WO2016137266A2 - Pharmaceutical composition containing eperisone and pelubiprofen - Google Patents

Abstract

Disclosed is a pharmaceutical composition containing pelubiprofen, eperisone, and a water insoluble polymer.

Description

Pharmaceutical Compositions Containing Eperisone and Felubiprofen

The present invention relates to a pharmaceutical composition containing eferison and pelubiprofen. More specifically, the present invention relates to a formulation characterized in that the release pattern of pelubiprofen and the release pattern of eferison are different from each other. Furthermore, the present invention relates to a pharmaceutical composition characterized by slowing the release of pelubiprofen, inhibiting elution in the gastrointestinal tract, and causing major elution in the small intestine.

Pelubiprofen is a nonsteroidal anti-inflammatory drug (NSAID) developed by the applicant as the 12th domestic new drug and is a drug used for pain treatment. Pelubiprofen is a cyclogenase inhibitor and is used for the treatment of osteoarthritis, rheumatoid arthritis, low back pain and the like.

Eperisone acts as a relaxant in musculoskeletal smooth muscle and vascular smooth muscle, and is used to treat painful muscular spasms associated with musculoskeletal disorders and spastic paralysis caused by neurological diseases.

In general, it is known that the treatment effect can be increased by co-administering drugs having different mechanisms when treating pain, and in fact, many of these combination prescriptions are made. Since most NSAIDs and epherisons are released as single drugs, patients have to take two drugs at the same time. Therefore, the combination needs to be developed in terms of convenience.

Drugs and muscle relaxants of the NSAID family are currently available in the form of immediate release. Eperisone is taken three times a day, and most NSAID drugs are taken several times a day.

In general, immediate release drugs are to be taken several times a day, so the fluctuation of drug concentration in the blood is large, so there is a high possibility of side effects. In addition, the immediate release agent is low in the ease of taking the medication compliance of the patient is lowered, thereby reducing the effect of the drug because the blood drug concentration does not maintain the treatment area. Therefore, the use of such immediate release preparation causes problems such as an increase in the therapeutic effect and duration of treatment, and efforts have been made to develop the immediate release preparation as a controlled release preparation.

In particular, in the case of NSAID drugs, the frequency of exposure in the gastrointestinal tract is increased by taking several times a day, thereby increasing the incidence of gastrointestinal side effects. In order to improve the gastrointestinal side effects, attempts have been made to prepare NSAID drugs as enteric preparations to reduce gastric exposure and to be administered with NSAIDs and gastritis treatments, and controlled release agents that reduce the daily dose. ought.

Korean Laid-Open Patent Publication No. 2014-0118412 discloses a sustained-release preparation composition containing eferison as an active ingredient, wherein the eferison pharmaceutical composition having storage and pH stability is 50 to 90% by weight; 1-20% by weight of hydroxypropylmethylcellulose (HPMC) as a release controlling agent; And a sustained release formulation composition containing epheryson as an active ingredient comprising 5 to 45% by weight of controlled release polymer. In addition, Korean Laid-Open Patent Publication No. 2012-52080 relates to an epherizone-containing sustained-release tablet and a method for preparing the same, wherein the eperison includes polyvinylacetate, vinylpyrrolidone-vinylacetate copolymer, and hydroxypropylmethylcellulose. Compositions in sustained-release form are disclosed. However, the formulations disclosed in the preceding patent literature, on the basis of the known fact that epherisone is unstable in the alkaline region, lower the ambient pH environment of epherisone in the formulation (e.g. 5.6 or less), and therefore, it does not relate to a technique for preferably expressing the dissolution pattern of eferison. In particular, in combination formulations comprising eferison and pelubiprofen, it is important that the release of eferison from the formulation is mostly in the gastrointestinal tract, but no prior formulations have been disclosed.

In addition, as a pharmaceutical preparation containing felubiprofen, Korean Patent Publication No. 922519, which was previously filed by the present applicant, includes felrubiprofen having an average particle diameter of 1 to 30 μm as an active ingredient. A pharmaceutical preparation for oral administration for anti-inflammatory analgesics, which has a dissolution rate and stability, containing an excipient such as lactose and the like, is improved.

