KR20210147955A - Sustained release metformin coated tablets controlled by osmotic pressure and preparation method thereof - Google Patents

Abstract

A sustained-release coated tablet containing metformin as an active ingredient according to the present invention has a dissolution profile very similar to that of currently commercially available metformin sustained-release tablets, has robustness in the osmotic pressure section of the human body, and has an effect of not tearing a coating layer, and thus has an excellent effect of increasing the dosage compliance by having a small size of tablet.

Description

Sustained release metformin coated tablets controlled by osmotic pressure and a method for preparing the same

It relates to a sustained-release metformin-coated tablet with controlled release by osmotic pressure and a method for preparing the same.

Metformin is a biguanide-based drug for oral treatment of non-insulin-dependent diabetes mellitus. Metformin has a mechanism of increasing the use of sugar in the muscle and inhibiting the production of sugar in the liver, and is used as a first-line drug for the prevention and treatment of diabetes.

Metformin is currently marketed as a hydrochloride salt, and a high dose of 500 mg to 1000 mg must be administered at a time. Inconvenient disadvantages of taking it appear.

Currently, metformin sustained-release tablets that are taken once a day have been developed, but these formulations still have the disadvantage of increasing the tablet size due to the use of various excipients to control the release of metformin, so there is room for difficulty swallowing in elderly patients and pediatric patients. , which may lead to low dosing compliance.

In the prior art, in order to maintain the blood concentration of a water-soluble drug, a matrix system, an osmotic pressure control system, a gastric retention system, etc. that provide a sustained-release or delayed-release formulation have been used. KR 10-2007-0021565 (Patent Document 1) discloses that a composition containing metformin and a matrix agent capable of controlling the release rate of metformin is slug, and then a matrix is prepared by a dry granulation method, and a film-like coating layer is formed on the surface. It has been described with respect to a metformin sustained-release tablet that is slowly released at a constant rate. The matrix formulation using the hydrophilic or hydrophobic polymer disclosed in KR 10-2007-0021565 has the advantage of being simple and easy to manufacture, but since a large amount of excipients is used, the size of the formulation increases, and an excessive amount of drug is initially released. Zero-order release is practically difficult because the release rate of the drug decreases after a certain period of time.

As disclosed in KR 10-2014-0007247 (Patent Document 2), US 1999/06024 (Patent Document 3), the method of drilling a hole with a laser drill after coating the semi-permeable film is an expensive equipment point, operator or work There are problems such as the point that the size of the hole through which the drug is released is not constant depending on the environment, the deviation is severe depending on the size of the hole, the manufacturing cost is high, and the dumping of the drug due to the breakage of the formulation in vivo.

In the case of KR 10-2013-0139010 (Patent Document 4) and KR 10-2008-0001772 (Patent Document 5) in which ethyl cellulose coating is performed on the granules, the process time is very long in the case of the granule coating step, and the granules are separated from each other. There is a problem in that it requires a skilled technique to uniformly coat in order not to agglomerate.

In the case of KR 10-2008-0001772 (Patent Document 5), KR 10-2005-0097269 (Patent Document 6), and KR 10-2001-0041958 (Patent Document 7), 100% by weight of metformin in proportion to the amount of metformin Since 40% to 100% by weight or more is required, the amount of the sustained-release carrier and the active ingredient is already inconvenient to take, and compliance with the medication may be lowered. Therefore, since various kinds of pharmaceutical additives are added, the size of the tablet becomes larger, which is inconvenient to take.

When the drug is released through the semi-permeable membrane coating and pore-forming agent as in WO 1999/47125 (Patent Document 8), most of ethanol, methanol, isopropyl alcohol, methylene chloride, acetone, etc. are used to dissolve the coating material when the semi-permeable outer layer is formed. It uses an organic solvent and has problems with environmental pollution and residual solvent.

When the initial dissolution rate is increased by including a drug in the coating solution as in KR 10-2008-0092885 (Patent Document 9), there may be problems in terms of stability, including burst strength of the coating layer. Accordingly, the present inventors studied the invention of a formulation containing metformin as an active ingredient in order to solve the above disadvantages.

One object of the present invention is to provide a sustained-release metformin-coated tablet comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient, the release of which is controlled by osmotic pressure, and the tablet volume is reduced by reducing the dosage of excipients.

In order to achieve the above object,

One aspect of the present invention provides an inner core tablet comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient; and

As a sustained-release metformin-coated tablet comprising a; a hydrophobic polymer, and a coating layer comprising propylene glycol,

It provides a sustained-release metformin-coated tablet, characterized in that the weight ratio of the propylene glycol to the hydrophobic polymer is 1: 0.1 to 1: 10.

The sustained-release coated tablet containing metformin according to the present invention as an active ingredient has a dissolution profile very similar to that of the currently commercially available metformin sustained-release tablet, has robustness in the osmotic pressure section of the human body, and has the effect of not tearing the coating layer, Since the size of the tablet is small, it has an excellent effect of increasing the dosage compliance.

1 is a view showing the dissolution evaluation results of tablets according to Examples 1-1 to 11-1 and Comparative Example 1.
2a and 2b are views showing the results of confirming the tensile strength and elongation at break of the tablet coating films according to Example 8-1 and Example 9-1 before and after hydration, respectively.
3 is a view showing the results of checking the burst strength at 30 minutes, 1 hour, and 2 hours of dissolution in order to confirm the physical properties of the tablet according to Example 8-1.
4 is a view showing the results of checking the rupture strength at 30 minutes, 1 hour, and 2 hours of dissolution in order to confirm the physical properties of the tablet according to Example 9-1.
5 is a view summarized by comparing the results of confirming the physical properties of the tablets according to Example 8-1 and Example 9-1.
6 to 8 show the dissolution patterns of tablets according to the content of the pore former (di-mannitol) and the plasticizer (propylene glycol) in Examples 3-1 to 5-1 and Example 6, respectively. -1 to Example 8-1 and Example 9-1 to Example 11-1 is a diagram showing the dissolution evaluation results of the tablets.
9 is a photograph showing the results of confirming the tearing of the coating layer according to the content of the pore former (di-mannitol) and the plasticizer (propylene glycol).
10 is a view showing the dissolution evaluation results of the tablets according to Examples 9-2 to 9-5 and Comparative Example 1 in order to evaluate the dissolution pattern according to the weight of the coating layer.
11 to 14 are diagrams showing the dissolution evaluation results of the tablet according to Example 9-3 in order to evaluate the dissolution pattern in the comparative dissolution test 4 conditions (pH 1.2, pH 4.0, distilled water, pH 6.8).
15 to 17 are diagrams showing the results of evaluating the dissolution aspect of the tablet according to the osmotic pressure environment of the eluate.
18 to 23 are diagrams showing the results of confirming the dissolution pattern of each tablet when the rotation speed of the paddle is 100 rpm and 150 rpm, respectively.

