KR20170001664A - Combination formulation comprising mosapride and rabeprazole - Google Patents

Abstract

The present invention relates to a composite preparation of mosapride and rabeprazole, having various formulations. The composite preparation produced by the present invention enables immediate drug release without reduction in the elution rate due to interactions between mosapride and rabeprazole, thereby exhibiting increased drug elution rate and bioavailability. In addition, the composite preparation of mosapride and rabeprazole shows product stability, and remarkably reduces an amount of diluting agents used therein, thereby increasing administration compliance in patients due to the size of the formulations.

Description

Combination formulation comprising mosapride and rabeprazole.

The present invention relates to a combination preparation of simfried and rabeprazole having various formulations.

Mosapride selectively stimulates only the serotonin 5-HT4 receptor present in the sarcomere plexus as selective serotonin 5-hydroxytryptamine 4 (hereinafter, referred to as '5-HT4') receptor agonist This acetylcholine accelerates the release of acetylcholine at the nerve endings, and this acetylcholine contracts smooth muscle of the digestive tract and promotes digestive tract movement, resulting in diabetic gastropathy, dyspepsia, gastritis, , Gastroesphageal reflux disease (gastroesophageal reflux disease). Mossafrid has no fear of arrhythmia or cardiogenic death due to the prolongation of QT interval in the non-selective 5-HT4 receptor agonist Sissaflide, and has no dopamine-2 (D-2) receptor antagonism, CNS) side effects (extrapyramidal symptoms), hyperprolactinemia (lactation, feminized breast), and other side effects.

In addition, rabeprazole is a benzimidazole derivative that inhibits gastric acid secretion. It inhibits H ⁺ / K ⁺ ATPase on the acid secretion surface of the parietal cell of the gastric mucosa, Is known as a proton pump inhibitor (PPI). In addition, it has been attracting attention as a therapeutic agent for stomach, duodenal ulcer and the like by causing basal acid secretion and inhibition of acid secretion by stimulation.

The combination of the two components having similar drug efficacy can be used in place of the co-administration, improves the patient's convenience of medication, and is advantageous in terms of economics rather than taking each single agent in combination, There is a fear of a change in pattern or a side effect in the body. However, there have been no studies on combination preparations of moscafried and rabeprazole.

It is an object of the present invention to provide a combination formulation of various forms comprising moscapride or a pharmaceutically acceptable salt thereof and rabeprazole or a pharmaceutically acceptable salt thereof.

In order to achieve the above object, the present invention relates to a composition comprising rabeprazole or a pharmaceutically acceptable salt thereof as an inner core and an outer layer of the composition as a composition comprising a mothafide or a pharmacologically acceptable salt thereof The present invention provides a combined preparation having a permeable core structure.

The present invention also relates to a composition comprising rabeprazole in the form of enteric coated tablets or a pharmaceutically acceptable salt thereof and a capsule comprising encapsulated a composition comprising a multiply packed form of mothafide or a pharmaceutically acceptable salt thereof, Thereby providing a combined preparation having the structure.

The present invention also relates to a pharmaceutical composition comprising a composition comprising rabeprazole in the form of enteric-coated tablets or a pharmaceutically acceptable salt thereof, and a composition comprising a mash fide comprising at least one tablet or a pharmaceutically acceptable salt thereof A complex preparation having a capsule structure is provided.

In addition, the present invention relates to a composition comprising rabeprazole in the form of enteric coated pellets or a pharmaceutically acceptable salt thereof, and a composition comprising a composition comprising a mothafide comprising at least one tablet or a pharmaceutically acceptable salt thereof A complex preparation having a capsule structure is provided.

Hereinafter, the present invention will be described in detail.

(4-amino-5-chloro-2-ethoxy-N- [4- (4-fluorobenzyl) -2-morpholinyl] methylbenzamide), a component of the complex preparation of the present invention, (5-HT) receptors on the gastrointestinal cholinergic nerve to promote the release of acetylcholine at the nerve end. The acetylcholine promotes smooth muscle movement in the gastrointestinal tract, resulting in strong gastrointestinal motility and gastrointestinal motility It is known that it is advantageous to manufacture the composition with a slow release half-life of the serotonin receptor, which is a discharge-promoting action, so that the release agent can be gradually released while controlling the drug release rate by using a slow release base. Thus, it is preferred that sustained release formulations containing a composition comprising moscapride or a pharmaceutically acceptable salt thereof exhibit the property of continuously releasing the active ingredient for 24 hours. In the present invention, the pharmaceutically acceptable salt of the mosaaphride may be a mothafide citrate or a citric acid salt, or may exist in the form of their hydrates. In the present specification, there is a case where the mosaaphride or a pharmaceutically acceptable salt thereof is named as the first active ingredient.

In addition, rabeprazole, a component of the combined preparation of the present invention, is a benzimidazole derivative and inhibits gastric acid secretion and has a structure represented by the following formula (2). Rabeprazole is known as a proton pump inhibitor (PPI) that inhibits H ⁺ / K ⁺ ATPase and inhibits gastric acid secretion on the acid secretion surface of the gastric mucosa parietal cell. Secretion and stimulation of the acid secretion inhibition caused by stomach, duodenal ulcers and has been attracting attention as a remedy. The pharmaceutically acceptable salt of rabeprazole in the present invention may be rabeprazole sodium salt, but is not limited thereto. In the present specification, rabeprazole or a pharmaceutically acceptable salt thereof is sometimes referred to as a second active ingredient.

The combination preparation of the present invention can reduce the burden on patients having functional digestive disorders receiving the monofilament by separately administering rabeprazole as a therapeutic agent for gastric ulcer, It is possible to accelerate the release of the drug to improve the dissolution rate and bioavailability of the drug as well as to improve the stability of the product and significantly reduce the content of the excipient.

As one embodiment of the present invention, there is provided a combination preparation having a core-shell composition (first composition) having a rabeprazole composition (second composition) as an inner core and a core-shell structure surrounding the outer layer of the rabeprazole composition do.

As shown in FIG. 1, the rabeprazole composition may take a formulation in the form of an enteric coating tablet, and the mimic primed composition may take a granular form, but is not limited to the above formulation. In addition, as described above, since the simulated free composition is advantageous in that it is eluted slowly due to a short half-life of blood, it can contain not only the granules in the form of the immediate layer as in Fig. 1 but also the granules in the form of a sustained- have.

The first active ingredient, moscafide or a pharmaceutically acceptable salt thereof may be contained in an amount of 0.1 to 10 parts by weight, more specifically 1 to 5 parts by weight, based on 100 parts by weight of the total combined preparation, It does not.

The first active ingredient may be contained in an amount of 1 to 20 parts by weight, more specifically 3 to 15 parts by weight, based on 150 parts by weight of the first composition. If the first composition is an immediate-release composition, it may be contained in an amount of 3 to 7 parts by weight based on 150 parts by weight of the first composition, and if it is a sustained-release composition, it may be included in an amount of 8 to 13 parts by weight based on 150 parts by weight of the first composition.

According to an embodiment of the present invention, the granular form of the simulated freed composition may include a chewing layer (immediate-release composition) including an excipient, a disintegrant, a binder or a lubricant in addition to the first active ingredient; (Sustained-release composition) form including an excipient, a disintegrant, a release-controlling agent, a binder or a lubricant in addition to the first active ingredient, and may include both of these layers.

Non-limiting examples of excipients for use in the combination preparations of the present invention may each be independently lactose, mannitol, glucose, sorbitol, dextrin, sucrose, or a mixture thereof. Lactose improves the ease of tableting and facilitates the formation of water-soluble channels when coexisting with hydroxypropylmethylcellulose (HPMC) in the effluent, and plays a role in maintaining the tablet form. In addition, lactose is mixed with high viscosity HPMC to enable homogeneous mixing with a simulated pride salt (eg, simaflid citrate, simaflid citrate) and HPMC. The excipient in the first composition may be included in an amount of 20 to 40 parts by weight, specifically 25 to 35 parts by weight, based on 100 parts by weight of the total combined preparation. The excipient may be contained in an amount of 30 to 100 parts by weight, more specifically 50 to 90 parts by weight, based on 150 parts by weight of the first composition. If the first composition is an immediate-release composition, it may be contained in an amount of 80 to 90 parts by weight based on 150 parts by weight of the first composition, and if it is a sustained-release composition, it may be included in an amount of 50 to 60 parts by weight based on 150 parts by weight of the first composition.

The disintegrant used in the combination preparation of the present invention is used for absorbing moisture to accelerate the disintegration of the preparation to improve the dissolution of the simfried or rabeprazole and the salt thereof. Non-limiting examples of disintegrants used in the present invention are each independently selected from the group consisting of Croscamellose sodium, Sodium starch glycolate, microcrystalline cellulose, Crospovidone cross- linked povidone) and other commercially useful polyvinylpyrrolidone (PVP, Povidone), low substituted hydroxypropylcellulose (low substituted), alginic acid, powdered cellulose, starch, sodium Sodium alginate, or a mixture thereof. Of these, low-substituted hydroxypropylcellulose and crospovidone are preferable. Disintegrants may additionally be added in a pharmaceutically acceptable manner in addition to the oral solid preparations, and a secondary disintegrant may be further used for the purpose of faster release of the formulation. The disintegrant in the first composition may be contained in an amount of 10 to 30 parts by weight, specifically 15 to 25 parts by weight, based on 100 parts by weight of the total composite preparation. The disintegrant may be contained in an amount of 20 to 60 parts by weight, more specifically 25 to 50 parts by weight, based on 150 parts by weight of the first composition. If the first composition is an immediate-release composition, it may be contained in an amount of 45 to 50 parts by weight based on 150 parts by weight of the first composition, and if it is a sustained-release composition, it may be contained in an amount of 25 to 30 parts by weight based on 150 parts by weight of the first composition.

