KR20230051096A - Pharmaceutical composition for treatment of diabetes with improved stability - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for the treatment of diabetes with improved stability, and more particularly, comprises a core containing metformin or a salt thereof and a drug coating layer containing alogliptin or a salt thereof, with a barrier coating layer therebetween It relates to a pharmaceutical composition with improved stability deterioration due to contact between two components, including.

Description

Pharmaceutical composition for treatment of diabetes with improved stability {Pharmaceutical composition for treatment of diabetes with improved stability}

The present invention relates to a pharmaceutical composition for the treatment of diabetes with improved stability, and more particularly, to a pharmaceutical composition comprising a core containing metformin or a salt thereof and a drug coating layer containing alogliptin or a salt thereof, including a barrier coating layer therebetween It relates to a pharmaceutical composition with improved stability deterioration due to contact between two components.

As a type of dipeptidyl peptidase IV (DPP-IV) inhibitor, Alogliptin is widely used as a treatment for type 2 diabetes, and diabetes is not properly controlled with metformin alone. It can be used in combination with metformin in patients with

Attempts have been made to develop a combination of alogliptin and metformin for useful effects such as ease of administration. As a result of a storage stability test in a solid formulation containing both alogliptin and metformin, degradation of alogliptin was confirmed, thereby improving its storage stability. improvement was required.

International Patent Publication No. 2020/098904 discloses a method for preparing a solid preparation for oral administration containing a DPP-IV inhibitor and metformin as active ingredients, and alogliptin in the document is sensitive to moisture in the presence of metformin and has poor stability. As it deteriorates, it has been reported that wet granulation with metformin is difficult.

In addition, Korean Patent No. 1536786 includes a first part containing alogliptin or a salt thereof and substantially free of metformin hydrochloride, and a second part containing metformin hydrochloride and substantially free of alogliptin and its salt. A formulation is disclosed. However, the stability of alogliptin may be deteriorated due to the contact between the components at the interface between the first and second parts of the formulation, and when a sustained-release agent is included in the first part including metformin hydrochloride, the dissolution of alogliptin is delayed. this can happen

In order to overcome the above problem, the inventors of the present invention further include a barrier layer between a core containing metformin or a salt thereof and a coating layer containing alogliptin or a salt thereof to confirm that dissolution and stability degradation problems are improved. has been completed.

KR 1536786 B1 WO 2020/098904 A1

Therefore, the problem to be solved by the present invention is to provide a pharmaceutical composition for the treatment of diabetes with improved stability that prevents deterioration in stability due to contact between two components at the interface and at the same time prevents the delay in dissolution of alogliptin by metformin sustained-release agent. .

The present inventors conducted various studies to improve stability by preventing contact between the two components, and as a result, a pharmaceutical composition with excellent stability including a barrier coating layer and a drug coating layer to which a coating agent with excellent compatibility with alogliptin and metformin was applied The present invention was completed by producing.

The present invention relates to (1) a core comprising metformin or a salt thereof; (2) a barrier coating layer coated on the core; and (3) a drug coating layer coated on the barrier coating layer and containing alogliptin or a salt thereof, wherein the drug coating layer contains 50 to 200 polyvinyl alcohol by weight of alogliptin or a salt thereof. A pharmaceutical composition comprising % by weight is disclosed. Hereinafter, the present invention will be described in detail.

core

In one embodiment of the present invention, the core may be an uncoated tablet containing metformin or an optically active form thereof or a salt thereof. The salt is a pharmaceutically acceptable salt that can be commonly used in the art, and for example, hydrochloride salts, magnesium salts, strontium salts, lithium salts, sodium salts, potassium salts, calcium salts, etc. may be used, but are limited thereto it is not going to be

In one embodiment of the present invention, the core may contain 250 to 1500 mg, preferably 500 to 1250 mg of metformin or a salt thereof.

In one embodiment of the present invention, the core may be 80 to 97% by weight based on the total weight of the pharmaceutical composition.

sustained release agent

The pharmaceutical composition according to one embodiment of the present invention may include a sustained-release agent in the core for a sustained-release effect of metformin or a salt thereof.

