KR102369679B1 - Pharmaceutical combination comprising DAPAGLIFLOZIN L-PROLINE and METFORMIN - Google Patents

Abstract

The present invention relates to a combination preparation containing dapagliflozin L-proline and metformin at the same time. Easy. In addition, the combination preparation may be usefully used for preventing or treating diabetes, diabetes-related diseases, or diabetic complications.

Description

Pharmaceutical combination comprising dapagliflozin L-proline and metformin

The present invention relates to a pharmaceutical combination formulation comprising dapagliflozin L-proline and metformin. Specifically, it includes a core layer comprising metformin, a first coating layer formed on the core layer, and a second coating layer formed on the first coating layer and comprising dapagliflozin L-proline, and medication compliance, storage It relates to a combination formulation with improved stability and property stability and excellent bioavailability.

Diabetes mellitus is one of the major causes of adult death worldwide, and the number of diabetic patients is rapidly increasing with the increase of the obese population, which is characterized by hyperglycemia due to excessive glucose production and peripheral insulin resistance. Plasma glucose is normally filtered in the renal glomeruli and actively reabsorbed in the proximal tubule. SGLT-2 is considered to be the major transporter involved in glucose reuptake at this site.

Therefore, selective inhibition of SGLT-2 (Sodium-Glucose linked Transporter 2) in diabetic patients can normalize plasma glucose by increasing urine glucose excretion without significant gastrointestinal side effects, improving insulin sensitivity, and delaying the onset of diabetic complications. . Accordingly, SGLT-2 inhibitors are attracting attention as preventive or therapeutic agents for diabetes, diabetes-related diseases, and diabetic complications.

Dapagliflozin, (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydro Roxymethyl)tetrahydro-2H-pyran-3,4,5-triol) is a compound of Formula 1 below, and is disclosed in U.S. Patent No. 6,515,117.

[Formula 1]

In addition, Korean Patent Registration No. 1493102 discloses (S)-propylene glycol (PG), (R)-PG, EtOH, ethylene glycol (EG), 1:2 L-proline, 1:1 L-proline, 1:1 Crystalline structures of dapagliflozin comprising L-proline hemihydrate and 1:1 L-phenylalanine are disclosed.

Since diabetes is a chronic disease and its condition is complex, the symptoms of the disease are often accompanied by various complications. Therefore, it is necessary to select a drug most suitable for each patient's condition at that time, and when each drug is used alone, a sufficient effect may not be obtained depending on the symptoms, and it is also necessary to increase the dose or to prolong the administration. Due to various problems such as the appearance of side effects, it is often difficult to select it in the clinical field. Therefore, in relation to a formulation for the treatment of diabetes, diabetes-related diseases and diabetic complications, a method of administering two or more drugs having different mechanisms rather than administering one drug alone has been proposed. However, when preparing a composite formulation in which two or more drugs are mixed, various factors such as interaction of two or more drugs, storage stability, and dissolution rate of individual drugs must be considered, so it is not easy to prepare a composite formulation.

In the case of manufacturing a combination formulation of dapagliflozin and metformin as a treatment for diabetes, a drug layering formulation may be selected due to different release patterns between drugs, but in this case, there are limitations in several aspects compared to the general tablet formulation. For example, the drug in the outer layer has a high probability of being exposed to the external environment, so it is necessary to solve the problem of stability.

In this regard, International Publication No. WO2012-031124 discloses a drug-coated formulation for a treatment for diabetes, mentions a formulation using an antioxidant as a stabilizer, and discloses the importance of securing stability in the drug-coated formulation.

Dapagliflozin and metformin are active ingredients in the product. Astrazeneca's Zikduo Tablets are marketed in Korea in a combination of four doses of the two ingredients. In the case of dapagliflozin 10mg and metformin 1000mg dose tablets, which are the highest doses of Zikduo, it is a double-layer tablet formulation with a weight of about 1,645 mg, and its size is not suitable for oral administration, and compliance with medication is poor.

Therefore, the present inventors have developed a drug-coated formulation containing dapagliflozin and metformin as active ingredients, reducing weight and size compared to existing formulations, thereby improving patient compliance, and improving storage stability and property stability of the formulation. A combination formulation having an excellent dissolution rate has been studied to arrive at the present invention.

The present invention is to improve the therapeutic effect and reduce side effects through administration of the combination formulation having various mechanisms by providing a combination formulation of dapagliflozin L-proline and metformin. In particular, the present invention improves medication compliance by reducing the weight and size of the formulation, improves storage stability and property stability of the formulation, and secures excellent dissolution rates of dapagliflozin L-proline and metformin to achieve optimal bioavailability An object of the present invention is to provide a pharmaceutical combination preparation having

In order to achieve the above object, the present invention provides a core comprising metformin or a pharmaceutically acceptable salt thereof; a first coating layer formed on the core; and a second coating layer formed on the first coating layer and comprising dapagliflozin L-proline and a coating base.

The pharmaceutically acceptable salt of metformin may be preferably metformin hydrochloride, but is not limited thereto.

The combination preparation may be used for prevention or treatment of diabetes, diabetes-related diseases or diabetic complications.

The coating base constituting the first coating layer may be one or more selected from the group consisting of hydroxypropyl methylcellulose, polyethylene glycol, and polyvinylpyrrolidone.