As the water-soluble polymer, a binder capable of dissolving in an organic solvent and enhancing the binding force of the preparation may be used in the combination preparation of the present invention. Non-limiting examples of binders that can be used include polyvinylpyrrolidone (povidone, a povidone K-30 having a molecular weight of 30 is used), microcrystalline cellulose, methylcellulose, calcium monohydrogen phosphate, spray dried lactose, gelatin and the like. The binder in the first composition may be included in an amount of 1 to 10 parts by weight, specifically 3 to 7 parts by weight, based on 100 parts by weight of the total combined preparation. The binder may be contained in an amount of 5 to 15 parts by weight, more specifically 7 to 13 parts by weight, based on 150 parts by weight of the first composition.

Non-limiting examples of lubricants that may be used in the combined preparation of the present invention may each be independently light silicic anhydride, silicon dioxide, talc, stearic acid, magnesium stearate, or mixtures thereof. The lubricant improves the fluidity of the granulate to increase the filling of the die, which is the lower part of the tablet machine, and reduces the friction between the granules and between the granules and the punch die, which is the upper part of the tablet machine Facilitating compression and release of tablets. The lubricant in the first composition may be included in an amount of 0.1 to 5 parts by weight, specifically 0.5 to 2.5 parts by weight, based on 100 parts by weight of the total complex preparation. The lubricant may be contained in an amount of 0.5 to 5 parts by weight, more preferably 1 to 3 parts by weight, based on 150 parts by weight of the first composition.

The sustained release agent (release control agent) contained in the sustained release layer of the simulated free composition may be used as a mixture of high viscosity hydroxypropyl methylcellulose and low viscosity hydroxypropyl methylcellulose, 1 to 20 parts by weight, particularly 5 to 15 parts by weight, based on the weight of the composition. The release control agent may be contained in an amount of 30 to 60 parts by weight, more specifically 40 to 50 parts by weight, based on 150 parts by weight of the sustained release first composition.

Instead of high viscosity hydroxypropyl methylcellulose (HPMC) used in the first composition of the sustained release type, waxes may be used, and similar dissolution patterns can be exhibited in this case as well. That is, it can be produced by mixing waxes with low viscosity HPMC instead of high viscosity HPMC as a sustained release controlling agent. At this time, waxes and low viscosity HPMC may be mixed at a weight ratio of 20: 1 to 5: 1. Non-limiting examples of waxes include but are not limited to waxes such as microcrystalline waxes, anionic waxes, anionic emulsified waxes, bleached waxes, carnauba waxes, cetyl esters waxes, beeswax, caster waxes, cationic emulsified waxes, Nonionic emulsified waxes, paraffins, petroleum waxes, wax waxes, white waxes, yellow waxes, mixtures thereof, and the like can be used as the emulsified waxes. Preferably, the waxes are effective when using a microcrystalline wax, carnauba wax, glyceryl behenate or the like. The waxes are preferably used in an amount of 20 to 32 parts by weight, more preferably in an amount of 24 to 31 parts by weight, based on 100 parts by weight of the whole composite preparation, but are not limited thereto.

In addition, the release-controlling agent constituting the sustained-release layer may be prepared by mixing a high-viscosity hydroxypropylmethylcellulose having a viscosity of 80,000 cps to 120,000 cps and a low viscosity hydroxypropylmethylcellulose having a viscosity of 2,000 cps to 20,000 cps at a ratio of 2.5 to 1: , The first active ingredient contained in the water elution solution at 37 ° C, pH 4.0, and water eluate was 25-45% of the total weight of the first active ingredient after 1 hour according to Method 2 of the Korean Pharmacopoeia (Paddle Method) 1 to 60% by weight of the total weight of the active ingredient, and 85% or more of the total weight of the first active ingredient after 24 hours.

According to another embodiment of the present invention, the release control agent is prepared by mixing the high viscosity hydroxypropylmethylcellulose and low-viscosity hydroxypropylmethylcellulose in a weight ratio of 1.2 to 1: 1, (Paddle method) at 37 ° C, pH 4.0, and 40-45% of the total weight of the first active ingredient after 1 hour of the first active ingredient contained in the water effluent, 70-75% of the first active ingredient total weight after 8 hours % Of the total weight of the first active ingredient, more than 90% of the total weight of the first active ingredient after 24 hours.

In addition, according to one embodiment of the present invention, the rabeprazole composition in the form of an enteric coated tablet may contain, in addition to the second active ingredient, an excipient, an alkalizing agent, a disintegrant, a binder or a lubricant. The excipient, disintegrant, binder and lubricant are as described above.

The second active ingredient rabeprazole or a pharmaceutically acceptable salt thereof may be contained in an amount of 0.1 to 10 parts by weight, more specifically 1 to 5 parts by weight, based on 100 parts by weight of the total combined preparation, It is not limited. The second active ingredient may be contained in an amount of 1 to 20 parts by weight, more specifically 5 to 15 parts by weight, based on 130 parts by weight of the second composition.

The excipient in the second composition may be included in an amount of 1 to 20 parts by weight, specifically 5 to 15 parts by weight, based on 100 parts by weight of the total complex preparation. The excipient may be contained in an amount of 30 to 60 parts by weight, more specifically 40 to 50 parts by weight, based on 130 parts by weight of the second composition.

The disintegrant in the second composition may be contained in an amount of 0.5 to 15 parts by weight, specifically 1 to 7 parts by weight, based on 100 parts by weight of the total complex preparation. The disintegrant may be contained in an amount of 5 to 20 parts by weight, more specifically 10 to 15 parts by weight, based on 130 parts by weight of the second composition.

The binder in the second composition may be included in an amount of 0.1 to 5 parts by weight, specifically 0.5 to 2.5 parts by weight based on 100 parts by weight of the total complex preparation. The binder may be contained in an amount of 0.5 to 10 parts by weight, more preferably 1 to 5 parts by weight, based on 130 parts by weight of the second composition.

The lubricant in the second composition may be included in an amount of 0.1 to 5 parts by weight, specifically 0.5 to 2.5 parts by weight, based on 100 parts by weight of the total combined preparation. The lubricant may be contained in an amount of 0.5 to 10 parts by weight, more preferably 1 to 5 parts by weight, based on 130 parts by weight of the second composition.

The second composition comprising rabeprazole or a salt thereof may contain an alkalizing agent, and the alkalizing agent in the second composition may be included in an amount of 1 to 20 parts by weight based on 100 parts by weight of the total combined preparation, And 5 to 15 parts by weight. The alkalizing agent may be contained in an amount of 30 to 60 parts by weight, more specifically 40 to 50 parts by weight, based on 130 parts by weight of the second composition. The alkalizing agent includes, but is not limited to, magnesium oxide, calcium carbonate, dibasic calcium phosphate, magnesium tricarbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, magnesium aluminum hydroxide, potassium hydroxide, sodium bicarbonate, , Sodium hydroxide, etc. may be used. Specifically, magnesium oxide and calcium hydroxide may be used.

The second composition comprising rabeprazole or a salt thereof may be in the form of enteric tablets which do not dissolve in the gastric acid and dissolve when the sertide is lowered into the small intestine. The enteric feed agent in the second composition may be contained in an amount of 0.1 to 10 parts by weight, specifically 1 to 5 parts by weight, based on 100 parts by weight of the total complex preparation. The enteric coating agent may be contained in an amount of 1 to 20 parts by weight, more specifically 5 to 15 parts by weight, based on 130 parts by weight of the second composition.

In addition, the first and second compositions may be finally coated with a coating agent to complete a combined preparation of the sustained-release tablet. The coating agent may include, but is not limited to, hydroxypropylmethylcellulose (HPMC) or Opadyl-OY-C-7000A may be used, and may be included in an amount of 0.1 to 5 parts by weight, specifically 0.5 to 2.5 parts by weight, based on 100 parts by weight of the total combined preparation.

According to one embodiment of the present invention, the combination preparation of the present invention can be produced by a method for producing a combination preparation including the following steps.

i) preparing enteric coated tablets containing rabeprazole or a pharmaceutically acceptable salt thereof, excipients and an alkalizing agent;

ii) preparing a quick release granulate containing a simulated pride or a pharmaceutically acceptable salt thereof;

iii) preparing a sustained release granulate containing a simulated frit or a pharmaceutically acceptable salt thereof and a release control agent;

iv) tableting the fast-releasing granules and sustained-release granules prepared in step ii) and the sustained-release granules prepared in step ii) above as an outer layer and tableting the tablets using the enteric-coated tablet prepared in step i) as inner core; And

v) coating the pressed cores.

In the above production method, steps i) to iii) may be produced in any order, and may be produced at the same time.

In another aspect of the present invention, there is provided a combination preparation in the form of a capsule comprising a rabeprazole composition (second composition) in enteric coated tablet form and a simulated free composition (first composition) in multi-layer tablet form .

As shown in FIG. 2, the rabeprazole composition may take a formulation in the form of enteric coated tablets, and the simulated free composition may take the form of a multilayer tablet. The present invention provides a combination preparation in the form of a capsule comprising each of these compositions.

Also, as described above, it is preferable that the mimic primer composition is eluted slowly due to a short half-life of blood serum. As shown in FIG. 2, a multi-layer tableter in which a middle layer is inserted between adjacent layers can be used.

The first effective ingredient, moscafide or a pharmaceutically acceptable salt thereof may be contained in an amount of 0.1 to 10 parts by weight, more specifically 2 to 7 parts by weight, based on 100 parts by weight of the total combined preparation, It does not.

The first active ingredient may be contained in an amount of 1 to 20 parts by weight, more specifically 2 to 15 parts by weight, based on 75 parts by weight of the first composition. If the first composition is an immediate-release composition, it may be contained in an amount of 2 to 5 parts by weight based on 75 parts by weight of the first composition, and if it is a sustained-release composition, it may be included in an amount of 8 to 13 parts by weight based on 75 parts by weight of the first composition.

According to an embodiment of the present invention, the multi-layer tablet form of the simulated free composition may include a first layer, a core layer including an excipient, a disintegrant, a binder or a lubricant, and the like; In addition to the first active ingredient, it may include a sustained release form including an excipient, a disintegrant, a release control agent, a binder or a lubricant, And the form thereof is not limited. On the other hand, the inner layer may be inserted between the inner layers. The excipient, disintegrant, binder, lubricant, and release control agent are as described above.