The above formulations are based on three doses per day, because pelubiprofen is a drug with a short half-life, so it needs to be taken several times a day to effectively control pain. However, NSAIDs such as pelubiprofen have low medication compliance when taken several times a day and increase the frequency of drug exposure to the gastrointestinal tract, thereby increasing the incidence of gastrointestinal side effects. Therefore, if the number of doses can be reduced as a pharmaceutical formulation containing pelubiprofen as an active ingredient, it is expected that the ease of taking and the side effects of the gastrointestinal tract will be reduced. .

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

Korean Patent Publication No. 167078 discloses a sustained release oral dosage form comprising ibuprofen and the like as an active ingredient, comprising a plurality of drug particles dispersed in a hydrophilic, water-swellable polymer.

However, the sustained release formulations disclosed so far have merely focused on delaying the release of the drug from the formulation and have not been in mind with the reduction of gastrointestinal side effects of pelubiprofen.

That is, a novel combination of pelubiprofen and eperison to reduce the gastrointestinal side effects of pelubiprofen to achieve an effective release pattern to achieve sustained release, and to make the release of eferison most in the gastrointestinal tract No bar

The present invention provides a novel sustained-release formulation for reducing the gastrointestinal side effects while slowing the release of felubiprofen in a novel pharmaceutical formulation comprising felubiprofen and eperison. do.

More specifically, in the novel pharmaceutical preparations containing pelubiprofen and eperison, when the sustained release of the dosage form containing pelubiprofen, the gastrointestinal side effects due to pelubiprofen eluted from the stomach are It is a problem to provide a novel sustained-release preparation which maximizes the dissolution rate of pelubiprofen in the small intestine while minimizing the dissolution rate of pelubiprofen in the gastrointestinal tract.

Furthermore, in a novel pharmaceutical formulation comprising pelubiprofen and epherisone, it is a challenge to provide a novel sustained release formulation, wherein the release of eperison is mostly in the gastrointestinal tract.

According to the present invention, the administration of pelubiprofen and epherisone once or twice a day can have an analgesic effect for 12 hours or 24 hours, and the treatment is provided by providing the ease of administration to the patient by reducing the frequency of drug administration. Increasing effectiveness and reducing gastrointestinal side effects.

In the present invention, by developing a combination of controlled release of pelubiprofen and epherisone, it is expected to improve the ease of taking, increase the therapeutic effect and reduce the duration of treatment, and also minimize the side effects such as gastrointestinal side effects I would like to.

One aspect of the present invention may be a double tablet consisting of a first layer containing felubipropene and a second layer containing eferison, but is not limited thereto, and may be embodied in conventional formulations such as nuclear tablets or capsules. have.

The preparation of the present invention contains pelubiprofen and epherisone as active ingredients, and the following characteristics exist in formulating and sustaining-release each of these active ingredients.

First, with respect to felubiprofen, since felrubiprofen has a half-life within 6 hours, a plurality of daily administrations are necessary to effectively control pain. Therefore, sustained release of pelubiprofen is advantageous in terms of dose compliance, but in order to prevent gastrointestinal side effects, it is additionally required to suppress drug release in the gastrointestinal tract and to continue drug release in the small intestine region as much as possible. do.

Conventional sustained release means used in the prior art utilizes the technical idea of forming a gel layer to prolong the erosion of the formulation and slow the diffusion of the drug when the formulation is in contact with body fluids, generally a hydrogel such as a cellulose polymer or It is usually selected from water soluble polymers such as polyethylene oxide or methacrylate polymers.

However, in the case of pelubiprofen, when a sustained release material selected from a conventional water-soluble polymer is used, the drug is eluted in the gastrointestinal tract. However, since felluprofen is a drug capable of expressing gastrointestinal side effects, it is necessary to reduce the dissolution of the drug in the gastrointestinal tract and promote the release for a prolonged time in the small intestine. Not desirable

Therefore, the present inventors earnestly studied the sustained-release pharmaceutical formulation containing felubiprofen, surprisingly, when containing the felubiprofen and the water-insoluble polymer as the release control polymer, the release of the drug in the gastrointestinal tract The present invention has been completed by finding that the sustained release is limited in the small intestine region.

