard solution were analyzed under the following conditions according to the liquid chromatograph method.

Column: X terra RP-18, 250 mm × 4.6 mm × 5 μm or equivalent

Detector: Ultraviolet absorbance photometer (wavelength 210 nm)

Column temperature: 45 ℃

Flow rate: 1.0 mL / min

Buffer: Potassium dihydrogenphosphate 1.36 g was precisely weighed and placed in 1000 mL water, adjusted to pH 6.8 using dilute potassium hydroxide solution, filtered and degassed.

Diluent: Buffer and acetonitrile were mixed at a ratio of 7: 3.

Mobile Phase A: Buffer, acetonitrile and methanol were mixed at a ratio of 95: 2.5: 2.5.

Mobile phase B: Acetonitrile and water were mixed at a ratio of 85:15.

Time (min)	Mobile phase A (%)	Mobile phase B (%)
0.01	55	45
5.0	55	45
5.5	0	100
10.0	0	100
10.1	55	45
16.0	55	45

2) Leaded substance analysis

1-1) Preparation of Test Liquid

30 mg of cytagliptin was collected, put into a 100 mL flask, and diluted with a diluent to completely dissolve it, and then used as a sample solution after marking.

1-2) Analysis Method

10 μL of the sample solution was analyzed under the following conditions according to the liquid chromatograph method.

Column: X terra RP-18, 250 mm × 4.6 mm × 5 μm or equivalent

Detector: Ultraviolet absorbance photometer (wavelength 210 nm)

Column temperature: 45 ℃

Flow rate: 1.1 mL / min

Buffer: Potassium dihydrogenphosphate 1.36 g was precisely weighed and placed in 1000 mL water, adjusted to pH 6.8 using dilute potassium hydroxide solution, filtered and degassed.

Diluent: Buffer and acetonitrile were mixed at a ratio of 7: 3.

Mobile Phase A: Buffer, acetonitrile and methanol were mixed at a ratio of 95: 2.5: 2.5.

Mobile phase B: Acetonitrile and water were mixed at a ratio of 85:15.

Time (min)	Mobile phase A (%)	Mobile phase B (%)
0.01	95	5
30.0	48	52
50.0	45	55
55.0	15	85
60.0	15	85
60.1	95	5
70.0	95	5

3) Preparation and comparison of cytagliptin immediate release layer

3-1) Example 1

The present inventors coated the metformin sustained release layer with cytagliptin hydrochloride hydrate in place of cytagliptin phosphate hydrate according to the prior art (WO 2009-099734 A1). At this time, the amount of cytagliptin hydrochloride was adjusted so that 100 mg per tablet of cytagliptin was added.

Specifically, 113.4 g of citaliptin hydrochloride hydrate (Dr Reddy), 75 g of hypromellose 2910 (6 cp), 15 g of polyethylene glycol 3350, 30 g of kaolin, 1.274 g of propyl gallate, and 2 g of Lake No. 2 in ethanol 1408 g and purified water 352 g (80% ethanol) was added and stirred for 4 hours to prepare a coating solution. Subsequently, 1.2 kg of tablets containing metformin 1000 mg were put in a King Sejong coating machine 30SFC and coated with the prepared coating solution at an air supply temperature of 60 to 80 ° C., and then the coating time was measured. The contents and the degree of generation of the flexible substance were evaluated.

As a result, the coating time measured was within 2 hours, the content was 99.2%, and no degradation product was observed.

3-2) Example 2

The present inventors prepared a coating solution having a low content of ethanol in Example 3-1 to compare the coating performance. Specifically, metformin was coated according to the prior art (WO 2009-099734 A1). At this time, the amount of the cytagliptin salt triad was adjusted so that 100 mg per tablet may be added.

