KR20150044670A - Controlled-release pharmaceutical composition of propionic acid derivatives - Google Patents

Abstract

In the present invention, provided is a pharmaceutical composition including pelubiprofen and a controlled release polymer wherein the controlled release polymer is a non-aqueous polymer. In the present invention, provided is a novel sustained-release preparation for releasing pelubiprofen slowly and for reducing side effects in gastro-intestinal tract.

Description

TECHNICAL FIELD [0001] The present invention relates to a controlled-release pharmaceutical composition comprising a propionic acid-based pharmaceutical composition,

The present invention relates to a pharmaceutical composition comprising a propionic acid-based non-steroidal anti-inflammatory analgesic agent, and more particularly to a pharmaceutical composition of controlled-release propionic acid-based pharmaceutical composition. More particularly, the present invention relates to a pharmaceutical composition comprising a propionic acid-based drug such as felubipropene and a release-controlling polymer, and more particularly, to a pharmaceutical composition comprising a water-insoluble polymer as a release-controlling polymer.

(±) - (E) -2- [4- (2- (Oxo-cyclohexylidenemethyl) -phenyl] propionic acid is a non-steroidal analgesic and antiinflammatory agent (NSAIDs)

This substance exhibits pharmacological activity for treating various kinds of diseases such as osteoarthritis, rheumatoid arthritis, musculoskeletal pain, post-operative sequelae, back pain, toothache, etc. Japanese Patent Application No. 1167548 and Japanese Patent No. 1637767 Japanese Patent Application No. 1984-142567). Pelubiprofen is a drug of prodrug type that is converted into a drug-effective substance by liver metabolism. It has a pharmacological mechanism of inhibiting the production of prostaglandin by inhibiting COX-2, which is a kind of cyclooxygenase, Compared to celecoxib, it is known to have equivalent or better pain relief.

As a pharmaceutical preparation containing felubipropene, there is Korean Patent No. 922519 previously filed by the present applicant, which contains felubipropene having an average particle diameter of 1 to 30 탆 as an active ingredient , Lactose, and the like, which are improved in dissolution rate and stability, for oral administration.

The above formulation is based on three doses per day, because felubiprofen is a short half-life drug, and it is necessary to take several doses per day to effectively control the pain.

However, in the case of NSAIDs such as felubiprofen, the compliance with medication is low when taken several times a day, and the incidence of gastrointestinal side effects is increased by increasing the frequency of exposure of the drug to the gastrointestinal tract.

Therefore, if it is possible to reduce the frequency of administration as a pharmaceutical formulation containing felubiprofen as an active ingredient, it is expected that ease of taking and convenience of gastrointestinal side effects will be reduced, .

Korean Patent Laid-Open Publication No. 2008-39400 discloses a sustained-release pharmaceutical composition of a water-soluble drug containing an active ingredient having a short half-life and a hydrophilic polymer.

Korean Patent Registration No. 167078 discloses a sustained-release oral formulation containing ibuprofen or the like as an active ingredient, which comprises a plurality of drug particles dispersed in a hydrophilic, water-swellable polymer.

However, the sustained-release formulation disclosed so far focuses only on delaying the release of the drug from the formulation, not the reduction of gastrointestinal side effects of felubiprofen.

Japanese Patent No. 1167548 Japanese Patent No. 1637767 Korean Patent No. 922519 Korean Patent No. 167078

Disclosure of the Invention The present invention provides a novel sustained-release preparation capable of reducing the side effects of gastrointestinal tract while releasing the release of feluviprofen.

More specifically, in order to prevent the occurrence of side effects of gastrointestinal tract caused by felubiprofen eluted from the stomach when the formulation containing felviropene is simply solubilized, the dissolution rate in the gastrointestinal tract is extremely small, And to provide a novel sustained release preparation which maximizes the dissolution rate.

To solve this problem, the following means are provided.

In a pharmaceutical composition comprising felubipropene and a release-controlling polymer, the pharmaceutical composition is characterized in that the release-controlling polymer is a water-insoluble polymer.

In the pharmaceutical composition, the pharmaceutical composition is characterized in that the composition is eluted at less than 30% for 2 hours in the gastric region (pH 1.2 eluate).

