KR20140140353A - Oral combined formulation with improved stability and compatibility - Google Patents

Abstract

The present invention relates to a H_2-acceptor antagonist and a combination including ecabet or a pharmaceutically acceptable salt thereof and, more specifically, to a combination of oral tablet compositions comprising a drug compartment including the H_2-acceptor antagonist and a drug compartment including the ecabet or pharmaceutically acceptable salt thereof. The combination can satisfy inhibition of acid secretion and gastric mucosa protection at the same time, and can solve a drug interaction problem such as drug absorption inhibition between active compounds and the like.

Description

TECHNICAL FIELD [0001] The present invention relates to an oral complex tablet composition having improved stability and drug interaction,

The present invention relates to a combination preparation comprising a H ₂ -receptor antagonist and ecarvet or a pharmaceutically acceptable salt thereof, more particularly a drug compartment containing an H ₂ -receptor antagonist and ecavet or a pharmaceutically acceptable salt thereof And a medicament compartment containing the drug compartment. The complex tablet for oral use according to the present invention provides not only a combination agent capable of simultaneously satisfying gastric acid secretion inhibition and gastric mucosal protection, but also an oral complex tablet having improved drug interaction problems such as inhibition of drug absorption between active ingredients.

Gastrointestinal disease refers to gastric lesions such as gastritis or gastric ulcer caused by the action of gastric acid and pepsin. Such gastric diseases include attack factors such as gastric acid, pepsin or Helicobacter pylori, gastric mucosal blood flow ), Mucus secreted from mucous membrane, secretion of alkaline secretion, or tissue regeneration ability.

In order to treat such gastrointestinal diseases, various methods for suppressing the aforementioned attack factors, namely, histamine-2 receptor antagonists, proton pump inhibitors, and methods for inhibiting the activity of pepsin Or a method of killing Helicobacter pylori.

The histamine-2 receptor antagonist inhibits the action of Histamine secreted from the cell on histamine-2 receptor present in the gastric wall cells, thereby reducing the production of cAMP. The cAMP And the secretion of hydrogen ions in the gastric wall cells is decreased. In particular, ranitidine is marketed as Zanthin, developed by GSK, and is effective in improving gastric ulcer, gastric mucosal lesions (erosion, hemorrhage, eruption, edema), and suppressing the secretion of attack factors such as gastric acid to treat gastric ulcer It is known. However, it is known that the H ₂ receptor antagonist drug is not effective for diseases such as acute gastritis caused by ethanol, so that the gastric mucosal protective ability is not good and its effect is not persistent, so that the recurrence rate is high in the treatment of gastrointestinal diseases have.

In addition, EkaBet granules are effective for improving gastric ulcer, gastric mucosal lesions (erosion, hemorrhage, eruption, edema) by strengthening gastric mucosal protective effect by forming a covering layer on gastric mucosa with Gastrex granule, However, there is a problem that the secretion of gastric acid is not inhibited. In addition, there is a foreign body in the ebony granules.

Therefore, it is necessary to study a combination preparation which can simultaneously satisfy gastric acid suppression and gastric mucosal protection.

However, ecarvette is in the form of pentahydrate, and when it is prepared in tablets, surface stability is remarkably lowered by moisture, so coating is generally required, but there is a problem in that when the coating is heated at 40 to 50 ° C, the hydrate falls off and the dissolution rate is inhibited . Since ranitidine is weak against light and heat and is highly hygroscopic, it has a problem of low stability and browning, so it is necessary to improve the stability of the two components when preparing the combination preparation.

Also, in the case of combination preparations, there is a need to improve drug interaction problems such as inhibition of drug absorption among active ingredients. In other words, the dissolution patterns of the EACAbet and H ₂ - receptor antagonists are almost similar but they are absorbed in the stomach and small intestine. In the case of the simple combination formulation, the highly viscous Ekabet is surrounded by the H ₂ - in H ₂ - it is a problem that inhibits the absorption of receptor antagonists, H ₂ - there is a need a time difference of drug release formulation for the improvement of the uptake inhibitory factor antagonists and eka bet combinations.

It is an object of the present invention to provide a complex tablet composition for the treatment or prevention of gastrointestinal diseases which can simultaneously satisfy gastric acid secretion inhibition and gastric mucosal protection.

It is a further object of the present invention to provide a pharmaceutical composition which improves drug interaction problems such as inhibition of drug absorption among active ingredients and provides time-lag drug release which can improve the therapeutic effect of gastric ulcer, gastric mucosal lesion and the like, Or a pharmaceutically acceptable salt thereof.

A further object of the present invention is to provide a process for the preparation of oral complex tablets comprising an inner core tablet containing an H ₂ -receptor antagonist and an outer core tablet containing ecarbette or a pharmaceutically acceptable salt thereof.

In order to solve the above-mentioned problems, one embodiment of the present invention is a pharmaceutical composition comprising a first drug compartment containing an H ₂ -receptor antagonist and a second drug compartment containing ecabet or a pharmaceutically acceptable salt thereof A complex tablet composition for oral administration is provided.