Hereinafter, the present invention will be described in detail.

Meanwhile, the embodiment of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiment described below. In addition, the embodiment of the present invention is provided in order to more completely explain the present invention to those of ordinary skill in the art. Furthermore, in the entire specification, "including" a certain element means that other elements may be further included, rather than excluding other elements, unless otherwise stated.

One aspect of the present invention provides an inner core tablet comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient; and

As a sustained-release metformin-coated tablet comprising a; a hydrophobic polymer, and a coating layer comprising propylene glycol,

It provides a sustained-release metformin-coated tablet, characterized in that the weight ratio of the propylene glycol to the hydrophobic polymer is 1: 0.1 to 1: 10.

The salt form of metformin may be, for example, metformin hydrochloride.

In this case, the weight ratio of the propylene glycol to the hydrophobic polymer may be 1:1 to 1:7, and most preferably 1:3 to 1:5.

The hydrophobic polymer may be included in an amount of 0.5% to 15% by weight with respect to the total weight of the tablet, may be 1% to 14%, may be 2% to 12%, most preferably 3% to 11% can However, if the weight ratio of the hydrophobic polymer to the total weight of the tablet is less than 2%, tearing of the film may occur.

The hydrophobic polymer can be used without limitation as long as it is a polymer having hydrophobic properties used pharmaceutically, for example, polyvinyl acetate, polyvinyl acetate dispersion, polyvinyl acetate dispersion (solid content), ethyl cellulose, cellulose acetate, or A methacrylic acid ester copolymer may be used, and one or more may be selected for use.

The active ingredient, metformin or a pharmaceutically acceptable salt thereof, may be included in an amount of 55% to 90% by weight based on the total weight of the tablet, and may be included in an amount of 60% to 87% by weight, and most preferably 65% to 84% by weight. % by weight.

The coating layer may further include a pore-forming agent, if it is a pore-forming agent used pharmaceutically, it may be used without particular limitation, for example, mannitol, di-mannitol, polyvinylpyrrolidone, sorbitol , polyethylene glycol, propylene glycol, triethyl citrate, lactose, starch, diethyl phthalate, or sodium chloride may be used, and one or more types may be selected and used. Preferably, mannitol or di-mannitol may be used.

The inner core tablet may further include a hydrophilic polymer, and as long as it is a pharmaceutically used hydrophilic polymer, it can be selected and used without limitation. For example, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, Sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, methyl cellulose, low-substituted hydroxypropyl cellulose, xanthan gum, or acacia gum may be used, and one or more types may be selected and used.

The coating layer may further include one or more hydrophilic plasticizers, for example, the hydrophilic plasticizer may be used by selecting one or more of triethyl citrate, glycerin, triacetin, or polyethylene glycol. .

The coating layer may further include a pharmaceutically acceptable excipient. The excipient of the present application may be selected and used without limitation as long as it is an excipient commonly used pharmaceutically, for example, magnesium stearate, microcrystalline cellulose, croscarmellose sodium, lactose, dextrose, sucrose, dextrate, mannitol, It may be sorbitol, xylitol, sodium chloride, magnesium chloride, calcium hydrogen phosphate, or citric acid, and one or more types may be used.

The coating layer is a semi-permeable coating layer, and is a coating layer whose release is controlled by osmotic pressure.

The weight ratio of the inner core tablet to the coating layer may be 1:0.05 to 1:0.5, 1:0.07 to 1:0.4, and most preferably 1:0.09 to 1:0.35.

The tablet is preferably prepared by a wet granulation method, mixing an active ingredient and a hydrophilic polymer mixture, granulating the mixture and a binder mass to form a wetting agent, drying step, granulation step may include

The coating layer or sustained-release coating layer may be prepared by separately preparing a sustained-release coating solution containing a hydrophobic polymer and a sustained-release coating solution containing one or more pharmaceutically acceptable additives and mixing them before coating.

Hereinafter, Examples and Experimental Examples of the present invention will be specifically illustrated and described below. However, the Examples and Experimental Examples to be described below are only illustrative of a part of the present invention, and are not limited thereto.

<Examples 1-1 to 1-3>

Table 1 below shows the composition table per tablet of Examples 1-1 to 1-3.

Ingredients (mg) Example 1-1 Example 1-2 Examples 1-3 inner core tablet metformin hydrochloride 1000 1000 1000 polyvinylpyrrolidone 85 85 85 magnesium stearate 15 15 15 coating layer polyvinyl acetate 7.5 15 22.5 hydroxy propyl methylcellulose 36.6 73.3 109.9 di-mannitol 7.1 14.1 21.2 triethyl citrate 6.4 12.7 19.1 talc 26.2 52.3 78.5 propylene glycol 10.6 21.2 31.8 glycerin - - - Sum 1194.4 1288.6 1383.0

Step 1: Preparation of inner core tablet

1000 mg of metformin hydrochloride was granulated with a polyvinylpyrrolidone (Kollidon® 30) solution in a high shear mixer, sieved through a 14 mesh sieve, and then dried at 70° C. using a fluidized bed dryer. After the dry granules were granulated through an 18 mesh sieve, they were lubricated with magnesium stearate, and the lubricated granules were compressed with a rotary tablet press equipped with a 22.2 x 11.1 mm rectangular punch to make tablets. At this time, the hardness of the tablet shall be 18 kgf or more.

Step 2: Preparation of sustained-release coating solution-1

After dissolving 36.6 mg of hydroxypropyl methylcellulose (PHARMACOAT ® 645) in 500 mg of distilled water, 26.2 mg of talc was added thereto. The above dose is a dose per tablet, and for the convenience of the manufacturing process, 219.6 g of hydroxypropyl methylcellulose corresponding to 6000 tablets and 157.2 g of talc in 1000 g of distilled water were accurately weighed and prepared.

Step 3: Preparation of sustained-release coating solution-2

It was prepared by uniformly mixing 22.6 mg of polyvinyl acetate dispersion (Kollicoat ® SR 30 D) (7.5 mg as solids), 7.1 mg of di-mannitol, 6.4 mg of triethyl citrate, and 10.6 mg of propylene glycol. The above dose is a dose per tablet, and for the convenience of the manufacturing process, 135.6 g of polyvinyl acetate dispersion (45.0 g as solid content), 42.6 g of di-mannitol, 38.4 g of triethyl citrate, 63.6 g of propylene glycol, corresponding to 6000 tablets It was prepared by accurately weighing g.

Step 4: Preparation of sustained-release coating solution mixture

A sustained-release coating solution mixture was prepared by uniformly mixing the sustained-release coating solution-1 and the sustained-release coating solution-2 prepared in steps 2 and 3, respectively.