The excipient in the first composition may be included in an amount of 20 to 40 parts by weight, specifically 25 to 35 parts by weight, based on 100 parts by weight of the total combined preparation. The excipient may be contained in an amount of 15 to 50 parts by weight, more specifically 20 to 45 parts by weight, based on 75 parts by weight of the first composition. If the first composition is an immediate-release composition, it may be contained in an amount of 30 to 45 parts by weight based on 75 parts by weight of the first composition, and may be contained in an amount of 20 to 30 parts by weight based on 75 parts by weight of the first composition.

The disintegrant in the first composition may be contained in an amount of 10 to 30 parts by weight, specifically 15 to 25 parts by weight, based on 100 parts by weight of the total composite preparation. The disintegrant may be contained in an amount of 5 to 35 parts by weight, more specifically 10 to 30 parts by weight, based on 75 parts by weight of the first composition. If the first composition is an immediate-release composition, it may be contained in an amount of 20 to 30 parts by weight based on 75 parts by weight of the first composition, and if it is a sustained-release composition, it may be included in an amount of 10 to 20 parts by weight relative to 75 parts by weight of the first composition.

The binder in the first composition may be included in an amount of 1 to 10 parts by weight, specifically 2 to 7 parts by weight, based on 100 parts by weight of the total combined preparation. And may be contained in an amount of 0.5 to 10 parts by weight, more specifically 1 to 7 parts by weight, based on 75 parts by weight of the first composition.

The lubricant in the first composition may be included in an amount of 0.05 to 5 parts by weight, specifically 0.1 to 2.5 parts by weight, based on 100 parts by weight of the total complex preparation. The lubricant may be contained in an amount of 0.1 to 5 parts by weight, more specifically 0.5 to 2 parts by weight, based on 75 parts by weight of the first composition.

The sustained release agent (release control agent) contained in the sustained release layer of the simulated free composition may be used as a mixture of high viscosity hydroxypropyl methylcellulose and low viscosity hydroxypropyl methylcellulose, 1 to 20 parts by weight, and more specifically, 3 to 10 parts by weight. And may be contained in an amount of 10 to 40 parts by weight, more specifically 20 to 30 parts by weight, based on 75 parts by weight of the first composition of the sustained release type.

In addition, the release control agent constituting the sustained-release layer preferably has a weight ratio of high-viscosity hydroxypropylmethylcellulose having a viscosity of 80,000 cps to 120,000 cps and low-viscosity hydroxypropylmethylcellulose having a viscosity of 2,000 cps to 20,000 cps of 2.5 to 1: 1, The first active ingredient contained in the eluate at 37 ° C, pH 4.0, and the water eluate according to Method 2 (paddle method) of the Korean Pharmacopoeia dissolution Assay Method was used in an amount of 1.75 to 1: 1, 25-45% of the total weight of the first active ingredient, 60-80% of the total weight of the first active ingredient after 8 hours, and 85% or more of the total weight of the first active ingredient after 24 hours.

In addition, according to one embodiment of the present invention, the rabeprazole composition in the form of an enteric coated tablet may contain, in addition to the second active ingredient, an excipient, an alkalizing agent, a disintegrant, a binder or a lubricant. The excipient, disintegrant, binder and lubricant are as described above.

The second active ingredient rabeprazole or a pharmaceutically acceptable salt thereof may be contained in an amount of 0.1 to 10 parts by weight, more specifically 1 to 5 parts by weight, based on 100 parts by weight of the total combined preparation, It is not limited. The second active ingredient may be contained in an amount of 1 to 20 parts by weight, more specifically 5 to 15 parts by weight, based on 130 parts by weight of the second composition.

The excipient in the second composition may be included in an amount of 1 to 20 parts by weight, specifically 5 to 15 parts by weight, based on 100 parts by weight of the total complex preparation. The excipient may be contained in an amount of 30 to 60 parts by weight, more specifically 35 to 50 parts by weight, based on 130 parts by weight of the second composition.

The disintegrant in the second composition may be contained in an amount of 0.5 to 15 parts by weight, specifically 1 to 7 parts by weight, based on 100 parts by weight of the total complex preparation. The disintegrant may be contained in an amount of 5 to 30 parts by weight, more specifically 10 to 20 parts by weight, based on 130 parts by weight of the second composition.

The binder in the second composition may be included in an amount of 0.1 to 5 parts by weight, specifically 0.5 to 2.5 parts by weight based on 100 parts by weight of the total complex preparation. The binder may be contained in an amount of 0.5 to 10 parts by weight, more preferably 1 to 5 parts by weight, based on 130 parts by weight of the second composition.

The lubricant in the second composition may be included in an amount of 0.1 to 5 parts by weight, specifically 0.5 to 2.5 parts by weight, based on 100 parts by weight of the total combined preparation. The lubricant may be contained in an amount of 0.5 to 10 parts by weight, more preferably 1 to 5 parts by weight, based on 130 parts by weight of the second composition.

The second composition comprising rabeprazole or a salt thereof may contain an alkalizing agent such as magnesium oxide when used as a vial, and the alkalizing agent in the second composition may be included in an amount of 1 to 20 parts by weight based on 100 parts by weight of the total combined preparation Specifically, 5 to 15 parts by weight. And 30 to 60 parts by weight, more specifically 35 to 50 parts by weight, based on 130 parts by weight of the second composition.

The second composition comprising rabeprazole or a salt thereof may be in the form of enteric tablets which do not dissolve in the gastric acid and dissolve when the sertide is lowered into the small intestine. The enteric feed agent in the second composition may be contained in an amount of 0.1 to 10 parts by weight, specifically 1 to 5 parts by weight, based on 100 parts by weight of the total complex preparation. And 1 to 20 parts by weight, more specifically 5 to 15 parts by weight, based on 130 parts by weight of the second composition.

In addition, the capsule used in the combination preparation of the present invention may be a hard or soft capsule. The base material of the capsules may be selected from the group consisting of hypromellose, pluran, gelatin, polyvinyl alcohol, and mixtures thereof. However, it is not limited thereto, and materials usually used as capsules, Can be included.

According to one embodiment of the present invention, the combination preparation of the present invention can be produced by a method for producing a combination preparation including the following steps.

i) preparing enteric coated tablets containing rabeprazole or a pharmaceutically acceptable salt thereof, excipients and an alkalizing agent;

ii) preparing a quick release granulate containing a simulated pride or a pharmaceutically acceptable salt thereof;

iii) preparing a sustained release granulate containing a simulated frit or a pharmaceutically acceptable salt thereof and a release control agent;

iv) tableting the immediate-release granule and the sustained-release granule to produce a simulated pride-containing multiple tablet; And

v) filling the hard capsules with the coated primer-coated multiple tablets and rabeprazole enteric coated tablets.

In the above manufacturing method, steps i) to iii) may be manufactured in any order, and may be manufactured at the same time, and the simulated free-containing multiple crystals may have a final hardness of about 10 to 14 MPa.

In another embodiment of the present invention, there is provided a combination preparation comprising a rabeprazole composition (second composition) in the form of an enteric coated tablet and a capsule composition (first composition) comprising at least one tablet, to provide.

As shown in FIG. 3, the rabeprazole composition can take a formulation in the form of enteric coated tablet, and the mimic primed composition can be composed of one or more tablets, preferably two tablets of slow release and sustained release, It does not. The present invention may be in the form of a capsule comprising each of these compositions.

The first effective ingredient, moscafide or a pharmaceutically acceptable salt thereof may be contained in an amount of 0.1 to 15 parts by weight, more specifically 3 to 10 parts by weight, based on 100 parts by weight of the total combined preparation, It does not.

The first active ingredient may be contained in an amount of 1 to 20 parts by weight, more specifically 2 to 15 parts by weight, based on 75 parts by weight of the first composition. If the first composition is an immediate-release composition, it may be contained in an amount of 3 to 7 parts by weight based on 150 parts by weight of the first composition, and if it is a sustained-release composition, it may be included in an amount of 8 to 13 parts by weight based on 150 parts by weight of the first composition.

According to a preferred embodiment of the present invention, the morph-free composition comprises at least one inert diluent, including an excipient, a disintegrant, a binder or a lubricant in addition to the first active ingredient; And one or more sustained release formulations including excipients, disintegrants, release control agents, binders or lubricants, etc., in addition to the first active ingredient. These sustained-release and intrathecal rabeprazole compositions in the form of coated tablets, May be used as a combination preparation in the form of a capsule. Herein, excipients, disintegrants, binders, lubricants, release control agents, and capsules are as described above.

The excipient in the first composition may be included in an amount of 10 to 40 parts by weight, specifically 20 to 30 parts by weight, based on 100 parts by weight of the total complex preparation. The excipient may be contained in an amount of 15 to 50 parts by weight, more specifically 20 to 45 parts by weight, based on 75 parts by weight of the first composition. If the first composition is an immediate-release composition, it may be contained in an amount of 30 to 45 parts by weight based on 75 parts by weight of the first composition, and may be contained in an amount of 20 to 30 parts by weight based on 75 parts by weight of the first composition.

The disintegrant in the first composition may be included in an amount of 5 to 30 parts by weight, specifically 10 to 20 parts by weight, based on 100 parts by weight of the total complex preparation. The disintegrant may be contained in an amount of 5 to 35 parts by weight, more specifically 10 to 30 parts by weight, based on 75 parts by weight of the first composition. If the first composition is an immediate-release composition, it may be contained in an amount of 20 to 30 parts by weight based on 75 parts by weight of the first composition, and if it is a sustained-release composition, it may be included in an amount of 10 to 20 parts by weight relative to 75 parts by weight of the first composition.

The binder in the first composition may be included in an amount of 1 to 10 parts by weight, specifically 3 to 7 parts by weight, based on 100 parts by weight of the total combined preparation. And may be contained in an amount of 0.5 to 10 parts by weight, more specifically 1 to 7 parts by weight, based on 75 parts by weight of the first composition.

