KR20160124368A

KR20160124368A - PHARMACEUTICAL COMPOSITION WITH INCREASED BIOAVAILABILITY COMPRISING PROPIONIC ACID DERIVED NSAIDs AND PPI

Info

Publication number: KR20160124368A
Application number: KR1020150054564A
Authority: KR
Inventors: 김광석; 홍일기; 박명신; 이지은; 염호준; 송세현; 손세일; 이홍우
Original assignee: 대원제약주식회사
Priority date: 2015-04-17
Filing date: 2015-04-17
Publication date: 2016-10-27

Abstract

The present invention relates to a pharmaceutical composition comprising: pelubiprofen which is a non-steroidal anti-inflammatory drug (NSAID); a proton pump inhibitor (PPI); or a pharmaceutically acceptable salt thereof, and also containing an alkalizing agent as an additive. The pharmaceutical composition contentedly improves the elution rate of pelubiprofen by mixing the alkalizing agent.

Description

TECHNICAL FIELD [0001] The present invention relates to a pharmaceutical composition comprising a non-steroidal anti-inflammatory drug (NSAID) based on propionic acid and a proton pump inhibitor (PPI)

The present invention relates to a pharmaceutical composition comprising felubipropene and one or more proton pump inhibitors (PPI) for the prevention and treatment of gastrointestinal disorders associated with felubiprofen, a propionic acid nonsteroidal antiinflammatory drug (NSAID) .

Pelubiprofen, a propionic acid nonsteroidal antiinflammatory drug (NSAID), is a COX-2 inhibitor, a type of cyclooxygenase, used in the treatment of osteoarthritis, rheumatoid arthritis and back pain. NSAIDs, including felubipropene, are one of the most commonly used drugs in the world, but their use frequently involves gastrointestinal side effects such as peptic ulcer and indigestion.

Most of these gastrointestinal side effects, which occur in 20-40% of NSAID users, occur in the stomach and small intestine, and can be caused by symptoms such as dyspepsia, erosion, gastritis, duodenitis and ulcers, and anemia due to excessive bleeding In extreme cases, it can pose a threat to life.

Various studies have been conducted to solve the gastrointestinal side effects of such NSAIDs. In Korean Patent Laid-Open No. 167078, there has been proposed a method in which a solution containing ibuprofen, which contains a plurality of drug particles dispersed in a hydrophilic, water- Sexual oral formulations are disclosed.

However, if it is designed as a delayed drug formulation, it may provide convenience to patients in terms of adherence to medication and may reduce gastrointestinal side effects, but the frequency and time for exposure of the drug to the gastrointestinal tract is still maintained, There is a need for measures to address gastrointestinal side effects.

Other methods for solving gastrointestinal side effects of NSAIDs include Esomeprazole, Dexlansoprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole, An anti-ulcer agent such as a proton pump inhibitor (PPI) such as Ilaprazole, Tenatoprzole, Leminoprazole and Nepaprazole can be administered simultaneously or in advance with the NSAID, Gastrointestinal side effects There have been studies to improve the symptoms of high-risk patients.

However, some anti-ulcer drugs, such as PPI, are prone to degradation and transformation in acid-reactive and neutral media. Accordingly, in Korean Patent Laid-Open Publication No. 2013-115593, an alkalizing agent is added to a layer containing PPI in a two-layer tablet containing NSAID and PPI to improve the stability of PPI, A preparation for creating an environment of a condition is disclosed.

However, the felubipropene used as an NSAID in the present invention is a poorly soluble drug in a low pH range, and thus bioavailability of the gastrointestinal tract needs to be improved for rapid pharmacological action in the gastrointestinal tract. As means for improving the dissolution rate of general oral preparations, there is a method of improving the dissolution rate of the oral preparation, such as addition of a surfactant, a method using a solid dispersion, a method of reducing the particle size such as nano- In the method of controlling the particle size of the active ingredient, the smaller the particle size, the greater the reactivity with other excipients contained in the formulation. In addition, the surfactant needs to be verified in many aspects in terms of the compatibility with the main component, and there is a problem in that the manufacturing cost is increased because the production of the solid dispersion becomes complicated.