In the pharmaceutical composition, the pharmaceutical composition is characterized in that at least 50% of the composition is eluted in the small area (pH 6.8 eluate) for 2 hours.

In the pharmaceutical composition, the water-insoluble polymer may be selected from the group consisting of cellulose derivatives such as carbomer, carboxymethylcellulose calcium, cellulose acetate phthalate, methylcellulose, hydroxypropylmethylcellulose phthalate, microcrystalline lead, white lead, carnauba lead, And a wax such as lead, a methacrylate copolymer, ethylcellulose, polyvinylacetate, collidol esal, and mixtures thereof.

According to the present invention, by taking pelubiprofen twice a day, it is possible to exhibit analgesic effect for 24 hours. By reducing the number of drug administration, it is possible to provide the patient with ease of use, thereby increasing the therapeutic effect and improving the gastrointestinal side effect .

FIG. 1 is a graph showing an elution pattern according to a ratio of collidon-Sart. FIG.
2 is a graph showing the pH 1.2 elution pattern of Example 1 and Comparative Examples 3 and 4. FIG.
FIG. 3 is a graph showing the pH 6.8 elution patterns of Example 1 and Comparative Examples 3 and 4. FIG.
4 is a graph showing the results of animal experiments of Example 1 and conventional feluviprofen formulations.

It is difficult to provide a sustained release oral dosage form of a drug that has the potential to develop short half-life and gastrointestinal side effects. If you have a short half-life, the drug can only remain in the blood for a short time, so activity lasts only in a short time. For such drugs, multiple daily prescriptions (three, four or five or more times daily) may be required to maintain a constant drug concentration in the blood above the effective concentration.

Multiple daily doses are inconvenient, and patient compliance is very low. Thus, a slow-release dosage form that allows a reduced dosage frequency, such as twice daily, would be more desirable.

In addition, for drugs that are capable of manifesting gastrointestinal side effects, it is of course advantageous to reduce drug elution in the gastrointestinal tract and promote release over extended periods of time in the small intestine. In particular, in the case of NSAIDs, sustained release of the drug in the gastrointestinal tract should be avoided in that it increases the risk of side effects.

Since felubiprofen has a half-life of less than 6 hours, multiple administrations per day are necessary to effectively control pain. Therefore, in order to prevent the occurrence of gastrointestinal side effects, it is necessary to suppress the drug release in the gastrointestinal region as far as possible and to continuously release the drug in the small intestine region do.

Conventional conventional sustained release means utilize a technique that, when contacted with body fluids, forms a gel layer to extend the erosion of the formulation and slow the diffusion of the drug.

Typical sustained release ingredients are usually selected from water-soluble polymers such as hydrogels, such as cellulose polymers, or polyethylene oxide or methacrylate polymers.

However, in the case of felubipropene, when a sustained release material selected from conventional water-soluble polymers is used, elution of the drug in the gastrointestinal area becomes active, so that it is not preferable to use such conventional water-soluble polymers.

The inventors of the present invention have conducted intensive studies on a sustained-release pharmaceutical composition containing felubipropene. As a result, it has been surprisingly found that when the felubiprofen and the release-controlling polymer include a water-insoluble polymer, And that it is possible to achieve continuous standing emission in the small intestine area, thus completing the present invention.

Specifically, the present invention provides a pharmaceutical composition comprising felubipropene and a release-controlling polymer, wherein the release-controlling polymer is a water-insoluble polymer.

Examples of the water-insoluble polymer include cellulose derivatives such as carbomer, carboxymethylcellulose calcium, cellulose acetate phthalate, methylcellulose and hydroxypropylmethylcellulose phthalate, waxes such as microcrystalline lead, white lead, carnauba wax, Methacrylate copolymers, ethylcellulose, polyvinylacetate, collidol esal, and mixtures thereof. Particularly, the preferred water-insoluble polymer is collidol es.