The lubricant in the first composition may be included in an amount of 0.1 to 5 parts by weight, specifically 0.5 to 2.5 parts by weight, based on 100 parts by weight of the total complex preparation. And may be contained in an amount of 0.1 to 5 parts by weight, more specifically 0.5 to 3 parts by weight, based on 75 parts by weight of the first composition.

The sustained release agent (release control agent) contained in the sustained release layer of the simulated free composition may be used as a mixture of high viscosity hydroxypropyl methylcellulose and low viscosity hydroxypropyl methylcellulose, 1 to 20 parts by weight, particularly 5 to 15 parts by weight, based on the weight of the composition. And may be contained in an amount of 10 to 40 parts by weight, more specifically 20 to 30 parts by weight, based on 75 parts by weight of the first composition of the sustained release type.

In addition, the release control agent constituting the sustained-release tablet preferably has a weight ratio of high-viscosity hydroxypropylmethylcellulose having a viscosity of 80,000 cps to 120,000 cps: low viscosity hydroxypropylmethylcellulose having a viscosity of 2,000 cps to 20,000 cps of 2.5 to 1: 1, preferably 1.75 At a temperature of 37 ° C, pH 4.0, and a water effluent, according to Method 2 (Paddle Method) of the Korean Pharmacopoeia dissolution Assay, 1 hour after the first active ingredient was mixed with 1: 1 To 45% of the total weight of the first active ingredient, 60 to 80% of the total weight of the first active ingredient after 8 hours, and 85% or more of the total weight of the first active ingredient after 24 hours.

In addition, according to one embodiment of the present invention, the rabeprazole composition in the form of an enteric coated tablet may contain, in addition to the second active ingredient, an excipient, an alkalizing agent, a disintegrant, a binder or a lubricant. The excipient, disintegrant, binder and lubricant are as described above.

The second active ingredient rabeprazole or a pharmaceutically acceptable salt thereof may be contained in an amount of 0.1 to 10 parts by weight, more specifically 1 to 5 parts by weight, based on 100 parts by weight of the total combined preparation, It is not limited. The second active ingredient may be contained in an amount of 1 to 20 parts by weight, more specifically 5 to 15 parts by weight, based on 130 parts by weight of the second composition.

The excipient in the second composition may be included in an amount of 5 to 30 parts by weight, specifically 10 to 20 parts by weight, based on 100 parts by weight of the total complex preparation. The excipient may be contained in an amount of 30 to 60 parts by weight, more specifically 35 to 50 parts by weight, based on 130 parts by weight of the second composition.

The disintegrant in the second composition may be contained in an amount of 0.5 to 15 parts by weight, specifically 1 to 7 parts by weight, based on 100 parts by weight of the total complex preparation. The disintegrant may be contained in an amount of 5 to 30 parts by weight, more specifically 10 to 20 parts by weight, based on 130 parts by weight of the second composition.

The binder in the second composition may be included in an amount of 0.1 to 5 parts by weight, specifically 0.5 to 2.5 parts by weight based on 100 parts by weight of the total complex preparation. The binder may be contained in an amount of 0.5 to 10 parts by weight, more preferably 1 to 5 parts by weight, based on 130 parts by weight of the second composition.

The lubricant in the second composition may be included in an amount of 0.1 to 5 parts by weight, specifically 0.5 to 2.5 parts by weight, based on 100 parts by weight of the total combined preparation. The lubricant may be contained in an amount of 0.5 to 10 parts by weight, more preferably 1 to 5 parts by weight, based on 130 parts by weight of the second composition.

The second composition comprising rabeprazole or a salt thereof may contain an alkalizing agent such as magnesium oxide when used as a vial, and the alkalizing agent in the second composition may be included in an amount of 1 to 30 parts by weight based on 100 parts by weight of the total combined preparation Specifically, 10 to 20 parts by weight. And 30 to 60 parts by weight, more specifically 35 to 50 parts by weight, based on 130 parts by weight of the second composition.

The second composition comprising rabeprazole or a salt thereof may be in the form of enteric tablets which do not dissolve in the gastric acid and dissolve when the sertide is lowered into the small intestine. The enteric feed agent in the second composition may be contained in an amount of 0.1 to 10 parts by weight, specifically 1 to 5 parts by weight, based on 100 parts by weight of the total complex preparation. And 1 to 20 parts by weight, more specifically 5 to 15 parts by weight, based on 130 parts by weight of the second composition.

According to one embodiment of the present invention, the combination preparation of the present invention can be produced by a method for producing a combination preparation including the following steps.

i) preparing enteric coated tablets containing rabeprazole or a pharmaceutically acceptable salt thereof, excipients and an alkalizing agent;

ii) preparing a cosolvent containing a simulated pride or a pharmaceutically acceptable salt thereof;

iii) preparing a sustained release containing a simulated free or its pharmaceutically acceptable salt and a controlled release agent; And

iv) filling the capsule with the intact, sustained, and enteric coated tablets.

In the above production process, steps i) to iii) may be produced in any order and may be produced at the same time, and the internal and external dilution may have a final hardness of the order of 10 to 14 MPa.

In another aspect of the present invention, there is provided a combination preparation in the form of a capsule comprising a rabeprazole composition (second composition) in the form of enteric coating pellets and a simulated free composition (first composition) comprising at least one tablet do.

As shown in FIG. 4, the rabeprazole composition may take the form of enteric coated pellets, and the simulated free composition may be composed of at least one tablet, preferably two tablets of slow-release and sustained-release. The present invention may be a composite preparation in the form of a capsule containing each of these compositions.

The first effective ingredient, moscafide or a pharmaceutically acceptable salt thereof may be contained in an amount of 0.1 to 15 parts by weight, more specifically 3 to 10 parts by weight, based on 100 parts by weight of the total combined preparation, It does not.

The first active ingredient may be contained in an amount of 1 to 20 parts by weight, more specifically 2 to 15 parts by weight, based on 75 parts by weight of the first composition. If the first composition is an immediate-release composition, it may be contained in an amount of 2 to 7 parts by weight based on 75 parts by weight of the first composition, and may be contained in an amount of 8 to 13 parts by weight based on 75 parts by weight of the first composition.

According to a preferred embodiment of the present invention, the morph-free composition comprises at least one inert diluent, including an excipient, a disintegrant, a binder or a lubricant in addition to the first active ingredient; And one or more sustained release formulations including excipients, disintegrants, release-controlling agents, binders or lubricants in addition to the first active ingredient. These sustained-release and intrathecal rabeprazole compositions in the form of coating pellets, May be used as a combination preparation in the form of a capsule. The excipient, disintegrant, binder, lubricant, and release control agent are as described above.

The excipient in the first composition may be included in an amount of 20 to 40 parts by weight, specifically 25 to 35 parts by weight, based on 100 parts by weight of the total combined preparation. The excipient may be contained in an amount of 15 to 50 parts by weight, more specifically 20 to 45 parts by weight, based on 75 parts by weight of the first composition. If the first composition is an immediate-release composition, it may be contained in an amount of 30 to 45 parts by weight based on 75 parts by weight of the first composition, and may be contained in an amount of 20 to 30 parts by weight based on 75 parts by weight of the first composition.

The disintegrant in the first composition may be contained in an amount of 10 to 30 parts by weight, specifically 15 to 25 parts by weight, based on 100 parts by weight of the total composite preparation. The disintegrant may be contained in an amount of 5 to 35 parts by weight, more specifically 10 to 30 parts by weight, based on 75 parts by weight of the first composition. If the first composition is an immediate-release composition, it may be contained in an amount of 20 to 30 parts by weight based on 75 parts by weight of the first composition, and if it is a sustained-release composition, it may be included in an amount of 10 to 20 parts by weight relative to 75 parts by weight of the first composition.

The binder in the first composition may be included in an amount of 1 to 10 parts by weight, specifically 3 to 7 parts by weight, based on 100 parts by weight of the total combined preparation. The binder may be contained in an amount of 0.5 to 10 parts by weight, more preferably 1 to 7 parts by weight, based on 75 parts by weight of the first composition.

The lubricant in the first composition may be included in an amount of 0.1 to 5 parts by weight, specifically 0.5 to 2.5 parts by weight, based on 100 parts by weight of the total complex preparation. The lubricant may be contained in an amount of 0.1 to 5 parts by weight, more specifically 0.5 to 3 parts by weight based on 75 parts by weight of the first composition.

The sustained release agent (release control agent) contained in the sustained release layer of the simulated free composition may be used as a mixture of high viscosity hydroxypropyl methylcellulose and low viscosity hydroxypropyl methylcellulose, 1 to 20 parts by weight, particularly 5 to 15 parts by weight, based on the weight of the composition. The release control agent may be contained in an amount of 10 to 40 parts by weight, more specifically 20 to 30 parts by weight, based on 75 parts by weight of the sustained release first composition.

In addition, the release control agent constituting the sustained-release tablet preferably has a weight ratio of high-viscosity hydroxypropylmethylcellulose having a viscosity of 80,000 cps to 120,000 cps: low viscosity hydroxypropylmethylcellulose having a viscosity of 2,000 cps to 20,000 cps of 2.5 to 1: 1, preferably 1.75 At a temperature of 37 ° C, pH 4.0, and a water effluent, according to Method 2 (Paddle Method) of the Korean Pharmacopoeia dissolution Assay, 1 hour after the first active ingredient was mixed with 1: 1 To 45% of the total weight of the first active ingredient, 60 to 80% of the total weight of the first active ingredient after 8 hours, and 85% or more of the total weight of the first active ingredient after 24 hours.

In addition, according to one embodiment of the present invention, the rabeprazole composition in the form of enteric coated pellets may contain, in addition to the second active ingredient, an excipient, a coater agent, an enteric agent, and the like. Herein, the excipient, coater agent, and enteric coating agent are as described above.