The present inventors have found that the dissolution rate of felubipropene, which shows poor solubility at pH 1.2, which is an acidic condition, is greatly improved by the alkalizing agent during the evaluation of the preparation of the examples through the present invention. That is, the alkalizing agent added for the stability of PPI greatly improved the solubility of felubipropene, which was poorly soluble under acidic conditions.

Accordingly, the present invention aims to provide an agent which not only improves the stability of PPI by adding an alkalizing agent to a basic environment, but also can increase the bioavailability by improving gastrointestinal dissolution rate of felubiprofen The purpose.

The present invention provides a pharmaceutical composition comprising a non-steroidal anti-inflammatory drug (NSAID), felubiprofen, a proton pump inhibitor (PPI), and an alkalizing agent as a stabilizing agent.

The PPI of the present invention can be used in combination with other therapeutic agents such as Esomeprazole, Dexlansoprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole, Ilaprazole, A pharmaceutically acceptable salt thereof, Tenatoprzole, Leminoprazole, Nepaprazole, a pharmaceutically acceptable salt thereof, a precursor and a mixture thereof.

The alkalizing agent of the present invention may be selected from the group consisting of calcium hydroxide, ethanolamine, potassium hydrogen carbonate, potassium citrate, sodium hydrogen carbonate, sodium hydroxide citrate, sodium hydroxide, calcium silicate, arginine, magnesium oxide, calcium carbonate, Sodium dihydrogen phosphate, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminum hydroxide, sodium borate, and meglumine.

According to an embodiment of the present invention, the alkalizing agent may be prepared in an amount of 2 to 20 parts by weight based on 1 part by weight of PPI.

The pharmaceutical composition of the present invention may be prepared by mixing the felubiprofen, the PPI, the alkalizing agent, the excipient, and the binder, combining them using an appropriate solvent, drying and sizing them to prepare tablet granules or granules for filling, And then adding a pharmaceutically acceptable excipient such as a lubricant to the granulated product.

In addition, the pharmaceutical composition of the present invention can be prepared in various forms of formulation, and in one embodiment, the present invention can be prepared in a single schedule containing felubiprofen, PPI and alkalizing agent in one layer .

In one embodiment, the invention can be made with tablets containing compartments containing the non-steroidal anti-inflammatory drug pelubiprofen and a compartment containing a proton pump inhibitor and an alkalizing agent as an additive. Where each compartment may be separated by known formulation techniques.

In one embodiment, the present invention can be prepared with a two-layer tablet consisting of a first layer containing felubiprofen and optionally an alkalizing agent and a second layer containing a PPI and an alkalizing agent. The first layer may or may not contain an alkalizing agent. By making the alkalizing agent exist in the same layer as the PPI, the storage stability of the PPI can be improved. At the same time, even if the felubipropene and the alkalizing agent are present in the same layer or are not present in the same layer, The microenvironment can be provided to increase the bioavailability by improving the dissolution rate of felubiprofen.

In one embodiment, the present invention can be prepared with capsules containing felubiprofen, PPI and an alkalizing agent.

Hereinafter, the characteristics and kinds of each component constituting the pharmaceutical combination preparation of the present invention will be described in detail with reference to examples. However, the present invention is not limited to the examples.

(Single definition manufacturing)

Example 1.

45 g of felubiprofen, 50.31 g of lactose, 21.6 g of S omeprazole Mg ₂ H ₂ O, 120 g of mannitol and 180 g of arginine were respectively weighed and mixed. 8 g of hypromellose was dissolved in an aqueous 80% ethanol solution to prepare a binding solution, and the resulting mixture was granulated. After the granules were dried and sized, 15 g of low-substituted hydroxypropylcellulose and 5 g of magnesium stearate were further added thereto, followed by mixing and tabletting to prepare tablets.