That is, according to the present invention, the dissolution rate of pelubiprofen in the gastrointestinal region is minimized to reduce the gastrointestinal exposure of the drug to reduce gastrointestinal side effects, and the bioavailability is maximized in the small intestine region, which is the main absorption site of the drug. Increase the treatment effect.

In particular, when the sustained release of pelubiprofen using a water-insoluble polymer in the release control polymer, it is possible to minimize the release in the gastrointestinal region and to maximize the release in the small intestine region, unlike other conventional NSAID drugs. It's an amazing discovery in that it's another unusual phenomenon. Examples of the water-insoluble polymer include carbomer, calcium carboxymethyl cellulose, cellulose acetate phthalate, methyl cellulose and ethyl cellulose. Group consisting of cellulose derivatives selected from hydroxypropylmethyl cellulose phthalate, waxes such as microcrystalline lead, white lead, carnauba lead, light lead, lead emulsion, methacrylate copolymer, polyvinylacetate, collidone SL and mixtures thereof One or more kinds selected from can be used.

On the other hand, eferison, another active ingredient of the present invention, unlike pelubiprofen, rather, most of the release is preferably performed in the gastrointestinal tract, which is easily broken down into the piperidine ring in an alkaline environment. This is because it has very unstable characteristics. In other words, since the efericone is decomposed due to the low stability when released in the small intestine region, which is an alkaline environment, the controlled release of the efericone should be designed to be mostly released in the gastrointestinal region.

In this regard, the inventors of the present invention, when the sustained release of the pelubiprofen using the water-insoluble polymer, and at the same time to release the eferison using a water-soluble or non-aqueous polymer, the eferison is different from the pelubiprofen Otherwise, most of the shapes released in the gastrointestinal tract were found. At this time, as the water-insoluble polymer for controlled release of eferisone, a water-insoluble polymer for controlled release of pelubipropene may be used, and as the water-soluble polymer for controlled release of efericone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydride Cellulose derivatives selected from hydroxymethylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose sodium, hydroxypropylmethylcellulose acetate succinate, hydroxyethylmethylcellulose, guar gum, locust bean gum, tragacanta, carrageenan, Gums selected from acacia gum, gum arabic, gellan gum, xanthan gum, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl acetal diethylamino acetate, and the like.

On the other hand, in the case of sustained release of pelubiprofen using the non-aqueous polymer as a release controlling polymer, the dissolution rate of pelubiprofen in the gastrointestinal area for 2 hours is less than 30%. This means that the release of felubiprofen in the gastrointestinal tract is extremely limited, and in the case of using a conventional sustained release material, a large amount of felubiprofen is released in the gastrointestinal tract, which is a characteristic of the present invention. Configure. In particular, it is surprising that the drug release in the gastrointestinal tract is suppressed by the combination of pelubiprofen and the water-insoluble polymer, because for other active ingredients belonging to the NSAID, for example, ketoprofen or roxof Lofen and the like do not reduce drug release in the gastrointestinal tract even when combined with a water-insoluble polymer. In other words, it is assumed that the drug release in the gastrointestinal tract is lowered by the combination with the water-insoluble polymer and the expression of adverse gastrointestinal side effects is a unique characteristic achieved by the combination of the pelubiprofen and the water-insoluble polymer.

In the present invention, in the case of controlling release of felubiprofen using a non-aqueous polymer, the dissolution rate of felubiprofen in the small intestine region during 2 hours is 50% or more. This means that felubiprofen is continuously released in the small intestine area, thus, it is possible to achieve a release pattern that exhibits the efficacy of the drug while reducing the frequency of administration.

Furthermore, in the case of sustained release of pelubiprofen using a non-aqueous polymer as a release control polymer and a water-soluble or non-aqueous polymer as a release control polymer of eferison, for 2 hours in the gastrointestinal tract of eferison The dissolution rate of is 60% or more. This means that the release of eperison is mostly in the gastrointestinal tract.