In addition, the coating base of the second coating layer may be one or more selected from the group consisting of polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinylpyrrolidone, preferably polyvinyl alcohol-polyethylene glycol graft copolymer. can be used

The composite formulation of the present invention may further include a third coating layer formed on the second coating layer and including a pigment. In this case, the third coating layer may include a polyvinyl alcohol-polyethylene glycol graft copolymer.

In addition, the composite formulation of the present invention may further include a stabilizer in the second coating layer, and the stabilizer may be at least one selected from the group consisting of sodium citrate and butylhydroxytoluene.

In this case, the sodium citrate relative to dapagliflozin L-proline may be included in a weight ratio of 10:1 to 0.2:1, and the butylhydroxytoluene to dapagliflozin L-proline is 10:1 to 1:1 by weight. can be included as

In addition, the combined preparation of the present invention may be in the form of a tablet having a weight of 1,500 mg or less.

The present invention comprises the steps of preparing a core comprising metformin or a pharmaceutically acceptable salt thereof; forming a first coating layer including a coating base on the core; and forming a second coating layer comprising dapagliflozin L-proline and a coating base on the first coating layer.

In this case, the manufacturing method may further include the step of forming a third coating layer formed on the second coating layer and including a pigment, and the second coating layer may be prepared to further include a stabilizer.

The pharmaceutical combination formulation comprising dapagliflozin L-proline and metformin according to the present invention has improved storage stability and property stability, and is easy to take for a long time due to high convenience in taking it. In addition, the combination formulation shows an excellent dissolution rate and excellent in vivo absorption rate, so it can be used as a preventive or therapeutic agent for diabetes, diabetes-related diseases, and diabetic complications.

1 shows the total amount of related substances produced by dapagliflozin L-proline in Examples 1 to 4 and Comparative Examples 2 to 8.
2 shows the total amount of related substances produced in Examples 1 to 4 and Comparative Examples 1 to 8 of metformin hydrochloride.
3 shows the dissolution rate of dapagliflozin L-proline in Examples 1 and 4 and Comparative Examples 2, 3, and 8.
4 shows the dissolution rates of metformin hydrochloride in Examples 1 and 4 and Comparative Examples 1, 2, 3, and 8.
Figure 5 shows the dissolution rate of dapagliflozin L-proline in the control drug, Example 5, Comparative Examples 9 and 10.
6 is a photograph of the tablets of the control drug (Jikduo tablet), Example 5 and Comparative Example 14 for visual comparison of tablet properties.
7 shows the dissolution rate of dapagliflozin L-proline in the control drug, Examples 5 and 6 and Comparative Examples 16 and 17.

Dapagliflozin L-proline, a SGLT-2 inhibitor for the prevention or treatment of diabetes, diabetes-related diseases, and diabetic complications, improves insulin sensitivity by increasing urine glucose excretion without significant gastrointestinal side effects, and the development of diabetic complications by delaying the normalization of plasma glucose.

Dapagliflozin L-proline that can be used in the present invention is a crystalline complex of Formula 2 below.

[Formula 2]

(In Formula 2, x is 1 or 2, and y is 0 to 1)

Metformin is a biguanide antihyperglycemic drug used to treat non-insulin dependent diabetes mellitus (NIDDM). Metformin increases the sensitivity to insulin in peripheral tissues, inhibits the absorption of glucose from the gastrointestinal tract, and reduces the production of blood glucose in the liver. Metformin does not stimulate the secretion of insulin and has the action of reducing the amount of insulin in the blood and protecting the blood vessels. In addition, since it reduces body fat and does not cause hypoglycemia, it is a drug suitable for use in patients with obesity, hyperlipidemia, or patients who cannot control blood sugar ideally as a food control.

The pharmaceutically acceptable salt of metformin usable in the present invention may be selected from the group consisting of hydrochloride, succinate, fumarate, methanesulfonate, benzenesulfonate, and toluenesulfonate, but is not limited thereto.

In the pharmaceutical combination preparation of the present invention, dapagliflozin L-proline may be included in an amount of 5 to 20 mg as dapagliflozin, and dapagliflozin L-proline is metformin and a pharmaceutically acceptable salt thereof. It may be included in an amount of 0.1 wt% to 10 wt%.

The pharmaceutical combination formulation of the present invention is a conventional formulation in the pharmaceutical field, for example, tablets, capsules, beads, beadlets, granules, It may be formulated as a preparation for oral administration, such as pills, troches, solutions, suspensions, or preparations for parenteral administration.

Excipients that may be added to the present invention include, but are not limited to, lactose, starch, cellactose, dextrin, microcrystalline cellulose, potassium monohydrogen phosphate, calcium carbonate, and saccharides.

The binder includes, but is not limited to, polyvinylpyrrolidone derivatives such as povidone and copovidone, cellulose derivatives such as methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, starch, gelatin, and the like.

Disintegrants include crospovidone, pregelatinized starch, corn starch, methylcellulose, hydroxypropylmethylcellulose, sodium starch glycolate, croscarmellose sodium, low-substituted hydroxypropylcellulose, sodium starch glycolate, starch, starch pregelatinized starch, alginic acid, or a sodium salt thereof, but is not limited thereto.