Step 5: Coating process

94.4 mg (Example 1-1), 188.6 mg (Example 1-2), 283.0 mg (Example 1- 3) A weight coated one was obtained.

The following are conditions of the coating process.

Flow rate: 8.0 mL/min

Spray gun nozzle orifice: 0.5 mm (ψ)

Fan speed: 11 m/min

<Examples 2-1 to 2-3>

Table 2 below shows the composition table per tablet of Examples 2-1 to 2-3.

Ingredients (mg) Example 2-1 Example 2-2 Example 2-3 inner core tablet metformin hydrochloride 1000 1000 1000 polyvinylpyrrolidone 85 85 85 magnesium stearate 15 15 15 coating layer polyvinyl acetate 7.4 14.9 22.3 hydroxy propyl methylcellulose 36.3 72.6 108.9 di-mannitol 7 14 21 triethyl citrate 6.3 12.6 18.9 talc 25.9 51.9 77.8 propylene glycol 7 14 21 glycerin 7 14 21 Sum 1196.9 1294.0 1390.9

Step 1: Preparation of inner core tablet

Inner core tablets were prepared in the same manner as in Examples 1-1 to 1-3.

Step 2: Preparation of sustained-release coating solution-1

After dissolving 36.3 mg of hydroxypropyl methylcellulose (PHARMACOAT ® 645) in 500 mg of distilled water, 25.9 mg of talc was added thereto. The above dose is a dose per tablet, and for the convenience of the manufacturing process, 217.8 g of hydroxypropyl methylcellulose corresponding to 6000 tablets and 155.4 g of talc in 1000 g of distilled water were accurately weighed and prepared.

Step 3: Preparation of sustained-release coating solution-2

It was prepared by uniformly mixing 22.4 mg of polyvinyl acetate dispersion (Kollicoat ® SR 30 D) (7.4 mg as solids), 7.0 mg of di-mannitol, 6.3 mg of triethyl citrate, 7.0 mg of propylene glycol, and 7.0 mg of glycerin. . The above dose is a dose per tablet, and for the convenience of the manufacturing process, 134.4 g of polyvinyl acetate dispersion corresponding to 6000 tablets (44.4 g as solid content), 42.0 g of di-mannitol, 37.8 g of triethyl citrate, 42.0 of propylene glycol g, was prepared by accurately weighing 42.0 g of glycerin.

Step 4: Preparation of sustained-release coating solution mixture

A coating solution mixture was prepared in the same manner as in Examples 1-1 to 1-3.

Step 5: Coating process

96.9 mg (Example 2-1), 194.0 mg (Example 2-2), 290.9 mg (Example 2- 3) A weight coated one was obtained.

The coating process was performed under the same conditions as in Examples 1-1 to 1-3.

<Examples 3-1 and 3-2>

Table 3 below shows the composition table per tablet of Examples 3-1 and 3-2.

Ingredients (mg) Example 3-1 Example 3-2 inner core tablet metformin hydrochloride 1000 1000 polyvinylpyrrolidone 85 85 magnesium stearate 15 15 coating layer polyvinyl acetate 48.1 96.2 hydroxy propyl methylcellulose 25.9 51.8 di-mannitol - - triethyl citrate 4.5 9 talc 18.5 37 propylene glycol - - glycerin - - Sum 1197.0 1294.0

Step 1: Preparation of inner core tablet

Inner core tablets were prepared in the same manner as in Examples 1-1 to 1-3.

Step 2: Preparation of sustained-release coating solution-1

After dissolving 25.9 mg of hydroxypropyl methylcellulose (PHARMACOAT ® 645) in 500 mg of distilled water, 18.5 mg of talc was added thereto. The above dose is a dose per tablet, and for the convenience of the manufacturing process, 155.4 g of hydroxypropyl methylcellulose corresponding to 6000 tablets and 111.0 g of talc in 1000 g of distilled water were accurately weighed and prepared.

Step 3: Preparation of sustained-release coating solution-2

It was prepared by uniformly mixing 160.3 mg of polyvinyl acetate dispersion (Kollicoat ® SR 30 D) (48.1 mg as solids) and 4.5 mg of triethyl citrate. The above dose is a dose per tablet, and for the convenience of the manufacturing process, 961.8 g (288.5 g as solid content) of a polyvinyl acetate dispersion corresponding to 6000 tablets and 27.0 g of triethyl citrate were accurately weighed and prepared.

Step 4: Preparation of sustained-release coating solution mixture

A coating solution mixture was prepared in the same manner as in Examples 1-1 to 1-3.

Step 5: Coating process

The sustained-release coating mixture prepared in step 4 was sprayed and coated on the inner core tablet prepared in step 1 to obtain coated tablets having a weight of 97.0 mg (Example 3-1) and 194.0 mg (Example 3-2).

The coating process was performed under the same conditions as in Examples 1-1 to 1-3.

<Examples 4-1 and 4-2>

Table 4 below shows the composition table per tablet of Examples 4-1 and 4-2.

Ingredients (mg) Example 4-1 Example 4-2 inner core tablet metformin hydrochloride 1000 1000 polyvinylpyrrolidone 85 85 magnesium stearate 15 15 coating layer polyvinyl acetate 48.1 96.2 hydroxy propyl methylcellulose 25.9 51.8 di-mannitol 2.5 5 triethyl citrate 4.5 9 talc 18.5 37.0 propylene glycol - - glycerin - - Sum 1199.5 1299.0

Step 1: Preparation of inner core tablet

Core tablets were prepared in the same manner as in Examples 1-1 to 1-3.

Step 2: Preparation of sustained-release coating solution-1

A sustained-release coating solution-1 was prepared in the same manner as in Examples 3-1 and 3-2.

Step 3: Preparation of sustained-release coating solution-2

It was prepared by uniformly mixing 160.3 mg of polyvinyl acetate dispersion (Kollicoat ® SR 30 D) (48.1 mg as solids), 4.5 mg of triethyl citrate, and 2.5 mg of di-mannitol. The above dose is a dose per tablet, and for the convenience of the manufacturing process, 961.8 g of polyvinyl acetate dispersion (288.5 g as solid content), 27.0 g of triethyl citrate, and 15.0 g of di-mannitol were accurately weighed for 6000 tablets. .

Step 4: Preparation of sustained-release coating solution mixture

A coating solution mixture was prepared in the same manner as in Examples 1-1 to 1-3.

Step 5: Coating process

The sustained-release coating mixture prepared in step 4 was sprayed and coated on the inner core tablet prepared in step 1 to obtain coated tablets having a weight of 99.5 mg (Example 4-1) and 199.0 mg (Example 4-2).

The coating process was carried out under the same conditions as in Examples 1-1 to 1-3.

<Examples 5-1 and 5-2>

Table 5 below shows the composition table per tablet of Examples 5-1 and 5-2.

