KR102229798B1 - Bilayered tablet composite formulation comprising metformin and losartan - Google Patents

Abstract

The present invention relates to a two-layer tablet composite formulation containing metformin and losartan and a method for manufacturing the same, and the two-layer tablet composite formulation of the present invention exhibits excellent preventive and therapeutic effects against diabetes and hypertension by simultaneously containing metformin and losartan. , It can be very useful for diabetic and hypertensive patients by developing a formulation capable of simultaneously securing the sustained-release dissolution of metformin and the immediate-release dissolution of losartan.

Description

TECHNICAL FIELD [BILAYERED TABLET COMPOSITE FORMULATION COMPRISING METFORMIN AND LOSARTAN}

The present invention relates to a two-layer tablet composite formulation comprising metformin and losartan, and a method for producing the same.

Metformin, a biguanide-based diabetes drug, is an oral anti-hyperglycemic drug mainly used in the treatment of non-insulin dependent diabetes mellitus (NIDDM). It is known that metformin's glycemic control mechanism acts independently of insulin secretion, and, for example, activates glucose transporters in the liver. Metformin induces weight loss in diabetic patients, reduces blood triglycerides and low-density lipoproteins, and increases high-density lipoproteins. Therefore, metformin can be used as a primary drug for insulin-independent diabetic patients showing insulin resistance.

^{Currently, metformin is marketed under the brand name of glucophage (GLUCOPHAGE ®} , Merck) in its hydrochloride tablet form, and glucophage tablets contain 250mg, 500mg, or 1,000mg metformin hydrochloride, and its administration is effective and Considering both aspects of tolerance, the maximum required dose of 2,550 mg per day is not exceeded. Side effects associated with the use of metformin include loss of appetite, bloating, nausea, and diarrhea, and appear in 20 to 30% of patients taking it. Most of the side effects are transient and disappear after 2-3 weeks after taking it, but if diarrhea or severe abdominal distension does not disappear, it is better to stop taking it. Rarely, skin rashes and hives may occur. These side effects can be partially avoided by methods of using sustained-release formulations that can reduce minimal and/or sustained doses or reduce the number of dosing.

Existing metformin sustained-release formulations have been prepared by using a polymer material or by controlling the release according to the osmotic pressure. For example, Korean Patent No. 1043816 uses metformin, a selected hydrophobic sustained-release carrier, and a swellable polymer to provide metformin sustained-release tablets that control the drug release rate by blocking water expansion due to hydration of the swellable polymer and water penetration due to the hydrophobic polymer. It is starting. In addition, Korean Patent No.0772980 is a sustained-release formulation for oral administration of metformin containing polyethylene oxide and natural gum, which is a hydrophilic polymer as a sustained-release carrier. A system capable of maintaining concentration is disclosed.

On the other hand, losartan is 2-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imine As a common name for dazole-5-methanol, US Patent No. 5,608,075; 5,138,069; 5,153,197, etc. In particular, Rosatan potassium is currently sold under the trade name ^{Cozaar ®.} Rosatan blocks the binding of angiotensin II, a vasoconstrictor, to receptors to treat hypertension and heart failure, treat ischemic peripheral circulation disorders, myocardial ischemia (angina pectoris), prevent progression of heart failure after myocardial infarction, and diabetic It is used to treat neuropathy and glaucoma.

More than 50% of type 2 diabetic patients have high blood pressure, and the 2011 Korean Diabetes Association'Guidelines for the Treatment of Hypertension in Diabetic Patients' recommends angiotensin receptor antagonists as the primary drug for controlling blood pressure in diabetic patients. A combination of two components with different medicinal effects can be substituted for concurrent administration, improving the convenience of taking the patient's medication, and has an economic advantage over taking each single drug together.

