KR20200048516A - A pharmaceutical composition of combination - Google Patents

Abstract

Disclosed is a pharmaceutical composition which contains: celecoxib or a pharmaceutically acceptable salt thereof; olmesartan medoxomil; and a disintegrating agent, as active components. According to the present invention, it is possible to improve the bioavailability and therapeutic effects by improving the dissolution rate of a medicine for treating osteoarthritis and a medicine for treating hypertension.

Description

Combination pharmaceutical composition {A pharmaceutical composition of combination}

The present invention relates to a combination pharmaceutical composition comprising celecoxib, an anti-inflammatory analgesic, and olmesartan medoxomil, a therapeutic agent for hypertension.

Celecoxib is an anti-inflammatory analgesic, and is known to be particularly effective in treating osteoarthritis.

Osteoarthritis is a degenerative joint disease, a disease accompanied by gradual loss of articular cartilage in local joints and associated secondary changes and symptoms. Due to gradual damage or degenerative changes in cartilage protecting the joints, damage to the bones and ligaments forming the joints occurs, resulting in inflammation and pain.

Olmesartan medoxomil is a drug used as a treatment for hypertension.

The pressure in the blood vessels of the human body changes from time to time, and when you exercise, it rises, and when you stabilize, it decreases. If you measure the blood pressure more than 140/90 mmHg more than twice, you can define it as hypertension. Normal blood pressure is 120/80 mmHg or less, and in the case of blood pressure between 120/80 mmHg and 140/90 mmHg, it is referred to as pre-stage hypertension.

Current antihypertensive drugs include diuretics, drugs that inhibit sympathetic function, calcium channel blocker (CCB), angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), and renin Inhibitors, vasodilators, and the like are used.

Among these antihypertensive drugs, angiotensin receptor blockers (hereinafter referred to as "ARB") have not only lowered blood pressure, but also have effects such as preserving ventricular function, preventing and preventing fibrosis, and are increasingly being used as a therapeutic agent for hypertension. ARB drugs include, after the development of losartan, valsartan, candesartan, irbesartan, telmisartan, eprosartan, Olmesartan and the like have been developed and used as blood pressure lowering agents.

Most patients with osteoarthritis disease use two or more drugs to treat osteoarthritis, and hypertensive patients also use two or more drugs to control blood pressure.

As human lifespan increases, the number of patients who have both osteoarthritis and high blood pressure is increasing as they reach old age. In order to treat osteoarthritis and hypertension, these patients have to take 4 to 8 drugs every day 3 times a day. Osteoarthritis and hypertension are chronic diseases and should be taken for a long time. Therefore, patients should take the osteoarthritis treatment agent and the hypertension treatment agent at the same time for a long period of time, and since the number of prescribed drugs is large, the compliance with medication is significantly reduced.

In particular, there is no effective solution for resolving medication compliance for patients with osteoarthritis and hypertension, which are typical senile chronic diseases.

In addition, when formulated and administered as a combination formulation for oral administration, there is a problem that two drugs may affect each other's dissolution. To solve this problem, conventionally, a method of adding a large amount of excipients such as a disintegrant and a release base has been used. However, the disintegrants and release agents added as described above may interact with drugs and other excipients in the formulation, thereby lowering the bioavailability. It is not.

U.S. Patent No. 5,466,823

The present invention is to improve medication compliance by developing a combination drug containing two drugs to simultaneously treat osteoarthritis and hypertension. Accordingly, the present invention is to provide a combination agent of celecoxib, a drug for treating osteoarthritis, and olmesartan, a drug for treating high blood pressure.

On the other hand, celecoxib is low in solubility in water and has a large dosage, so when celecoxib is prepared as a combination formulation for co-administration with olmesartan, celecoxib will interfere with the elution of olmesartan. Can be.

The present invention solves these problems so that both celecoxib and olmesartan disintegrate and dissolve quickly, thereby improving the absorption rate and absorption rate into the gastrointestinal tract and providing a solid oral dosage form that can improve the therapeutic effect. It is to do.

In order to solve the above problems, the pharmaceutical composition of the present invention is celecoxib or a pharmaceutically acceptable salt thereof; Olmesartan medoxomil or a pharmaceutically acceptable salt thereof; And certain disintegrants.

According to the present invention, it is possible to improve medication compliance of patients with osteoarthritis and hypertensive disease. In addition, according to the present invention, it is possible to improve the bioavailability and therapeutic effect by improving the dissolution rate of the drug for treating osteoarthritis and the drug for treating hypertension.

1 is a graph showing the dissolution test results for the tablets prepared in Examples.

The present invention is celecoxib or a pharmaceutically acceptable salt thereof; Olmesartan or a pharmaceutically acceptable ester thereof or a pharmaceutically acceptable salt thereof; And it relates to a solid preparation for oral administration containing a disintegrant.