The second active ingredient rabeprazole or a pharmaceutically acceptable salt thereof may be contained in an amount of 0.1 to 15 parts by weight, more specifically 3 to 10 parts by weight, based on 100 parts by weight of the total combined preparation, It is not limited. The second active ingredient may be contained in an amount of 1 to 20 parts by weight, more specifically 5 to 15 parts by weight, based on 55 parts by weight of the second composition.

The excipient in the second composition may be included in an amount of 1 to 25 parts by weight, specifically 10 to 20 parts by weight, based on 100 parts by weight of the total complex preparation. The excipient may be contained in an amount of 20 to 50 parts by weight, more specifically 25 to 40 parts by weight, based on 55 parts by weight of the second composition.

The coating agent in the second composition may be included in an amount of 0.5 to 10 parts by weight, specifically 1 to 5 parts by weight, based on 100 parts by weight of the total combined preparation. The coating agent may be contained in an amount of 1 to 10 parts by weight, more specifically 3 to 8 parts by weight based on 55 parts by weight of the second composition.

The enteric feed agent in the second composition may be contained in an amount of 0.1 to 10 parts by weight, specifically 1 to 7 parts by weight, based on 100 parts by weight of the total complex preparation. The enteric coating agent may be contained in an amount of 1 to 20 parts by weight, more specifically 5 to 15 parts by weight, based on 55 parts by weight of the second composition.

When the second composition comprising rabeprazole or a salt thereof is used as pellets, talc and / or titanium oxide may be used as the excipient. Talc and titanium oxide may be used in an amount of 0.01 to 3 parts by weight , More specifically 0.1 to 1 part by weight. And 0.05 to 3.0 parts by weight, more specifically 0.1 to 2.0 parts by weight, based on 55 parts by weight of the second composition.

According to one embodiment of the present invention, the combination preparation of the present invention can be produced by a method for producing a combination preparation including the following steps.

i) preparing enteric coated pellets containing rabeprazole or a pharmaceutically acceptable salt thereof, excipients, coagulants and enteric feeds;

ii) preparing a cosolvent containing a simulated pride or a pharmaceutically acceptable salt thereof;

iii) preparing a sustained release containing a simulated free or its pharmaceutically acceptable salt and a controlled release agent; And

iv) filling the capsule with the intact, sustained, and intestinal coating pellets.

In the above production method, steps i) to iii) may be produced in any order, and may be produced at the same time.

The combination preparation of the present invention may be taken before or after the meal, but it is generally accepted that taking the medicine at the time of fasting is less affected by food.

The combined preparation of the present invention may be effective for the prevention, treatment or amelioration of gastrointestinal diseases, and may also be useful for improving digestive symptoms.

The gastrointestinal disorder may be referred to as various names such as chronic dyspepsia, non-ulcerative dyspepsia, chronic diarrhea, irritable bowel, irritable bowelitis, chronic gastritis, chronic abdominal pain, neurogenic gastroenteritis and gastrointestinal pain, constipation, diarrhea, vomiting It is a disease that has various symptoms repeatedly. Examples include various symptoms occurring in the gastrointestinal tract, but the type is not limited thereto. In addition, the gastrointestinal symptoms include dyspepsia and are specifically classified according to the Rome Criteria, more specifically functional dyspepsia classified in the Rome III Diagnostic Criteria for Functional Gastrointestinal Disorders But is not limited thereto.

Since the combined preparation of the present invention can greatly reduce the content of the excipient, the preparation size can be made small in spite of being a combination preparation, and convenience and convenience of the patient can be improved. According to a preferred embodiment of the present invention, the total weight of the combination preparation of the present invention may be 500 mg or less, preferably 400 mg or less, more preferably 300 mg or less, and most preferably 210 mg or less.

In addition, since the combined preparation of the present invention is prepared as a sustained-release or sustained-release layer using a release-controlling agent, the active ingredient and the active metabolite continuously maintain a constant concentration in the plasma for a considerable period of time, And consequently the drug adaptability to the patients is increased to increase the compliance of the medication. In addition, the synergistic effect and the economic effect of the combination administration of rabeprazole, which inhibits gastric acid secretion, Very useful.

The combined preparation prepared according to the present invention enables rapid release of drug without deterioration of elution due to interaction of mosaic fibril and rabeprazole, thereby showing improved drug dissolution rate and bioavailability, , The content of the excipient can be greatly reduced, and the compliance of the patient with the medication can be increased due to the size of the formulation.

FIG. 1 shows an example of a combination preparation according to the present invention, which is a simplified schematic diagram of a combined preparation sustained-release preparation containing rabeprazole core.
Figure 2 illustrates an example of a combination formulation according to the present invention, wherein the rabeprazole tablet and the mosaic fϊld tritium tablet represent a schematic representation of the combination formulation contained in the capsules.
FIG. 3 shows an example of a combination preparation according to the present invention, which is a schematic view of a combination preparation containing a capsule preparation containing a cosmeal formulation and a sustained-release tablet for sustained-release and rabeprazole preparation.
FIG. 4 shows an example of a combination preparation according to the present invention. FIG. 4 is a schematic view of a combination preparation containing a capsule preparation and a sustained-release formulation, a sustained-release formulation and a rabeprazole pellet.
FIG. 5 is a graph showing the changes in the average dissolution rate of the combination preparation having a press-coated tablet prepared according to Examples 1 to 3 with time.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are for further illustrating the present invention, and the scope of the present invention is not limited by these examples.

One. Example  1 to 3: Rabeprazole The nucleus  included Simulated fly  Sustainable Combined Formulation ( High- )

1-1. Rabeprazole Long coat  Manufacture of tablets

D-mannitol, magnesium oxide, low-substituted hydroxypropylcellulose (L-HPC) and crospovidone were mixed with sodium rabeprazole according to the ingredients and amounts thereof described in Table 1 below, Hydroxypropylcellulose (HPC) was added and the mixture was granulated and dried in a cabinet dryer at 50 to 60 ° C for 1 to 2 hours (LOD 2% or less). After sizing, the mixture was actively mixed with sodium stearyl fumarate. This mixture was tableted to a weight of 120 mg per tablet, and then film-coated using a conventional coating method using ACRYL-EZE ^® II (product name of Colorcon Co.) for rabeprazole containing 10 mg of rabeprazole sodium Enteric coated tablets were prepared.

1-2. Simulated fly Immediate layer Granular  Produce

The microfibrillated citric acid dihydrate, microcrystalline cellulose, lactose hydrate, and low-substituted hydroxypropyl cellulose (L-HPC) were mixed in accordance with the ingredients and amounts thereof in the inner layer of the outer layer in Table 1, Povidone K-30 was dissolved and granulated. The mixture was dried in a cabinet dryer at 50 to 60 ° C for 1 to 2 hours (LOD 2% or less). After sizing, the remaining lubricants were mixed.

1-3. Simulated fly West floor Granular  Produce

Lactose hydrate, low viscosity hydroxypropyl methylcellulose (4000 cps, HPMC 2910), high viscosity hydroxypropyl methylcellulose (100,000 or less), or the like, according to the content of ingredients described in the middle layer of the outer layer of Table 1, cPP, HPMC 2208) and low-substituted hydroxypropylcellulose (L-HPC) were mixed and ethanol and povidone K-30 dissolved in ethanol was added thereto beforehand, And dried for 2 hours (LOD 2% or less). After sizing, the remaining lubricants were mixed.

1-4. Rabeprazole The nucleus  included Simulated fly  Seojungjeong Composite Manufacturing

The coated tablet for rabeprazole enteric coated tablets prepared by weighing 130.0 mg per tablet according to the following Table 1 is used as the inner core. The coated tablet for rabeprazole enteric coated tablets was supplied to the inner core feeder of a tablet press (Kilian, Killian type), and 150.0 mg per tablet of the simulated free tablet granules according to the embodiment of Table 1 was supplied to the first outer- And 150.0 mg per one tablet of the sustained-release granules was supplied to the second outer-layer granule feeder according to the embodiment of Table 1, and the tablets were compressed into the core tablets. The coating solution was dispersed or dissolved in ethanol to prepare a coating solution. The coating solution (Sejong Machinery Co., SFC-30) was sprayed onto the coating solution (Sejong Machinery Co., SFC-30) To prepare a press-coated tablet. The formulation diagram of the press-coated tablet is shown in Fig.

division Classification ingredient Example 1 Example 2 Example 3

of mine

nucleus

tablet

chief ingredient Rabeprazole sodium 10.00 10.00 10.00 Excipient D-mannitol 44.00 44.00 44.00 Alkalizing agent Magnesium oxide 45.00 45.00 45.00 Binder Hydroxypropylcellulose 3.00 3.00 3.00 Disintegration Low-substituted hydroxypropylcellulose 12.00 12.00 12.00 Disintegration Crospovidone 3.00 3.00 3.00 Lubricant Sodium stearyl fumarate 3.00 3.00 3.00 Intestine ACRYL-EZE ^® II 10.00 10.00 10.00 Inner nuclear system (mg / tablet) 130 130 130

outside

layer


chief ingredient Mosaic pride citrate dihydrate 5.29 5.29 5.29 Excipient Microcrystalline cellulose 47.29 47.29 47.29 Excipient Lactose baggage 37.52 37.52 37.52 Disintegration Low-substituted hydroxypropylcellulose 48 48 48 Binder Povidone K-30 10 10 10 Lubricant Light anhydrous silicic acid 0.66 0.66 0.66 Lubricant Magnesium stearate 1.24 1.24 1.24 Fasting sub-total (mg / tablet) 150 150 150

outside


layer



chief ingredient Mosaic pride citrate dihydrate 10.58 10.58 10.58 Excipient Microcrystalline cellulose 26 26 26 Excipient Lactose baggage 29.56 29.56 29.56 Soviet firearms Low viscosity Hydroxypropylmethylcellulose
( HPMC  2910) 16 18 20 Soviet firearms High viscosity Hydroxypropylmethylcellulose
( HPMC  2208) 28 26 24 Binder Povidone K-30 10 10 10 Disintegration Low-substituted hydroxypropylcellulose 28 28 28 Lubricant Light anhydrous silicic acid 0.62 0.62 0.62 Lubricant Magnesium stearate 1.24 1.24 1.24 Western subtotals (mg / tablet) 150 150 150 Coater Opadry-OY-C-7000A 5 5 5 High- Total (mg / tablet) 435 435 435

1-5. in vitro  Test result

In Table 1, the dissolution rate test was carried out in vitro on the press-coated tablets of Examples 1 to 3. The dissolution profile of the active ingredient, simaflid citrate, dihydrate sustained release preparation was confirmed over time in the pH 4.0 dissolution solution of Korean Pharmacopoeia. The results are shown in Table 2 and FIG.