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

The pharmaceutical compositions of the present invention can be prepared in various forms of formulations, such as single tablets, double tablets or capsules. In one embodiment of the present invention, a water-soluble or non-aqueous polymer is included in the first layer containing felubiprofen, and the water-soluble or non-aqueous polymer is included in the second layer containing epherizone to form a bilayer tablet. Can be.

The content of the water-insoluble polymer in the double tablet may be included in an amount of 1% by weight to 50% by weight based on the total weight of the composition constituting each layer, based on the felubipropene layer and the eferison layer, The content may be included in an amount of 10% by weight to 60% by weight, and the content of epherisone in an amount of 20% by weight to 60% by weight.

According to one embodiment, the preparation according to the present invention is prepared by mixing pelubiprofen or epherisone with an excipient and a binder, and then using a suitable solvent, followed by drying to prepare tableting granules or filling granules. Then, it can be prepared by adding pharmaceutically acceptable excipients such as water-insoluble polymers and lubricants. Alternatively, other assembly methods commonly known in the art may be used.

As the excipient, lactose, calcium hydrogen phosphate, starch, polyol may be used, and mannitol, isomalt, xylitol may be used as the polyol; As the binder, hydroxypropyl cellulose, polysaccharide may be used, and as the polysaccharide, xanthan gum and carrageenan may be used; As the disintegrant, carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose, starch can be used; As the lubricant, magnesium stearate and talc can be used.

The content of the additives can be appropriately used by those skilled in the art according to a specific prescription, 10 to 50% by weight of excipient, 1 to 25% by weight of binder, 1 to 25% by weight of disintegrant, lubricant It may be included in 0.5 to 10% by weight.

The form of the pharmaceutical preparation for oral administration according to the present invention is preferably double tablets. Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the technical spirit of the present invention should not be construed as being limited thereto.

Example

Example 1 Preparation of Sustained-Release Tablet Using Collidone SR and Hypromellose

90 g of pelubiprofen, 90 g of lactose, and 4.6 g of hydroxypropyl cellulose were mixed, combined with water, and dried to form. To the sieved material, 25 g of collidone AL and 4.6 g of magnesium stearate were added to prepare a pelubipropene mixture.

Separately from the above, 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.

Example 2 Preparation of Sustained-Release Tablet Using Ethyl Cellulose and Hypromellose

90 g of pelubiprofen, 90 g of lactose, and 4.6 g of hydroxypropyl cellulose were mixed, combined with water, and dried to form. 25 g of ethyl cellulose and 4.6 g of magnesium stearate were added to the sieved material to prepare a pelubiprofen mixture.

Separately from the above, 150 g of eferison hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were mixed, combined with ethanol, and dried. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.

Example 3 Preparation of Sustained-Release Tablet Using Eudragit RS and Hypromellose

90 g of pelubiprofen, 90 g of lactose monohydrate, 4.6 g of hydroxypropyl cellulose, and 25 g of eudragit RS were combined and then combined with ethanol, followed by drying. 4.6 g of magnesium stearate was added to the sieved material and mixed to prepare a pelubipropene mixture.

Separately from the above, 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.

Example 4 Preparation of Sustained-Release Tablet Using Hypromellose Phthalate and Hypromellose

90 g of pelubiprofen, 90 g of lactose, and 4.6 g of hydroxypropyl cellulose were mixed, combined with water, and dried to form. To the sieved material, 25 g of hypromellose phthalate and 4.6 g of magnesium stearate were added and mixed to prepare a pelubipropene mixture.

Separately from the above, 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.

Example 5 Preparation of Sustained-Release Tablet Using Acrylic Ise and Hypromellose

90 g of pelubiprofen, 90 g of lactose, and 4.6 g of hydroxypropyl cellulose were mixed, combined with water, and dried to form. To the sieved material, 25 g of acrylic acid and 4.6 g of magnesium stearate were added and mixed to prepare a pelubipropene mixture.

Separately from the above, 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.

Example 6 Preparation of Sustained-Release Tablet Using Carbomer and Hypromellose

90 g of pelubiprofen, 90 g of lactose, and 4.6 g of hydroxypropyl cellulose were mixed, combined with water, and dried to form. 25 g of carbomer and 4.6 g of magnesium stearate were added to the sieved material and mixed to prepare a felrubiprofen mixture.