When such a water-insoluble polymer is used as a release-controlling polymer, the dissolution rate in the gastric region for 2 hours is less than 30%. This means that the release of felubiprofen in the gastrointestinal tract is extremely limited. In the case of using conventional sustained release materials, a large amount of felubiprofen is released in the gastric region, . In particular, it is surprising that the release of drug in the gastrointestinal tract is inhibited by the combination of felubipropene and the water-insoluble polymer because, in the case of other active ingredients belonging to NSAIDs, for example, And the combination of the non-water-soluble polymer and the ropenes does not lower the drug release in the gastric region. That is, it is presumed that the combination of the water-insoluble polymer and the non-water-soluble polymer causes the lowering of drug release in the gastrointestinal region, thereby lowering the expression of gastrointestinal side effects, which is a unique characteristic achieved by the combination of felubipropene and the water-insoluble polymer.

In the present invention, when the water-insoluble polymer is used as a release-controlling polymer, the dissolution rate in the small intestine region for 2 hours is 50% or more. This means that felubiprofen is continuously released in the small intestine area, thus indicating that it is possible to achieve a release pattern that demonstrates the efficacy of the drug while reducing the number of administrations.

In the present invention, the drug release in the gastrointestinal region and the small intestine is based on the pH 1.2 eluate and the pH 6.8 eluate.

On the other hand, the content of the water-insoluble polymer may be 5 wt% to 50 wt% based on the total weight of the composition, and the content of felubipropene may be 10 wt% to 50 wt% based on the total weight of the composition.

The pharmaceutical composition of the present invention may be prepared by mixing the feluviprofen, the excipient and the binder, combining the mixture with an appropriate solvent, drying and forming the granules to prepare tablet granules or granules for filling, Or a pharmaceutically acceptable salt thereof. Alternatively, other assembly methods commonly known in the art may be used.

Examples of the excipient include lactose, calcium hydrogen phosphate, starch and polyol, and as the polyol, mannitol, isomalt and xylitol can be used; As the binding agent, hydroxypropyl cellulose and polysaccharide can be used, and as the polysaccharide, xanthan gum and carrageenan can be used; Examples of the disintegrant include carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, and starch; Magnesium stearate and talc may be used as the lubricant.

The content of the additives may be suitably used by those skilled in the art according to a specific prescription. The content of the additives may be 10 to 50 wt%, binder 1 to 25 wt%, disintegrant 1 to 25 wt%, lubricant 1 to 10 wt% %. ≪ / RTI >

The form of the pharmaceutical preparation for oral administration according to the present invention may be most preferably a tablet from the viewpoint of patient convenience. However, other suitable preparations such as powders, capsules, granules, syrups and the like can also be used, and they can be manufactured into various oral dosage forms by conventional methods.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, it should be understood that the following examples are provided for a better understanding of the present invention, and are not to be construed as limiting the technical scope of the present invention.

Example

Example 1: Preparation of sustained release agent using collidon sial

90 g of felubiprofen, 90 g of lactose hydrate, and 4.6 g of hydroxypropylcellulose were mixed and then mixed with water. The mixture was dried at 60 캜 until the loss on drying became 2.0% or less, and the mixture was sized using a 20-mesh sieve. 25.0 g of colloid SAL and 4.6 g of magnesium stearate were added to the sizing product, mixed and then compressed.

Example 2 Preparation of sustained release agent using ethylcellulose

90 g of felubiprofen, 90 g of lactose hydrate, and 4.6 g of hydroxypropylcellulose were mixed and then mixed with water. The mixture was dried at 60 캜 until the loss on drying became 2.0% or less, and the mixture was sized using a 20-mesh sieve. To the sieved product, 25.0 g of ethylcellulose and 4.6 g of magnesium stearate were added and mixed, followed by compression.

Example 3: Preparation of sustained release agent using ydrazyl sulphate

90 g of felubiprofen, 90 g of lactose hydrate, 4.6 g of hydroxypropylcellulose, and 25.0 g of yuduragials were mixed and mixed with ethanol and dried at 60 캜 until the weight loss on drying became 2.0% or less, Respectively. 4.6 g of magnesium stearate was added to the sizing product, mixed and then compressed.

Example 4: Preparation of sustained release agent using hypromellose phthalate

90 g of felubiprofen, 90 g of lactose hydrate, and 4.6 g of hydroxypropylcellulose were mixed and then mixed with water. The mixture was dried at 60 캜 until the loss on drying became 2.0% or less, and the mixture was sized using a 20-mesh sieve. 25.0 g of hypromellose phthalate and 4.6 g of magnesium stearate were added to the sizing product, followed by mixing and tableting.