Ingredients (mg) Example 5-1 Example 5-2 inner core tablet metformin hydrochloride 1000 1000 polyvinylpyrrolidone 85 85 magnesium stearate 15 15 coating layer polyvinyl acetate 48.1 96.2 hydroxy propyl methylcellulose 25.9 51.8 di-mannitol 5 10 triethyl citrate 4.5 9 talc 18.5 37 propylene glycol - - glycerin - - Sum 1202.0 1304.0

Step 1: Preparation of inner core tablet

Core tablets were prepared in the same manner as in Examples 1-1 to 1-3.

Step 2: Preparation of sustained-release coating solution-1

A sustained-release coating solution-1 was prepared in the same manner as in Examples 3-1 and 3-2.

Step 3: Preparation of sustained-release coating solution-2

It was prepared by uniformly mixing 160.3 mg of polyvinyl acetate dispersion (Kollicoat ® SR 30 D) (48.1 mg as solids), 4.5 mg of triethyl citrate, and 5.0 mg of di-mannitol. The above dose is a dose per tablet, and for the convenience of the manufacturing process, 961.8 g of polyvinyl acetate dispersion (288.5 g as solid content), 27.0 g of triethyl citrate, and 30.0 g of di-mannitol were accurately weighed for 6000 tablets. .

Step 4: Preparation of sustained-release coating solution mixture

A coating solution mixture was prepared in the same manner as in Examples 1-1 to 1-3.

Step 5: Coating process

The sustained-release coating mixture prepared in step 4 was sprayed and coated on the inner core tablet prepared in step 1 to obtain coated tablets having a weight of 102.0 mg (Example 5-1) and 204.0 mg (Example 5-2).

The coating process was carried out under the same conditions as in Examples 1-1 to 1-3.

<Examples 6-1 to 6-3>

Table 6 below shows the composition table per tablet of Examples 6-1 to 6-3.

Ingredients (mg) Example 6-1 Example 6-2 Example 6-3 inner core tablet metformin hydrochloride 1000 1000 1000 polyvinylpyrrolidone 85 85 85 magnesium stearate 15 15 15 coating layer polyvinyl acetate 48.1 96.2 144.3 hydroxy propyl methylcellulose 25.9 51.8 77.7 di-mannitol - - - triethyl citrate 4.5 9 13.5 talc 18.5 37 55.5 propylene glycol 7.5 15 22.5 glycerin - - - Sum 1204.5 1309.0 1413.5

Step 1: Preparation of inner core tablet

Core tablets were prepared in the same manner as in Examples 1-1 to 1-3.

Step 2: Preparation of sustained-release coating solution-1

A sustained-release coating solution-1 was prepared in the same manner as in Examples 3-1 and 3-2.

Step 3: Preparation of sustained-release coating solution-2

It was prepared by uniformly mixing 160.3 mg of polyvinyl acetate dispersion (Kollicoat ® SR 30 D) (48.1 mg as solids), 4.5 mg of triethyl citrate, and 7.5 mg of propylene glycol. The above dose is a dose per tablet, and for the convenience of the manufacturing process, 961.8 g of polyvinyl acetate dispersion (288.5 g as a solid content), 27.0 g of triethyl citrate, and 45.0 g of propylene glycol, corresponding to 6000 tablets, are accurately weighed and prepared. did.

Step 4: Preparation of sustained-release coating solution mixture

A coating solution mixture was prepared in the same manner as in Examples 1-1 to 1-3.

Step 5: Coating process

104.5 mg (Example 6-1), 209.0 mg (Example 6-2), 313.5 mg (Example 6-) by spraying and coating the sustained-release coating mixture prepared in step 4 on the inner core tablet prepared in step 1 3) A weight coated one was obtained.

The coating process was performed under the same conditions as in Examples 1-1 to 1-3.

<Examples 7-1 to 7-3>

Table 7 below shows the composition table per tablet of Examples 7-1 to 7-3.

Ingredients (mg) Example 7-1 Example 7-2 Example 7-3 inner core tablet metformin hydrochloride 1000 1000 1000 polyvinylpyrrolidone 85 85 85 magnesium stearate 15 15 15 coating layer polyvinyl acetate 48.1 96.2 144.3 hydroxy propyl methylcellulose 25.9 51.8 77.7 di-mannitol 2.5 5 7.5 triethyl citrate 4.5 9 13.5 talc 18.5 37 55.5 propylene glycol 7.5 15 22.5 glycerin - - - Sum 1207.0 1314.0 1421.0

Step 1: Preparation of inner core tablet

Core tablets were prepared in the same manner as in Examples 1-1 to 1-3.

Step 2: Preparation of sustained-release coating solution-1

A sustained-release coating solution-1 was prepared in the same manner as in Examples 3-1 and 3-2.

Step 3: Preparation of sustained-release coating solution-2

It was prepared by uniformly mixing 160.3 mg of polyvinyl acetate dispersion (Kollicoat ® SR 30 D) (48.1 mg as solids), 4.5 mg of triethyl citrate, 7.5 mg of propylene glycol, and 2.5 mg of di-mannitol. The above dose is a dose per tablet, and for the convenience of the manufacturing process, 961.8 g of polyvinyl acetate dispersion corresponding to 6000 tablets (288.5 g as solid content), 27.0 g of triethyl citrate, 45.0 g of propylene glycol, 15.0 of di-mannitol It was prepared by accurately weighing g.

Step 4: Preparation of sustained-release coating solution mixture

A coating solution mixture was prepared in the same manner as in Examples 1-1 to 1-3.

Step 5: Coating process

107.0 mg (Example 7-1), 214.0 mg (Example 7-2), 321.0 mg (Example 7-) by spraying and coating the sustained-release coating mixture prepared in step 4 on the inner core tablet prepared in step 1 3) A weight coated one was obtained.

The coating process was carried out under the same conditions as in Examples 1-1 to 1-3.

<Examples 8-1 to 8-3>

Table 8 below shows the composition table per tablet of Examples 8-1 to 8-3.

Ingredients (mg) Example 8-1 Example 8-2 Example 8-3 inner core tablet metformin hydrochloride 1000 1000 1000 polyvinylpyrrolidone 85 85 85 magnesium stearate 15 15 15 coating layer polyvinyl acetate 48.1 96.2 144.3 hydroxy propyl methylcellulose 25.9 51.8 77.7 di-mannitol 5 10 15 triethyl citrate 4.5 9 13.5 talc 18.5 37 55.5 propylene glycol 7.5 15 22.5 glycerin - - - Sum 1209.5 1319.0 1428.5

Step 1: Preparation of inner core tablet

Core tablets were prepared in the same manner as in Examples 1-1 to 1-3.