Accordingly, the present inventors confirmed that a combination formulation of metformin and losartan having different mechanisms of action can be usefully used in the treatment of patients with diabetes and hypertension at the same time, and as a result of intensive studies, it is possible to maintain a stable release pattern of losartan. The present invention was completed by developing a complex formulation of metformin and losartan.

delete

delete

delete

delete

delete

1) Korean Patent No. 1043816 2) Korean Patent No.0772980 3) U.S. Patent No. 5,608,075 4) U.S. Patent No. 5,138,069 5) U.S. Patent No. 5,153,197

It is an object of the present invention to provide a solid pharmaceutical complex formulation containing metformin or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof, and showing a rapid release pattern of losartan, and a method for preparing the same. will be.

In order to achieve the above object, the present invention

1) a sustained-release layer containing metformin or a pharmaceutically acceptable salt thereof, and a release controlling agent; And 2) losartan or a pharmaceutically acceptable salt thereof, and an immediate-release layer containing a disintegrant, wherein the sustained-release layer is a first layer and an immediate-release layer is a second layer. .

In addition, the present invention

a) preparing a sustained-release layer granules containing metformin or a pharmaceutically acceptable salt thereof, and a release controlling agent;

b) preparing immediate-release granules containing losartan or a pharmaceutically acceptable salt thereof, and a disintegrant; And

c) preparing a two-layer tablet using the sustained-release granules as a first layer and the immediate-release granules as a second layer

It provides a method for producing a two-layer tablet composite formulation comprising a.

The oral composite formulation according to the present invention can maintain a stable blood concentration by delaying-controlling the release rate of metformin while simultaneously containing metformin and losartan, as well as securing a rapid dissolution pattern of losartan at a low pH. Therefore, it can be usefully used in the prevention or treatment of diabetes and hypertension.

1 is a graph showing the dissolution rate of losartan according to accelerated storage conditions of the composite formulations of Example 1 and Comparative Examples 4 and 5. FIG.
2 is a graph showing the dissolution rate of losartan according to accelerated storage conditions of the composite formulations of Examples 1 to 3 and Comparative Example 1. FIG.
3 is a graph showing the dissolution rate of metformin according to accelerated storage conditions of the composite formulations of Examples 1 to 3 and Comparative Examples 1, 3 and 5. FIG.

The present invention relates to 1) metformin or a pharmaceutically acceptable salt thereof, and a sustained-release layer containing a release controlling agent; And 2) losartan or a pharmaceutically acceptable salt thereof, and an immediate-release layer containing a disintegrant, wherein the sustained-release layer is a first layer and an immediate-release layer is a second layer. .

Hereinafter, the characteristics and types of each component constituting the two-layer tablet composite formulation of the present invention will be described in detail.

1) a sustained-release layer containing metformin or a pharmaceutically acceptable salt thereof

In the composite formulation of the present invention, the sustained-release layer may contain metformin or a pharmaceutically acceptable salt thereof, and a release controlling agent.

The sustained-release layer includes metformin or a pharmaceutically acceptable salt thereof as a first pharmacologically active ingredient, and examples thereof include metformin, metformin hydrochloride, and metformin hydrochloride is preferred.

The metformin or a pharmaceutically acceptable salt thereof may be contained in an amount of 250mg to 1000mg, preferably 500mg to 1000mg per unit dosage form, but is not limited thereto.

The sustained-release layer is selected from the group consisting of swellable polymer components such as hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, ethylcellulose, polyethylene oxide, guar gum, locust bean gum, and mixtures thereof in order to control the release rate of metformin. Release control agents may be included, and hydroxypropylmethylcellulose is preferred.

The release controlling agent may be included in an amount of 25 to 65% by weight, preferably 35 to 55% by weight, based on the total weight of the sustained-release layer.

In addition, the sustained-release layer may further include a pharmaceutically acceptable additive, if necessary. As the pharmaceutically acceptable additive, an appropriate amount of commonly used diluents, stabilizers, binders and lubricants may be used.