In addition, the pharmaceutical preparation of the present invention may further include a pH adjuster, a suspending agent, a preservative, a flavoring agent, a coloring agent, a sweetener, an adsorbent, and the like, if necessary. The content of these additives is not particularly limited in the present invention and may be appropriately adjusted as necessary.

The present invention relates to a core comprising metformin or a pharmaceutically acceptable salt thereof; a first coating layer formed on the core; and a second coating layer formed on the first coating layer and comprising dapagliflozin L-proline and a coating base.

The coating base constituting the first coating layer may be one or more selected from the group consisting of hydroxypropyl methylcellulose, polyethylene glycol and polyvinylpyrrolidone, and improve stability by separating dapagliflozin L-proline and metformin make it

In addition, the coating base constituting the second coating layer may be one or more selected from the group consisting of polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinylpyrrolidone, and is prepared by mixing with dapagliflozin L-proline. 1 By being applied to the surface of the coating layer, the pharmacologically active ingredient can be rapidly released after taking the drug.

The composite formulation of the present invention may further include a third coating layer formed on the second coating layer and containing a pigment, preferably polyvinyl alcohol-polyethylene glycol graft copolymer.

By including a pigment in the third coating layer, the properties of the formulation can be improved, and proper dissolution of the drug can be ensured by including the polyvinyl alcohol-polyethylene glycol graft copolymer.

The pigment of the present invention is an additive added for coloring the preparation, and includes all pigments that can be used in pharmaceuticals.

In addition, the present invention may further include a stabilizer in the second coating layer, and the stabilizer included in the second coating layer is a material having an antioxidant effect, and suppresses generation of related substances under oxidative conditions. The stabilizer may be selected from the group consisting of butylhydroxytoluene, propyl gallate, sodium hydrogen carbonate, magnesium carbonate, calcium carbonate, meglumine, sodium citrate, and combinations thereof.

The stabilizer may be included in an amount of 0.01 to 40 parts by weight based on 100 parts by weight of the second coating layer. When the stabilizer is sodium citrate, sodium citrate relative to dapagliflozin L-proline may be included in a weight ratio of 10:1 to 0.2:1, and when the stabilizer is butylhydroxytoluene, dapagliflozin L- Proline to butylhydroxytoluene may be included in a weight ratio of 10:1 to 1:1.

In addition, the formulation of the present invention may be in the form of a tablet having a weight of 1,500 mg or less, and is manufactured at a reduced weight than the existing combination formulation containing dapagliflozin and metformin (Jikduo tablet, tablet weight 1,645 mg). Medication compliance can be improved.

In addition, the present invention comprises the steps of preparing a core comprising metformin or a pharmaceutically acceptable salt thereof; forming a first coating layer including a coating base on the core; and forming a second coating layer comprising dapagliflozin L-proline and a coating base on the first coating layer.

In this case, the manufacturing method may further include the step of forming a third coating layer formed on the second coating layer and including a pigment, and the second coating layer may be prepared to further include a stabilizer.

Hereinafter, the present invention will be described in more detail through examples. These examples are for illustrating the present invention in more detail, and the scope of the present invention is not limited by these examples.

[Examples 1 to 4]

Preparation of dapagliflozin L-proline and metformin combination formulation

A metformin core was prepared with the components and contents shown in Table 1 below, and the process is as follows. After mixing metformin hydrochloride with hypromellose 2208, hypromellose 2910 and locust bean gum, purified water was used to perform wet granulation using a high shear unit. After drying and sizing, final mixing with silicon dioxide was performed. After final lubrication with magnesium stearate, it was compressed to 20 kp using a tablet press.

ingredient mg/T metformin hydrochloride 1000.0 Hypromellose 2208 270.0 hypromellose 2910 8.0 locust bean gum 40.0 Purified water (330.0) silicon dioxide 7.0 magnesium stearate 15.0 Sum 1,340.0

A composite formulation was prepared by coating the metformin core with a first coating layer containing a coating base and a second coating layer containing dapagliflozin L-proline and a stabilizer at the components and contents shown in Table 2 below.

At this time, the first coating layer was coated by using a coating machine (SEJONG, SFC-30) after mixing hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), and polyvinylpyrrolidone (PVP) in purified water. .

The second coating layer is a mixture of dapagliflozin L-proline, polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat IR, BASF), polyvinylpyrrolidone, sodium citrate and butylhydroxytoluene in a mixed solvent of ethanol and water ( 3:7 weight ratio) and then coated using a coater. After coating, it was dried to prepare a composite formulation for oral use.

ingredient Example 1 Example 2 Example 3 Example 4 first coating layer Hydroxypropyl methylcellulose (mg) 32.0 Polyethylene glycol (mg) 4.3 Polyvinylpyrrolidone (mg) 4.3 Purified water (ml) (500.0) Total weight of coating base (mg) 40.6 second coating layer Dapagliflozin L-proline (mg) 15.6 15.6 15.6 15.6 Polyvinyl alcohol-polyethylene glycol graft copolymer (mg) 20.2 20.2 20.2 20.2 Polyvinylpyrrolidone (mg) 2.8 2.8 2.8 2.8 Sodium citrate (mg) 10.0 5.0 50.0 - Butylhydroxytoluene (mg) - - - 1.0 Ethanol (ml) (300.0) (300.0) (300.0) (300.0) water (ml) (600.0) (600.0) (600.0) (600.0) Coating base weight (mg) 48.6 43.6 88.6 39.6

[Comparative Example 1]

Preparation of metformin hydrochloride core

A core containing metformin hydrochloride was prepared in the same manner as in Example 1, except for omitting the process of coating with the first coating layer and the second coating layer in Example 1.