Preferably, the first drug compartment and the first drug compartment are in the form of mini-tablets, or the first drug compartment is in the form of a nucleus, and the second drug compartment may be in the form of a pellet. The first drug compartment may further include a coating layer formed outside thereof, and the second drug compartment may further include a coating layer formed outside the first drug compartment. Specifically, the oral complex tablet composition may include a tablet core of the first drug compartment and an outer core tablet formed on the outside of the tablet core and containing ecarbette or a pharmaceutically acceptable salt thereof.

In addition, the coating layer formed on the first drug compartment may include one or more enteric coatings selected from the group consisting of hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose phthalate (HPMCP) and methacrylic acid copolymer Mechanism. The coating layer formed on the second drug compartment may include at least one compound selected from the group consisting of Opadyl (TM) II, Opadry AMB, Opadyl 200F.

The H ₂ -receptor antagonist may be selected from the group consisting of cimetidine, ranitidine, famotidine, nizatidine, and laputidine.

The first drug compartment or the second drug compartment may contain at least one ingredient selected from the group consisting of pharmaceutically acceptable excipients, binders, disintegrants and glidants as a carrier, more specifically, the total weight of the tablet A pharmaceutically acceptable carrier comprising from 0.5 to 20% by weight of a pharmaceutically acceptable excipient, from 1 to 10% by weight of a binder, from 1 to 10% by weight of a disintegrant and from 1 to 3% by weight of a lubricant, .

The complex tablet composition according to the present invention may be one which is eluted within 30% by weight of ranitidine and 90% by weight or more of ecavet in 2 hours in a buffer of pH 1.2.

The complex tablet for oral use according to the present invention can be used as a preventive or therapeutic agent for gastrointestinal inflammatory diseases.

Hereinafter, the present invention will be described in more detail.

The present invention relates to an oral complex tablet composition comprising an H ₂ -receptor antagonist and ecarbette or a pharmaceutically acceptable salt thereof.

As a result of Beagle Dog PK test, the drug absorption inhibition of ranitidine by ecavet was occurred when the drug of ecavet and ranitidine was administered concomitantly, and the elution pattern of ecavet and ranitidine were similar to each other, It is the stomach and small intestine. However, in the case of the simple combination preparation of the drug, there is a problem that the highly viscous eczacet is coated with ranitidine at the top to inhibit the absorption of ranitidine at the upper part of the small intestine. As a result of Beagle dog test, it was confirmed that about 50% of the specific absorption rate of ranitidine was inhibited by absorption. Therefore, it was found that a time-release drug release formulation is required to improve the absorption inhibiting factors of the combination preparation containing lanitidine and ecarbet.

The complex tablet according to the present invention comprises a delayed-release first drug compartment compartment containing an H ₂ -receptor antagonist and a quick-release second compartment containing ecarbette or a pharmaceutically acceptable salt thereof .

The first drug compartment and the first drug compartment may be in the form of mini-tablets, or the first drug compartment may be in the form of a nucleus, and the second drug compartment may be in the form of a pellet. The first drug compartment may further include a coating layer formed outside thereof, and the second drug compartment may further include a coating layer formed outside the first drug compartment. Specifically, the oral complex tablet composition comprises a core of the first drug compartment and an outer core tablets formed on the outer side of the core tablets and containing a pharmaceutically acceptable carrier, ecarbette or a pharmacologically acceptable salt thereof, . ≪ / RTI > The complex tablet composition according to the present invention can be manufactured in a form contained in one packaging unit in an appropriate amount considering the appropriate dosage per unit dosage form when the first drug compartment and the first drug compartment are in the form of a mini tablet have.

In the present specification, the term "tablet" means a tablet having a size of 5 to 10 mm in diameter, and the term "tablet" means a tablet having a particle size smaller than that of the tablet, and having a size of 1 to 3 mm do.

The outer core tablets comprise a core of the first drug compartment, ecarvet or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and optionally a coating layer formed thereon.

The complex tablet according to the present invention is capable of releasing a drug over time for improving the absorption inhibiting factors of the H ₂ -receptor antagonist and the Ecarbet combination preparation, thereby improving drug interaction problems such as inhibition of drug absorption among active ingredients, It is possible to maximize the therapeutic effect such as mucosal lesion.

The complex tablet according to the present invention is released in a buffer solution having a pH of 1.2 to not more than 30% by weight, preferably not more than 20% by weight of ranitidine in 2 hours, and elaborates more than 90% by weight, preferably not less than 93% .

In a complex tablet composition according to the present invention, the first drug compartment containing the H ₂ -receptor antagonist preferably comprises an enteric coating layer of the first drug compartment for imparting delayed release properties. In addition, the second drug compartment containing ecarbette or a pharmaceutically acceptable salt thereof may include a coating layer having a water-proofing property to enhance the stability of the ecarbette.