Step 2: Preparation of sustained-release coating solution-1

A sustained-release coating solution-1 was prepared in the same manner as in Examples 3-1 and 3-2.

Step 3: Preparation of sustained-release coating solution-2

It was prepared by uniformly mixing 160.3 mg of polyvinyl acetate dispersion (Kollicoat ® SR 30 D) (48.1 mg as solids), 4.5 mg of triethyl citrate, 7.5 mg of propylene glycol, and 5.0 mg of di-mannitol. The above dose is a dose per tablet, and for the convenience of the manufacturing process, 961.8 g of a polyvinyl acetate dispersion corresponding to 6000 tablets (288.5 g as a solid content), 27.0 g of triethyl citrate, 45.0 g of propylene glycol, 30.0 of di-mannitol It was prepared by accurately weighing g.

Step 4: Preparation of sustained-release coating solution mixture

A coating solution mixture was prepared in the same manner as in Examples 1-1 to 1-3.

Step 5: Coating process

109.5 mg (Example 8-1), 219.0 mg (Example 8-2), 228.5 mg (Example 8-) by spraying and coating the sustained-release coating mixture prepared in step 4 on the inner core tablet prepared in step 1 3) A weight coated one was obtained.

The coating process was carried out under the same conditions as in Examples 1-1 to 1-3.

<Examples 9-1 to 9-6>

Table 9 below shows the composition table per tablet of Examples 9-1 to 9-6.

Ingredients (mg) Example 9-1 Example 9-2 Example 9-3 Example 9-4 Example 9-5 Example 9-6 inner core tablet metformin hydrochloride 1000 1000 1000 1000 1000 1000 polyvinylpyrrolidone 85 85 85 85 85 85 magnesium stearate 15 15 15 15 15 15 coating layer polyvinyl acetate 48.1 62.5 72.1 81.8 96.2 144.3 hydroxy propyl methylcellulose 25.9 33.7 38.9 44 51.8 77.7 di-mannitol - - - - - - triethyl citrate 4.5 5.9 6.8 7.7 9 13.5 talc 18.5 24.1 27.8 31.5 37 55.5 propylene glycol 15 19.5 22.5 25.5 30 45 glycerin - - - - - - Sum 1212.0 1245.7 1268.1 1290.5 1324.0 1436.0

Step 1: Preparation of inner core tablet

Inner core tablets were prepared in the same manner as in Examples 1-1 to 1-3.

Step 2: Preparation of sustained-release coating solution-1

A sustained-release coating solution-1 was prepared in the same manner as in Examples 3-1 and 3-2.

Step 3: Preparation of sustained-release coating solution-2

It was prepared by uniformly mixing 160.3 mg of polyvinyl acetate dispersion (Kollicoat ® SR 30 D) (48.1 mg as solids), 4.5 mg of triethyl citrate, and 15.0 mg of propylene glycol. The above dose is a dose per tablet, and for the convenience of the manufacturing process, 961.8 g of polyvinyl acetate dispersion (288.5 g as solid content), 27.0 g of triethyl citrate, and 90.0 g of propylene glycol, corresponding to 6000 tablets, are accurately weighed and prepared. did.

Step 4: Preparation of sustained-release coating solution mixture

A coating solution mixture was prepared in the same manner as in Examples 1-1 to 1-3.

Step 5: Coating process

112.0 mg (Example 9-1), 145.7 mg (Example 9-2), 168.1 mg (Example 9-) by spraying and coating the sustained-release coating mixture prepared in step 4 on the inner core tablet prepared in step 1 3), 190.5 mg (Example 9-4), 224.0 mg (Example 9-5), 336.0 mg (Example 9-6) weights were obtained as coated.

The coating process was performed under the same conditions as in Examples 1-1 to 1-3.

<Examples 10-1 and 10-2>

Table 10 below shows the composition table per tablet of Examples 10-1 and 10-2.

Ingredients (mg) Example 10-1 Example 10-2 inner core tablet metformin hydrochloride 1000 1000 polyvinylpyrrolidone 85 85 magnesium stearate 15 15 coating layer polyvinyl acetate 48.1 96.2 hydroxy propyl methylcellulose 25.9 51.8 di-mannitol 2.5 5.0 triethyl citrate 4.5 9.0 talc 18.5 37.0 propylene glycol 15 30 glycerin - - Sum 1214.5 1329.0

Step 1: Preparation of inner core tablet

Core tablets were prepared in the same manner as in Examples 1-1 to 1-3.

Step 2: Preparation of sustained-release coating solution-1

A sustained-release coating solution-1 was prepared in the same manner as in Examples 3-1 and 3-2.

Step 3: Preparation of sustained-release coating solution-2

It was prepared by uniformly mixing 160.3 mg of polyvinyl acetate dispersion (Kollicoat ® SR 30 D) (48.1 mg as solids), 4.5 mg of triethyl citrate, 15.0 mg of propylene glycol, and 2.5 mg of di-mannitol. The above dose is a dose per tablet, and for the convenience of the manufacturing process, 961.8 g of polyvinyl acetate dispersion (288.5 g as solid content), 27.0 g of triethyl citrate, 90.0 g of propylene glycol, 15.0 of di-mannitol corresponding to 6000 tablets It was prepared by accurately weighing g.

Step 4: Preparation of sustained-release coating solution mixture

A coating solution mixture was prepared in the same manner as in Examples 1-1 to 1-3.

Step 5: Coating process

The sustained-release coating mixture prepared in step 4 was sprayed and coated on the inner core tablet prepared in step 1 to obtain coated tablets having a weight of 114.5 mg (Example 10-1) and 229.0 mg (Example 10-2).

The coating process was carried out under the same conditions as in Examples 1-1 to 1-3.

<Examples 11-1 to 11-3>

Table 11 below shows the composition table per tablet of Examples 11-1 to 11-3.

Ingredients (mg) Example 11-1 Example 11-2 Example 11-3 inner core tablet metformin hydrochloride 1000 1000 1000 polyvinylpyrrolidone 85 85 85 magnesium stearate 15 15 15 coating layer polyvinyl acetate 48.1 96.2 144.3 hydroxy propyl methylcellulose 25.9 51.8 77.7 di-mannitol 5 10 15 triethyl citrate 4.5 9.0 13.5 talc 18.5 37.0 55.5 propylene glycol 15 30 45 glycerin - - - Sum 1217.0 1334.0 1451.0

Step 1: Preparation of inner core tablet

Core tablets were prepared in the same manner as in Examples 1-1 to 1-3.

Step 2: Preparation of sustained-release coating solution-1

A sustained-release coating solution-1 was prepared in the same manner as in Examples 3-1 and 3-2.