Separately from the above, 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.

Example 7 Preparation of Sustained-Release Tablet Using Polyvinylacetate and Hypromellose

90 g of pelubiprofen, 90 g of lactose, and 4.6 g of hydroxypropyl cellulose were mixed, combined with water, and dried to form. The granules were combined into a suspension in which 25 g of polyvinylacetate was dispersed, and then dried and stipulated. Then, 4.6 g of magnesium stearate was added and mixed to prepare a pelubipropene mixture.

Separately from the above, 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.

Example 8 Preparation of Sustained-Release Tablet Using Collidone SR and Hydroxypropyl Cellulose

90 g of pelubiprofen, 90 g of lactose, and 4.6 g of hydroxypropyl cellulose were mixed, combined with water, and dried to form. To the sieved material, 25 g of collidone AL and 4.6 g of magnesium stearate were added to prepare a pelubipropene mixture.

Separately from the above, 150 g of eferison hydrochloride, 120 g of lactose hydrate, and 4 g of hydroxypropyl cellulose were mixed and then combined with ethanol, followed by drying. 50 g of hydroxypropyl cellulose, 60 g of prosolve, and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.

Example 9 Preparation of Sustained-Release Tablet Using Collidone SR and Carbomer

90 g of pelubiprofen, 90 g of lactose, and 4.6 g of hydroxypropyl cellulose were mixed, combined with water, and dried to form. To the sieved material, 25 g of collidone AL and 4.6 g of magnesium stearate were added to prepare a pelubipropene mixture.

Separately from the above, 150 g of eferison hydrochloride, 120 g of lactose hydrate, and 4 g of hydroxypropyl cellulose were mixed and then combined with ethanol, followed by drying. 40 g of carbomer, 60 g of prosolve, and 3 g of magnesium stearate were added to the sieved material, and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.

Example 10 Preparation of Sustained-Release Tablet Using Collidone AL and Eudragit RS

90 g of pelubiprofen, 90 g of lactose, and 4.6 g of hydroxypropyl cellulose were mixed, combined with water, and dried to form. To the sieved material, 25 g of collidone AL and 4.6 g of magnesium stearate were added to prepare a pelubipropene mixture.

Separately from the above, 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 4 g of hydroxypropyl cellulose, and 100 g of eudragitacese were combined and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.

Example 11 Preparation of Sustained-Release Tablet Using Collidone SR

90 g of pelubiprofen, 90 g of lactose, and 4.6 g of hydroxypropyl cellulose were mixed, combined with water, and dried to form. To the sieved material, 25 g of collidone AL and 4.6 g of magnesium stearate were added to prepare a pelubipropene mixture.

Separately from the above, 150 g of epherisone hydrochloride, 120 g of lactose hydrate, and 4 g of hydroxypropyl cellulose were mixed and then combined with ethanol, followed by drying. 100 g of collidone AL, 60 g of prosolve, and 3 g of magnesium stearate were added to the sieved material, and the mixture was mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.

Example 12 Preparation of Sustained-Release Tablets According to the Collidone SL Ratio

90 g of pelubiprofen, 90 g of lactose, and 4.6 g of hydroxypropyl cellulose were mixed, combined with water, and dried to form. 10 g of collidone AL and 4.6 g of magnesium stearate were added to the sieved material to prepare a felubiprofen mixture.

Separately from the above, 150 g of eferison hydrochloride, 120 g of lactose hydrate, 4 g of hydroxypropyl cellulose, and 50 g of hypromellose were mixed and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.

Example 13. Preparation of Sustained-Release Tablet According to Collidone-AL Rate

90 g of pelubiprofen, 90 g of lactose, and 4.6 g of hydroxypropyl cellulose were mixed, combined with water, and dried to form. 40 g of collidone AL and 4.6 g of magnesium stearate were added to the sieved material to prepare a felubiprofen mixture.