Wherein the enteric coating layer formed on the outside of the first drug compartment includes an enteric coating base, and the enteric coating base comprises hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose phthalate (HPMCP), and methacrylic acid And at least one compound selected from the group consisting of copolymers. Preferably, the methacrylic acid copolymer is a commercially available Eudragit L100-55 (Degussa, Germany) as a poly (methacrylic acid-ethyl acrylate) copolymer.

The enteric coating layer may contain 1 to 10% by weight of an enteric coating agent based on the total weight of the complex tablet.

The waterproof coating layer formed on the outside of the second drug compartment includes a waterproof coating agent, and the waterproof coating agent is preferably one or more selected from the group consisting of Opadry II, Opadry AMB, Opadyl 200F Do. More preferred is Opadry 200F.

The waterproof coating layer may contain waterproofing agent such as Opadry 200F in an amount of 1 to 10% by weight.

The complex tablet has an effect as a preventive or therapeutic agent for gastrointestinal inflammatory diseases, which is a known medicinal effect of an active ingredient, ecarbet or a pharmaceutically acceptable salt thereof, and an H ₂ -receptor antagonist.

The active ingredient ecabbet or a pharmaceutically acceptable salt thereof used in the present invention can be exemplified by ecarbad sodium, and ecarbad sodium is a sulfohydroabietic acid- 1 sodium-5 hydrate, which is known to be extracted from pine rosin. This ectavat sodium reduces the activity of pepsin, a protease, to minimize the digestion and stimulation of the gastric mucosa, while maintaining the concentration of gastric mucus properly, thus protecting the gastric mucosa. It is known that it is difficult to obtain a stabilized aqueous solution of sodium saccharin because the solubility of ecarvet sodium in an aqueous solution greatly varies with temperature and becomes very low at a pH of less than 7.

[Chemical Formula 1]

Another active ingredient used in the present invention, H ₂ -receptor antagonist, is a drug that inhibits the binding of histamine to the H ₂ -receptor of gastric acid-secreting parietal cell, which promotes gastric acid secretion. Exemplary H ₂ < RTI ID = 0.0 _> Receptor antagonists are cimetidine, ranitidine, nizatidine and famotidine and they can generally be used in the form of their pharmaceutically acceptable salts, especially hydrochlorides, preferably ranitidine or its salts.

In one embodiment of the present invention, ecabbet or a pharmaceutically acceptable salt thereof contained in the complex tablet may be contained in an amount of 20 to 90% by weight based on the total weight of the complex tablet, The content of the drug contained in the tablet may be 250 to 1000 mg. The H ₂ receptor antagonist may be included in an amount of 1 to 70% by weight based on the total weight of the complex tablet. For example, the content of the drug contained in one tablet may be 2.5 to 800 mg, more preferably 5-400 mg can do.

The pharmaceutically acceptable carrier to be contained in the complex tablet according to the present invention may include at least one selected from the group consisting of excipients, binders, disintegrants and glidants. Specifically, the pharmaceutically acceptable carrier is present in an amount of 0.5 to 20% by weight of a pharmaceutically acceptable excipient, 1 to 10% by weight of a binder, 1 to 10% by weight of a disintegrant and 1 to 10% 3% by weight of a lubricant. In the preparation of the granules according to the present invention, in addition to the above excipients, binders, disintegrants, and glidants, conventional methods for preparing granules, which are well known in the pharmaceutical arts, .

The excipient serves to improve the ease of tableting and maintain the tablet form. Such excipients may be at least one selected from the group consisting of microcrystalline cellulose, hydroxypropyl cellulose, corn starch, potato starch, wheat starch, dextrin, methyl cellulose, lactose, mannitol, saccharide, glucose, fructose and combinations thereof. The excipient may comprise from 0.5% to 20% by weight of the composition.

The binder may be a cellulose polymer such as ethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose; Insoluble acrylate ammonio methacrylate copolymers, and polyacrylates such as polymethacrylic copolymers; Polyvinylpyrrolidone (povidone), vinylpyrrolidone-vinyl acetate copolymer (povidone), polyvinyl alcohol, shellac, alginic acid, sodium alginate, starch, pregelatinized starch, Its derivatives, quar gum, polyethylene glycol, and the like. Among the acrylic polymers, insoluble acrylate ammonio methacrylate copolymer (Eudragit RL100 or RS100 or Eudragit RL30D or RS30D), polyacrylate (Eudragit NE30D), or methacrylic copolymer (Eudragit L100-55 or Eudragit L30D, Eudragit E100 , Eudragit EPO) can be used alone or in combination. It may preferably be one or a mixture of two or more selected from polyvinylpyrrolidone, hydroxypropylcellulose, dextrin, gelatin, methylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, polyvinyl alcohol and gum arabic . The binding agent may be contained in an amount of 1 to 10% by weight based on the total weight of the complex tablet.