Step 3: Preparation of sustained-release coating solution-2

It was prepared by uniformly mixing 160.3 mg of polyvinyl acetate dispersion (Kollicoat ® SR 30 D) (48.1 mg as solids), 4.5 mg of triethyl citrate, 15.0 mg of propylene glycol, and 5.0 mg of di-mannitol. The above dose is a dose per tablet, and for the convenience of the manufacturing process, 961.8 g of a polyvinyl acetate dispersion (288.5 g as a solid content) corresponding to 6000 tablets, 27.0 g of triethyl citrate, 90.0 g of propylene glycol, 30.0 of di-mannitol It was prepared by accurately weighing g.

Step 4: Preparation of sustained-release coating solution mixture

A coating solution mixture was prepared in the same manner as in Examples 1-1 to 1-3.

Step 5: Coating process

117.0 mg (Example 11-1), 234.0 mg (Example 11-2), 351.0 mg (Example 11-) by spraying and coating the sustained-release coating mixture prepared in step 4 on the inner core tablet prepared in step 1 3) A weight coated one was obtained.

The coating process was carried out under the same conditions as in Examples 1-1 to 1-3.

<Comparative Example 1>

As a reference drug, a commercially available Glucophage XR 1000 mg tablet (Merck, Inc.) was purchased and used. The composition of glucophage is known to be composed of metformin, sodium carboxymethylcellulose, magnesium stearate, microcrystalline cellulose, purified water, and hypromellose.

<Experimental Example 1> Evaluation of dissolution rate

Sample solution preparation

The tablets prepared in Examples 1-1 to 11-1 and the eluates in Comparative Example 1 were taken as samples. For evaluation of dissolution rate, a dissolution test was carried out at 100 rpm at 37 ° C in pH 6.8 buffer according to Method 2 of the dissolution test method of the Korean Pharmacopoeia. After 1, 2, and 6 hours, 3 mL of the eluate was taken and a membrane filter having a 0.45 μm pore. The filtered filtrate was used as the sample solution.

Standard solution preparation

Accurately take 100.0 mg of metformin hydrochloride standard, put it in a 100 mL volumetric flask, add 50 mL of the mobile phase, shake it with ultrasonic waves for 10 minutes to completely dissolve it, and then cool it to room temperature and add the mobile phase to make 100 mL. This was diluted with an appropriate amount of mobile phase to prepare standard solutions of 250, 50, 25, 5, and 1 μg/mL.

HPLC analysis conditions

Mobile phase: buffer and acetonitrile 9:1 (v/v) mixture (buffer composition: 0.5 g/L sodium heptanesulfonate in water and 0.5 g/L sodium chloride in water); Titrated to pH 3.85 with 0.06 M phosphoric acid before final dilution)

Column: 3.9 mm x 150 mm; 15 μm C18 column

Column temperature: 30 °C

Detector: UV 218 nm

Flow rate: 1.0 mL/min

Injection volume: 20 μL

As described above, the dissolution rates of the tablets according to Comparative Example 1 and Examples 1-1 to 11-1 were evaluated, and are shown in FIG. 1 and Table 12 below. In addition, in order to evaluate the dissolution pattern similarity of Comparative Example 1 (control drug) and Examples 1-1 to 11-1 (test drug), a similarity factor (f ₂ ) was obtained and compared, and the results are shown in Table 12 below. shown together. The similarity factor f ₂ is the logarithmic reciprocal square root transformation of the square error implied, and is a value that measures the similarity in dissolution rate (%) between the two curves.

1 hour dissolution rate (%) 2 hours dissolution rate (%) 6 hours dissolution rate (%) f ₂ Comparative Example 1 21.3 40.1 78.4 - Example 1-1 100.1 100.3 101.3 11.4 Example 2-1 100.1 99.8 101.3 11.6 Example 3-1 35.7 55.5 102.1 37.9 Example 4-1 41.6 79.8 101.1 26.9 Example 5-1 44.8 77.4 99.8 28.7 Example 6-1 15.8 42.9 93.2 51.5 Example 7-1 21.3 50.0 92.0 52.5 Example 8-1 24.2 47.1 95.2 43.4 Example 9-1 16.5 41.3 91.7 54.2 Example 10-1 25.0 60.3 98.8 38.8 Example 11-1 27.0 63.0 99.9 36.7

As can be seen from FIG. 1 , in Examples 1-1 and 2-1, a large amount of initial drug burst occurred due to tearing. The dissolution pattern similarity factor was highest in Example 9-1.

<Experimental Example 2> Confirmation of tensile strength and elongation at break of the coating film

In order to confirm the burst phenomenon of the tablet according to the weight ratio of propylene glycol in the coating solution, the mechanical strength (Tensile strength) and the flexibility (Elongation) of the membrane can be evaluated. Accordingly, in order to confirm the tensile strength and elongation at break of the coating film before and after dissolution of the tablets prepared in Examples 8-1 and 9-1, experiments were conducted as follows.

Specifically, 5 mL of the coating solution of Examples 8-1 and 9-1 was loaded into a 150 ф-sized Petri dish at room temperature using a micropipette, and then dried at 40° C. for 14 hours in a flat plate dryer to prepare a film. Then, it was cut into 1.5 cm x 3.0 cm. After that, the film was immersed in a cortical tube filled with distilled water at room temperature to hydrate for 2 hours, and then the tensile strength and elongation at break of the coating layer were measured using a texture analyzer (TAXT plus). In the test, the tensile strength and elongation at break were measured by calculating the distance to the point where the film completely breaks and the applied force by stretching the film at a rate of 0.1 cm/s after holding the film in tensile grip at room temperature. The results are shown in Table 13 and FIGS. 2A and 2B below.

refine state tensile strength
(N/mm) elongation at break
(%) Example 8-1 Jeon 0.78±0.08 1.69±0.55 after 0.03±0.01 101.96±20.06 Example 9-1 Jeon 0.21±0.11 5.97±1.03 after 0.02±0.01 217.46±21.69

As a result, as the weight ratio of propylene glycol in the coating solution increased, it was confirmed that the tensile strength decreased and the elongation at break increased in Example 9-1, in which the ratio of propylene glycol was higher than in Example 8-1. could

<Experimental Example 3> Confirmation of the burst strength of the tablet

In order to check the rupture strength of the tablet according to the weight ratio of the polyvinyl acetate dispersion, which is a hydrophobic polymer, and propylene glycol, which is a plasticizer, in the coating solution, the tablets prepared in Examples 8-1 and 9-1 were used as follows. experimented.