[Comparative Examples 2 to 8]

Preparation of dapagliflozin L-proline and metformin combination formulation

An oral composite formulation was prepared under the same conditions and methods as in Example 1, except that the first coating layer and the second coating layer were coated with the components and contents of Table 3 below.

ingredient Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 first coating layer Hydroxypropyl methylcellulose (mg) - 32.0 polyethylene glycol
(mg) 4.3 polyvinylpyrrolidone
(mg) 4.3 Purified water (ml) (500.0) Total weight of coating base
(mg) 40.6 second coating layer Dapagliflozin L-proline (mg) 15.6 15.6 15.6 15.6 15.6 15.6 15.6 Polyvinyl alcohol-polyethylene glycol graft copolymer (mg) 20.2 20.2 20.2 20.2 20.2 20.2 - Hydroxypropyl methylcellulose (mg) - - - - - - 20.2 polyvinylpyrrolidone
(mg) 2.8 2.8 2.8 2.8 2.8 2.8 2.8 propyl gallate - 1.36 - - - - - tartrate - - 10.0 - - - - tocopherol - - - 10.0 - - - sodium bicarbonate - - - - 10.0 - - sodium edetate - - - - - 10.0 - sodium citrate - - - - - - 10.0 Ethanol (ml) (300.0) (300.0) (300.0) (300.0) (300.0) (300.0) (300.0) water (ml) (600.0) (600.0) (600.0) (600.0) (600.0) (600.0) (600.0) Coating base weight (mg) 38.6 39.96 48.6 48.6 48.6 48.6 48.6

[Experimental Example 1]

Confirmation of stability of combination formulations

In the formulations of Examples 1 to 4, and Comparative Examples 2 to 8, including dapagliflozin L-proline in the second coating layer, the production of dapagliflozin L-proline related substances was confirmed.

In addition, the formulations of Examples 1 to 4 and Comparative Examples 1 to 8 containing metformin hydrochloride were evaluated for stability of metformin hydrochloride.

For stability evaluation, the complex formulation was placed in an HDPE bottle and stored for one month at 60° C. and 75% relative humidity, followed by liquid chromatography under the conditions described below.

The results of generation of related substances of dapagliflozin L-proline are shown in Table 5 and FIG. 1, and the results of generation of related substances of metformin hydrochloride are shown in Tables 6 and 2 of FIG.

<Test conditions>

Storage conditions: 40℃, relative humidity 75%, light-shielded glass container

Test time points: Initial, 2 weeks, 4 weeks, 8 weeks

Analysis subject: Total amount of related substances produced in dapagliflozin L-proline and metformin hydrochloride

<Dapagliflozin L-proline analog analysis conditions>

Column: Liquid chromatography column (Ascentis Express RP-Amide) with a particle diameter of 5 μm in a stainless tube with an inner diameter of about 4.6 mm and a length of about 15 cm

Mobile phase: A → phosphate buffer solution, B → acetonitrile

time (minutes) mobile phase A mobile phase B 0 → 5 70 30 5 → 30 70 → 40 30 → 60 30 → 40 40 → 30 60 → 70 40 → 60 30 70 60 → 61 30 → 70 70 → 30 61 → 75 70 30

Detector: Ultraviolet absorbance spectrometer (measurement wavelength 220 nm)

Flow rate: 0.8 ml/min

Column temperature: 30°C

<Metformin hydrochloride related substance analysis conditions>

Column: A column for liquid chromatography with a particle diameter of 5 μm in a stainless tube with an inner diameter of about 4.6 mm and a length of about 5 cm (Phenomenex Luna SCX)

Mobile phase: phosphate buffer: acetonitrile = 41:9 (v/v)

Detector: Ultraviolet absorbance spectrometer (measurement wavelength 205 nm)

Flow rate: 2.0 ml/min

Column temperature: 30°C

sample Early harsh 2 weeks harsh 4 weeks harsh 8 weeks Example 1 0.00 0.20 0.37 0.59 Example 2 0.00 0.23 0.37 0.53 Example 3 0.00 0.22 0.39 0.54 Example 4 0.00 0.20 0.44 0.53 Comparative Example 2 0.00 0.59 0.74 0.52 Comparative Example 3 0.00 0.48 0.71 1.79 Comparative Example 4 0.00 0.51 0.74 1.93 Comparative Example 5 0.00 0.45 0.77 1.67 Comparative Example 6 0.00 0.42 0.69 1.63 Comparative Example 7 0.00 0.42 0.71 1.73 Comparative Example 8 0.00 0.22 0.42 0.55

sample Early harsh 2 weeks harsh 4 weeks harsh 8 weeks Example 1 < LOQ < LOQ 0.06 0.09 Example 2 < LOQ < LOQ 0.06 0.10 Example 3 < LOQ < LOQ 0.05 0.09 Example 4 < LOQ < LOQ 0.07 0.12 Comparative Example 1 < LOQ < LOQ 0.06 0.09 Comparative Example 2 < LOQ < LOQ 0.05 0.09 Comparative Example 3 < LOQ < LOQ 0.08 0.13 Comparative Example 4 < LOQ < LOQ 0.07 0.10 Comparative Example 5 < LOQ < LOQ 0.05 0.12 Comparative Example 6 < LOQ < LOQ 0.08 0.13 Comparative Example 7 < LOQ < LOQ 0.09 0.14 Comparative Example 8 < LOQ < LOQ 0.08 0.15