The test conditions used for the dissolution test are as follows.

Specimen: The tablets of Examples 1 to 3

Elution test solution: pH 4.0 in the Korean Pharmacopoeia dissolution assay

Amount of eluent: 900 ml, Test temperature: 37 ± 0.5 ° C

Test method: Korean Pharmacopoeia dissolution test No. 2 (paddle method), 50 rotations per minute

Sampling: The eluate is taken at each sample collection time, filtered with a 0.45 μm filter to prepare the sample solution, and the eluate is taken,

Analysis equipment: Ultraviolet spectrophotometer (UV-Vis), absorbance 273 nm

division
Average dissolution rate (%) in pH 4.0 dissolution test solution 0.5
time One
time 2
time 3
time 5
time 6
time 8
time 10
time 12
time 24
time Example 1 35.5 37.4 46.5 49.5 56.3 59.5 65.4 72.4 77.5 82.1 Example 2 34.4 38.5 45.6 50.8 58.6 62.4 67.5 73.5 79.3 84.6 Example 3 36.8 40.9 48.1 53.9 62.5 64.8 72.3 77.9 86.4 95.6

As for the dissolution rate according to time in Table 2, all of the sustained-release tablets of simfried citrate hydrochloride having all of the present invention had a dissolution rate of not less than 80% for 24 hours, showing continuous release of the active ingredient. The sustained-release tablet of Example 3 showed a dissolution profile of more than 95% for 24 hours, showing a very suitable dissolution profile for once-a-day administration. On the other hand, in Examples 1 and 2, the weight ratio of high viscosity hydroxypropylmethylcellulose (HPMC 2208) in the sustained release agent was relatively high as compared with the active ingredient, and the dissolution rate of the tablets was sustained to 24 hours or more there was. Thus, it can be seen that the sustained-release tablet of the present invention can easily control the elution characteristics according to the content of the hydrophilic polymer of hydroxypropylmethylcellulose contained in the high viscosity to the low viscosity.

2. Example  4 to 5: Rabeprazole Enteric coating tablets and Simulated fly  Preparation of triple-positive combination preparation

2-1. Rabeprazole Long coat  Manufacture of tablets

D-mannitol, magnesium oxide, low-substituted hydroxypropylcellulose (L-HPC) and crospovidone were mixed with rabeprazole sodium and the components described in the enteric coating tablets of Table 3 below, (HPC) was added thereto, and the mixture was granulated. The mixture was dried in a cabinet dryer at 50 to 60 ° C for 1 to 2 hours (LOD 2% or less). After sizing, the mixture was actively mixed with sodium stearyl fumarate. This mixture was tableted to a weight of 120 mg per tablet, and then film-coated using a conventional coating method using ACRYL-EZE ^® II (product name of Colorcon Co.) for rabeprazole containing 10 mg of rabeprazole sodium Enteric coated tablets were prepared.

2-2. Simulated fly  First and third Immediate layer Granular  Produce

(Microcrystalline cellulose, lactose hydrate, and low-substituted hydroxypropyl cellulose (L-HPC) were mixed according to the components and amounts thereof described in Table 3 below, The povidone K-30 solution was added, granulated, and dried in a cabinet dryer at 50 to 60 ° C for 1 to 2 hours (LOD 2% or less). After sizing, the remaining lubricants were mixed.

2-3. Simulated fly  Second West floor Granular  Produce

According to the ingredient contents described in the middle layer of the triplet of Table 3 below, the microfibrillated citrate dihydrate was mixed with microcrystalline cellulose, lactose hydrate, low viscosity hydroxypropyl methylcellulose (4000 cps, HPMC 2910), high viscosity hydroxypropyl methylcellulose 100,000 cps, HPMC 2208) and low-substituted hydroxypropylcellulose (L-HPC) were mixed, and then povidone K-30 dissolved in ethanol was added in advance to coalesce and granulate. Dried for 2 hours (LOD 2% or less). After sizing, the remaining lubricants were mixed.

2-4. Rabeprazole Enteric coated tablets  And Simulated fly  Sue castle Triplet  Manufacture of compound preparation

Mossafried triplets were prepared using the granules of the immediate and extended layers of Mossafrid 1 to 3 prepared according to the examples in Table 3 below. The granules of the first immediate layer, the second sustained release layer and the third immediate-release layer were sequentially charged and tabletted using a triple tablet machine, and the resulting tablet had a weight of 225.0 mg per tablet, a preload and a main pressure, and a final three-point definite hardness of 10 to 14 MPa Were prepared in triplicate. The prepared mosapride triplet and the prepared coating tablet for rabeprazole enteric coating were sequentially filled into hard capsules of size No. 0 to No. 2 to prepare a coated tablet for rabeprazole enteric coating and a sustained release triplet combination preparation. The formulation diagram of the combination preparation is shown in Fig.

division Classification ingredient Example 4 Example 5


Intestinal
Coating



chief ingredient Rabeprazole sodium 10 10 Excipient D-mannitol 44 29 Alkalizing agent Magnesium oxide 45 30 Binder Hydroxypropylcellulose 3 3 Disintegration Low-substituted hydroxypropylcellulose 12 12 Disintegration Crospovidone 3 3 Lubricant Sodium stearyl fumarate 3 3 Intestine ACRYL-EZE ^® II 10 10 Long coat  Subtotal (mg / tablet) 130 100
1st

Immediate layer



chief ingredient Mosaic pride citrate dihydrate 2.645 2.645 Excipient Microcrystalline cellulose 21 21 Excipient Lactose baggage 21.405 21.405 Disintegration Low-substituted hydroxypropylcellulose 24 24 Binder Povidone K-30 5 5 Lubricant Light anhydrous silicic acid 0.33 0.33 Lubricant Magnesium stearate 0.62 0.62 Fasting sub-total (mg / tablet) 75 75

Second

West floor




chief ingredient Mosaic pride citrate dihydrate 10.58 10.58 Excipient Microcrystalline cellulose 13 13 Excipient Lactose baggage 9.49 9.49 Sustainable fire system Low viscosity hydroxypropyl methylcellulose (HPMC 2910) 8 8 Sustainable fire system High viscosity hydroxypropyl methylcellulose
(HPMC 2208) 14 14 Binder Povidone K-30 5 5 Disintegration Low-substituted hydroxypropylcellulose 14 14 Lubricant Light anhydrous silicic acid 0.31 0.31 Lubricant Magnesium stearate 0.62 0.62 Western subtotals (mg / tablet) 75 75

Third

Immediate layer


chief ingredient Mosaic pride citrate dihydrate 2.645 2.645 Excipient Microcrystalline cellulose 21 21 Excipient Lactose baggage 21.405 21.405 Disintegration Low-substituted hydroxypropylcellulose 24 24 Binder Povidone K-30 5 5 Lubricant Light anhydrous silicic acid 0.33 0.33 Lubricant Magnesium stearate 0.62 0.62 Fasting sub-total (mg / tablet) 75 75 Triplet Triple Electrostatic System (mg / tablet) 225 225 Composite Total (mg / tablet) 355 325

2-5. in vitro  Test result

In Table 3, the dissolution rate test was conducted in vitro on the triple-containing complex preparations of Examples 4 and 5. The dissolution profile of the active ingredient, simaflid citrate, dihydrate, sustained release preparation was confirmed over time in the pH 4.0 dissolution solution of the Korean Pharmacopoeia. The results are shown in Table 4 below.

The test conditions used for the dissolution test are as follows.

Specimen: In Table 3, the triple-containing complex preparations of Examples 4 and 5

Elution test solution: pH 4.0 in the Korean Pharmacopoeia dissolution assay

Amount of eluent: 900 ml, Test temperature: 37 ± 0.5 ° C

Test method: Korean Pharmacopoeia dissolution test No. 2 (paddle method), 50 rotations per minute

Sampling: The eluate is taken at each sample collection time, filtered with a 0.45 μm filter to prepare the sample solution, and the eluate is taken,

Analysis equipment: Ultraviolet spectrophotometer (UV-Vis), absorbance 273 nm

division
Average dissolution rate (%) in pH 4.0 dissolution test solution 0.5
time One
time 2
time 3
time 5
time 6
time 8
time 10
time 12
time 24
time Example 4 32.3 39.5 47.1 53.2 62.5 68.8 72.3 77.9 86.4 95.6 Example 5 33.4 38.2 46.6 52.6 60.6 69.4 73.5 79.5 85.3 96.3

As for the dissolution rate according to time in Table 4, all of the simulated free citric acid salt formulations of the combination preparation of Examples 4 and 5 were not significantly different from those of the simulated free double-tableted tablets of the present invention, To the surface of the substrate. Also, it was confirmed that the preparations of both Examples had a hardness of about 10-14 Mpa and the disintegration of the tablets within 10 minutes after the disintegration test in water did not show any significant difference in the physico-chemical properties.

In particular, the combined preparation of Example 5 did not cause any penile disorder in the rabeprazole enteric coated tablets despite the fact that the content of D-mannitol, which is an excipient, and magnesium oxide, which is an alkalizing agent, were partially reduced, As the content was reduced, it was easy to fill even the smaller hard capsule No. 2 as compared with the combination preparation of Example 4, which was easy to fill the hard capsule No. 0 size. It is confirmed that when the hard capsule to be filled is large or the size of the capsule is small, it is easy for the patient to take the medicine when developing the medicine and has the advantage of improving the compliance of the formulation.