Specifically, the tablets of Examples 8-1 and 9-1 were eluted according to the dissolution test method performed in Experimental Example 1, and physical properties after taking out the tablets at preset sampling times of 30 minutes, 1 hour, and 2 hours Using an analyzer (Texture analyzer, TAXT plus), a 6 mm probe was mounted and force was applied to the tablet at a speed of 0.1 cm/sec. The test was set by the compression method. The results are shown in Table 14 and FIGS. 3 to 5 below.

burst strength Example 8-1 Example 9-1 30 minutes 50.47±11.07 64.75±3.69 1 hours 40.25±12.42 41.99±6.66 2 hours 8.54±4.37 22.91±1.8

As a result of the burst strength test, it was confirmed that the tablet according to Example 9-1 in which the weight ratio of propylene glycol as a plasticizer and polyvinyl acetate as a hydrophobic polymer was about 1:3 had high burst strength, and gastric retention time of 2 hours It can be seen that it has a burst strength of more than 2N (the burst strength applied to the tablet in the gastrointestinal tract) during the period. (References

Kamba, Masaharu, et al. "A unique dosage form to evaluate the mechanical destructive force in the gastrointestinal tract." International journal of pharmaceutics 208.1-2 (2000): 61-70.

Ali, R., M. Walther, and R. Bodmeier. "Cellulose acetate butyrate: Ammonio methacrylate copolymer blends as a novel coating in osmotic tablets." AAPS PharmSciTech 19.1 (2018): 148-154.)

Through this, it was found that the rupture strength of the tablet was more affected by the membrane flexibility among the tensile strength and the membrane elongation.

<Experimental Example 4> Dissolution evaluation according to the capacity of the pore former and plasticizer

In order to confirm the drug release pattern according to the doses of the pore former (di-mannitol) and the plasticizer (propylene glycol), the contents of di-mannitol and propylene glycol were shown in Example 3- Experiments were performed using tablets prepared according to Examples 1 to 11-1.

The tablets according to Examples 3-1 to 5-1 do not contain propylene glycol but contain 0 mg, 2.5 mg, and 5 mg of di-mannitol, respectively, and Examples 6-1 to 8 The tablets according to -1 are all tablets containing 7.5 mg of propylene glycol and 0 mg, 2.5 mg, and 5 mg of di-mannitol, respectively, and the tablets according to Examples 9-1 to 11-1 are all Since it is a tablet containing 15 mg of propylene glycol and 0 mg, 2.5 mg, and 5 mg of di-mannitol, respectively, the drug release rate according to the di-mannitol content can be confirmed through FIGS. 6 to 8 below. In addition, the drug release rate according to the propylene glycol content can be confirmed by comparing the experimental results of FIGS. 6 to 8 with each other. The experiment was carried out according to the dissolution test method according to Example 2, and each was carried out three times. The rate constant (K) was calculated according to the zero-order reaction rate equation using a dissolution rate near 0 to 60%. The results are shown in Table 15 and FIGS. 6 to 8 below.

Rate constant (K) according to the amount of di-mannitol in the coating solution Di-mannitol (mg) 0 2.5 5 propylene glycol
(mg) 0 36.76 (Example 3-1) 40.28 (Example 4-1) 39.26 (Example 5-1) 7.5 34.61 (Example 6-1) 34.83 (Example 7-1) 38.36 (Example 8-1) 15 36.30 (Example 9-1) 37.17 (Example 10-1) 40.79 (Example 11-1)

As a result, as can be seen through Table 15 and FIGS. 6 to 8, as the content of di-mannitol in the coating solution increases, the release rate of the drug increases, and when an appropriate amount of propylene glycol is used, the release rate decreases. Able to know.

<Experimental Example 5> Confirmation of tearing of the coating layer due to the capacity of the pore former and plasticizer

In order to check the tearing of the tablet coating layer during the dissolution test of Experimental Example 1 according to the doses of the pore former (di-mannitol) and the plasticizer (propylene glycol), the contents of di-mannitol and propylene glycol are shown in the table below. It was confirmed whether the coating layer was torn by using the same tablet as in 16. The results are shown in Table 16 and FIG. 9 below.

Whether to tear depending on the amount of propylene glycol in the coating solution Di-mannitol (mg) 0 2.5 5 propylene glycol
(mg) 0 ○ (Example 3-1) ○ (Example 4-1) ○ (Example 5-1) 7.5 × (Example 6-1) × (Example 7-1) × (Example 8-1) 15 × (Example 9-1) × (Example 10-1) × (Example 11-1)

As a result, in the tablets according to Examples 3-1, 4-1, and 5-1, which are tablets not containing propylene glycol as a plasticizer, tearing of the coating layer was confirmed, and propylene glycol was 7.5 mg The tablets according to Examples 6-1 to 11-1 contained above did not show tearing of the coating layer.

In addition, although not included in the results of Experimental Example 5, in Experimental Example 1, it is seen that tears appear in the tablets according to Examples 1-1 and 1-2, so even if propylene glycol is contained, polyvinyl acetate dispersion It can be seen that tearing occurs when the content of the tablet is 5% or less based on the total weight of the tablet.

<Experimental Example 6> Evaluation of dissolution according to increase in coating weight

In order to confirm the dissolution pattern of the tablet according to the weight of the coating, the comparative example, which is a commercially available tablet, and the tablet prepared in Examples 9-2, 9-3, 9-4, and 9-5 were used. to evaluate the amount of drug release. The total contents of the tablets according to Examples 9-2 to 9-5 were 1245.7 mg, 1268.1 mg, 1290.5 mg, and 1324.0 mg, respectively, and the weight of the inner core tablet was all 1100 mg. The experiment was carried out according to the dissolution test method according to Example 2. 1000 mg of glucophage XR of Comparative Example 1 used as a control drug was evaluated as a sustained-release tablet at 1 hour, 2 hours, and 6 hours, when the average dissolution was around 30%, 50%, and 80%. The results are shown in Table 17 and FIG. 10 below.

Example 9-2 Example 9-3 Example 9-4 Example 9-5 F ₂ 53.43 51.46 43.80 39.75 rate constant K 39.1 36.3 35.4 34.9 Tablet weight (mg) 1245.7 1268.1 1290.5 1324.0

In this case, the F ₂ value is a similarity factor, and is a value for whether the reference drug and the test drug show a similar profile at the time of comparison, and it is generally evaluated as equal if the value is 50 or more. The F ₂ value was calculated according to the following equation.

[Equation 1]

n: number of time points

R _t : Average dissolution rate of reference drug

T _t : Average dissolution rate of test drug

As can be seen from Table 17, in the case of Examples 9-2 and 9-3, since the F2 value is 50 or more, it can be seen that the dissolution profile is equivalent to that of the commercially available tablet according to Comparative Example 1.