The disintegrant is a mixture of one or more kinds selected from sodium starch glycolate, crosophobidon, sodium croscarmellose sodium, low substituted hydroxypropyl cellulose, starch and carboxymethylcellulose calcium, preferably sodium starch glycolate , Crospovidone, sodium croscarmellose sodium, low-substituted hydroxypropylcellulose, starch, and a mixture of two or more selected from carboxymethylcellulose calcium, for example sodium carboxymethyl cross-linked internally as croscarmellose sodium It is also known as cellulose (Ac-Di-Sol). The disintegrant is preferably contained in an amount of 1 to 10% by weight based on the total weight of the complex tablet.

The lubricant improves the fluidity of the powder and increases the filling of the die, which is the lower part of the tablet machine. The friction between the powder and the punch-die, which is the upper part of the powder and granulator, To facilitate compression and release of the tablet. Wherein the lubricant is at least one selected from the group consisting of talc, sodium aluminosilicate, silicon dioxide, magnesium metasilicate aluminate, magnesium stearate, sodium stearyl fumarate, and glycerol palmitostearate. It can be the best.

The lubricant is preferably contained in an amount of 1 to 3% by weight based on the total weight of the complex tablet. When the amount of the lubricant is less than 1% by weight, it is difficult to tablet the tablets. When the amount of the lubricant is more than 1% by weight, the binding force is weakened and capping phenomenon occurs. .

As a preferred example of the pharmaceutically acceptable carrier according to the present invention, the excipient is at least one selected from the group consisting of lactose and anhydrous crystalline cellose, and the binder is at least one selected from the group consisting of hypromellose, copovidone, and hydroxy Propylcellulose, and the disintegrant is at least one selected from the group consisting of hydroxypropylcellulose and croscarmellose sodium, and the lubricant is at least one selected from the group consisting of silicon dioxide and magnesium stearate ≪ / RTI >

The complex tablet may further comprise at least one pharmaceutically acceptable additive. The pharmaceutically acceptable additives may be at least one selected from the group consisting of a coloring agent, a sweetener, a preservative, an acidifier, a flavoring agent, a flavoring agent and a thickening agent. Examples of the sweetener include sugars such as sucrose, sucrose and glucose syrup; Sugar alcohols such as mannitol, sorbitol and xylitol; Synthetic sweeteners such as cyclamate sodium, saccharin sodium, aspartame, sucralose, acesulfame potassium, stevia and the like; Glycyrrhizin and its salts; Or honey. Examples of the preservative include alkyl parabens such as methyl paraben and propyl paraben; Or benzoic acid such as sodium benzoate. Examples of the acidulant include citric acid, ascorbic acid and malic acid. Examples of the flavor include refined oils such as menthol, camphor and mint oil, mint oil and cinnamon oil; Or pineapple, orange, or drink flavor. Examples of the wetting agent include refined oils such as aminoacetic acid, lemon oil, and orange oil. Examples of the thickener include cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose and carboxymethylcellulose, polyvinylpyrrolidone Lauridone, sodium alginate, sodium chondroitin sulfate, agar powder, gelatin, guar gum or xanthan gum. If desired, colorants may be included in the tablets of the present invention and may be incorporated into the tablets of titanium dioxide, iron oxide, magnesium carbonate, calcium sulfate, magnesium oxide, magnesium hydroxide, aluminum lakes, such as Blue No. 1 Aluminum Lake, One selected or a mixture of two or more may be used.

Another embodiment of the present invention provides a method of preparing an inner core formulation comprising an H ₂ -receptor antagonist and a pharmaceutically acceptable carrier, forming a coating layer thereon, preparing a coated inner core formulation; Mixing the coated inner core tablet with granules of ecarbet or a pharmaceutically acceptable salt thereof to prepare an outer core tablets, and then preparing a tablet of the present invention. And a waterproof coating layer may be further included on the outside of the press-coated core.

Alternatively, one embodiment of the present invention provides a method for preparing a coated tablet, comprising: preparing a mini tablet containing a H ₂ -receptor antagonist and a pharmaceutically acceptable carrier; forming an enteric coating layer on the outside of the tablet; Preparing a mini tablet containing ecarbet or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier and forming a waterproof coating layer on the outside thereof to prepare a coated mini tablet; And a method for producing a complex tablet comprising the coated mini tablet.

The H ₂ - press-coated tablet or a mini tablet containing receptor antagonist, specifically, H ₂ - receptor antagonists and mixed with a pharmaceutically acceptable carrier and compressed into tablets and the tablet core or mini-tablets coated on its outside is coated with an enteric coating Can be manufactured.

The drug reservoir containing the ecarbette may be a mini tablet containing ecarbet or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier and may optionally be coated with a waterproof coating liquid on the outside to form a coated tablet A mini tablet can be manufactured.

The granules containing the H ₂ -receptor antagonist and the granules containing Ecarbet can be prepared by tabletting with a tablet press with a tabletting machine to form a core tablet and optionally forming an additional coating layer on the outside of the tablet press have.

The preparation of the core using the tablet machine, the preparation of the core tablet using the tablet press machine, the preparation of the tablet, and the formation of the coating layer may be performed by a conventional method known in the art, and are not particularly limited. The coating method can be coated with a conventional coating machine such as, for example, Manesty Accelacota, Driam Coater or Hi-coater. After the coating layer is formed, it may be left in a coater or transferred to a drying oven or a high temperature drier.