3. Example  6 to 7: Simulated fly Genus  And Rabeprazole Enteric coated tablets  Compound preparation ( Complex compound )

3-1. Rabeprazole Long coat  Manufacture of tablets

D-mannitol, magnesium oxide, low-substituted hydroxypropyl cellulose (L-HPC) and crospovidone were mixed with rabeprazole sodium and the components described in the enteric coated tablet of Table 5 below, (HPC) was added thereto, and the mixture was granulated. The mixture was dried in a cabinet dryer at 50 to 60 ° C for 1 to 2 hours (LOD 2% or less). After sizing, the mixture was actively mixed with sodium stearyl fumarate. This mixture was tableted to a weight of 120 mg per tablet, and then film-coated using a conventional coating method using ACRYL-EZE ^® II (product name of Colorcon Co.) for rabeprazole containing 10 mg of rabeprazole sodium Enteric coated tablets were prepared.

3-2. Simulated fly Justice  Produce

(Microcrystalline cellulose, lactose hydrate, and low-substituted hydroxypropyl cellulose (L-HPC) were mixed with the monofilament citric acid dihydrate and the low-substituted hydroxypropyl cellulose (L-HPC) 30 was melted and granulated, and dried in a cabinet dryer at 50 to 60 ° C for 1 to 2 hours (LOD 2% or less). After sizing, the remaining lubricants were mixed. The mixture was tableted in a conventional manner with a weight of 75 mg per tablet and a hardness in the range of 10 to 14 MPa to prepare a propolis solution containing the simpia fruct citric acid salt hydrate.

3-3. Simulated fly  Manufacture of West Jungjeong

Lactose hydrate, low viscosity hydroxypropyl methylcellulose (4000 cps, HPMC 2910), high viscosity hydroxypropyl methylcellulose (100,000 cps, HPMC (trade name), and the like) according to the ingredient contents described in Table 5 below. 2208) and low-substituted hydroxypropylcellulose (L-HPC), and then poured the povidone K-30 dissolved in ethanol in advance to coalesce and granulate, and dried in a cabinet dryer at a temperature of 50 to 60 ° C for 1 to 2 hours (LOD 2% or less). After sizing, the remaining lubricants were mixed. The mixture was tableted in a conventional manner at a hardness in the range of 10 to 14 Mpa and 75 mg weight per tablet to prepare a sustained-release tablet containing the simulated pride citric acid salt hydrate.

3-4. Simulated fly Genus  And Rabeprazole Enteric coated tablets  Composite manufacturing

The coated tablets prepared in accordance with the examples of Table 5 below were filled sequentially using coating preparations for hard capsule preparation, and the combined preparations were prepared. The hard capsules were packed in No. 0 to No. 2 hard capsules to prepare a combined preparation containing the coated tablet for the simulated free flow and the sustained-flowing tablet and the rabeprazole enteric coated tablet. The formulation diagram of the combination preparation is shown in Fig.

division Classification ingredient Example 6 Example 7


Intestinal
Coating



chief ingredient Rabeprazole sodium 10 10 Excipient D-mannitol 44 29 Alkalizing agent Magnesium oxide 45 30 Binder Hydroxypropylcellulose 3 3 Disintegration Low-substituted hydroxypropylcellulose 12 12 Disintegration Crospovidone 3 3 Lubricant Sodium stearyl fumarate 3 3 Intestine ACRYL-EZE ^® II 10 10 Long coat  Subtotal (mg / tablet) 130 100


Deceleration



chief ingredient Mosaic pride citrate dihydrate 5.29 5.29 Excipient Microcrystalline cellulose 21 21 Excipient Lactose baggage 18.76 18.76 Disintegration Low-substituted hydroxypropylcellulose 24 24 Binder Povidone K-30 5 5 Lubricant Light anhydrous silicic acid 0.33 0.33 Lubricant Magnesium stearate 0.62 0.62 Subtotal Subtotal (mg / tablet) 75 75



West




chief ingredient Mosaic pride citrate dihydrate 10.58 10.58 Excipient Microcrystalline cellulose 13 13 Excipient Lactose baggage 9.49 9.49 Sustainable fire system Low viscosity hydroxypropyl methylcellulose (HPMC 2910) 8 8 Sustainable fire system High viscosity hydroxypropyl methylcellulose
(HPMC 2208) 14 14 Binder Povidone K-30 5 5 Disintegration Low-substituted hydroxypropylcellulose 14 14 Lubricant Light anhydrous silicic acid 0.31 0.31 Lubricant Magnesium stearate 0.62 0.62 Subtotal Slightness (mg / tablet) 75 75 Composite Total (mg / tablet) 280 250

3-5. in vitro Test result

In Table 5, the dissolution rate test was carried out in vitro on the combination preparations of Examples 6 and 7. The dissolution profile of the active ingredient, simaflid citrate, dihydrate sustained-release preparation was confirmed over time at pH 4.0 in the Korean Pharmacopoeia dissolution test liquid, and the results are shown in Table 6 below.

The test conditions used for the dissolution test are as follows.

Specimen: In Table 5, the combination preparation of Examples 6 and 7

Elution test solution: pH 4.0 in the Korean Pharmacopoeia dissolution assay

Amount of eluent: 900 ml, Test temperature: 37 ± 0.5 ° C

Test method: Korean Pharmacopoeia dissolution test No. 2 (paddle method), 50 rotations per minute

Sampling: The eluate is taken at each sample collection time, filtered with a 0.45 μm filter to prepare the sample solution, and the eluate is taken,

Analysis equipment: Ultraviolet spectrophotometer (UV-Vis), absorbance 273 nm

division
Average dissolution rate (%) in pH 4.0 dissolution test solution 0.5
time One
time 2
time 3
time 5
time 6
time 8
time 10
time 12
time 24
time Example 6 31.5 38.4 46.1 52.3 61.5 69.8 73.3 79.9 85.4 96.8 Example 7 32.2 37.3 45.6 53.9 60.8 68.4 74.5 78.5 86.2 97.3

As for the dissolution rate with time in Table 6, all of the simulated free citric acid hydrogels of the combination preparation of Examples 6 and 7 were not significantly different from those of the simulated free double purification tablets of the present invention, and the active ingredients were continuously To the surface of the substrate. Also, it was confirmed that the preparations of both Examples had a hardness of about 10-14 Mpa and the disintegration of the tablets within 10 minutes after the disintegration test in water did not show any significant difference in the physico-chemical properties.

In particular, the combined preparation of Example 7 did not cause any penile disturbance in rabeprazole-containing tablets, despite the fact that the content of D-mannitol, an excipient, and magnesium oxide, which is an alkalizing agent, were partially reduced, As the content was reduced, the hard capsule No. 2 was easier to fill than the complex formulation of Example 6, which was easy to fill in hard capsule No. 0 size. It is confirmed that when the hard capsule to be filled is large or the size of the capsule is small, it is easy for the patient to take the medicine when developing the medicine and has the advantage of improving the compliance of the formulation.

4. Example  8 to 9: Simulated fly Genus  And Rabeprazole Long coat Pellet  Compound preparation ( Complex compound  Granules)

4-1. Rabeprazole Long coat Pellet  Produce

According to the ingredients and the amount of the enteric coating pellets shown in Table 7 below, a solution of rabeprazole sodium and hydroxypropylmethylcellulose (HPMC), polyethylene glycol (PEG), talc and titanium oxide in pre- First, the white sugar was coated with a fluidized bed coater at 60 to 70 ° C and 40% RH humidity, and a solution 2 of hydroxypropylmethylcellulose phthalate (HPMCP), polyethylene glycol (PEG), talc and titanium oxide dissolved in ethanol Second coating was conducted under the same coating conditions with the tea coating solution, followed by drying for 30 minutes to prepare coating pellets for rabeprazole enteric coating.

4-2. Simulated fly Justice  Produce

(Microcrystalline cellulose, lactose hydrate, low-substituted hydroxypropylcellulose (L-HPC)) was mixed with the monofilament citric acid dihydrate according to the ingredients and amounts thereof in Table 7 below, 30 was melted and granulated, and dried in a cabinet dryer at 50 to 60 ° C for 1 to 2 hours (LOD 2% or less). After sizing, the remaining lubricants were mixed. The mixture was tableted in a conventional manner with a weight of 75 mg per tablet and a hardness in the range of 10 to 14 MPa to prepare a propolis solution containing the simpia fruct citric acid salt hydrate.

4-3. Simulated fly  Manufacture of West Jungjeong

Lactose hydrate, low viscosity hydroxypropyl methylcellulose (4000 cps, HPMC 2910), high viscosity hydroxypropyl methylcellulose (100,000 cps, HPMC (trade name), and the like) according to the ingredient contents described in Table 7 below. 2208) and low-substituted hydroxypropylcellulose (L-HPC), and then poured the povidone K-30 dissolved in ethanol in advance to coalesce and granulate, and dried in a cabinet dryer at a temperature of 50 to 60 ° C for 1 to 2 hours (LOD 2% or less). After sizing, the remaining lubricants were mixed. The mixture was tableted in a conventional manner at a hardness in the range of 10 to 14 Mpa and 75 mg weight per tablet to prepare a sustained-release tablet containing the simulated pride citric acid salt hydrate.