As shown in Table 5 and Figure 1, in the case of Examples 1 to 3 and Comparative Example 8 in which sodium citrate was added as a stabilizer in the evaluation of the total amount of related substances produced in the formulation containing dapagliflozin L-proline, Comparative Examples 2 to 7 showed a more stable aspect. In addition, in Example 4 to which butylhydroxytoluene was added, stability was similar to that of the formulation to which sodium citrate was added. However, in Comparative Examples 2 to 7 in which other stabilizers were added, there was no effect of improving stability.

As shown in Table 6 and FIG. 2, in the case of metformin hydrochloride, similar stability was confirmed without any difference between the formulations of Examples and Comparative Examples.

Therefore, it can be seen that sodium citrate and butylhydroxytoluene as stabilizers of dapagliflozin L-proline are suitable for improving stability.

[Experimental Example 2]

Confirmation of dissolution of combination formulations

Examples 1, 4 and Comparative Example 1, using 1,000 mL of a pH 6.8 phosphate solution according to the first method (Basket) of the United States Pharmacopoeia (USP) dissolution test at 37 ° C. and rotation speed 100 rpm; A dissolution test was performed on the formulations of 2, 3, and 8.

After the start of the test, the dapagliflozin L-proline tablet part is 0, 5, 10, 15, 20, 30 minutes, and the metformin hydrochloride core is 0, 1, 2, 4, 6, 8, 10, 12 hours dissolution test solution sample was collected and subjected to liquid chromatography under the following conditions, and the dissolution rate was calculated.

The dissolution rates of dapagliflozin L-proline are shown in Tables 7 and 3 below, and the dissolution rates of metformin hydrochloride are shown in Tables 8 and 4 below.

<Dapagliflozin L-proline elution analysis liquid chromatography conditions>

- Column: A column for liquid chromatography with a particle diameter of 5 μm in a stainless tube with an inner diameter of about 4.6 mm and a length of 15 cm (Zorbax SC-C8, Agilent Zorbax)

- Column temperature: 25℃

- Sample injection volume: 10 μL

- Mobile phase: pH7.2 phosphate buffer/acetonitrile = 60/40 (v/v)

- Flow rate: 1.0 mL/min

- Detector: UV light absorption spectrometer (measurement wavelength 240 nm)

<Metformin hydrochloride dissolution analysis liquid chromatography conditions>

- Column: Column for liquid chromatography with a particle diameter of 5 ㎛ in a stainless tube with an inner diameter of about 4.6 mm and a length of 5 cm (Phenomenez Luna SCX)

- Column temperature: 30℃

- Sample injection volume: 5 μL

- Mobile phase: phosphate buffer/acetonitrile = 3/1 (v/v)

- Flow rate: 2.0 mL/min

- Detector: UV light absorption spectrometer (measurement wavelength 240 nm)

Dissolution time (min) and dissolution rate (%) sample 0 5 10 15 20 30 Example 1 0.0 78.5 90.4 94.5 98.4 99.2 Example 4 0.0 74.2 89.1 96.5 97.3 98.9 Comparative Example 2 0.0 73.4 88.8 93.8 98.4 99.9 Comparative Example 3 0.0 77.4 84.2 89.5 99.0 100.3 Comparative Example 8 0.0 14.4 33.8 49.1 59.1 90.9

Dissolution time (hour) and dissolution rate (%) sample 0 One 2 4 6 8 10 12 Example 1 0.0 29.4 44.3 64.0 77.9 88.6 92.8 96.8 Example 4 0.0 30.8 46.2 67.4 82.5 92.8 96.6 98.7 Comparative Example 1 0.0 31.2 46.9 67.6 82.0 91.3 94.4 98.7 Comparative Example 2 0.0 28.5 42.4 62.5 76.7 88.0 93.1 97.9 Comparative Example 3 0.0 30.7 45.7 66.0 80.4 92.2 96.2 98.7 Comparative Example 8 0.0 31.7 47.6 68.4 82.8 91.9 95.3 99.9

As shown in Table 7 and FIG. 3, in Examples 1 and 4 and Comparative Examples 2 and 3, similar dissolution rates of dapagliflozin L-proline were shown, and it was confirmed that there was no dissolution difference depending on the type of stabilizer. However, in the case of Comparative Example 8, in which the coating base of the second coating layer was changed from polyvinyl alcohol-polyethylene glycol graft copolymer to hydroxypropylmethyl cellulose, it was confirmed that the dissolution rate was very slow compared to other formulations. Therefore, it can be seen that in the case of dapagliflozin L-proline having immediate release properties, a polyvinyl alcohol-polyethylene glycol graft copolymer coating base is suitable.