Specifically, 113.4 g of citaliptin hydrochloride hydrate (Dr Reddy), 75 g of hypromellose 2910 (6 cp), 15 g of polyethylene glycol 3350, 30 g of kaolin, 1.274 g of propyl gallate, and 2 g of Lake No. 2 in ethanol 352 g and 1408 g (20% ethanol) of purified water were added and stirred for 4 hours to prepare a coating solution. Subsequently, 1.2 kg of tablets containing metformin 1000 mg were put in a King Sejong coating machine 30SFC and coated with the prepared coating solution at an air supply temperature of 60 to 80 ° C., and then the coating time was measured. The contents and the degree of generation of the flexible substance were evaluated.

As a result, the measured coating time was within 5 hours, the estimated content was 100.6%, and no degradation product was observed.

3-3) Comparative Example 1

The present inventors prepared a coating solution containing cytagliptin phosphate instead of cytagliptin hydrochloride for comparison with cytagliptin hydrochloride, and coated metformin according to the prior art (WO 2009-099734 A1) with the prepared coating liquid.

Specifically, 120 g of cytagliptin phosphate hydrate (Biochem), 75 g of hypromellose 2910 (6 cp), 15 g of polyethylene glycol 3350, 30 g of kaolin, 1.274 g of propyl gallate, and 2 g of Lake Blue No. 2 were purified water. 1760 g was added and stirred for 4 hours to prepare a coating solution. Subsequently, 1.2 kg of tablets containing metformin 1000 mg were placed in a Sejong coating machine 30SFC, coated with the prepared coating solution at an air supply temperature of 60 to 80 ° C., and the coating time was measured. (Degradation product) analysis was performed to evaluate the content and the degree of generation of lead substances.

As a result, the coating time measured was 8 hours, and the estimated content was 98.4%. In addition, no degradation products were observed.

3-4) Comparative Example 2

The present inventors prepared a coating solution using a solvent having a high ethanol content, unlike Example 3-3, and tried to compare the coating performance. Metformin was coated according to the prior art (WO 2009-099734 A1) with the prepared coating liquid.

Specifically, 120 g of cytagliptin phosphate hydrate (Biochem), 75 g of hypromellose 2910 (6 cp), 15 g of polyethylene glycol 3350, 30 g of kaolin, 1.274 g of propyl gallate, and 2 lake of Blue No. 80 1760 g of% ethanol was added and stirred for 4 hours to prepare a coating solution. Thereafter, 1.2 kg of tablets containing metformin 1000 mg were placed in a Sejong coating machine 30SFC, coated with the prepared coating solution at an air supply temperature of 60 to 80 ° C., and then the coating time was measured, and the content was evaluated by the content analysis method described above.

As a result, the coating time measured was about 2 hours, and the estimated content was 74.7%. The reason for this low content is that the physical dissipation occurred when spraying the coating liquid due to poor solubility of cytagliptin phosphate hydrate in ethanol.

As a result of this analysis, due to the low content of cytagliptin, it was not appropriate to evaluate the flexible substance (decomposition product). Thus, the coating liquid prepared to contain cytagliptin phosphate was controlled at room temperature and air supply temperature of 60 ° C by adjusting the temperature of the preparation tank. After exposure for 48 hours, the degradation products of the coating solution were evaluated. At this time, the cytagliptin hydrochloride was also compared.

The results are shown in FIG. As shown in FIG. 3, it was confirmed that the degradation products detected at about 29 minutes were significantly increased in the cytagliptin phosphate hydrate coating solution exposed to 60 ° C. for 48 hours, while the result was not found in the cytagliptin hydrochloride hydrate.

As described above, in Examples, the solubility of cytagliptin phosphate and hydrochloride was compared, and coating time, content, and minutes after coating cytagliptin with different coating solvents according to the prior art (WO 2009-099734 A1). Seafood was evaluated.

As a result of evaluating the coating time, content, and the possibility of increasing the degradation product, it was found that it is preferable to use cytagliptin hydrochloride for the formulation including the cytagliptin immediate release layer and to include a high volatile solvent such as ethanol in the coating solution. Could. The specific form of the formulation including the cytagliptin immediate release layer is shown in FIG. 4.