The present invention provides a complex tablet containing an inner core formulation containing an H ₂ -receptor antagonist and an outer core formulation containing an Ecarbet agent and a method for producing the same, thereby improving drug interaction problems such as drug absorption inhibition between active ingredients, , Gastric mucosal lesion and the like can be improved, stability of ecabet is improved, and time-release drug release of H ₂ -receptor antagonist and ecabbet can be provided.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a view showing a complex tablet in the form of a press-coated tablet according to an embodiment of the present invention; FIG.
FIG. 2 is a graph showing a comparison between the ecabat component of Comparative Example 1 and Gastrex, a control drug in the pharmacokinetics test.
3 is a graph comparing the ranitidine component of Comparative Example 1 with the xanthan gum, the reference drug, in the pharmacokinetics test.
FIG. 4 is a graph showing a graph comparing the ecabat component of the complex tablet of Example 3 with Gastrex, the control drug in the pharmacokinetics test. FIG.
Fig. 5 is a graph showing a comparison of the ranitidine component in the complex tablet of Example 3 with the xanthan gum, the reference drug, in the pharmacokinetic test.
6 shows the drug elution profile of Comparative Example 2 in the eluent.
Fig. 7 shows dissolution profiles of ecabet in the complex tablet of Example 3 in the effluent. Fig.
Fig. 8 shows the dissolution profile of ranitidine in the complex tablet of Example 4 in the pH 1.2 eluate. Fig.
Fig. 9 shows dissolution profiles of ranitidine in the complex tablet of Example 4 in the pH 6.8 eluate. Fig.

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.

Example  1: Compound purification ( High- )

1-1. Manufacture of a core composed of ranitidine granules

Ranitidine hydrochloric acid, microcrystalline cellulose copovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and silicon dioxide were sieved in a total of about 30 mesh and mixed in a drum mixer at 20 rpm for 10 minutes at a content ratio shown in Table 1 below. Respectively. Then, magnesium stearate was added to the mixture, and granules were mixed in a drum mixer at 20 rpm for 3 minutes.

1-2. Manufacture of coated nuclei of ranitidine

The ranitidine nuclei prepared in Example 1-1 were sub-coated with a 5% ethanol solution of hypromellose in a pan coater at a refining temperature of 30 ° C and then coated with Eudragit L100-55, talc, triethyl citrate triethyl citrate, TEC) at a refining temperature of 30 ° C.

1-3. Manufacture of Effervescent tablets containing coated nuclei of ranitidine

A mixture of effervescent sodium, anhydrous lactose, copovidone and croscarmellose sodium in an amount of about 30 mesh was mixed in a drum mixer at 20 rpm for 10 minutes, magnesium stearate was added thereto at a rate of 20 rpm And mixed in a drum mixer for 3 minutes. The ranitidine-coated core obtained in Example 1-2 was tableted using a tablet press with a core inner core and an outer core of eccabetic as the outer core.

1-4. Coated coating

A 5% coating solution of hypromellose was prepared with 100% ethanol as a solvent. Subsequently, a tablet coating solution was sub-coated with a tablet coating solution at a refining temperature of 30 ° C and a 50% ethanol aqueous solution was used as a solvent to prepare a 10% And the emulsion was coated at a temperature of about 30 캜.

Example  2: Compound purification ( High- )

2-1. Manufacture of a core composed of ranitidine granules

Rhenitidine hydrochloric acid, microcrystalline cellulose, hypromellose, croscarmellose sodium and silicon dioxide were sieved in a total of about 30 mesh and mixed in a drum mixer at 20 rpm for 10 minutes by the content ratio shown in Table 1 below. Then, magnesium stearate was added to the mixture, and the granules were mixed in a drum mixer at 20 rpm for 3 minutes.

2-2. Manufacture of coated nuclei of ranitidine

The ranitidine nuclei prepared in Example 2-1 were coated with a 5% ethanol solution of povidone and sub-coated at a purification temperature of about 40 ° C in a pan coater. Then, Eudragit hydroxypropylmethylcellulose phthalate, Talc, and TEC were added thereto, The coating solution was coated at a refining temperature of about 30 캜.

2-3. Manufacture of elecavidin-coated tablets containing ranitidine coated nuclei

Sodium cetearate, microcrystalline cellulose, copovidone, croscarmellose sodium and silicon dioxide were sieved using a total of about 30 mesh and then mixed in a drum mixer at 20 rpm for 10 minutes at a content ratio shown in Table 2 below. Magnesium stearate sieved with a mesh was added and mixed into a drum mixer at 20 rpm for 3 minutes, followed by tableting with a pressurized medium.

2-4. Press-coated tablet

The same procedure as in Example 1-4 was followed.