In the present invention, the sustained-release layer is preferably in the form of a tablet, and metformin or a pharmaceutically acceptable salt thereof, a release controlling agent, and other pharmaceutically acceptable excipients are mixed and granulated and then tableted to form a sustained-release layer in the form of a tablet. Can be manufactured. The sustained-release layer thus prepared constitutes the first layer in the composite formulation of the present invention.

According to one embodiment of the present invention, metformin hydrochloride, microcrystalline cellulose, hydroxypropylmethylcellulose and locust bean gum are mixed, kneaded with purified water, and dried to prepare granules. Subsequently, a lubricant may be added to the prepared granules to be lubricated for a certain period of time, and then a sustained-release layer in the form of a tablet may be prepared by applying a constant tableting pressure.

2) an immediate release layer containing losartan or a pharmaceutically acceptable salt thereof

In the composite formulation of the present invention, the immediate-release layer may contain losartan or a pharmaceutically acceptable salt thereof, and a certain amount of a disintegrant, and may exhibit optimal pharmacological activity by immediate-release-dissolution.

The immediate-release layer includes losartan or a pharmaceutically acceptable salt thereof as a second pharmacologically active ingredient, for example, losartan, losartan potassium, and the like, and losartan potassium is preferred.

The losartan or a pharmaceutically acceptable salt thereof may be contained in an amount of 25 mg to 200 mg, preferably 50 mg to 100 mg per unit dosage form, but is not limited thereto.

The immediate-release layer contains a disintegrant selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidon, and mixtures thereof in order to control the release rate of losartan. Can be done, and crospovidone is preferred.

The disintegrant may be included in an amount of 2.5 to 14.5% by weight, preferably 5 to 10% by weight, based on the total weight of the immediate release layer. If the disintegrant is used in excess of 14.5% by weight, tablet properties may be poor due to moisture absorption in the air during storage, and when used in less than 2.5% by weight, the dissolution may be delayed due to the release control agent in the first layer.

In addition, the immediate release layer may further include a pharmaceutically acceptable additive, if necessary. As the pharmaceutically acceptable additive, an appropriate amount of commonly used diluents, stabilizers, binders and lubricants may be used.

In the present invention, the immediate-release layer is preferably in the form of a tablet, and the immediate-release layer in the form of a tablet by mixing and granulating losartan or a pharmaceutically acceptable salt thereof, a disintegrant and other pharmaceutically acceptable additives, etc. Can be manufactured. The immediate release layer thus prepared constitutes the second layer in the composite formulation of the present invention.

According to one embodiment of the present invention, granules are prepared by mixing potassium losartan, microcrystalline cellulose, lactose and crospovidone. Subsequently, a lubricant may be added to the prepared granules to be lubricated for a certain period of time, and then a constant tableting pressure may be applied to prepare an immediate release layer in the form of a tablet.

Rosatan, an active ingredient included in the second layer, may not exhibit an immediate-release elution pattern due to the release controlling agent included in the first layer. This is because the release control agent used for sustained-release elution expands the tablet in an aqueous solution state, and delays the elution by adsorbing some losartan due to its high viscosity. In order for losartan to exhibit its optimal efficacy, stable release must be achieved even at low pH. In the present invention, by including a certain amount of disintegrant, preferably 2.5 to 14.5% by weight of the disintegrant based on the total weight of the immediate-release layer, in the immediate-release layer containing losartan, the losartan is rapidly disintegrated and then eluted to express optimal efficacy. Makes this possible.

In addition, the present invention comprises the steps of: a) preparing a sustained-release layer granules containing metformin or a pharmaceutically acceptable salt thereof, and a release controlling agent; b) preparing immediate-release granules containing losartan or a pharmaceutically acceptable salt thereof, and a disintegrant; And c) preparing a two-layer tablet using the sustained-release granules as a first layer and the immediate-release granules as a second layer.