Separately from the above, 150 g of eferison hydrochloride, 120 g of lactose hydrate, 4 g of hydroxypropyl cellulose, and 50 g of hypromellose were mixed and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.

Example 14 Preparation of Sustained-Release Tablet According to the Collidone-SR Ratio

90 g of pelubiprofen, 90 g of lactose, and 4.6 g of hydroxypropyl cellulose were mixed, combined with water, and dried to form. 60 g of collidone AL and 4.6 g of magnesium stearate were added to the sieved material to prepare a felubiprofen mixture.

Separately from the above, 150 g of eferison hydrochloride, 120 g of lactose hydrate, 4 g of hydroxypropyl cellulose, and 50 g of hypromellose were mixed and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.

Example 15 Preparation of Sustained-Release Tablet Using Collidone SR and Hydroxypropyl Cellulose

90 g of pelubiprofen, 90 g of lactose, and 4.6 g of hydroxypropyl cellulose were mixed, combined with water, and dried to form. To the sieved material, 25 g of collidone AL and 4.6 g of magnesium stearate were added and mixed to prepare a pelubiprofen mixture.

Separately from the above, 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Magnesium stearate was added to each of the two prepared mixtures and mixed to prepare a mixture, which was then compressed into a single tablet.

Example 16 Preparation of Sustained-Release Tablet Using Ethyl Cellulose and Hydroxypropyl Cellulose

90 g of pelubiprofen, 90 g of lactose, and 4.6 g of hydroxypropyl cellulose were mixed, combined with water, and dried to form. 25 g of ethyl cellulose was added to the sieved material and mixed to prepare a pelubipropene mixture.

Separately from the above, 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined and then combined with ethanol, followed by drying. 60 g of prosolve was added to the formulation and mixed to prepare an eferison hydrochloride mixture. Magnesium stearate was added to each of the two prepared mixtures and mixed to prepare a mixture, which was then compressed into a single tablet.

Example 17 Preparation of Sustained-Release Tablet Using Collidone AL and Hypromellose

90 g of pelubiprofen, 90 g of lactose, and 4.6 g of hydroxypropyl cellulose were mixed, combined with water, and dried to form. 25 g of collidone AL and 4.6 g of magnesium stearate were added to the sieved material to prepare a pelubiprofen mixture, which was compressed into tablets.

Separately from the above, 150 g of eferison hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined, and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. The inner core tablet was prepared using the core tablet obtained from the pelubipropene mixture as the inner core, and the inner core tablet was prepared using an inner core tablet press machine together with the eferison hydrochloride mixture.

Example 18. Preparation of Sustained-Release Tablet Using Collidone SR and Hypromellose

90 g of pelubiprofen, 90 g of lactose, and 4.6 g of hydroxypropyl cellulose were mixed, combined with water, and dried to form. 25 g of collidone AL and 4.6 g of magnesium stearate were added to the sieved material to prepare a pelubipropene mixture, which was compressed using a tableting machine equipped with a fine tablet punch.

Separately from the above, 150 g of eferison hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined, and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture, which was compressed using a tablet press equipped with a fine tablet punch. The micro tablets corresponding to each dose were filled into capsules using a suitable capsule filling machine.

Comparative example

Comparative Example 1. Preparation of sustained-release tablet using hypromellose

90 g of pelubiprofen, 90 g of lactose, and 4.6 g of hydroxypropyl cellulose were mixed, combined with water, and dried to form. 25 g of hypromellose and 4.6 g of magnesium stearate were added to the sieved material and mixed to prepare a felrubiprofen mixture.

Separately from the above, 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.

Comparative Example 2. Preparation of sustained-release tablet using hydroxypropyl cellulose and hypromellose

90 g of pelubiprofen, 90 g of lactose, and 4.6 g of hydroxypropyl cellulose were mixed, combined with water, and dried to form. 25 g of hydroxypropyl cellulose and 4.6 g of magnesium stearate were added to the sieved material, followed by mixing to prepare a felrubiprofen mixture.

Separately from the above, 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.