In the present invention, olmesartan medoxomil is preferably used as the pharmaceutically acceptable ester of olmesartan.

Specifically, the present invention is celecoxib or a pharmaceutically acceptable salt thereof; And olmesartan medoxomil or a pharmaceutically acceptable salt thereof.

The tablet composition of the present invention comprises a disintegrant selected from the group consisting of sodium croscarmellose, sodium starch glycolate and crospovidone, and preferably contains croscarmellose sodium as the disintegrant.

As one aspect of the present invention, the celecoxib or a pharmaceutically acceptable salt thereof and the olmesartan medoxomil or a pharmaceutically acceptable salt thereof are preferably included in the form of granules, respectively. That is, the tablet pharmaceutical composition of the present invention includes celecoxib or a pharmaceutically acceptable salt thereof in the form of granules, and also olmesartan medoxomil or a pharmaceutically acceptable salt thereof is separately included in the form of granules. It is desirable.

Here, the granules containing olmesartan medoxomil or a pharmaceutically acceptable salt thereof may include a disintegrant selected from the group consisting of croscarmellose sodium, sodium starch glycolate and crospovidone, preferably Contains croscarmellose sodium as a disintegrant.

The amount of disintegrant used in the present invention is preferably 4 to 12% based on the total weight of the tablet.

The granules can be easily prepared by a person skilled in the art by a method such as a wet granulation method or a dry granulation method. It is preferably prepared by the method of wet granulation.

The tablet composition of the present invention may further include a filler, a binder, and a lubricant. For example, as a filler, lactose, microcellac, mannitol, corn starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, etc. can be used, and as a binder, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrroli Money can be used, and crospovidone, magnesium stearate, etc. can be used as a lubricant.

The tablet composition according to the present invention is preferably prepared as a monolayer tablet, and is used for the treatment of osteoarthritis and hypertension.

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are only for illustrating the present invention, and the spirit or the protection scope of the present invention is not limited by the examples.

Example

Example 1.

Example 1-1. Preparation of celecoxib granules

Celecoxib granules are prepared by the following method according to the composition and content of Table 1 below.

Dissolve sodium lauryl sulfate in 57 mg of purified water to prepare a binder solution. Separately, celecoxib, microcellac, crospovidone, and polyvinylpyrrolidone K30 were sieved through 35 mesh to prepare a mixture. The binder solution was put into this mixture and combined to form 18 mesh. The erected mixture is dried at 50 ° C.

Composition and content of celecoxib granules
Celecoxib granules ingredient Unit (mg) Cerexiv 200 Micro cell lock 77 Crospovidone 10 Polyvinylpyrrolidone K30 3 Sodium lauryl sulfate 10

Example 1-2. Preparation of olmesartan medoxomil granules

Olmesartan medoxomil granules are prepared according to the composition and content of Table 2 below.

Olmesartan medoxomil, lactose, sodium starch glycolate and polyvinylpyrrolidone K30 were sieved through 35 mesh to prepare a mixture. After adding the appropriate amount of purified water to the mixture and coalescing, it is established as 18 mesh. The erected mixture is dried at 50 ° C.

Composition and content of olmesartan medoxomil granules
Olmesartan granules ingredient Unit (mg) Olmesartan Medoxomil 20 Lactose 58.5 Sodium starch glycolate 20 Polyvinylpyrrolidone K30 1.5

Example 1-3. Preparation of tablets

After mixing the prepared celecoxib granules and olmesartan granules in proportion, 15 mg of crospovidone sieved with 35 mesh and 5 mg of magnesium stearate were mixed to prepare a final mixture.

The final mixture was compressed into a single tablet press (CARVER) to prepare a composite single layer tablet. A punch and die having a size of 14 mm were used for the tableting machine.

Example 2

Example 2-1: Preparation of granules containing celecoxib

Celecoxib granules were prepared in the same manner as in Example 1-1.

Example  2-2: Olmesartan Medoxomil  Preparation of containing granules

Olmesartan medoxomil granules are prepared according to the composition and content of Table 3 below.

Olmesartan medoxomil, lactose, sodium starch glycolate and polyvinylpyrrolidone K30 were sieved through 35 mesh to prepare a mixture. After adding the appropriate amount of purified water to the mixture to combine, it is established as 18 mesh. The erected mixture is dried at 50 ° C.

Composition and content of olmesartan medoxomil granules
Olmesartan granules ingredient Example 2 (mg) Olmesartan Medoxomil 20 Lactose 38.5 Sodium starch glycolate 40 Polyvinylpyrrolidone K30 1.5

Example 2-3: Preparation of tablets

After mixing the prepared celecoxib granules and olmesartan granules in proportion, 15 mg of crospovidone sieved with 35 mesh and 5 mg of magnesium stearate are mixed to prepare a final mixture.