4-4. Simulated fly Genus  And Rabeprazole Long coat Pellet  Composite manufacturing

The composite pellets prepared in accordance with the examples of Table 7 below were filled sequentially by using a rigid capsule preparation equipment, and coating pellets for rabeprazole intestine were sequentially filled. The hard capsules were packed in No. 0 to No. 2 hard capsules to prepare a combined preparation containing the coating pellets for the simulated free spinning, the sustained spinning and the rabeprazole enteric coating. For reference, the formulation diagram of the combination preparation is shown in Fig.

division Classification ingredient Example 8 Example 9


Intestinal
coating
Pellets


chief ingredient Rabeprazole sodium 10 10 Excipient White sugar 30 30 Coater Hydroxypropylmethylcellulose
(HPMC) 5 5 Intestine Hydroxypropylmethylcellulose
Phthalate (HPMCP) 8 12 Excipient Polyethylene glycol (PEG) One One Excipient Talc 0.5 One Excipient Titanium oxide 0.5 One Long coat Pellets  Sub total (mg / C) 55 60


Deceleration



chief ingredient Mosaic pride citrate dihydrate 5.29 5.29 Excipient Microcrystalline cellulose 21 21 Excipient Lactose baggage 18.76 18.76 Disintegration Low-substituted hydroxypropylcellulose 24 24 Binder Povidone K-30 5 5 Lubricant Light anhydrous silicic acid 0.33 0.33 Lubricant Magnesium stearate 0.62 0.62 Subtotal Subtotal (mg / tablet) 75 75



West




chief ingredient Mosaic pride citrate dihydrate 10.58 10.58 Excipient Microcrystalline cellulose 13 13 Excipient Lactose baggage 9.49 9.49 Sustainable fire system Low viscosity hydroxypropyl methylcellulose (HPMC 2910) 8 8 Sustainable fire system High viscosity hydroxypropyl methylcellulose
(HPMC 2208) 14 14 Binder Povidone K-30 5 5 Disintegration Low-substituted hydroxypropylcellulose 14 14 Lubricant Light anhydrous silicic acid 0.31 0.31 Lubricant Magnesium stearate 0.62 0.62 Subtotal Slightness (mg / tablet) 75 75 Composite Total (mg / tablet) 205 210

4-5. in vitro  Test result

In Table 7, the dissolution rate test was conducted in vitro on the combination preparations of Examples 8 and 9. The dissolution profile of the active ingredient, simaflid citrate, dihydrate, sustained release preparation was confirmed over time in the pH 4.0 dissolution solution of the Korean Pharmacopoeia. The results are shown in Table 8 below.

The test conditions used for the dissolution test are as follows.

Specimen: In Table 7, the combination preparation of Examples 8 and 9

Elution test solution: pH 4.0 in the Korean Pharmacopoeia dissolution assay

Amount of eluent: 900 ml, Test temperature: 37 ± 0.5 ° C

Test method: Korean Pharmacopoeia dissolution test No. 2 (paddle method), 50 rotations per minute

Sampling: The eluate is taken at each sample collection time, filtered with a 0.45 μm filter to prepare the sample solution, and the eluate is taken,

Analysis equipment: Ultraviolet spectrophotometer (UV-Vis), absorbance 273 nm

division
Average dissolution rate (%) in pH 4.0 dissolution test solution 0.5
time One
time 2
time 3
time 5
time 6
time 8
time 10
time 12
time 24
time Example 8 33.7 37.4 45.1 53.2 60.3 65.5 72.1 78.9 86.4 95.1 Example 9 34.2 39.3 44.6 54.6 61.9 67.3 73.2 79.5 87.2 96.2

As for the dissolution rate with time in Table 8, all of the simulated free citric acid hydrogels of the combination preparation of Examples 8 and 9 showed no significant difference in dissolution pattern with the simulated free double purification tablet of the present invention, and the active ingredients were continuously To the surface of the substrate. In addition, the combination preparation of Examples 8 and 9 was easy to fill in hard capsules No. 0 to No. 2.

5. Rabeprazole  salt Long coat  Refined in vitro  Dissolution test result

The dissolution rate test was carried out in vitro on the combination preparation of the present invention. The dissolution profile of the coated tablet for rabeprazole sodium, which is another active ingredient, over time in pH 9.0 of the Korean Pharmacopoeia dissolution test was confirmed, and the results are shown in Table 9 below.

The test conditions used for the dissolution test are as follows.

Samples: Coating tablets for rabeprazole sodium in the combination preparations of Examples 1 to 9

Elution test solution: pH 9.0 (3.0915 g of boric acid + 3.7275 g of KCl + 0.832 g of NaOH based on 1 L of water)

Amount of eluent: 900 ml, Test temperature: 37 ± 0.5 ° C

Test method: Korean Pharmacopoeia dissolution test No. 2 (paddle method), 50 rotations per minute

Sampling: Take the eluate for each sample collection time and immediately analyze the sample solution filtered with a 0.45 μm filter

Analysis equipment: Ultraviolet spectrophotometer (UV-Vis), absorbance 284 nm, Cell 1.0 cm

division
Average dissolution rate (%) in pH 9.0 dissolution test solution 15 minutes 30 minutes 45 minutes Examples 1 to 9 5.71 56.24 101.29

The rabeprazole sodium drug has a disadvantage in that it is difficult to dissolve the drug under the general conditions because it has a disadvantage in that the drug is decomposed when the drug is decomposed at a predetermined time under acidic conditions to pH of 6.8 or less and the drug stability is poor. , It was confirmed that the formulation could be designed by performing dissolution test with high stability.

Claims (20)

A first composition comprising mosapride or a pharmaceutically acceptable salt thereof as a first active ingredient, and
A second composition comprising rabeprazole or a pharmaceutically acceptable salt thereof as a second active ingredient. The method according to claim 1,
Wherein the combination preparation has a second composition as the inner core and the first composition has a strong core structure that surrounds the outer layer of the second composition. 3. The method of claim 2,
Wherein the second composition is in the form of enteric coated tablets and the first composition is in the form of granules. 3. The method of claim 2,
The first composition comprises
A first layer comprising a first active ingredient, an excipient, a disintegrant, a binder and a lubricant,
A sustained-release formulation comprising a first active ingredient, an excipient, a disintegrant, a release-controlling agent, a binder and a glidant, or both. 5. The method of claim 4,
The release control agent may be prepared by mixing a high viscosity hydroxypropylmethylcellulose having a viscosity of 80,000 cps to 120,000 cps and a low viscosity hydroxypropylmethylcellulose having a viscosity of 2,000 cps to 20,000 cps in a ratio of 2.5 to 1:
The first active ingredient contained in the aqueous solution at 37 ° C, pH 4.0, and water eluate was 25-45% of the total weight of the first active ingredient after 1 hour according to Method 2 of the Korean Pharmacopoeia (Paddle Method) Wherein the composition satisfies a dissolution profile of 60 to 80% of the total weight of the active ingredient and more than 85% of the total weight of the first active ingredient after 24 hours. 6. The method of claim 5,
The weight ratio of the high viscosity hydroxypropyl methylcellulose to the low viscosity hydroxypropyl methylcellulose is from 1.2 to 1: 1,
The first active ingredient contained in the aqueous solution at 37 ° C, pH 4.0, and water effluent was 40-45% of the total weight of the first active ingredient after 1 hour according to Method 2 of the Korean Pharmacopoeia (Paddle Method) Wherein the composition satisfies a dissolution profile that elutes at least 70% to 75% of the total weight of the active ingredient and at least 90% of the total weight of the first active ingredient after 24 hours. The method according to claim 1,
Wherein the combined preparation is in the form of a capsule comprising a second composition in enteric coated tablet form and a first composition in multi-layer tablet form. 8. The method of claim 7,
The first composition comprises
At least one immediate-release layer comprising a first active ingredient, an excipient, a disintegrant, a binder and a glidant; And one or more sustained release layers comprising a first active ingredient, an excipient, a disintegrant, a release control agent, a binder and a lubricant. 8. The method of claim 7,
Wherein the second composition comprises a second active ingredient, an excipient, an alkalizing agent, a binder, a disintegrant and a glidant, wherein the excipient or the alkalizing agent has a content of 30 to 60 parts by weight relative to 130 parts by weight of the second composition, Compound preparation. 10. The method of claim 9,
Wherein the excipient or the alkalizing agent has an amount of 35 to 50 parts by weight based on 130 parts by weight of the second composition, respectively. The method according to claim 1,
Wherein the combined preparation is in the form of a capsule comprising a second composition in the form of enteric coated tablet and a first composition comprising at least one tablet. 12. The method of claim 11,
The first composition comprises
A first active ingredient, an excipient, a disintegrant, a binder and a glidant; And at least one sustained release comprising a first active ingredient, an excipient, a disintegrant, a release control agent, a binder and a lubricant. 12. The method of claim 11,
Wherein the second composition comprises a second active ingredient, an excipient, an alkalizing agent, a binder, a disintegrant and a glidant, wherein the excipient or the alkalizing agent has a content of 30 to 60 parts by weight relative to 130 parts by weight of the second composition, Compound preparation. 14. The method of claim 13,
Wherein the excipient or the alkalizing agent has an amount of 35 to 50 parts by weight based on 130 parts by weight of the second composition, respectively. The method according to claim 1,
Wherein the combined preparation is in the form of a capsule comprising a second composition in the form of enteric coated pellets and a first composition comprising at least one tablet. 16. The method of claim 15,
The first composition comprises
A first active ingredient, an excipient, a disintegrant, a binder and a glidant; And at least one sustained release comprising a first active ingredient, an excipient, a disintegrant, a release control agent, a binder and a lubricant. 16. The method of claim 15,
Wherein the second composition comprises a second active ingredient, an excipient, a coating agent and an enteric feedstock, wherein the enteric feedstock has a content of from 1 to 20 parts by weight relative to 55 parts by weight of the second composition. 16. The method of claim 15,
Wherein the second composition comprises 0.05 to 3.0 parts by weight of talc and / or titanium oxide relative to 55 parts by weight of the second composition as an excipient. i) preparing enteric coated tablets containing rabeprazole or a pharmaceutically acceptable salt thereof, excipients and an alkalizing agent;
ii) preparing a quick release granulate containing a simulated pride or a pharmaceutically acceptable salt thereof;
iii) preparing a sustained release granulate containing a simulated frit or a pharmaceutically acceptable salt thereof and a release control agent;
iv) tableting the immediate-release granule and the sustained-release granule to produce a simulated pride-containing multiple tablet; And
v) filling said hard capsule with said coated primer-coated multiple tablet and rabeprazole-coated tablet tablet. 20. The method of claim 19,
Wherein the simulated fly containing multiple definite final hardness is 10 to 14 MPa.

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