Example 2.

Tablets were prepared in the same manner as in Example 1, except that 180 g of calcium hydroxide was used instead of arginine as an alkalizing agent.

Example 3.

In Example 1, instead of arginine as an alkaline agent, 180 g of dihydrogen phosphate was used to prepare tablets using the same production method.

Example 4.

In Example 1, instead of arginine, which is an alkalizing agent, 180 g of magnesium oxide was used to prepare tablets using the same production method.

Comparative Example 1

Tablets were prepared in the same manner as in Example 1, except that 180 g of microcrystalline cellulose was used instead of arginine as an alkalizing agent.

Comparative Example 2

In Example 1, 180 g of lactose was added in place of arginine, which is an alkalizing agent, to prepare tablets by the same production method.

Example 5.

45 g of felubiprofen, 61.31 g of lactose, 10 g of rabeprazole, 120 g of mannitol and 180 g of magnesium carbonate were respectively weighed and mixed. 8 g of hypromellose was dissolved in an aqueous 80% ethanol solution to prepare a binding solution, and the resulting mixture was granulated. After the granules were dried and sized, 15 g of low-substituted hydroxypropylcellulose and 5 g of magnesium stearate were further added thereto, followed by mixing and tabletting to prepare tablets.

Example 6.

Tablets were prepared in the same manner as in Example 5, except that 45 g of meglumine was used instead of magnesium carbonate as an alkalizing agent.

Example 7.

Tablets were prepared in the same manner as in Example 5, except that 180 g of meglumine was used instead of magnesium carbonate as an alkalizing agent.

Comparative Example 3

In Example 5, instead of magnesium carbonate as the alkalizing agent, 180 g of microcrystalline cellulose was used to prepare tablets by the same production method.

Comparative Example 4

In Example 5, instead of 180 g of magnesium carbonate as an alkalizing agent, 10 g of magnesium carbonate was used to prepare tablets using the same production method.

Example 8.

45 g of felubiprofen, 50.31 g of lactose, 20 g of omeprazole, 120 g of mannitol and 180 g of sodium dihydrogenphosphate were respectively weighed and mixed. 8 g of hypromellose was dissolved in an aqueous 80% ethanol solution to prepare a binding solution, and the resulting mixture was granulated. After the granules were dried and sized, 15 g of low-substituted hydroxypropylcellulose and 5 g of magnesium stearate were further added thereto, followed by mixing and tabletting to prepare tablets.

Example 9.

In Example 8, 45 g of calcium carbonate was used instead of sodium dihydrogenphosphate, which is an alkalizing agent, to prepare tablets using the same production method.

Example 10.

In Example 8, instead of sodium dihydrogenphosphate as an alkalizing agent, 180 g of calcium carbonate was used to prepare tablets using the same production method.

Comparative Example 5

A tablet was prepared in the same manner as in Example 8, except that 180 g of microcrystalline cellulose was used instead of sodium dihydrogenphosphate as an alkalizing agent.

Comparative Example 6

In Example 8, instead of 180 g of sodium dihydrogenphosphate as an alkalizing agent, 10 g of dihydrogenphosphate was used to prepare tablets using the same production method.

Example 11.

45 g of felubiprofen, 55.31 g of lactose, 15 g of lansoprazole, 120 g of mannitol and 180 g of magnesium hydroxide were respectively weighed and mixed. 8 g of hypromellose was dissolved in an aqueous 80% ethanol solution to prepare a binding solution, and the resulting mixture was granulated. After the granules were dried and sized, 15 g of low-substituted hydroxypropylcellulose and 5 g of magnesium stearate were further added thereto, followed by mixing and tabletting to prepare tablets.

Example 12.

A tablet was prepared in the same manner as in Example 11, except that 40 g of calcium silicate was used instead of magnesium hydroxide as an alkalizing agent.

Example 13.

A tablet was prepared in the same manner as in Example 11, except that 100 g of calcium silicate was used instead of magnesium hydroxide as an alkalizing agent.