Example  3: Compound purification ( High- )

3-1. Manufacture of a core composed of ranitidine granules

Ranitidine hydrochloric acid, microcrystalline cellulose, hydroxypropylcellulose, croscarmellose sodium and silicon dioxide were sieved using about 30 mesh sieves and mixed in a drum mixer at 20 rpm for 10 minutes at a content ratio shown in Table 1 below. Then, magnesium stearate was added to the mixture, granules were mixed in a drum mixer at 20 rpm for 3 minutes, and the granules were compressed to prepare a core composed of ranitidine granules.

3-2. Manufacture of coated nuclei of ranitidine

Intramuscular coating was performed in the same manner as in the ranitidine coating tablet according to Example 1-2.

3-3. Manufacture of erbatide core tablets containing lanitidine enteric tablets

Sodium saccharin, sodium croscarmellose sodium and silicon dioxide were sieved using a total of about 30 mesh, and then magnesium stearate sieved in 30 mesh was sieved at a ratio of the components listed in Table 2 below, And the mixture was mixed in a drum mixer at 20 rpm for 3 minutes, and then compressed into a press-formed core.

3-4. Coated coating

The same procedure as in Example 1-4 was followed.

Example  4. Complex Purification ( Mini tablet )

4-1. Manufacture of Ranitidine Mini Tablets

The granules were prepared in the same manner as in Example 3-1, and then tableted with a mini tablet.

4-2. Ranitidine Mini Tablet Coating Coating

Using a fluidized bed coater, a mini tablet containing ranitidine hydrochloric acid was sub-coated with a 5% hypromellose coating solution prepared by dissolving 100% ethanol in a solvent at 30 ° C or less under conditions of 100% ethanol, 10% Eudragit L100 -55, TEC, and Talc.

4-3. Manufacture of ecarbet mini tablet

The granules were prepared in the same manner as in Example 3-1, and then tableted with a mini tablet.

4-4. Eka Bet Mini tablet waterproof coating

Using a fluidized bed coater, a mini tablet containing ecarbad sodium was sub-coated with a 5% hippocamellose coating solution prepared by dissolving 100% ethanol in a solvent at a temperature of about 30 ° C, and then, 50% ethanol The coating solution was prepared by coating the aqueous solution with 10% Opadyl 200 F as a solvent.

Tables 1 to 3 below show the blending components and contents of Examples 1 to 4.

Composition of drug compartment and coating layer containing lanitidine Purpose of blending Ingredients Content (mg) Example
One Example
2 Example
3 Example
4 core chief ingredient Ranitidine hydrochloric acid 84 84 84 84 Excipient Microcrystalline cellulose 20 70 4 84 Binder Hypromellose - 20 - - Binder Co-povidone 3 - - - Binder Hydroxypropylcellulose - - One 6 Disintegration Low-substituted hydroxypropylcellulose 14 - - - Disintegration Croscarmellose sodium 6 3 8 9 Lubricant Silicon dioxide 1.5 0.5 2 2 Lubricant Magnesium stearate 1.5 2 One 2 Coating layer Sub-coating agent Hypromellose 3 - 3 4 Sub-coating agent Povidone - 4 - - Long coat coater Eudragit L100-55 8.4 - 8.4 8.4 Long coat coater HPMCP - 8.4 - - Anti-adhesion agent talc 0.25 0.25 0.25 0.25 Plasticizer TEC 0.84 0.84 0.84 0.84

Composition of drug compartment containing ecarbette Purpose of blending Ingredients content Example 1 Example 2 Example 3 Example 4 chief ingredient Sodium carbonate 500 500 500 500 Excipient Anhydrous lactose 16 - - - Excipient Microcrystalline cellulose - 16 - - Binder Co-povidone 6 43 39 39 Disintegration Croscarmellose sodium 27 13 15 13 Lubricant Silicon dioxide - 3 6 3 Lubricant Magnesium stearate 6 6 5 6

Coating layer composition (Example 1-3) of the outer core layer of the core tablet (Example 1-3) or nose of the mini tablet containing ecarbette (Example 4) Purpose of blending Ingredients content Example 1 Example 2 Example 3 Example 4 Sub-coating agent Hypromellose 12 - 12 12 Sub-coating agent Povidone - 12 - - Waterproof coating agent Opa Dry 200F 23 24 21 25

Comparative Example  One. Sodium carbonate  Granule Ranitidine hydrochloric acid  Preparation of two-layer tablets composed of granules

(1) Preparation of two-layer tablets

Cocobaldehyde, cocobodone, cocamelose sodium, silicon dioxide, and stearic acid hydrochloride were sieved with about 30 mesh sieves, mixed for 5 minutes, and magnesium stearate was added to prepare granules.

In addition, ranitidine hydrochloric acid, microcrystalline cellulose, hypromellose, croscarmellose sodium and silicon dioxide were sieved using about 30 mesh sieves, and magnesium stearate was added thereto to prepare granules.

The above-described saccharide granules and ranitidine granules were tableted in two layers to prepare a two-layer tablet.