In one embodiment of the present invention, the sustained-release agent is hydroxypropyl cellulose, methyl cellulose, carrageenan, glyceryl behenate, hydrogenated castor oil, hydrogenated vegetable oil, stearic acid, polyvinyl acetate, polyvinyl alcohol, povidone, polyethylene glycol, hydrogel Roxyethyl cellulose, hypromellose, polyethylene oxide, sodium carboxymethyl cellulose, carbomer, sodium alginate, or mixtures thereof may be used.

In one embodiment of the present invention, product examples of sustained-release agents include Eudragit RS100, RSPO, RS30D, RL100, RLPO, RL30D, NE30D, NE40D (Rohm Pharma), Kollidon SR, Kollicoat ( Kollicoat) SR30D, etc., and one or more selected from them may be used.

In one embodiment of the present invention, the sustained-release agent may be included in 5 to 50% by weight, preferably 10 to 35% by weight, based on the weight of the core.

Polymer for coating

In one embodiment of the present invention, the barrier coating layer and the drug coating layer may be coated with a coating agent containing a coating polymer and a coating adjuvant.

The pharmaceutical composition according to one embodiment of the present invention may include a barrier coating layer and a drug coating layer using a coating polymer having excellent compoundability.

In one embodiment of the present invention, the coating polymer in the coating agent is polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), hypromellose (HPMC), polyvinyl alcohol-polyethylene glycol copolymer (PVA-PEG copolymer ), hydroxypropyl starch, dimethylaminoethyl methacrylateㆍmethyl methacrylate copolymer, ethyl methacrylate -chlorotrimethylammonium methacrylate copolymer, methacrylic acidㆍethyl acrylate copolymer, hypromellose acetate succinate and hypro It may be mellose phthalate or a mixture thereof.

In one embodiment of the present invention, the drug coating layer may have excellent drug safety effects by including polyvinyl alcohol as a coating polymer.

In one embodiment of the present invention, examples of products of the coating agent include 85A 680001 White, 85A 620000 Yellow, 85A 620007 Yellow, 85A620015 Yellow, 20A 28381 White, 88A 180040 White, etc., including polyvinyl alcohol, and polyvinyl alcohol-polyethylene It may be 321A 180025 White in which Kollicoat IR including a glycol copolymer is used, and one or more selected from these may be used, but is not limited thereto.

barrier coating layer

In one embodiment of the present invention, the barrier coating layer may be included in 1 to 8% by weight, preferably 1.5 to 6% by weight, more preferably 2 to 4% by weight, based on the total weight of the pharmaceutical composition.

In one embodiment of the present invention, the barrier coating layer may be included in 1 to 6% by weight, preferably 2 to 5% by weight, more preferably 2.5 to 4% by weight, based on the weight of the core.

In one embodiment of the present invention, the barrier coating layer is polyvinyl alcohol, hydroxypropyl cellulose, hypromellose, polyvinyl alcohol-polyethylene glycol copolymer, hydroxypropyl starch, dimethylaminoethyl methacrylate as a coating polymer. It may include methyl acrylate copolymer, ethyl methacrylate-chlorotrimethylammonium ethyl methacrylate copolymer, methacrylic acid/ethyl acrylate copolymer, hypromellose acetate succinate and hypromellose phthalate, or mixtures thereof, preferably Preferably, it may include polyvinyl alcohol, hydroxypropyl cellulose, hypromellose, or polyvinyl alcohol-polyethylene glycol copolymer.

In one embodiment of the present invention, the barrier coating layer may include 30 to 200% by weight, preferably 40 to 180% by weight, more preferably 50% by weight of the coating polymer relative to the weight of alogliptin or a salt thereof in the drug coating layer. to 170% by weight.

In one embodiment of the present invention, the barrier coating layer may include 5 to 40 mg of the coating polymer, preferably 7 to 35 mg, and more preferably 10 to 30 mg.

In one embodiment of the present invention, the barrier coating layer may contain 15 to 100% by weight of the coating polymer, preferably 25 to 80% by weight, more preferably 35 to 65% by weight, based on the total weight of the barrier coating layer. can

In one embodiment of the present invention, the barrier coating layer may include talc, titanium oxide, pigment, etc. as a coating aid.

drug coating layer

In one embodiment of the present invention, the drug coating layer may be a coating layer containing alogliptin or an optically active form thereof or a salt thereof. The salt is a pharmaceutically acceptable salt that can be commonly used in the art, and for example, a metal salt or ammonium salt such as benzoate, magnesium salt, strontium salt, lithium salt, sodium salt, potassium salt, calcium salt may be used. may be, but is not limited thereto.