Comparative Example 7

In Example 11, instead of magnesium hydroxide as the alkalizing agent, 180 g of microcrystalline cellulose was used to prepare tablets by the same production method.

Comparative Example 8

In Example 11, instead of 180 g of magnesium hydroxide as the alkalizing agent, 10 g of magnesium hydroxide was used to prepare tablets using the same production method.

Example 14.

45 g of felubiprofen, 55.31 g of lactose, 22.6 g of pantoprazole sodium, 120 g of mannitol and 180 g of sodium hydrogencarbonate were respectively weighed and mixed. 8 g of hypromellose was dissolved in an aqueous 80% ethanol solution to prepare a binding solution, and the resulting mixture was granulated. After the granules were dried and sized, 15 g of low-substituted hydroxypropylcellulose and 5 g of magnesium stearate were further added thereto, followed by mixing and tabletting to prepare tablets.

Example 15.

A tablet was prepared in the same manner as in Example 14 by using 45 g of magnesium hydroxide instead of sodium hydrogencarbonate as an alkalizing agent.

Example 16.

A tablet was prepared in the same manner as in Example 14, except that 180 g of magnesium hydroxide was used instead of sodium hydrogencarbonate as an alkalizing agent.

Comparative Example 9

Tablets were prepared in the same manner as in Example 14 except that 180 g of microcrystalline cellulose was used instead of sodium hydrogencarbonate as an alkalizing agent.

Comparative Example 10.

Tablets were prepared in the same manner as in Example 14 by using 10 g of sodium hydrogencarbonate instead of 180 g of sodium hydrogencarbonate as an alkalizing agent.

(Two-layer definition)

Example 17.

1.5 g of hypromellose was dissolved in purified water to prepare a binding solution, 45 g of felubipropene and 50 g of lactose were mixed, and the binding solution was added to prepare granules. After drying and sizing the granules, 4 g of low-substituted hydroxypropylcellulose and 1 g of magnesium stearate were added and mixed to prepare a felubiprofen mixture.

6.5 g of hypromellose was dissolved in 80% ethanol aqueous solution to prepare a binding solution. 21.6 g of S omeprazole Mg ₂ H ₂ O, 50.31 g of lactose, 180 g of arginine and 70 g of mannitol were mixed and granulation was performed by adding the binding solution. After drying and sizing the granules, 11 g of low-substituted hydroxypropylcellulose and 4 g of magnesium stearate were added and mixed to prepare an S-omeprazole mixture.

A two-layer tablet was prepared by using the felubiprofen mixture as the first layer and the S-omeprazole mixture as the second layer. At this time, the tablet was tableted using a two-layer tablet press (Sejong Pharmatech, SWTLF-BZ-3).

Example 18.

3 g of hypromellose was dissolved in purified water to prepare a binding solution, 45 g of felubiprofen, 50 g of lactose and 90 g of arginine were mixed, and the binding solution was added to prepare granules. After the granules were dried and sized, 7 g of low-substituted hydroxypropylcellulose and 2 g of magnesium stearate were added and mixed to prepare a felubiprofen mixture.

5 g of hypromellose was dissolved in a 80% aqueous ethanol solution to prepare a binding solution. 21.6 g of S omeprazole Mg ₂ H ₂ O, 50.31 g of lactose, 90 g of arginine and 70 g of mannitol were mixed, and the binding solution was added thereto to prepare granules. After drying and sizing the granules, 8 g of low-substituted hydroxypropylcellulose and 3 g of magnesium stearate were added and mixed to prepare an S-omeprazole mixture.

Example 19.

6.5 g of hypromellose was dissolved in 80% ethanol aqueous solution to prepare a binding solution. 21.6 g of S omeprazole Mg ₂ H ₂ O, 50.31 g of lactose, 180 g of magnesium oxide and 70 g of mannitol were mixed and granulation was performed by adding a binding solution. After drying and sizing the granules, 11 g of low-substituted hydroxypropylcellulose and 1 g of magnesium stearate were added and mixed to prepare an S-omeprazole mixture.