(2) Coating

A 5% coating solution was prepared using hypromellose in 100% ethanol, and sub-coating was performed at a purification temperature of about 40 캜. Then, Opaque Dry 200F was prepared by using a 50% aqueous ethanol solution to prepare a 10% coating solution, and the two-layer tablet obtained in the above (1) was coated at a purification temperature of about 40 캜.

Table 4 below shows the ingredients and amounts.

Purpose of blending Ingredients Usage (g) Composition ratio Ecarbet granule water chief ingredient Sodium carbonate 500 62.11 Binder Co-povidone 39 4.84 Disintegration Croscarmellose sodium 13 1.61 Lubricant Silicon dioxide 3 0.37 Lubricant Magnesium stearate 6 0.75 Lanitidine
Granule chief ingredient Ranitidine hydrochloride 84 10.43 Excipient Microcrystalline cellulose 97.5 12.11 Binder Hypromellose 20 2.48 Disintegration Croscarmellose sodium 3 0.37 Lubricant Silicon dioxide 0.5 0.06 Lubricant Magnesium stearate 2 0.25 Subcoating machine Hypromellose 16 1.99 Coater Opa Dry 200F 21 2.61 total 805 100.00

Comparative Example  2. During coating process Ekavet  Manufacture of prescription of low dissolution rate problem

(1) Preparation of Ekavet Tablets

The components of eucalyptus layer and composition of Example 3 shown in Table 2 were sieved with about 30 mesh of ecarbet sodium, microcrystalline cellulose, hydroxypropylcellulose, croscarmellose sodium and silicon dioxide, Magnesium stearate sieved with a mesh was added and mixed in a drum mixer at 20 rpm for 3 minutes, and then tableted to prepare an ecabetone single tablet.

 (2) Coating of Ekavet Tablets

A 5% coating solution was prepared using hypromellose in 100% ethanol, subcoating at a refining temperature of 50 ° C, and a 10% coating solution was prepared using Opaquat 200F in a 50% Lt; RTI ID = 0.0 > C < / RTI > That is, in Examples 3 and 4, both the subcoating, enteric coating, and waterproof coating were prepared at about 30 ° C, and Comparative Example 2 was prepared at about 50 ° C for both the subcoat and the general coating.

Experimental Example  1: Oral administration pharmacokinetic test

The double tablet of Comparative Example 1 and the tablets prepared according to Example 3 were administered using Beagle Dog, and the PK assay was performed. In this experiment, Gastrex was used as a control agent for the ecabbet 3 × 3 cross-over test, and stanchion was used as the control agent for the 3 × 3 cross-over test of ranitidine.

These experiments were conducted to demonstrate the problem of drug interactions between the two drugs, and the experimental results are shown in Tables 5 and 6 and FIGS. 2 to 5.

Ekavet 3 × 3 cross test (n = 12) division Comparative Example 1 Example 3 Cmax AUC
((ng / ml) * Hr.) Cmax AUC
((ng / ml) * Hr.) Treaty 11460 49609 9378 42691 Test drug 11494 54233 8771 44547 Determination value 100.3 109.3 93.5 104.3 standard 80 ~ 125 80 ~ 125 80 ~ 125 80 ~ 125

Ranitidine 3 × 3 cross-over test (n = 12) division Comparative Example 1 Example 3 Cmax AUC
((ng / ml) * Hr.) Cmax AUC
((ng / ml) * Hr.) Treaty 75.35 156.41 75.35 156.41 Test drug 21.30 76.81 64.75 136.48 Determination value 28.3 49.1 85.9 87.3 standard 80 ~ 125 80 ~ 125 80 ~ 125 80 ~ 125

In the case of Comparative Example 1, the AUC of ranitidine was reduced by about 50% as compared with the control drug. This means that there is a drug interaction that interferes with the absorption of the above-released ecarbet ranitidine.

On the other hand, in the case of Example 3, the carvette was released and absorbed from above, and the ranitidine was released from the upper part of the small intestine, absorbed by about 87%, and drug interaction was minimized.

Experimental Example  2: Oral administration elution pattern test

The tablets prepared in Example 3 and Comparative Example 2 were subjected to a dissolution test using the Korean Pharmacopoeia dissolution assay Method 2 paddle method. The elution was carried out at a temperature of 37 ± 0.5 ° C using 900 ml of a buffer solution having a pH of 1.2. In this dissolution rate test, Gastrex was used as a control. The drug elution rate was expressed as a percentage of the weight of the elecavetes dissolved in the tablets contained in the above-mentioned Examples and Comparative Examples, based on the weight of the elixir.

Table 7 shows the dissolution profile of Comparative Example 2 in the pH 1.2 eluate (Fig. 6), and Table 8 shows the elution profile of the coating process resolution formulation of Example 3 in the pH 1.2 eluate (Fig. 7 ).