<Experimental Example 7> Comparative dissolution test dissolution evaluation in 4 conditions

In order to confirm the dissolution behavior of the tablet in various pH environments, using the commercially available tablet according to Comparative Example 1 and the tablet prepared in Example 9-3, pH 1.2, pH 4.0, DW (distilled water), pH 6.8 conditions The amount of drug release was evaluated. The experiment was conducted according to the dissolution test method according to Example 2, and 1000 mg of glucophage XR of Comparative Example 1 used as a reference drug was a sustained-release tablet, and the average dissolution was around 30%, 50%, and 80%. It was evaluated at 1 hour, 2 hours, and 6 hours. The results are shown in Table 18 and FIGS. 11 to 14 below.

pH 1.2 pH 4.0 D.W. pH 6.8 F2 57.01 61.76 58.33 51.46

As a result of dissolution evaluation of the tablet according to Example 9-3 under the 4 conditions of the comparative dissolution test, it was confirmed that the F2 value was 50 or higher in all 4 conditions. It can be seen that the dissolution profile is equivalent to that of the tablet of Comparative Example 1.

<Experimental Example 8> Dissolution evaluation according to the osmotic pressure environment of the eluate

In order to confirm the drug release kinetics of the sustained-release metformin-coated tablets whose release is controlled by osmotic pressure, Comparative Examples 1 and Examples in the eluate corresponding to 0.36 MPa, 3.6 MPa, 7.2 MPa (fasting 0.7 MPa, eating 2.0 MPa), respectively The tablets according to 9-3 were evaluated for dissolution. The experiment was carried out according to the dissolution test method according to Example 2. The results are shown in FIGS. 15 to 17 .

As a result, in the case of Example 9-3, when the external osmotic pressure was increased, the dissolution pattern was changed, and it was confirmed that the drug release power was due to the osmotic pressure.

<Experimental Example 9> Dissolution evaluation at rpm dissolution test

In order to confirm the effect of drug dissolution according to the dissolution test rpm, dissolution evaluation was performed for the tablets according to Comparative Example 1 and Examples 6-1 to 11-1 when the rpm was 100 rpm and 150 rpm. The experiment was carried out according to the dissolution test method according to Example 2. F2 values between 100 rpm and 150 rpm were obtained, and the results are shown in Tables 19, 20, and 18 to 23 below.

Comparative Example 1 Example
6-1 Example
7-1 Example
8-1 Example
9-1 Example
9-3 Example
10-1 Example
11-1 F2 66.74 80.05 62.96 67.63 82.91 85.30 73.65 75.36

Speed constant K according to rpm 100 rpm 150 rpm Comparative Example 1 32.35 33.86 Example 6-1 34.61 35.40 Example 7-1 34.83 35.70 Example 8-1 38.36 38.26 Example 9-1 36.88 36.60 Example 9-3 36.30 36.07 Example 10-1 37.17 37.59 Example 11-1 40.79 40.74

As a result, it can be seen that when the dissolution test was performed under two conditions in which the rotational speed of the paddle was set to 100 rpm and 150 rpm, there was no difference in the dissolution pattern according to the rotational speed of the paddle. This confirms the stable drug release as designed.

<Experimental Example 10> Size comparison with existing commercial products

In order to directly compare the sizes of the tablets according to Example 9-3 and Comparative Example 1, which show the most stable drug release through the above experiment, the lengths of the major axis and the minor axis were measured and shown in Table 21 below.

Long axis (mm) Short axis (mm) thickness (mm) tablet volume
(mm ³ ) medium 21.0 10.2 8.0 - Comparative Example 1 22.15 10.6 8.25 808.9 Example 9-3 22.3 10.7 5.3 700.7

From the above results, it can be seen that the volume of the tablet according to Example 9-3 was reduced by 13% compared to the commercially available tablet according to Comparative Example 1 (glucophage XR 1000 mg). Therefore, the tablet according to Example 9-3 has a dissolution pattern similar to that of the commercially available tablet according to Comparative Example 1, has robustness in the osmotic pressure section of the human body, as well as the coating layer is not torn and the tablet size is small. It has an excellent effect of increasing compliance.

As mentioned above, although the present invention has been described in detail through preferred examples and experimental examples, the scope of the present invention is not limited to specific examples and should be construed according to the appended claims. In addition, those skilled in the art should understand that many modifications and variations are possible without departing from the scope of the present invention.

Claims (15)

an inner core tablet comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient; and
As a sustained-release metformin-coated tablet comprising a; a hydrophobic polymer, and a coating layer comprising propylene glycol,
The sustained-release metformin-coated tablet, characterized in that the weight ratio of the propylene glycol to the hydrophobic polymer is 1:0.1 to 1:10.
According to claim 1,
The weight ratio of the propylene glycol to the hydrophobic polymer is 1:1 to 1:7, the sustained-release metformin-coated tablet.
According to claim 1,
The hydrophobic polymer is included in an amount of 0.5% to 15% by weight based on the total weight of the tablet, the sustained-release metformin-coated tablet.
According to claim 1,
The hydrophobic polymer is polyvinyl acetate, ethyl cellulose, cellulose acetate, and at least one selected from the group consisting of methacrylic acid ester copolymer, sustained-release metformin-coated tablet.
According to claim 1,
Wherein the metformin is included in an amount of 55% to 90% by weight based on the total weight of the tablet, the sustained-release metformin-coated tablet.
According to claim 1,
The coating layer further comprises a pore former, the sustained-release metformin-coated tablet.
7. The method of claim 6,
The pore former is one selected from the group consisting of mannitol, polyvinylpyrrolidone, sorbitol, polyethylene glycol, propylene glycol, triethyl citrate, lactose, starch, diethyl phthalate, and sodium chloride. More than that, a sustained-release metformin-coated tablet.
According to claim 1,
The inner core tablet further comprises a hydrophilic polymer, the sustained-release metformin-coated tablet.
9. The method of claim 8,
The hydrophilic polymer is polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, carboxymethylcellulose, methylcellulose, low-substituted hydroxypropylcellulose, xanthan gum, And at least one selected from the group consisting of acacia gum, sustained-release metformin-coated tablets.
According to claim 1,
The coating layer, triethyl citrate, glycerin, triacetin, and one or more hydrophilic plasticizers selected from the group consisting of polyethylene glycol, the sustained-release metformin-coated tablet further comprising.
According to claim 1,
The coating layer further comprises a pharmaceutically acceptable excipient, sustained-release metformin-coated tablet.
According to claim 1,
The coating layer is a semi-permeable coating layer, a sustained-release metformin coated tablet.
According to claim 1,
The excipient is selected from the group consisting of magnesium stearate, microcrystalline cellulose, croscarmellose sodium, lactose, dextrose, sucrose, dextrate, mannitol, sorbitol, xylitol, sodium chloride, magnesium chloride, calcium hydrogen phosphate and citric acid. One or more kinds of, sustained-release metformin-coated tablets.
According to claim 1,
The weight ratio of the inner core tablet and the coating layer is 1:0.05 to 1:0.5, the sustained-release metformin-coated tablet.
According to claim 1,
The tablet is manufactured by a wet granulation method, a sustained-release metformin-coated tablet.

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