Comparative Example 11.

6.5 g of hypromellose was dissolved in a 80% aqueous ethanol solution to prepare a binding solution. 21.6 g of S omeprazole Mg ₂ H ₂ O, 50.31 g of lactose, 180 g of microcrystalline cellulose and 70 g of mannitol were mixed and the binding solution was added to prepare granules. After drying and sizing the granules, 11 g of low-substituted hydroxypropylcellulose and 4 g of magnesium stearate were added and mixed to prepare an S-omeprazole mixture.

Comparative Example 12.

3 g of hypromellose was dissolved in purified water to prepare a binding solution, 45 g of felubiprofen, 50 g of lactose and 90 g of microcrystalline cellulose were mixed and the binding solution was added to prepare granules. After the granules were dried and sized, 7 g of low-substituted hydroxypropylcellulose and 2 g of magnesium stearate were added and mixed to prepare a felubiprofen mixture.

5 g of hypromellose was dissolved in 80% ethanol aqueous solution to prepare a binding solution. 21.6 g of S omeprazole Mg ₂ H ₂ O, 50.31 g of lactose, 90 g of microcrystalline cellulose and 70 g of mannitol were mixed and granulation was performed by adding a binding solution. After drying and sizing the granules, 8 g of low-substituted hydroxypropylcellulose and 3 g of magnesium stearate were added and mixed to prepare an S-omeprazole mixture.

(Preparation of capsules)

Example 20.

45 g of felubiprofen, 50.31 g of lactose, 21.6 g of S omeprazole Mg ₂ H ₂ O, 120 g of mannitol and 180 g of arginine were respectively weighed and mixed. 8 g of hypromellose was dissolved in an aqueous 80% ethanol solution to prepare a binding solution, and the resulting mixture was granulated. 15 g of low-substituted hydroxypropylcellulose and 5 g of magnesium stearate were further added and mixed, and a No. 1 capsule was filled with a Profiller 1100 filling machine (Torpac, India) to prepare a capsule preparation .

Example 21.

A capsule was prepared in the same manner as in Example 19, except that 180 g of magnesium oxide was used instead of arginine.

Example 22

21.6 g of S-omeprazole Mg ₂ H ₂ O, 180 g of arginine and 6 g of hypromellose were dissolved in an aqueous 80% ethanol solution to prepare a binding solution. After the granules were dried and sized, 10 g of low-substituted hydroxypropylcellulose and 3 g of magnesium stearate were further added and mixed, followed by tableting in the form of four mini tablets to prepare small tablets.

120 g of mannitol, 45 g of felubiprofen and 50.31 g of lactose were respectively weighed and mixed. After 4 g of hypromellose was dissolved in 80% ethanol aqueous solution to prepare a binding solution, an agarose granule was prepared in this mixture. 5 g of low-substituted hydroxypropylcellulose and 2 g of magnesium stearate were added and mixed to prepare a small-size tablet. The two tablets were filled in a No. 1 capsule using a Profiller 1100 filling machine (Torpac, India) To prepare a capsule preparation.

Comparative Example 13.

45 g of felubiprofen, 50.31 g of lactose, 21.6 g of S omeprazole Mg ₂ H ₂ O, 120 g of mannitol and 180 g of microcrystalline cellulose were respectively weighed and mixed. 8 g of hypromellose was dissolved in an aqueous 80% ethanol solution to prepare a binding solution, and the resulting mixture was granulated. 15 g of low-substituted hydroxypropylcellulose and 5 g of magnesium stearate were further added and mixed, and the capsules were filled using a Profiller 1100 filling machine (Torpac, India) to prepare capsules.

Comparative Example 14

180 g of arginine used in Example 21 was replaced with 180 g of microcrystalline cellulose, and the tablets were prepared and filled in the same manner as described above to prepare capsules.