Example 5: Preparation of a sustained-release agent using acrylate

90 g of felubiprofen, 90 g of lactose hydrate, and 4.6 g of hydroxypropylcellulose were mixed and then mixed with water. The mixture was dried at 60 캜 until the loss on drying became 2.0% or less, and the mixture was sized using a 20-mesh sieve. 25.0 g of acrylic iz and 4.6 g of magnesium stearate were added to the sieved product, mixed and then compressed.

Example 6. Preparation of sustained release agent using carbomer

90 g of felubiprofen, 90 g of lactose hydrate, and 4.6 g of hydroxypropylcellulose were mixed and then mixed with water. The mixture was dried at 60 캜 until the loss on drying became 2.0% or less, and the mixture was sized using a 20-mesh sieve. To the sieved product, 25.0 g of carbomer and 4.6 g of magnesium stearate were added and mixed, followed by compression.

Example 7. Preparation of sustained release agent using polyvinyl acetate

90 g of felubiprofen, 90 g of lactose hydrate, and 4.6 g of hydroxypropylcellulose were mixed and then mixed with water. The mixture was dried at 60 캜 until the loss on drying became 2.0% or less, and the mixture was sized using a 20-mesh sieve. This sizing product was combined with a suspension in which 25.0 g of polyvinyl acetate was dispersed, dried at 60 DEG C until the weight loss on drying became 2.0% or less, and the mixture was sized using a 20 mesh sieve, and 4.6 g of magnesium stearate was added and mixed Respectively.

Example 8. Preparation of sustained release agent according to the ratio of collidon-sial

90 g of felubiprofen, 90 g of lactose hydrate, and 4.6 g of hydroxypropylcellulose were mixed and then mixed with water. The mixture was dried at 60 캜 until the loss on drying became 2.0% or less, and the mixture was sized using a 20-mesh sieve. 10.0 g of colloid sart and 4.6 g of magnesium stearate were added to the sizing product, mixed and then compressed.

Example 9. Preparation of sustained release agent according to the ratio of collidon-sial

90 g of felubiprofen, 90 g of lactose hydrate, and 4.6 g of hydroxypropylcellulose were mixed and then mixed with water. The mixture was dried at 60 캜 until the loss on drying became 2.0% or less, and the mixture was sized using a 20-mesh sieve. 40.0 g of colloid sial and 4.6 g of magnesium stearate were added to the sizing product, mixed and then compressed.

Example 10: Preparation of sustained release agent according to the ratio of collidon-sial

90 g of felubiprofen, 90 g of lactose hydrate, and 4.6 g of hydroxypropylcellulose were mixed and then mixed with water. The mixture was dried at 60 캜 until the loss on drying became 2.0% or less, and the mixture was sized using a 20-mesh sieve. To the sizing product, 65.0 g of colidone esal and 4.6 g of magnesium stearate were added and mixed, followed by compression.

Comparative Example 1. Preparation of a sustained-release preparation using hypromellose

90 g of felubiprofen, 90 g of lactose hydrate, and 4.6 g of hydroxypropylcellulose were mixed and then mixed with water. The mixture was dried at 60 캜 until the loss on drying became 2.0% or less, and the mixture was sized using a 20-mesh sieve. 25.0 g of hypromellose and 4.6 g of magnesium stearate were added to the sizing product, followed by mixing and tableting.

Comparative Example 2: Preparation of sustained release agent using hydroxypropylcellulose

90 g of felubiprofen, 90 g of lactose hydrate, and 4.6 g of hydroxypropylcellulose were mixed and then mixed with water. The mixture was dried at 60 캜 until the loss on drying became 2.0% or less, and the mixture was sized using a 20-mesh sieve. To the sieved product, 25.0 g of hydroxypropylcellulose and 4.6 g of magnesium stearate were added and mixed, followed by tableting.

Comparative Example 3: Preparation of sustained release agent using sodium losoprofen sodium

After mixing 90 g of sodium loxoprofen, 90 g of lactose hydrate and 4.6 g of hydroxypropylcellulose, the mixture was combined with water, dried at 60 캜 until a drying loss of 2.0% or less was obtained, and the mixture was sized using a 20-mesh sieve. 25.0 g of colloid SAL and 4.6 g of magnesium stearate were added to the sizing product, mixed and then compressed.