The mixture was prepared in the same manner as in the tableting procedure of Examples 1-3 to prepare a single-layer tablet.

Example 3

Example 3-1. Preparation of celecoxib-containing granules

Celecoxib granules were prepared in the same manner as in Example 1-1.

Example  3-2. Olmesartan Medoxomil  Preparation of containing granules

Olmesartan medoxomil granules are prepared according to the composition and content of Table 4 below.

Olmesartan medoxomil, lactose, croscarmellose sodium, and polyvinylpyrrolidone K30 were sieved through a 35 mesh to prepare a mixture. After adding the appropriate amount of purified water to the mixture and coalescing, it is established as 18 mesh. The erected mixture was dried at 50 ° C.

Composition and content of olmesartan medoxomil granules
Olmesartan granules ingredient Example 3 (mg) Olmesartan Medoxomil 20 Lactose 58.5 Croscarmellose sodium 20 Polyvinylpyrrolidone K30 1.5

Example 3-3. Preparation of tablets

After mixing celecoxib granules and olmesartan granules in proportion, 15 mg of crospovidone sieved through 35 mesh and 5 mg of magnesium stearate were mixed to prepare a final mixture.

The mixture was prepared in the same manner as in the tableting procedure of Examples 1-3 to prepare a single-layer tablet.

Example 4.

Example 4-1 Preparation of celecoxib-containing granules

It was prepared in the same manner as the method for preparing celecoxib granules of Example 1-1.

Example  4-2 Olmesartan Medoxomil  Preparation of containing granules

Olmesartan medoxomil granules are prepared according to the composition and content of Table 5 below.

Olmesartan medoxomil, lactose, croscarmellose sodium, and polyvinylpyrrolidone K30 were sieved through a 35 mesh to prepare a mixture. After adding the appropriate amount of purified water to the mixture and coalescing, it is established as 18 mesh. The erected mixture is dried at 50 ° C.

Composition and content of olmesartan medoxomil granules
Olmesartan granules ingredient Example 4 (mg) Olmesartan Medoxomil 20 Lactose 38.5 Croscarmellose sodium 40 Polyvinylpyrrolidone K30 1.5

Example 4-3 Preparation of tablets

After mixing celecoxib granules and olmesartan granules in proportion, 15 mg of crospovidone sieved through 35 mesh and 5 mg of magnesium stearate were mixed to prepare a final mixture.

The mixture was prepared in the same manner as in the tableting procedure of Examples 1-3 to prepare a single-layer tablet.

Example 5

Example 5-1. Preparation of granules containing celecoxib

It was prepared in the same manner as the method for preparing celecoxib granules of Example 1-1.

Example  5-2. Olmesartan Medoxomil  Preparation of granules containing

Olmesartan medoxomil granules are prepared according to the composition and content of Table 6 below.

Olmesartan medoxomil, microcellac, crospovidone, and polyvinylpyrrolidone K30 were sieved through 35 mesh to prepare a mixture. After adding the appropriate amount of purified water to the mixture to combine, it is established as 18 mesh. The erected mixture is dried at 50 ° C.

Composition and content of olmesartan medoxomil granules
Olmesartan granules ingredient Example 5 (mg) Olmesartan Medoxomil 20 Lactose 58.5 Crospovidone 20 Polyvinylpyrrolidone K30 1.5

Example 5-3. Preparation of tablets

After mixing celecoxib granules and olmesartan granules in proportion, 15 mg of crospovidone sieved through 35 mesh and 5 mg of magnesium stearate are mixed to prepare a final mixture.

The mixture was prepared in the same manner as in the tableting procedure of Examples 1-3 to prepare a single-layer tablet.

Example  6.

Example 6-1 Preparation of granules containing celecoxib

It was prepared in the same manner as the method for preparing celecoxib granules of Example 1.

Example  6-2. Olmesartan Medoxomil  Preparation of containing granules

Olmesartan medoxomil granules are prepared according to the composition and content of Table 7 below.

Olmesartan medoxomil, lactose, crospovidone, and polyvinylpyrrolidone K30 were sieved through 35 mesh to prepare a mixture. After adding the appropriate amount of purified water to the mixture to combine, it is established as 18 mesh. The erected mixture is dried at 50 ° C.

Composition and content of olmesartan medoxomil granules
Olmesartan granules ingredient Example 6 (mg) Olmesartan Medoxomil 20 Lactose 38.5 Crospovidone 40 Polyvinylpyrrolidone K30 1.5

Example  6-3. Preparation of tablets

After mixing celecoxib granules and olmesartan granules in proportion, 15 mg of crospovidone sieved with 35 mesh and 5 mg of magnesium stearate are mixed to prepare a final mixture.