(Preparation of enteric pellets)

Example 23

21.0 g of S-omeprazole Mg 2 H 2 O, 120 g of arginine, 7 g of hypromellose and 5 g of talc were completely dissolved or dispersed using a mixture of purified water and ethanol, and then applied to spherical inert sugar granules fluidized with a fluidized bed coater to obtain pellets . Subsequently, protective coating was carried out using a base (trade name: Opadry) composed of polyvinyl alcohol and the like, and intestinal coating was carried out using a base (trade name: Acrylic Izu) composed of a methacrylic acid polymer.

120 g of mannitol, 45 g of felubiprofen and 50.31 g of lactose were respectively weighed and mixed. To 6 g of hypromellose was dissolved in 80% ethanol aqueous solution to prepare a binding solution, and the resulting mixture was granulated. After the granules were dried and sized, 15 g of the enteric pellets prepared above, low-substituted hydroxypropylcellulose, and 5 g of magnesium stearate were further added, mixed, and tableted to prepare tablets.

Example 24

120 g of mannitol, 45 g of felubiprofen, 50.31 g of lactose, 15 g of low-substituted hydroxypropylcellulose and 5 g of magnesium stearate were weighed and mixed, and a No. 1 capsule was loaded with a Profiller 1100 filling machine (Torpac, India) To prepare a capsule preparation.

Comparative Example 15

Tablets were prepared by the same preparation method using the same amount of microcrystalline cellulose instead of the arginine used in Example 22.

Comparative Example 16

Capsules were prepared by the same preparation method using the same amount of microcrystalline cellulose instead of the arginine used in Example 23.

(Preparation of an enteric preparation)

Example 25

21.6 g of S-omeprazole Mg 2 H 2 O, 120 g of arginine and 7 g of heptromelose were dissolved in an aqueous 80% ethanol solution to prepare a binding solution. After the granules were dried and sized, 6 g of low-substituted hydroxypropylcellulose and 3 g of magnesium stearate were added, and the mixture was tableted to prepare tablets. Subsequently, protective coating was carried out using a base (trade name: Opadry) composed of polyvinyl alcohol and the like, and intestinal coating was carried out using a base (trade name: Acrylic Izu) composed of a methacrylic acid polymer.

120 g of mannitol, 45 g of felubiprofen and 50.21 g of lactose were respectively weighed and mixed. After 5 g of hypromellose was dissolved in 80% ethanol aqueous solution to prepare a binding solution, an agarose granule was prepared in this mixture. After drying and sizing the granules, 10 g of low-substituted hydroxypropylcellulose and 3 g of magnesium stearate were further added and mixed to prepare a press-coated tablet having the above prepared tablet as a core.

Example 26

21.6 g of S-omeprazole Mg 2 H 2 O, 120 g of arginine and 6 g of hypromellose were dissolved in an aqueous 80% ethanol solution to prepare a binding solution. After drying and sizing the granules, 6 g of low-substituted hydroxypropylcellulose and 3 g of magnesium stearate were further added and mixed, followed by tableting in the form of four mini tablets to prepare small tablets.

A protective coating was carried out using a base (trade name: Opadry) composed of polyvinyl alcohol or the like, and enteric coating was carried out using a base material (trade name: Acrylic Iz) consisting of a methacrylic acid polymer.

120 g of mannitol, 45 g of felubiprofen and 50.31 g of lactose were respectively weighed and mixed. After 5 g of hypromellose was dissolved in 80% ethanol aqueous solution to prepare a binding solution, an agarose granule was prepared in this mixture. After the granules were dried and sized, 10 g of low-substituted hydroxypropylcellulose and 3 g of magnesium stearate were added and mixed to prepare a small-size tablet. Two tablets were filled in a No. 1 capsule using a Profiller 1100 filling machine (Torpac, India) To prepare a capsule preparation.

Comparative Example 17

The same procedure was followed to prepare core tablets using the same amounts of microcrystalline cellulose instead of the arginine used in Example 24.