Comparative Example 3. Preparation of Sustained-Release Tablet Using Sodium Roxoprofen

90 g of lysopropene sodium, 90 g of lactose monohydrate, and 4.6 g of hydroxypropyl cellulose were mixed, combined with water, and dried to form. To the sieved material, 25 g of collidone AL and 4.6 g of magnesium stearate were added and mixed to prepare a sodium lysopropene mixture.

Separately from the above, 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material, and mixed to prepare a mixture of the eferison hydrochloride layer. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.

Comparative Example 4. Preparation of Sustained-Release Tablet Using Ketoprofen

90 g of ketoprofen, 90 g of lactose monohydrate, and 4.6 g of hydroxypropyl cellulose were mixed and then combined with water, followed by drying and sizing. 25 g of collidone AL and 4.6 g of magnesium stearate were added to the sieved material and mixed to prepare a ketopropene mixture.

Separately from the above, 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.

Experimental Example

Experimental Example 1. Dissolution test of pelubiprofen according to the polymer

In the sustained release of felubiprofen, drug release in the gastrointestinal and small intestine regions was evaluated according to the use of non-aqueous and water-soluble polymers. The results of the dissolution test in pH 1.2 and pH 6.8 eluate are shown in Table 1 below.

The dissolution test was conducted in accordance with the Dissolution Test Method 1 (rotational sample method) of the Korean Pharmacopoeia General Test Method. After 1 hour and 2 hours after the start of the test, the eluate was collected, filtered and analyzed by HPLC. (unit %)

Table 1 pH pH 1.2 pH 6.8 time 1 hours 2 hours 1 hours 2 hours 4 hours Example 1 1.8 4.9 37.7 83.5 98.7 Example 2 1.3 8.3 21.3 55.4 78.4 Example 3 0.3 2.1 18.4 57.1 72.5 Example 4 1.5 3.3 77.8 98.8 99.7 Example 5 1.9 16.3 88.2 95.3 96.4 Example 6 13.5 21.3 16.3 55.8 77.8 Example 7 1.8 5.3 38.8 69.8 98.3 Comparative Example 1 33.8 54.6 32.8 59.3 85.1 Comparative Example 2 42.8 63.8 33.2 63.2 82.9

From the above experiments, it was found that the release of the drug in the gastrointestinal tract is extremely limited when the pelubiprofen is sustained by using the water-insoluble polymer. In addition, it was found that the drug release in the small intestine area is continuously maintained.

Experimental Example 2. Dissolution Test of Eperisone According to Polymer

In the sustained release of eferisone, drug release in the gastrointestinal tract was evaluated according to the use of a water-insoluble polymer and a water-soluble polymer. The results of the elution test in the pH 1.2 eluate are shown in Table 2 below.

The dissolution test was conducted in accordance with the Dissolution Test Method 1 (rotational sample method) of the Korean Pharmacopoeia General Test Method. After 1 hour and 2 hours after the start of the test, the eluate was collected, filtered and analyzed by HPLC. (unit %)

TABLE 2 pH pH 1.2 time 1 hours 2 hours Example 1 50.3 80.5 Example 8 46.3 80.1 Example 9 39.8 63.9 Example 10 53.8 91.5 Example 11 44.8 84.3

From the above experiments, it was found that in case of sustained release of epherisone using an appropriate polymer, a sustained release of the drug in the gastrointestinal tract and most drugs were released within 2 hours.

Experimental Example 3 Pelubiprofen Dissolution Test of Double and Single Tablets

The release pattern in the gastrointestinal and small intestine regions of the pelubiprofen sustained release composition using the water-insoluble polymer according to the form of the tablet was confirmed. The results of the dissolution test in pH 1.2 and pH 6.8 eluate are shown in Table 3 below.

The dissolution test was conducted in accordance with the Dissolution Test Method 1 (rotational sample method) of the Korean Pharmacopoeia General Test Method. After 1 hour, 2 hours and 4 hours after the start of the test, the eluate was collected, filtered and analyzed by HPLC. (unit %)

TABLE 3 pH pH 1.2 pH 6.8 time 1 hours 2 hours 1 hours 2 hours 4 hours Example 1 1.8 4.9 37.7 83.5 98.7 Example 2 1.3 8.3 21.3 55.4 78.4 Example 15 10.4 28.2 33.2 61.5 98.5 Example 16 15.8 29.0 34.5 81.3 99.7

From the above experiments, it was found that when the pelubiprofen was sustained by using a water-insoluble polymer, the release restriction of the drug in the gastrointestinal region was maximized in the double tablet form than in the single tablet form. In addition, it can be seen that the release of the drug in the small intestine area is continuously maintained.