Comparative Example 4. Preparation of a sustained-release preparation using keto-propene

90 g of ketoprofen, 90 g of lactose hydrate, and 4.6 g of hydroxypropylcellulose were mixed and then mixed with water. The mixture was dried at 60 DEG C until the weight loss on drying became 2.0% or less, and the mixture was sized using a 20 mesh sieve. 25.0 g of colloid SAL and 4.6 g of magnesium stearate were added to the sizing product, mixed and then compressed.

Experimental Example 1. Experimental study on the dissolution rate of felubipropene in the stomach area according to the polymer

The dissolution rate (%) in the pH 1.2 eluate was examined in order to evaluate the difference in drug release in the gastric region when the non-water-soluble polymer and the water-soluble polymer were used in the sustained release of felubiprofen. The tablets prepared in Examples 1 to 6 and the tablets prepared in Comparative Examples 1 and 2 were subjected to the following experiment.

The dissolution rate test was carried out according to the dissolution test method 1 (rotation specimen method) in the General Practice of the Korean Pharmacopoeia. Specifically, the eluate was eluted with 900 ml (pH 1.2 solution) and the temperature was 37 ± 0.5 ° C. After 1 hour and 2 hours from the start of the experiment, the eluate was taken out, filtered through a 0.45 mu m filter, and analyzed by UV. The results are shown in Table 1 (unit:%)

time 1 hours 2 hours Example 1 5.0 8.9 Example 2 2.3 5.1 Example 3 0.7 1.2 Example 4 1.7 2.4 Example 5 0.8 15.1 Example 6 15.1 25.3 Example 7 2.1 4.6 Comparative Example 1 30.2 56.0 Comparative Example 2 43.4 62.0

From the above experiments, it can be seen that the release of the drug in the gastrointestinal region is extremely limited when the felubiprofen is solubilized using the water-insoluble polymer.

Experimental Example 2. Elution rate of felubipropene in small intestine by polymer

The dissolution rate (%) in the pH 6.8 eluate was examined in order to evaluate the difference in drug release in the small intestine when felubiprofen was solubilized using a water-insoluble polymer and a water-soluble polymer. The tablets prepared in Examples 1 to 6 and the tablets prepared in Comparative Examples 1 and 2 were subjected to the following experiment.

The dissolution rate test was carried out according to the dissolution test method 1 (rotation specimen method) in the General Practice of the Korean Pharmacopoeia. Specifically, the eluate was eluted with 900 ml (pH 6.8) and the temperature was 37 ± 0.5 ° C. After 1 hour and 2 hours from the start of the experiment, the eluate was taken out, filtered through a 0.45 mu m filter, and analyzed by UV. The results are shown in Table 2. (Unit:%)

time 1 hours 2 hours 4 hours Example 1 39.7 88.7 95.5 Example 2 24.1 60.4 80.4 Example 3 19.5 55.1 70.5 Example 4 74.8 99.8 99.2 Example 5 89.3 94.3 95.4 Example 6 15.3 53.9 75.8 Example 7 36.9 75.4 95.1 Comparative Example 1 33.9 60.8 83.0 Comparative Example 2 34.6 61.2 81.2

From the above experiments, it can be seen that drug releasing is continuously maintained in the small intestine region when felubiprofen is released by using a water-insoluble polymer.

Experimental Example 3: Elution rate test of felubipropene according to the ratio of collidon-sial

The dissolution rate (%) of pH 6.8 was examined in order to examine the release pattern of the sustained release composition of felubiprofen in the small intestine region according to the ratio of collidon-sial.

The following experiments were conducted with the tablets prepared in Examples 1 and 7 to 9.

The dissolution rate test was carried out according to the dissolution test method 1 (rotation specimen method) in the General Practice of the Korean Pharmacopoeia. Specifically, the eluate was eluted with 900 ml (pH 6.8) and the temperature was 37 ± 0.5 ° C. After 1 hour, 2 hours and 4 hours from the start of the experiment, the eluate was taken out, filtered through a 0.45 mu m filter, and analyzed by UV. The results are shown in Table 3 and Fig.

time 1 hours 2 hours 4 hours Example 8 71.5 96.4 98.1 Example 1 39.7 88.7 95.5 Example 9 35.2 70.7 94.5 Example 10 27.5 54.1 80.3

Experimental Example 4: Elution rate test according to NSAIDs

In order to evaluate the dissolution rate in the gastrointestinal region and the small intestinal region of Example 1 and Comparative Examples 3 and 4, the dissolution rate (%) in the pH 1.2 and pH 6.8 eluate was examined.