Specifically, the method for preparing the dual-layer tablet composite formulation of the present invention includes: a) preparing a sustained-release layer granules according to a conventional manufacturing method using metformin or a pharmaceutically acceptable salt thereof and a release controlling agent, and b) rosartan or A pharmaceutically acceptable salt thereof, and 2.5 to 14.5% by weight of a disintegrant based on the total weight of the immediate-release granules were added to prepare immediate-release granules according to a conventional manufacturing method, and then c) the sustained-release granules were prepared. A two-layer tablet can be prepared by separating and tableting with a single layer and an immediate-release granule as a second layer. The composite formulation of the present invention thus prepared can be formulated in the form of a coated bilayer tablet according to a conventional formulation method and then used for oral administration.

Various processes involved in the preparation of the composite formulation according to the present invention can be performed based on conventional processes.

According to an embodiment of the present invention, first, a mixture is prepared by blending each of the components constituting each layer. Subsequently, if necessary, a granulating solvent such as purified water, ethanol, isopropanol or a combination thereof is added to the mixture obtained above and kneaded. At this time, other ingredients (eg, binders, wetting agents, buffering agents, etc.) as known in the art may be added to the granulation solvent. After lubricating the granules obtained above for a certain period of time by adding a lubricant, the two-layer according to the present invention is separated and tableted with the sustained-release granules as the first layer and the immediate-release granules as the second layer using a two-layer tablet press. Tablet complex formulations can be prepared.

Since the two-layer tablet composite formulation according to the present invention exhibits a dissolution profile similar to that of a commercial product under conditions of 37°C, 900 ml, and purified water (Test Examples 1 and 2), even after being prepared as an oral composite formulation, the drug efficacy equivalent to each single drug is expressed. This is possible. In addition, since the two-layer tablet composite formulation of the present invention can treat diabetes and hypertension at the same time by including all two pharmacologically active ingredients, metformin and losartan in one tablet, it is possible to improve the inconvenience of taking two tablets separately. It is significant that it has significantly improved the patient's medication convenience.

[Example]

Hereinafter, the present invention will be described in more detail by the following examples. However, the following examples are for illustrative purposes only, and the scope of the present invention is not limited thereto.

Example 1: Preparation of two-layer tablet containing metformin and losartan

Step 1: Preparation of slow-release granules containing metformin

In the composition of Table 1, metformin hydrochloride, hydroxypropylmethylcellulose HPMC 2208 (Shin-Etsu Chemical) , microcrystalline cellulose and locust bean gum were first mixed, and then combined with 200 mg of purified water per tablet, and dried at 60°C. Granules were prepared. The granules were passed through a 20 screen size using a sizing machine to prepare granules having a homogeneous particle size, and magnesium stearate was added to the granules thus prepared and lubricated for 5 minutes to prepare metformin sustained-release granules.

The composition of the western metformin layer mg/1 tablet Metformin hydrochloride 500 Microcrystalline cellulose 100 HPMC 2208 (100,000 SR) 340 Locust Bean Gum 50 Magnesium stearate 10 total 1000

Step 2: Preparation of immediate-release granules containing losartan

In the composition shown in Table 2 below, losartan potassium, microcrystalline cellulose, lactose, and crospovidone were first mixed for 30 minutes using an IBC blender (Yenchen, Taiwan) to prepare granules. Magnesium stearate was added to the prepared granules and lubricated for 5 minutes to prepare Rosatan immediate-release granules.

Composition of the immediate release layer of Rosatan mg/1 tablet Rosatan Potassium 100 Microcrystalline cellulose 180 Lactose 80 Crospovidone 20 Magnesium stearate 4 total 384

Step 3: bilayered tablet tableting

Using a two-layer tablet press, the granules containing metformin prepared in Step 1 are used as the first layer, and the granules containing the losartan prepared in Step 2 and the disintegrant (crosspovidone) are used as the second layer. A two-layer tablet having a hardness of 10-20 kp was prepared by applying a tableting pressure of 15 tons.