As shown in Table 8 and FIG. 4, the dissolution of the metformin hydrochloride core showed similar dissolution rates regardless of the presence or absence of the coating base and the type.

[Example 5 and Comparative Examples 9 and 10]

Preparation of dapagliflozin L-proline and metformin combination formulation

In order to compare the dissolution pattern of dapagliflozin L-proline according to the type of the second coating layer coating base, a composite formulation was prepared with the composition and content of Table 9 below. Polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol and hypromellose 2910 (p645 grade) were tested as coating bases. For smooth coating, polyethylene glycol 6000, a plasticizer, and polyvinylpyrrolidone, a water-soluble polymer, were tested for smooth coating. (K-30 grade) was used.

However, in the case of the polyvinyl alcohol-polyethylene glycol graft copolymer, polyethylene glycol 6000 was not used because the role of a plasticizer was not required. The amount of the drug coating part was selected so that the amount of solids in the total coating solution containing dapagliflozin was about 3% (w/w) compared to the core tablet containing metformin, and tablets were prepared according to the following detailed procedure.

First, metformin, hypromellose 2208, hypromellose 2910, and locust bean gum were mixed, and the resulting powder mixture was wet granulated using water. The obtained wet granulation mixture was dried using a fluidized bed dryer or drying oven. Silicon dioxide was added to the obtained metformin wet granules and mixed uniformly.

Magnesium stearate was added to the mixed primary mixture and homogeneously mixed for 5 minutes. The obtained mixture was tableted using a tableting machine to prepare metformin core tablets.

After dissolving all the solids in ethanol and purified water according to the prescription in Table 9 below, the spray rate and inlet temperature were adjusted so that the product temperature was maintained at about 35-40° C., and then the metformin core tablets were sprayed and coated.

ingredient Example 5 Comparative Example 9 Comparative Example 10 metformin
core tablet Metformin (mg) 1000.0 1000.0 1000.0 Hypromellose 2208 (mg) 270.0 270.0 270.0 Hypromellose 2910 (mg) 8.0 8.0 8.0 Locust Bean Gum (mg) 40.0 40.0 40.0 Purified water (ml) (330.0) (330.0) (330.0) Silicon dioxide (mg) 7.0 7.0 7.0 Magnesium Stearate (mg) 15.0 15.0 15.0 first coating layer Hypromellose 2910 (mg) 33.6 33.6 33.6 Polyethylene glycol 6000 (mg) 6.4 6.4 6.4 Ethanol (ml) (560.0) (560.0) (560.0) Purified water (ml) (240.0) (240.0) (240.0) second coating layer Dapagliflozin L-Proline (mg) 15.6 15.6 15.6 Polyvinyl alcohol-polyethylene glycol graft copolymer (mg) 20.2 - - polyvinyl alcohol (mg) - 20.2 - Hypromellose 2910 (mg) - - 20.2 Polyethylene glycol 6000 (mg) - 2.0 2.0 Polyvinylpyrrolidone (mg) 2.8 2.8 2.8 Ethanol (ml) (150.0) (150.0) (150.0) Purified water (ml) (150.0) (150.0) (150.0) Total weight (mg) 1418.6 1420.6 1420.6

[Experimental Example 3]

Confirmation of dissolution of combination formulations

The dissolution test was performed under the following conditions according to the first method (basket method) of the dissolution test of the Korean Pharmacopoeia for the combination preparation of Table 9 and the reference drug (Jikduo tablet, 10/1000 mg), and the results are shown in Tables 10 and 5 indicated.

<Dissolution test conditions>

- Dissolution method: Dissolution method 1 of the Korean Pharmacopoeia (basket method)

- Eluate: pH 6.8 solution

- Eluate volume: 1000 mL

- Dissolver temperature: 37.5℃

- Rotation speed: 100 rpm

- Number of test groups: 6

- Sample collection time: 5 minutes, 10 minutes, 15 minutes, 30 minutes and 45 minutes

<Sample analysis conditions>

- Detector: Ultraviolet absorbance spectrometer (measurement wavelength: 220nm)

- Column: A column filled with 2.7 um of amide phases for liquid chromatography in a stainless tube with an inner diameter of about 4.6 mm and a length of 150 mm.

- Flow rate: 1.0 ml/min

- Column temperature: 30℃

- Injection volume: 20 ul

- Mobile phase : A : B = 60 : 40 (v/v)

* Mobile phase A: Put 2.72 g of potassium dihydrogen phosphate in a 1000 mL volumetric flask, add purified water to make 1000.0 mL, and then add phosphoric acid to adjust the pH to 2.5

* Mobile phase B: acetonitrile

Dissolution time (min) and dissolution rate (%) sample 0 5 10 15 30 45 reference drug 0.0 65.4 87.6 92.2 95.0 95.5 Example 5 0.0 80.2 91.0 94.5 95.2 95.5 Comparative Example 9 0.0 22.9 63.5 78.8 92.2 94.9 Comparative Example 10 0.0 18.8 37.7 53.9 87.1 96.3

As a result of the dissolution test, in Example 5 using a polyvinyl alcohol-polyethylene glycol graft copolymer as a coating base, the dissolution rate of dapagliflozin L-proline was high, similar to that of the reference drug.