In one embodiment of the present invention, the drug coating layer may include 1 to 100 mg, preferably 5 to 60 mg, and more preferably 10 to 40 mg of alogliptin or a salt thereof.

In one embodiment of the present invention, the drug coating layer may be included in 1 to 15% by weight, preferably 2 to 10% by weight, more preferably 2.5 to 9% by weight, based on the total weight of the pharmaceutical composition.

In one embodiment of the present invention, the drug coating layer may include 50 to 200% by weight of polyvinyl alcohol, preferably 80 to 170% by weight, more preferably 100 to 140% by weight based on the weight of alogliptin or a salt thereof. % can be included.

In one embodiment of the present invention, the drug coating layer may include 5 to 100 mg of polyvinyl alcohol, preferably 10 to 80 mg, and more preferably 15 to 50 mg.

In one embodiment of the present invention, the drug coating layer may further include hydroxypropyl cellulose. Hydroxypropylcellulose may be included in an amount of 0.01 to 80% by weight, preferably 5 to 60% by weight, and more preferably 10 to 55% by weight, based on the weight of alogliptin or a salt thereof.

Hydroxypropylcellulose may contain 0.01 to 16 mg, preferably 0.1 to 13 mg, and more preferably 1 to 10 mg.

In one embodiment of the present invention, the drug coating layer may include polyvinyl alcohol and hydroxypropyl cellulose at a ratio of 10:1 to 1:1, preferably at a ratio of 9:1 to 4:1. can

In one embodiment of the present invention, the drug coating layer may contain 10 to 65% by weight of polyvinyl alcohol, preferably 20 to 50% by weight, more preferably 30 to 40% by weight, based on the total weight of the drug coating layer. can

In one embodiment of the present invention, the drug coating layer may include 0.01 to 30% by weight of hydroxypropylcellulose, preferably 0.1 to 25% by weight, more preferably 2 to 10% by weight, based on the total weight of the drug coating layer. can do.

In one embodiment of the present invention, the drug coating layer may include talc, titanium oxide, pigment, etc. as a coating aid.

pharmaceutical composition

In one embodiment of the present invention, the core; barrier coating layer; And a pharmaceutical composition may be prepared including a drug coating layer.

In one embodiment of the present invention, the pharmaceutical composition may further include a pharmaceutically acceptable disintegrant, for example, croscamellose sodium, sodium starch glycolate, pregelatinized Starch (Pregelatinized Starch) [Starch 1500 or Prejel], microcrystalline cellulose, crospovidone, cross-linked povidone, low substituted hydroxypropylcellulose, alginic acid, Carboxymethylcellulose calcium salt or sodium salt, colloidal silica collidal silica, guar gum, magnesium aluminum silicate, methylcellulose, powdery cellulose, It may be one or a mixture of two or more selected from the group consisting of starch and sodium alginate.

In one embodiment of the present invention, the pharmaceutical composition may include additives such as pharmaceutically acceptable excipients, binders, and lubricants.

In one embodiment of the present invention, additives such as pharmaceutically acceptable excipients, binders and lubricants are lactose, dextrin, mannitol, sorbitol, starch, calcium phosphate, microcrystalline cellulose, hydroxypropyl cellulose, povidone, polyvinyl alcohol, colloidal It may be silicon dioxide, stearic acid, glyceryl behenate, hydrogenated vegetable oil, hydrogenated castor oil, magnesium stearate, and talc, but is not limited thereto.

In one embodiment of the present invention, the pharmaceutical composition may be a tablet, capsule or granule, preferably a tablet.

In one embodiment of the present invention, the pharmaceutical composition may be further coated.

The pharmaceutical composition according to the present invention may have a stability improvement effect by including a barrier coating layer and a drug coating layer to which a coating agent having excellent compatibility with alogliptin and metformin is applied.