Comparative Example 18

Capsules were prepared by the same preparation method using the same amounts of microcrystalline cellulose instead of the arginine used in Example 25.

Experimental Example 1. Determination of dissolution rate of an oral preparation containing felubiprofen

The following test was carried out to determine the dissolution rate of the felubipropene formulations according to the difference in additives such as alkalizing agents.

The dissolution rate test was carried out according to the dissolution test method 2 (paddle method) in the Korean Pharmacopoeia general test method. After 15 minutes from the start of the experiment, the eluate was taken out, filtered through a 0.45 mu m filter, and analyzed by UV.

division Dissolution rate (%) division Dissolution rate (%) Example 1 85.8 Comparative Example 1 35.4 Example 2 84.4 Comparative Example 2 32.1 Example 3 84.7 Comparative Example 3 37.2 Example 4 82.1 Comparative Example 4 39.6 Example 5 78.4 Comparative Example 5 33.4 Example 6 72.1 Comparative Example 6 41.3 Example 7 81.2 Comparative Example 7 34.2 Example 8 80.3 Comparative Example 8 40.1 Example 9 79.1 Comparative Example 9 37.1 Example 10 84.1 Comparative Example 10 33.1 Example 11 82.3 Comparative Example 11 39.3 Example 12 79.5 Example 13 80.7 Example 14 81.4 Example 15 74.3 Example 16 83.7 Example 17 82.1 Example 19 83.7

As shown in Table 1, when a specific additive such as an alkalizing agent was used under pH 1.2 conditions exhibiting low solubility, felubiprofen showed a high dissolution rate of 70% or more. Therefore, the change of the pH in the body occurs by the specific formulation and the effect of increasing the solubility of felubiprofen was confirmed. There is room for rapid dissolution during the above residence time and an increase in bioavailability.

Experimental Example 2: Stability test of a preparation containing S-omeprazole

The stability tests were conducted on the combination preparations prepared in Examples and Comparative Examples.

Specifically, each of the above-mentioned formulations was packed with 1 g of silica gel in an HDPE bottle and stored at 50 ° C and 85% RH. After 3 months under the above conditions was measured for representative degradation products of the content of flexible material C of the S-omeprazole Mg2H ₂ O as a liquid chromatograph.

Accelerated conditions S-omeprazole soft substance C after storage division Alkalizing agent Flexible Substance (%) The rate of increase of the flexible substance C Early 3 months Example 1 Arginine 0.11 0.14 27.3% Example 2 Ca (OH) ₂ 0.10 0.12 20.0% Example 3 NaH ₂ PO ₄ 0.09 0.11 22.2% Example 4 MgO 0.11 0.14 27.3% Example 17 Arginine 0.08 0.10 25.0% Example 19 MgO 0.09 0.12 33.3% Example 20 Arginine 0.12 0.17 41.6% Example 21 MgO 0.13 0.18 38.4% Example 22 Arginine 0.08 0.12 50.0% Example 23 Arginine 0.09 0.11 22.2% Example 24 Arginine 0.09 0.13 44.4% Example 25 Arginine 0.11 0.14 27.3% Example 26 Arginine 0.12 0.18 50.0% Comparative Example 1 - 0.12 1.21 908.3% Comparative Example 2 - 0.11 0.68 518.2% Comparative Example 11 - 0.09 1.15 1177.7% Comparative Example 13 - 0.13 1.24 853.8% Comparative Example 14 0.12 1.11 825.0%

As shown in Table 2, it was confirmed that the combination preparation of the example to which the alkalizing agent was added exhibited excellent stability because the rate of increase of the flexible substance C of S-omeprazole was smaller than that of the comparative example in which the alkalizing agent was not added.

Experimental Example 3: Stability test of preparations containing rabeprazole, omeprazole, lansoprazole, and pantoprazole

Specifically, each of the above-mentioned formulations was packed with 1 g of silica gel in an HDPE bottle and stored at 50 ° C and 85% RH. After 3 months of the above conditions, the content of total flexible substances of PPIs rabeprazole, omeprazole, lansoprazole and pantoprazole was measured by liquid chromatogram.