On the other hand, it was found that Comparative Examples 9 and 10 using polyvinyl alcohol and hypromellose 2910 respectively showed a low 5-minute dissolution rate of about 20%. Therefore, it was found that polyvinyl alcohol-polyethylene glycol graft copolymer was suitable as a coating base to secure the dissolution rate of dapagliflozin L-proline.

[Comparative Examples 11 to 15]

Preparation of dapagliflozin L-proline and metformin complex formulation containing pigment

Dapagliflozin has the property of discoloration to yellow or pale yellow when exposed to external environment due to the characteristics of the drug. Although this is not a change that affects the efficacy and stability of the drug, there is a possibility that it may cause a decrease in medication adherence due to a change in cosmetic properties. In order to secure the stability of the properties of the drug containing dapagliflozin, it is preferable to add a coating using a pigment.

Combination formulations of Comparative Examples 11 to 15 in which a dye was additionally added were prepared compared to the formulation of Example 5. After dissolving all the solids in ethanol and purified water according to the prescription in Table 11 below, the spray rate and inlet temperature are adjusted so that the product temperature is maintained at about 35-40° C. was coated

ingredient Example 5 Comparative Example 11 Comparative Example 12 Comparative Example 13 Comparative Example 14 Comparative Example 15 metformin
core tablet Same as configuration in Table 9 first coating layer Same as configuration in Table 9 second coating layer Dapagliflozin L-Proline (mg) 15.6 15.6 15.6 15.6 15.6 15.6 Polyvinyl alcohol-polyethylene glycol graft copolymer (mg) 20.2 20.2 20.2 20.2 20.2 20.2 Polyvinylpyrrolidone (mg) 2.8 2.8 2.8 2.8 2.8 2.8 Titanium dioxide (mg) - 11.8 11.8 11.8 11.8 11.8 Yellow iron oxide (mg) - 0.7 0.7 0.7 0.7 0.7 Talc (mg) - 13.7 13.7 13.7 13.7 13.7 Polysorbate 80 (mg) - - 3.2 - - - Sodium Lauryl Sulfate (mg) - - - 3.2 - - Ethanol (ml) (150.0) (150.0) (150.0) (150.0) (50.0) (250.0) Purified water (ml) (150.0) (150.0) (150.0) (150.0) (250.0) (50.0) Total weight (mg) 1418.6 1444.8 1448.0 1448.0 1444.8 1444.8

[Experimental Example 4]

Confirmation of properties of complex formulations containing pigments

For the tablets of Table 11, the roughness and adhesiveness of the tablets were numerically quantified on a scale of 1 to 5, and are shown in Table 12 below. A larger number means rougher and more tacky.

Comparison drug (Jikduo tablet) Example 5 Comparative Example 11 Comparative Example 12 Comparative Example 13 Comparative Example 14 Comparative Example 15 surface roughness
(Roughness) 2 One 4 4 4 4 3 Sticky 2 2 2 3 3 4 4

As shown in Table 12, in the case of Example 5 containing no pigment, it was found that the roughness and adhesion of the tablet surface were similar to those of the control drug and were at a good level (FIG. 6). However, in the case of Comparative Example 11 using titanium dioxide (TiO2) and iron oxide yellow, which are representative pigments, the surface properties of the tablet were rough, and stickiness occurred even when talc was used as an anti-adhesive agent.

Accordingly, in Comparative Examples 12 and 13, polysorbate or sodium lauryl sulfate was added as a surfactant to reduce the tensile force of the coating solution, respectively, but it was confirmed that the roughness was similar and the adhesiveness was rather increased.

In addition, from Comparative Examples 14 and 15, in which the ratio of ethanol used in the manufacturing process was changed, it was confirmed that when the ratio of ethanol was high, the surface properties were improved but there was no improvement in adhesion.

Therefore, it was found that all of the composite formulations including the pigment in the second coating layer did not exhibit suitable surface roughness and adhesion, and thus property stability was lowered.

[Example 6 and Comparative Examples 16 and 17]

Preparation of dapagliflozin L-proline and metformin combination formulation containing a pigment in the third coating layer

From the results of Experimental Example 4, it was confirmed that when a dye was added to the coating solution of the second coating layer containing dapagliflozin L-proline, it did not have excellent tablet properties, and the drug coating layer (second coating layer) The separated outer coating layer (third coating layer) was introduced to prepare a tablet to which a pigment was added.

As shown in Table 13 below, Opadry® (manufactured by Colorcon) containing polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol or hypromellose 2910, respectively, together with a pigment and a plasticizer, was applied to the third coating layer. A complex formulation including a coating base was prepared.

The amount of each Opadry® was set to be about 3% (w/w) of the core tablet up to the previous step, and the type and amount of the solvent followed a commonly known method. After preparing the coating solution of the third coating layer according to the prescription in Table 13, the spray rate and the inlet temperature were adjusted so that the product temperature was maintained at about 35-40 ° C. The components of Opadry included in Example 6 and Comparative Examples 16 to 17 are as follows.