In addition, an improved dissolution effect can be expected by preventing the delayed dissolution of alogliptin by the sustained-release agent of the metformin-containing core.

1 is a schematic diagram showing the structure of a pharmaceutical composition with improved stability according to the present invention.
2 to 4 are graphs measuring tablet stability according to coating agent components and contents.

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

Examples and Comparative Examples. Preparation of pharmaceutical compositions

Examples 1 to 3, Comparative Examples 1 and 2

One) core

1000 mg of metformin hydrochloride, 30 mg of sodium carboxymethylcellulose, 306 mg of hypromellose, and 40 mg of polyvinylpyrrolidone K30 were put into a high-speed granulator and mixed, and a certain amount of purified water was added to further knead. After drying the prepared granules in a fluidized bed dryer, 14 mg of magnesium stearate was added to the dried granules to lubricate them. The lubricant was tableted to prepare uncoated tablets (1390 mg).

2) barrier coating layer

A barrier coating solution for forming a barrier coating layer surrounding a metformin-containing core was prepared using the components and contents of the coating agent shown in Table 1.

A barrier coating solution was prepared by adding the components and contents of the coating agent in Table 1 to purified water and stirring, and then spraying it onto the uncoated tablet prepared in the above step to form a barrier coating layer.

3) drug coating layer

A drug coating solution was prepared with the main component (alogliptin benzoate) and coating agents shown in Table 1. After dispersing the main component in purified water with an agitator and homogenizing with a homogenizer, a coating solution is prepared by mixing the coating agent in the dispersed solution, and the prepared barrier coating tablet is put into a coating machine, then the drug coating solution is sprayed and dried. Drug-coated tablets were prepared.

Comparative Example 1 Comparative Example 2 Example 1 Example 2 Example 3 Uncoated tablet with metformin 1390 1390 1390 1390 1390 barrier coating layer Polymer for coating PVA - - 21 22 22 HPC 13 42 - 6 3 HPMC 13 - - - - coating aid Talc, TiO2, pigment 16 2 26 18 21 drug coating layer API Alogliptin benzoate 17 17 17 17 17 Polymer for coating PVA - - 21 22 22 HPC 10 34 - 6 3 HPMC 10 - - - - coating aid Talc, TiO2, pigment 14 2 26 20 22 Total 1483 1487 1501 1501 1500

* Talc, TiO ₂ , and one or more pigments may be included as coating aids

Reference example 3

12.5 mg of Nesina tablets (17 mg of alogliptin benzoate), a commercial product, was used as a control drug.

Experimental Example 1. Stability effect according to barrier coating layer and drug coating layer coating agent

By analyzing the related substances of the tablets of Comparative Examples 1 to 2 and Examples 1 to 3, the RRT (Relative retention time) 1.2 and 1.22 peak positions, which show a marked increase in related substances compared to the peak position of the main component, were quantified to determine tablet stability according to the components and contents of the coating agent. The improvement effect was confirmed. The coated tablets prepared in Comparative Examples and Examples were packed in a sealed vial and an aluminum bag (Al-bag) with a rubber seal at 50 ° C and 75% relative humidity, and an increase in related substances was confirmed after 2 weeks of storage.

As a result of the experiment, it was confirmed that the tablets of Examples 1 to 3 containing PVA in the drug coating layer had less increase in related substances than the tablets of Comparative Examples 1 and 2, and thus had an excellent effect on stability. Also, similar to the tablets of Reference Example 3 (alogliptin single formulation), it was confirmed that the barrier coating layers of Examples 1 to 3 improved the decrease in stability of alogliptin due to contact with the metformin component (FIGS. 2 and 3).

No. RRT 1.2 (2W) RRT 1.22 (2W) Closed Vials Al-Bag Closed Vials Al-Bag Comparative Example 1 0.285 0.159 0.285 0.159 Comparative Example 2 0.678 0.643 0.359 0.322 Reference example 3 0.037 - 0.000 - Example 1 0.000 0.000 0.036 0.033 Example 2 0.089 0.088 0.077 0.077 Example 3 0.045 0.038 0.058 0.049

Examples 4 to 6

Based on the results of Experimental Example 1, the stability was further confirmed by changing only the coating polymer of the barrier coating layer, including PVA in the drug coating layer. The barrier coating layer was prepared in the same manner as in Example 1, except that the barrier coating layer was prepared as shown in Table 3 below.