The mixture was prepared in the same manner as in the tableting procedure of Examples 1-3 to prepare a single-layer tablet.

Experimental Example . Dissolution rate evaluation

For the tablets prepared in Examples 1 to 6, the dissolution rate of the olmesartan medoxomil component according to the type of disintegrant was compared.

end. Gum  Pharmacy ( Olmesartan Medoxomil  Dissolution test)

The tablets of Examples 1 to 6 and the commercially available olmesatan single tablet Olmetec® were each taken three tablets and were subjected to dissolution tests. As the eluent, the second solution of the Korean Pharmacopoeia Disintegration Test Method was used. The dissolution test was performed at 37 ° C and 50 rpm according to the second method (paddle method) of the Korean Pharmacopoeia Dissolution Test Method. 5 mL of each was taken at 5, 10, 15, 20, and 30 minutes, filtered through a membrane filter having a pore size of 0.45 μm, and then 1 mL of the filtrate was taken as the sample solution.

I. Standard solution preparation ( Olmesartan Medoxomil )

100 mg of olmesartan standard was accurately taken and placed in a 100 ml volumetric flask. Acetonitrile and distilled water were added at a ratio of 4: 1, respectively, and 70 ml of the diluted solution was added, followed by ultrasonic shaking for 15 minutes to completely dissolve. After cooling to room temperature, 30 ml of diluent was added to make 100 ml. Dilution with the appropriate amount of mobile phase to prepare a standard solution of 100, 50, 25, 12.5, 6.25, 3.125 μg / ml.

All. HPLC  Analysis conditions ( Olmesartan Medoxomil )

-Mobile phase: A mixture of acetonitrile and buffer at a ratio of 17:33 (v / v) was used. (Composition of buffer solution: 0.015 M monobasic potassium phosphate in water, adjusted with phosphoric acid to a pH of 3.4)

-Column: C18, 5μm, 150 x 4.60mm

-Column temperature: 40 °

-Detector: UV 250 nm

-Flow rate: 1 mL / min

-Injection volume: 20μL

la. Dissolution test results ( Olmesartan Medoxomil )

The dissolution rate results are shown in Table 8 and Figure 1 below:

Dissolution test results in pH 6.8 buffer
30-minute dissolution rate (%) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 71.9 83.0 84.7 66.9 72.0 71.4

Referring to Table 8 and Figure 1, in Examples 1 and 2 using sodium starch glycolate as a disintegrant, it was confirmed that the dissolution rate increased 30 minutes as the amount of disintegrant increased. In Examples 3 and 4 using sodium croscarmellose, it was found that the dissolution rate decreased as the amount of disintegrant increased. In Examples 5 and 6 using crospovidone, both examples showed similar dissolution rates.

Example 3 showed the best results for the 30-minute dissolution rate in pH 6.8 buffer. Example 2 also showed a relatively good dissolution profile compared to Example 3. In addition, when comparing the dissolution rate from 0 to 20 minutes, it was found that Example 3 showed the best initial dissolution rate. Therefore, it was confirmed that Example 3 shows the most suitable dissolution rate when compared with Comparative Example 1.

According to the present invention, it is possible to improve medication compliance of patients with osteoarthritis and hypertensive disease. In addition, according to the present invention, it is possible to improve the bioavailability and therapeutic effect by improving the dissolution rate of the drug for treating osteoarthritis and the drug for treating hypertension.

Claims (9)

Celecoxib or a pharmaceutically acceptable salt thereof; And olmesartan medoxomil or a pharmaceutical tablet composition for oral administration containing a pharmaceutically acceptable salt thereof. The pharmaceutical tablet composition according to claim 1, comprising a disintegrant selected from the group consisting of sodium croscarmellose, sodium starch glycolate and crospovidone. The pharmaceutical composition according to claim 1, comprising croscarmellose sodium as a disintegrant. The pharmaceutical composition according to claim 1, wherein the celecoxib or a pharmaceutically acceptable salt thereof and the olmesartan medoxomil or a pharmaceutically acceptable salt thereof are each included in the form of granules. The granules of claim 4, wherein the granules containing olmesartan medoxomil or a pharmaceutically acceptable salt thereof contain a disintegrant selected from the group consisting of croscarmellose sodium, sodium starch glycolate and crospovidone. Pharmaceutical composition to be made. The pharmaceutical composition according to claim 4, wherein the granules containing olmesartan medoxomil or a pharmaceutically acceptable salt thereof contain croscarmellose sodium as a disintegrant. The pharmaceutical composition according to any one of claims 1 to 6, wherein the pharmaceutical composition is a monolayer tablet. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is for treating osteoarthritis and hypertension. The pharmaceutical composition according to claim 7, further comprising a filler.

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