- Opadry QX yellow (Example 6): In addition to polyvinyl alcohol-polyethylene glycol graft copolymer, plasticizer and pigment included

- Opadry II 85F yellow (Comparative Example 16): In addition to polyvinyl alcohol, plasticizer and pigment included

- Opadry 03B yellow (Comparative Example 17): Including hypromellose 2910, plasticizer and pigment

ingredient Example 6 Comparative Example 16 Comparative Example 17 metformin
core tablet Same as configuration of Example 5 first coating layer Same as configuration of Example 5 second coating layer Same as configuration of Example 5 3rd coating layer Opadry QX yellow (mg) 42.5 - - Opadry II 85F yellow (mg) - 42.5 - Opadry 03B yellow (mg) - - 42.5 Ethanol (ml) - - (240.0) Purified water (ml) (150.0) (170.0) (120.0) Total weight (mg) 1461.1 1461.1 1461.1

[Experimental Example 5]

Confirmation of properties of the composite formulation including the third coating layer

For the tablets of Table 13, the roughness and adhesiveness of the tablets were quantified on a scale of 1 to 5 and shown in Table 14 below. A larger number means rougher and more tacky.

Comparison drug (Jikduo tablet) Example 6 Comparative Example 16 Comparative Example 17 surface roughness
(Roughness) 2 2 2 One Sticky 2 2 One 2

As can be seen in Table 14, it was confirmed that all the tablets subjected to the outer coating of the third coating layer exhibited good surface roughness and adhesion at a level similar to that of the reference drug. In other words, when a pigment is added to the same coating layer as dapagliflozin L-proline, tablet properties are significantly reduced, whereas the drug coating layer (second coating layer) and the outer coating layer (third coating layer) separated from the drug coating layer (third coating layer) containing a pigment In this case, it can be seen that the properties of the tablet are excellent, so that it is possible to secure good drug compliance and the marketability of the finished drug.

[Experimental Example 6]

Confirmation of dissolution of combination formulations

In order to confirm the drug release degradation that may occur by proceeding with the drug coating layer and the skin coating separated from the drug coating layer, the combination formulation of Table 14, the control drug (Jikduo tablet, 10/1000 mg), and Example 5 that does not contain a pigment The dissolution test was carried out in the same manner as in Experimental Example 3 for the combined formulation, and the results are shown in Table 15 and FIG. 7 .

Dissolution time (min) and dissolution rate (%) sample 0 5 10 15 30 45 reference drug 0.0 65.4 87.6 92.2 95.0 95.5 Example 5 0.0 80.2 91.0 94.5 95.2 95.5 Example 6 0.0 62.5 86.0 93.8 97.7 99.3 Comparative Example 16 0.0 48.8 67.7 83.9 97.1 96.3 Comparative Example 17 0.0 32.2 48.8 63.9 74.3 81.2

As a result of the dissolution test, in the case of Example 6 using a polyvinyl alcohol-polyethylene glycol graft copolymer (Opadry QX yellow) as a coating base, a dissolution rate similar to that of the reference drug was shown. Comparative Examples 16 and 17 using polyvinyl alcohol (Opadry II 85F yellow) and hypromellose 2910 (Opadry 03B yellow) respectively showed lower dissolution than the control drug.

That is, it can be seen that it is preferable to use a polyvinyl alcohol-polyethylene glycol graft copolymer together with a pigment in the third coating layer in order to secure a suitable dissolution rate while including a pigment in order to secure property stability.

Claims (15)

a core comprising metformin or a pharmaceutically acceptable salt thereof;
a first coating layer formed on the core; and
It is formed on the first coating layer and includes a second coating layer comprising dapagliflozin L-proline and a coating base,
The coating base included in the second coating layer is a composite formulation, characterized in that at least one selected from the group consisting of polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinylpyrrolidone.
delete delete The complex formulation of claim 1, further comprising a third coating layer formed on the second coating layer and comprising a pigment.
[Claim 5] The composite formulation of claim 4, wherein the third coating layer comprises a polyvinyl alcohol-polyethylene glycol graft copolymer.
The combination formulation according to claim 1, wherein the second coating layer further comprises a stabilizer.
The combination formulation according to claim 6, wherein the stabilizer is at least one selected from the group consisting of sodium citrate and butylhydroxytoluene.
The combination formulation according to claim 7, wherein the sodium citrate relative to dapagliflozin L-proline is included in a weight ratio of 10:1 to 0.2:1.
The combination formulation according to claim 7, wherein the butylhydroxytoluene to dapagliflozin L-proline is included in a weight ratio of 10:1 to 1:1.
The combination formulation according to claim 1, wherein the pharmaceutically acceptable salt of metformin is metformin hydrochloride.
The combination formulation according to claim 1, characterized in that it is a tablet having a weight of 1,500 mg or less.
preparing a core comprising metformin or a pharmaceutically acceptable salt thereof;
forming a first coating layer including a coating base on the core; and
Forming a second coating layer comprising dapagliflozin L-proline and a coating base on the first coating layer,
The coating base included in the second coating layer is a method for producing a composite formulation, characterized in that at least one selected from the group consisting of polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinylpyrrolidone.
13. The method of claim 12, further comprising the step of forming a third coating layer formed on the second coating layer and comprising a pigment.
The method of claim 12, wherein the second coating layer further comprises a stabilizer.
According to claim 1, Diabetes, diabetes-related disease or a pharmaceutical combination preparation for the prevention or treatment of diabetic complications.

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