Example 4 Example 5 Example 6 barrier coating layer Polymer for coating HPC - 28 - PVA-PEG 28 - - HPMC - - 28 coating aid Talc, TiO ₂ , pigment 18 18 18

Experimental Example 2. Stability effect according to barrier coating layer coating agent

The related substances of the tablets of Examples 1 and 4 to 6 were analyzed, and the RRT (Relative retention time) 1.22 peak position, which showed a marked increase in related substances compared to the peak position of the main component, was quantified to confirm the effect of improving tablet stability according to the components and contents of the coating agent. The coated tablet prepared in Example was packed in a sealed bottle and an aluminum bag at 50 ° C and 75% relative humidity, and an increase in related substances was confirmed after 4 weeks of storage.

As a result of the experiment, it was confirmed that the tablets of Examples 1 and 4 to 6 all had a small increase in related substances (less than 0.2), even in the results up to the 4th week, and had an excellent effect on stability (FIG. 4).

No. RRT 1.22 (4W) Bottle Al-Bag Example 4 0.115 0.110 Example 5 0.096 0.087 Example 6 0.079 0.079 Example 1 0.093 0.094

Claims (14)

(1) a core containing metformin or a salt thereof;
(2) a barrier coating layer coated on the core; and
(3) a pharmaceutical composition comprising a drug coating layer coated on the barrier coating layer and containing alogliptin or a salt thereof;
The drug coating layer is a pharmaceutical composition comprising 50 to 200% by weight of polyvinyl alcohol based on the weight of alogliptin or a salt thereof.
According to claim 1,
The barrier coating layer is polyvinyl alcohol, hydroxypropyl cellulose, hypromellose, polyvinyl alcohol-polyethylene glycol copolymer, hydroxypropyl starch, dimethylaminoethyl methacrylate/methyl methacrylate copolymer, ethyl methacrylate-methacrylic acid A pharmaceutical composition comprising at least one selected from the group consisting of chlorotrimethylammonium ethyl copolymer, methacrylic acid/ethyl acrylate copolymer, hypromellose acetate succinate, and hypromellose phthalate.
According to claim 1,
The pharmaceutical composition of claim 1 , wherein the core comprises 250 to 1500 mg of metformin or a salt thereof.
According to claim 1,
The drug coating layer is a pharmaceutical composition comprising 5 to 50 mg of alogliptin or a salt thereof.
According to claim 1,
The pharmaceutical composition wherein the drug coating layer contains 10 to 50 mg of polyvinyl alcohol.
According to claim 1,
The drug coating layer further comprises 0.01 to 80% by weight of hydroxypropylcellulose based on the weight of alogliptin or a salt thereof.
According to claim 6,
The pharmaceutical composition of claim 1, wherein the drug coating layer contains 0.01 to 16 mg of hydroxypropylcellulose.
According to claim 6,
The pharmaceutical composition of claim 1 , wherein the drug coating layer includes polyvinyl alcohol and hydroxypropyl cellulose in a ratio of 10:1 to 1:1.
According to claim 1,
The drug coating layer is a pharmaceutical composition containing 2 to 10% by weight relative to the total weight of the pharmaceutical composition.
According to claim 1,
The pharmaceutical composition comprising 1 to 5% by weight of the barrier coating layer based on the total weight of the pharmaceutical composition.
According to claim 1,
The pharmaceutical composition comprising 1 to 5% by weight of the barrier coating layer based on the weight of the core.
According to claim 1,
Wherein the core is a sustained-release tablet containing metformin or a salt thereof.
According to claim 12,
The core is a sustained-release agent as hydroxypropyl cellulose, methyl cellulose, carrageenan, glyceryl behenate, hydrogenated castor oil, hydrogenated vegetable oil, stearic acid, polyvinyl acetate, polyvinyl alcohol, povidone, polyethylene glycol, hydroxyethyl cellulose, heap A pharmaceutical composition comprising at least one selected from the group consisting of romellose, polyethylene oxide, sodium carboxylmethylcellulose, carbomer and sodium alginate.
The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a tablet, capsule or granule.

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