Experimental Example 3: Analysis of the dissolution rate of cytagliptin of the preparation including the cytagliptin immediate release layer

The present inventors have determined the dissolution rate of citagliptin of ZanmethexAlser tablet 100 mg / 1000 mg (manufacture number: M037400) and the citagliptin dissolution rate of a formulation prepared by coating the sustained release layer of metformin with citagliptin hydrochloride in Example 1 Comparison was made.

The dissolution rate of citaliptin in the formulation of Xanmet X RDS and the formulation of Example 1 was measured by dissolution test in purified water according to the Korean Pharmacopoeia Dissolution Test Method 2 (paddle method), rotational speed 100rpm.

The results are shown in FIG. As shown in Figure 5, it was confirmed that the formulation of Example 1 shows a dissolution rate of more than 80% within 30 minutes, similar to the Zanumet X R.

From the above description, those skilled in the art will appreciate that the present invention can be implemented in other specific forms without changing the technical spirit or essential features. In this regard, the embodiments described above are to be understood in all respects as illustrative and not restrictive. The scope of the present invention should be construed that all changes or modifications derived from the meaning and scope of the following claims and equivalent concepts rather than the detailed description are included in the scope of the present invention.

Claims (15)

1. (a) dissolving cytagliptin or a pharmaceutically acceptable salt thereof in a highly volatile solvent to prepare a coating solution; and

   (b) coating a sustained release layer with the coating solution;

   Method for producing a formulation comprising a cytagliptin immediate release layer.
2. The method of claim 1,

   The high volatile solvent is at least one selected from the group consisting of anisole, ethanol, acetone, butyl methyl ether, methyl ethyl ketone, methyl isobutyl ketone, pentane, heptane methanol, dichloromethane, the production method .
3. The method according to claim 1 or 2,

   Wherein the high volatile solvent comprises ethanol 20% or more of the total solvent weight, manufacturing method.
4. The method according to any one of claims 1 to 3,

   The pharmaceutically acceptable salt of cytagliptin is cytagliptin hydrochloride, the preparation method.
5. The method according to any one of claims 1 to 4,

   The coating solution further comprises one or more selected from the group consisting of hypromellose, polyvinyl alcohol, hydroxypropyl cellulose, povidone, polyethylene glycol, kaolin and propyl gallate.
6. The method according to any one of claims 1 to 5,

   The pharmaceutically acceptable salt of cytagliptin is included in an amount of 0.6 to 60 parts by weight based on 100 parts by weight of the solvent.
7. The method according to any one of claims 1 to 6,

   The manufacturing method is that the coating time is shortened without generating decomposition products.
8. The method according to any one of claims 1 to 7,

   The sustained release layer will include metformin or a pharmaceutically acceptable salt thereof.
9. The method according to any one of claims 1 to 8,

   The coating is performed by one or more methods selected from the group consisting of a fan coating method and a fluidized bed coating method.
10. The method according to any one of claims 1 to 9,

    The coating is carried out at a temperature of 50 to 90 ℃, manufacturing method.
11. (a) dissolving cytagliptin or a pharmaceutically acceptable salt thereof in a highly volatile solvent to prepare a coating solution; and

    (b) coating a sustained release layer with the coating solution;

    Cytagliptin immediate release layer coating method.
12. Cytagliptin immediate release layer coating composition comprising a cytagliptin hydrochloride and a high volatile solvent.
13. The method of claim 12,

    The cytagliptin hydrochloride is present in a dissolved state in a solvent.
14. A formulation prepared by the method of claim 1.
15. The method of claim 14,

    The preparation is a formulation of dissolution rate of more than 80% of cytagliptin within 60 minutes when the dissolution test in purified water according to the Korean Pharmacopoeia dissolution test method 2 (paddle method), rotation speed 100 rpm.

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