Time (minutes) The treaty (Gastrex) The dissolution rate (%) of ecarbet of Comparative Example 2 5 18.0 6.5 10 39.8 9.9 15 60.8 12.4 30 88.1 18.8 45 99.5 26.4 60 103.4 34.2

Time (minutes) The treaty (Gastrex) The dissolution rate (%) of ecarbet of Example 3 5 18.0 15.0 10 39.8 33.3 15 60.8 55.4 30 88.1 83.3 45 99.5 91.2 60 103.4 96.5

When the coating is carried out in the above temperature range as in Comparative Example 2, the hydrate falls off in the pentahydrate form, and the elution becomes extreme. However, in Examples 3 and 4, Likewise, when the waterproof coating was applied at 30 ° C or less, dissolution profiles similar to those of the control drug were exhibited.

Experimental Example  3: Mini tablet  Dissolution profile test

The dissolution test was carried out on the ritidine-containing minitablet prepared in Example 4 using the Korean Pharmacopoeia dissolution assay Method 2 paddle method. The eluent was 900 ml of the buffer solution of pH 1.2 and 900 ml of the buffer of pH 6.8, and was performed at 37 ± 0.5 ° C. In this dissolution rate test, stanchion was used as a control. The ranitidine drug elution rate was expressed as a percentage of the weight of the elecavetes to the weight of the ecarbet loaded in the tablets contained in the above Examples and Comparative Examples.

Table 9 below shows the dissolution profile of Example 4 in pH 1.2 eluate (Figure 8), and Table 10 below shows the elution profile of the coating process resolution formulation of Example 4 in pH 6.8 eluent 9). The results of the ranitidine elution profile of Example 4 in a pH 1.2 eluate providing an environment similar to the above showed a dissolution rate of 14.4% of the ranitidine loaded for 120 minutes, while the elution rate of the drug elution profile in the pH 6.8 eluate similar to intestinal environment As a result, it was confirmed that 93.4% of the loaded ranitidine eluted at 45 minutes eluted, and the intestinal environment elution was excellent. Therefore, in the case of the complex tablet using the mini tablet of Example 4, it was predicted that the elution from the top of the ranitidine could be suppressed to be relatively low and the elution in the intestines could be made very excellent.

Drug release profile in pH 1.2 eluate Time (minutes) The treaty (stoneware) (%) Of ranitidine dissolution in Example 4 5 14.6 0.0 10 31.0 0.0 15 45.6 1.7 30 75.9 1.2 45 91.7 3.0 60 96.4 5.9 90 100.3 10.1 120 100.4 14.4

pH 6.8 Drug dissolution profile in eluent Time (minutes) The treaty (stoneware) (%) Of ranitidine dissolution in Example 4 5 14.6 0.0 10 31.0 25.9 15 45.6 44.8 30 75.9 80.5 45 91.7 93.4 60 96.4 95.6 90 100.3 95.8 120 100.4 96.0

Claims (13)

A second drug compartment containing a H ₂ -receptor antagonist and a second drug compartment containing ecavet or a pharmaceutically acceptable salt thereof. 2. The oral complex tablet composition of claim 1, wherein the first drug compartment and the first drug compartment are in the form of mini-tablets. 2. The oral complex tablet composition according to claim 1, wherein the first drug compartment is in the form of a core and the second drug compartment is in the form of a pellet. 4. The oral complex tablet composition according to claim 3,
The first drug compartment,
Wherein the tablet is formed outside the nucleus and comprises ecarbette or a pharmaceutically acceptable salt thereof. 2. The oral complex tablet composition according to claim 1, wherein the first drug compartment further comprises a coating layer formed on the outside thereof. 6. The method of claim 5, wherein the coating layer comprises at least one enteric coating agent selected from the group consisting of hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose phthalate (HPMCP), and methacrylic acid copolymer Or a pharmaceutically acceptable salt thereof. The oral complex tablet composition according to claim 5, wherein the coating layer is contained in an amount of 1 to 10% by weight of a poly (methacrylic acid-ethyl acrylate) copolymer based on the total weight of the tablet 2. The oral complex tablet composition according to claim 1, wherein the second drug compartment further comprises a coating layer formed on the outside thereof. The oral complex tablet composition according to claim 8, wherein the coating layer comprises at least one compound selected from the group consisting of Opadyl II, Opadry AMB, and Opadyl 200F. 10. The oral complex tablet composition according to claim 9, wherein the coating layer contains Opadyl 200F in an amount of 1 to 10% by weight based on the total weight of the tablet. The oral conjugate of claim 1, wherein the H ₂ -receptor antagonist is selected from the group consisting of cimetidine, ranitidine, famotidine, nizatidine, and laputidine. Tablet composition. The pharmaceutical composition according to claim 1, wherein the first drug compartment or the second drug compartment comprises from 0.5 to 20% by weight of a pharmaceutically acceptable excipient, from 1 to 10% by weight of a binder, from 1 to 10% % Of a disintegrant and 1 to 3% by weight of a lubricant. The complex tablet composition for oral administration according to claim 1, wherein the complex tablet composition is eluted with a buffer solution having a pH of 1.2 to not more than 30% by weight of ranitidine and not less than 90% by weight of ecabeat within 2 hours.

Images