Examples 2 and 3 and Comparative Examples 1 and 2: Preparation of two-layer tablet containing metformin and losartan

A two-layer tablet including metformin in the first layer and losartan in the second layer was prepared in the same manner as in Example 1 using the ingredients and amounts (mg/tablet) shown in Table 3 below.

Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Formulation Two-story Two-story Two-story Two-story Two-story First floor
(Western floor) Metformin hydrochloride 500 500 500 500 500 Microcrystalline cellulose 100 100 100 100 100 Hydroxypropyl
Methyl cellulose 340 340 340 340 340 Locust Bean Gum 50 50 50 50 50 Magnesium stearate 10 10 10 10 10 Second floor
(Immediate release) Rosatan Potassium 100 100 100 100 100 Microcrystalline cellulose 180 180 180 180 180 Lactose 80 80 80 80 80 Crospovidone 20 10 60 0 80 Magnesium stearate 4 4 4 4 4 total 1384 1374 1424 1364 1444

Comparative Examples 3 to 5: Preparation of tablets and mixed tablets of each single component

A metformin sustained-release tablet containing only metformin (Comparative Example 3) and an immediate-release tablet containing only metformin (Comparative Example 3) by tableting the granules prepared using the composition shown in Table 4 and the method of Step 1 or Step 2 of Example 1, respectively ( Comparative Example 4) was prepared.

In addition, after preparing metformin-containing granules and losartan-containing granules using the same composition and method as in Steps 1 and 2 of Example 1, the two granules were simply mixed for 30 minutes and then compressed into a mixed tablet without a layer (Comparative Example 5) was prepared.

Comparative Example 3 Comparative Example 4 Comparative Example 5 Formulation Single tablet Single tablet Mixed tablets Metformin hydrochloride 500 - 500 Microcrystalline cellulose 100 - 100 Hydroxypropylmethylcellulose 340 - 340 Locust Bean Gum 50 - 50 Magnesium stearate 10 - 10 Rosatan Potassium - 100 100 Microcrystalline cellulose - 180 180 Lactose - 80 80 Crospovidone - 20 20 Magnesium stearate - 4 4 total 1000 384 1424

Examples 4 and 5: Preparation of two-layer tablet containing metformin and losartan

As shown in Table 5 below, a two-layer tablet containing metformin and losartan was prepared in the same manner as in Example 1, except that sodium starch glycolate and sodium croscarmellose were respectively used instead of crospovidone as a disintegrant. .

Example 1 Example 4 Example 5 Formulation Two-story Two-story Two-story Metformin hydrochloride 500 500 500 Microcrystalline cellulose 100 100 100 Hydroxypropylmethylcellulose 340 340 340 Locust Bean Gum 50 50 50 Magnesium stearate 10 10 10 Rosatan Potassium 100 100 100 Microcrystalline cellulose 180 180 180 Lactose 80 80 80 Crospovidone 20 - - Sodium starch glycolate - 20 - Croscarmellose Sodium - - 20 Magnesium stearate 4 4 4 total 1384 1384 1384

Test Example 1: Evaluation of dissolution of losartan in a complex formulation and a single formulation

For Examples 1 to 3 and Comparative Examples 1, 4 and 5, referring to the dissolution method of Losartan potassium tablets described in the 36th edition of the US Pharmacopoeia (USP36), 37°C, 900ml and The dissolution test was performed under the condition of purified water, but the sample solution was taken at 5, 10, 15 and 30 minutes after the test to confirm the dissolution pattern of losartan and to confirm whether it satisfies the standard (dissolution of 80% or more in 30 minutes). The results are shown in FIGS. 1 and 2.

As shown in FIG. 1, the formulation of Comparative Example 4, which is a single tablet of losartan immediate-release granules, satisfies the dissolution criteria, but the formulation of Comparative Example 5, which is a simple mixed tablet of Rosatan immediate-release granules and metformin sustained-release granules, decreased the dissolution of losartan. It can be seen that it does not satisfy the standards. This is because the elution of losartan is delayed by the release controlling agent of the metformin granules. On the other hand, the tablet of Example 1 exhibited a dissolution pattern of losartan equivalent to that of the single formulation (Comparative Example 4), even though each layer was prepared as a separate two-layer tablet.