Experimental Example 4. Dissolution test of pelubiprofen according to the ratio of collidone

In order to confirm the release pattern in the small intestine region of the Pelubiprofen sustained release composition according to the ratio of collidone RS, an elution test was performed in a pH 6.8 eluate, and the results are shown in Table 4.

The dissolution test was conducted in accordance with the Dissolution Test Method 1 (rotational sample method) of the Korean Pharmacopoeia General Test Method. After 1 hour, 2 hours and 4 hours after the start of the test, the eluate was collected, filtered and analyzed by HPLC. (unit %)

Table 4 pH pH 6.8 time 1 hours 2 hours 4 hours Example 12 68.9 97.4 98.8 Example 1 37.7 83.5 98.7 Example 13 34.3 71.5 95.8 Example 14 30.1 58.3 82.6

From the above experiments, it was found that the release of the drug in the small intestine area was sustained when the pelubiprofen was sustained by using an insoluble polymer in an appropriate ratio.

Experimental Example 5. Dissolution test according to NSAID

In order to evaluate the dissolution rate in the gastrointestinal and small intestine areas according to the NSAID type, dissolution test was performed in pH 1.2 and pH 6.8 eluate, and the results are shown in Table 5.

The dissolution test was conducted in accordance with the Dissolution Test Method 1 (rotational sample method) of the Korean Pharmacopoeia General Test Method. After 1 hour, 2 hours and 4 hours after the start of the test, the eluate was collected, filtered and analyzed by HPLC. (unit %)

Table 5 pH pH 1.2 pH 6.8 time 1 hours 2 hours 1 hours 2 hours 4 hours Example 1 1.8 4.9 37.7 83.5 98.7 Comparative Example 3 50.0 73.5 71.5 90.8 98.3 Comparative Example 4 62.3 78.8 60.5 89.6 96.1

From the above experiments, it was confirmed that the composition of the present invention through the combination of pelubiprofen and the water-insoluble polymer, the release of pelubiprofen in the gastrointestinal tract. On the other hand, in the case of other active ingredients belonging to the NSAID, for example, ketoprofen or loxoprofen was confirmed that drug release is not reduced in the gastrointestinal tract even when combined with a water-insoluble polymer.

Therefore, when the composition of the present invention is made of a combination of felubiprofen and a water-insoluble polymer, felubiprofen release is limited in the gastrointestinal tract and maximization of the release of eperison, It can be seen that the release is continuous. In addition, it was found that minimizing the expression of gastrointestinal side effects of pelubiprofen, ensuring the stability of the body of eperison, and controlling the pain efficiently by twice daily administration.

Claims (5)

A pharmaceutical composition comprising felubiprofen, epherisone and a water-insoluble polymer. 2. The pharmaceutical composition of claim 1, wherein the pelubiprofen is eluted at less than 30% for 2 hours in the gastrointestinal tract (pH 1.2 eluate). The pharmaceutical composition according to claim 2, wherein the pelubiprofen is eluted at 50% or more in the small intestine region (pH 6.8 eluate) for 2 hours. 2. The pharmaceutical composition according to claim 1, wherein the eferison is eluted at least 60% in the gastrointestinal tract (pH 1.2 eluate) for 2 hours. The method of claim 1, wherein the water-insoluble polymer is cellulose derivative, microcrystalline lead, white lead, carnauba lead, light lead, emulsifier selected from carbomer, carboxymethyl cellulose calcium, cellulose acetate phthalate, methyl cellulose, hydroxypropyl methyl cellulose phthalate Pharmaceutical composition, characterized in that selected from the group consisting of waxes such as lead, methacrylate copolymer, ethylcellulose, polyvinylacetate, collidone AL and mixtures thereof.