The dissolution rate test was carried out according to the dissolution test method 1 (rotation specimen method) in the General Practice of the Korean Pharmacopoeia. Specifically, the eluate was eluted with 900 ml (pH 1.2 solution and pH 6.8 solution), the temperature was 37 ± 0.5 ° C, and the rotation speed of the paddle was 100 rpm. The eluate of 1 hour, 2 hours and 4 hours after the start of the experiment was taken out and filtered with a 0.45 mu m filter and analyzed by UV. The results are shown in Table 4 and Figs. 2 and 3. (Unit:%)

pH 1.2 pH 6.8 time 1 hours 2 hours 1 hours 2 hours 4 hours Example 1 5.0 8.9 39.7 88.7 95.5 Comparative Example 3 55.1 72.1 73.5 93.7 99.8 Comparative Example 4 65.8 77.9 64.4 85.6 94.5

From the above experiments, it can be seen that the combination of felubipropene and the water-insoluble polymer inhibits drug release in the gastrointestinal tract. In the case of other active ingredients belonging to NSAIDs, for example, ketoprofen or loxoprofen, It can be seen that the drug release in the gastric region does not decrease even when combined with the water-soluble polymer.

Experimental Example 5. Experimental study on the dissolution rate of commercially available felubyil and felubiprofen controlled release preparations in the gastrointestinal tract

In order to evaluate the dissolution rate in commercially available Pelubic beads and the gastric region of Example 1, the elution amount (mg) in the pH 1.2 eluate was tested.

The dissolution rate test was carried out according to the dissolution test method 1 (rotation specimen method) in the General Practice of the Korean Pharmacopoeia. Specifically, the eluate was eluted with 900 ml (pH 1.2 solution) and the temperature was 37 ± 0.5 ° C. The eluate after 0.5 hour, 1 hour and 2 hours from the start of the experiment was filtered with a 0.45 mu m filter and analyzed by UV. The results are shown in Table 5. (Unit mg)

time 0.5 hours 1 hours 2 hours Felubi jung 27.3 28.6 29.8 Example 1 1.5 2.3 4.0

From the above experiments, it can be seen that when the felubiprofen is solubilized by using a water-insoluble polymer, the exposure of the drug to the gastrointestinal area is reduced by about 7.5 times as compared with the commercially available feluvic tablets.

From these experiments it can be seen that the release of the drug in the gastrointestinal tract is limited and the release in the small intestine area is continuous when the felubiprofen is released into the water-insoluble polymer, thus minimizing the manifestation of gastrointestinal side effects It can be seen that the control of pain can be efficiently controlled by administration twice a day at the same time as the administration.

Experimental Example 6. Animal Test Results (Beagle)

As a result of pharmacokinetics of Pelubicus and Peluvicus serotypes, the AUC of the Peluvicus serotypes administered 30mg / day and 45mg / twice / day was 2470 and 2515μg / L · hr, respectively, (Figure 4).

Claims (4)

A pharmaceutical composition comprising felubipropene and a release-controlling polymer, wherein the release-controlling polymer is a water-insoluble polymer. 2. The pharmaceutical composition according to claim 1, wherein the composition is eluted at less than 30% for 2 hours in the gastric region (pH 1.2 eluate). The pharmaceutical composition according to claim 2, wherein the composition is eluted by 50% or more in a small area (pH 6.8 eluate) for 2 hours. The nonaqueous electrolyte secondary battery according to claim 2 or 3, wherein the water-insoluble polymer is selected from the group consisting of cellulose derivatives selected from carbomer, carboxymethylcellulose calcium, cellulose acetate phthalate, methylcellulose, hydroxypropylmethylcellulose phthalate, microcrystalline lead, , Waxes selected from waxes and emulsified waxes, methacrylate copolymers, ethylcellulose, polyvinylacetate, colidon sial, and mixtures thereof.

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