In addition, by comparing the dissolution patterns of Examples 1 to 3 and Comparative Example 1 shown in FIG. 2, it is possible to know the appropriate amount of disintegrant required for the losartan granules. In the case of Comparative Example 1 without a disintegrant in the losartan granules, the dissolution rate was less than 80% 30 minutes after the test, and in Examples 1 to 3, 2.5% by weight or more of the disintegrant was used based on the weight of the losartan granules. If so, a satisfactory dissolution rate could be obtained. However, in the case of Comparative Example 2 in which the disintegrant was used in an amount of about 18% by weight, it was confirmed that the hardness of the tablet was weakened by absorbing moisture in the air when exposed to air, resulting in poor marketability. Therefore, when using a disintegrant of about 14.5% by weight in a weight ratio of 2.5% by weight to the granular part of Rosatan, and prepared as a double-layered tablet with the granular part of metformin, a composite formulation with high storage stability while exhibiting similar dissolution rate of Rosatan as a single formulation. Can be obtained.

Test Example 2: Evaluation of the dissolution of metformin in a complex formulation and a single formulation

For Examples 1 to 3 and Comparative Examples 1, 3, and 5, a dissolution test was conducted under conditions of 37° C., 1000 mL and pH 6.8 buffer with reference to the dissolution test method of metformin hydrochloride exted-release tablets of USP36. And the results are shown in FIG. 3.

As shown in FIG. 3, the dissolution patterns of metformin showed similar dissolution rates for both single tablets (Comparative Example 3), simple mixed composite formulations (Comparative Example 5), and double-layered tablet composite formulations (Examples 1 to 3 and Comparative Example 1). This is considered to be because metformin elution is not affected by the disintegrant of the losartan granules, and the elution pattern is determined only by the release controlling agent.

Claims (8)

1) a sustained-release layer containing metformin or a pharmaceutically acceptable salt thereof, and a release controlling agent; And 2) losartan or a pharmaceutically acceptable salt thereof, and an immediate-release layer containing a disintegrant, wherein the sustained-release layer is a first layer and an immediate-release layer is a second layer,
The release controlling agent is at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, ethylcellulose, and polyethylene oxide, and at least one selected from the group consisting of guar gum and locust bean gum. It includes, and is included in 25 to 65% by weight based on the total weight of the sustained-release layer,
The disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidon, and mixtures thereof, and 2.5 to 14.5% by weight based on the total weight of the immediate release layer. Is included as,
A two-layer tablet composite formulation in which a first layer as a sustained release layer and a second layer as an immediate release layer are successively stacked. delete delete The method of claim 1,
The metformin or a pharmaceutically acceptable salt thereof is characterized in that contained in an amount of 250mg to 1000mg per unit dosage form, a two-layer tablet composite formulation. delete delete The method of claim 1,
The losartan or a pharmaceutically acceptable salt thereof is characterized in that it is contained in an amount of 25mg to 200mg per unit dosage form, a double-layered tablet composite formulation. a) preparing a sustained-release layer granules containing metformin or a pharmaceutically acceptable salt thereof, and a release controlling agent;
b) preparing immediate-release granules containing losartan or a pharmaceutically acceptable salt thereof, and a disintegrant; And
c) preparing a two-layer tablet using the sustained-release granules as a first layer and the immediate-release granules as a second layer,
The release controlling agent is at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, ethylcellulose, and polyethylene oxide, and at least one selected from the group consisting of guar gum and locust bean gum. It includes, and is included in 25 to 65% by weight based on the total weight of the sustained-release layer granules,
The disintegrant is one or more selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidon, and mixtures thereof, based on the total weight of the immediate release layer. A method for producing a two-layer tablet composite formulation according to claim 1, which is contained in an amount of 14.5% by weight.

Images