Accelerated conditions Total preservatives of rabeprazole, omeprazole, lansoprazole, and pantoprazole after storage division Proton pump
Inhibitor Alkalizing agent Flexible Substance (%) Growth rate of total flexible materials Early 3 months Example 5 Rabeprazole MgCO ₃ 0.08 0.11 37.5% Example 6 Meglumine 0.11 0.16 54.5% Example 7 Meglumine 0.10 0.14 40.0% Comparative Example 3 - 0.11 0.89 709.1% Comparative Example 4 MgCO ₃ 0.09 0.41 355.5% Example 8 Omeprazole NaH ₂ PO ₄ 0.09 0.12 33.3% Example 9 CaCO ₃ 0.12 0.19 58.3% Example 10 CaCO ₃ 0.13 0.16 23.1% Comparative Example 5 - 0.12 0.79 558.3% Comparative Example 6 NaH ₂ PO ₄ 0.11 0.42 281.8% Example 11 Lansoprazole Mg (OH) ₂ 0.09 0.12 33.3% Example 12 Calcium silicate 0.11 0.16 54.5% Example 13 Calcium silicate 0.12 0.16 33.3% Comparative Example 7 - 0.10 0.93 830.0% Comparative Example 8 Mg (OH) ₂ 0.08 0.45 462.5% Example 14 Pantoprazole NaHCO ₃ 0.08 0.10 25.0% Example 15 Mg (OH) ₂ 0.12 0.19 58.3% Example 16 Mg (OH) ₂ 0.13 0.17 30.7% Comparative Example 9 - 0.11 0.87 690.9% Comparative Example 10 NaHCO ₃ 0.10 0.44 340.0%

As shown in Table 2 and Table 3, it was found that the combination agent of the example in which the alkalizing agent was added did not add the alkalizing agent or added less than 1 part by weight of the proton pump inhibitor, Respectively.

Claims

A pharmaceutical composition comprising a non-steroidal anti-inflammatory drug (NSAID), felubiprofen, and a proton pump inhibitor (PPI) or a pharmaceutically acceptable salt thereof, wherein the composition comprises an alkalizing agent as an additive.

3. The composition of claim 1, wherein the proton pump inhibitor is selected from the group consisting of Esomeprazole, Dexlansoprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole, Ilaprazole, ), Tenatoprzole, Leminoprazole, Nepaprazole, a pharmaceutically acceptable salt thereof, a precursor and mixtures thereof. The pharmaceutical composition according to claim 1, .

The method of claim 1, wherein the alkalizing agent is selected from the group consisting of calcium hydroxide, ethanolamine, potassium hydrogen carbonate, potassium citrate, sodium hydrogen carbonate, sodium hydroxide citrate, sodium hydroxide, calcium silicate, arginine, magnesium oxide, calcium carbonate, Wherein the medicament is selected from the group consisting of calcium phosphate, sodium dihydrogenphosphate, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminum hydroxide, sodium borate, meglumine, pharmaceutically acceptable salts thereof and mixtures thereof Gt;

The pharmaceutical composition according to claim 1, wherein the formulation of the pharmaceutical composition is tablets.

The composition of claim 1, wherein the formulation of the pharmaceutical composition is a capsule.

5. The formulation of claim 4, wherein the tablet is a single tablet comprising both a non-steroidal anti-inflammatory drug, felubiprofen, a proton pump inhibitor, and an alkalizing agent as an additive.

5. The formulation of claim 4, wherein the tablet comprises a compartment containing felubipropene, a non-steroidal anti-inflammatory drug, and a compartment containing a proton pump inhibitor and an alkalizing agent as an additive.

The capsule preparation according to claim 4, comprising a small tablet containing a non-steroidal anti-inflammatory drug, pelubiprofen, and a separate small tablet containing a proton pump inhibitor and an alkalizing agent.