KR101567937B1 - Multi-layer solid formulation having improved stability - Google Patents

Abstract

The present invention relates to a method for producing a multi-layered solid preparation having improved stability. More specifically, the present invention relates to a pharmaceutical composition comprising a first drug layer comprising ecabet or a pharmaceutically acceptable salt thereof, a stabilizing agent (alkalizing agent) and a pharmaceutically acceptable additive, ranitidine or its pharmaceutical And a second drug layer comprising a pharmaceutically acceptable excipient, and a method of making the same.

Description

[0001] The present invention relates to a multi-layer solid formulation having improved stability,

The present invention relates to a method for producing a multi-layered solid preparation having improved stability. More specifically, the present invention relates to a pharmaceutical composition comprising a first drug layer comprising ecabet or a pharmaceutically acceptable salt thereof, a stabilizing agent (alkalizing agent) and a pharmaceutically acceptable additive, ranitidine or its pharmaceutical And a second drug layer comprising a pharmaceutically acceptable excipient, and a method of making the same.

Gastritis, gastric ulcer, duodenitis, duodenal ulcer, reflux esophagitis are typical gastrointestinal diseases. Typical drugs used in the treatment of gastrointestinal diseases include ecabet and ranitidine.

Ecavet is an anti-ulcer agent that works directly on the gastric mucosa. It is strongly adhered to the gastric mucosa, protects the gastric mucosa from gastric acid and pepsin, irreversibly inactivates its activity by binding with pepsin and pepsinogen, urease, and ATPase, thereby exhibiting an antibacterial effect of Helicobacter pylori and inhibiting the attachment of Helicobacter pylori to the gastric mucosa.

Ranitidine is a representative compound of histamine type 2 receptor (H-2 receptor) antagonist. It is used for the treatment of diseases such as gastritis and gastric ulcer. It inhibits histamine action on histamine-2 receptor and reduces gastric acid secretion .

However, when a long-term use of ecabet is caused by gene mutation of Helicobacter pylori, there is a problem that resistance to drugs is generated, and there is a disadvantage in that it can not protect against secretion by stomach acid . Ranitidine is not effective against diseases such as acute gastritis caused by ethanol, and thus has a disadvantage that the gastric mucosa protection ability is poor and the therapeutic effect on the gastrointestinal tract is not continuous.

As described above, the method of treating gastrointestinal diseases of single ecabet or lanitidine shows a certain therapeutic effect on gastrointestinal lesions, but it is difficult to treat symptoms caused by other causes by removing only some of the main causes of gastrointestinal diseases, The side effects of the drug can not be sufficiently improved.

Recently, a clinical trial of inhibition of peptic ulcer recurrence has reported that the combination of ranitidine and ecarbeta inhibits the recurrence of gastric duodenal ulcer in a statistically significant manner compared with lanitidine monotherapy (Koizumi, W. et al., Hepatogastroenterology 50: 577 -581, 2003).

However, there is an inconvenience that patients should take tablets and take other granules when they take these drugs together because the currently available ephedrine preparations are in the form of granule packs and ranitidine hydrochloride is in tablets.

Therefore, if it is provided as a combination preparation that can take easily eracibet and ranitidine at once without taking the erabbet granules after ranitidine refining, the therapeutic effect can be improved significantly compared with the convenience of taking and taking only a single medicament It is expected to be.

However, the simple mixture of lanitidine and ecarbet may cause poor mixing and poor flowability of the granules, resulting in poor uniformity of content. The single dose of ecarbet is very large as 1 g, The size of the tablet becomes large. In addition, since ranitidine has hygroscopic properties and ecavetes contain a large amount of water, a special stabilization method is required when the water contains lanitidine and 18% water.

As another problem, ecarbette shows a pH of about 4.2 in aqueous solution and contains a large amount of water, so that ranitidine tends to react with ecarbet to promote decomposition. Ranitidine has poor stability under acidic or strong base conditions of pH 5 or below. Eccabtite contains a large amount of water and exhibits acidity, which promotes the decomposition of lanitidine. As a result, the stability of ranitidine is deteriorated by a large amount of water and acidic pH of the ecarbette.

Further, as a preliminary test result according to the present invention, when a combination preparation is prepared by mixing ranitidine hydrochloric acid and ecarbad sodium simultaneously, coagulation phenomenon occurs due to interaction of the two components, and the dissolution rate of the drug is lowered. If used in the human body in such a state, the oral absorption and bioavailability of the drug may be lowered, resulting in a decrease in the drug efficacy in the human body.

As a related art of the present invention, there has been proposed a technique (publication number: 2011-0105550) for ecabat single tablet, a medicinal composition composed of ranitidine, one kind of bismuth and sucralfate (publication number: 1993-0016095) (Publication number: 2012-0094253) and a pharmaceutical composition containing ranitidine and the like (publication number: 2012-0094253), but there is a description of a combination composition of lanitidine and ecarbet There is no prior art for purification, and furthermore, there is no indication of a complex agent that contains about 18% moisture in Ecavet and maintains the stability of weakly soluble ranitidine in water.

Therefore, it is urgently required to develop a combination preparation of saccharose and ranitidine, which improves the stability and inhibits coagulation phenomenon between components, thereby securing the dissolution rate of each component and minimizing the size of the tablet so as to be easy to take.

Under these circumstances, the inventors of the present invention have found that the use of a hydrophobic base which separates ecarbet and ranitidine into different layers and retarding the dissolution of ranitidine or the stabilization of ranitidine can be used to increase the convenience of administration and can be utilized in various formulations , Stability and dissolution rate can be improved. Thus, the present invention has been completed.

It is an object of the present invention to provide a multi-layered solid preparation with improved stability.

More specifically, one object of the present invention is to provide a pharmaceutical composition comprising a first drug layer comprising ecabet or a pharmaceutically acceptable salt thereof, a stabilizer (alkalizing agent) and a pharmaceutically acceptable additive, a ranitidine ) Or a pharmaceutically acceptable salt thereof, and a second drug layer comprising a pharmaceutically acceptable additive.

It is another object of the present invention to provide a pharmaceutical composition comprising a first drug layer comprising ecarbette or a pharmaceutically acceptable salt thereof, an alkalizing agent and a pharmaceutically acceptable additive, a second drug layer comprising ranitidine or a pharmaceutically acceptable salt thereof, And a second drug layer comprising a pharmaceutically acceptable excipient, and compressing said first drug layer and said second drug layer to produce a multi-layer formulation, wherein said multi- And a method for producing the same.

It is another object of the present invention to provide a pharmaceutical composition comprising a first drug layer comprising ecarbet or a pharmaceutically acceptable salt thereof, an alkalizing agent and a pharmaceutically acceptable additive, a pharmaceutically acceptable excipient which is pharmaceutically acceptable and which is not reactive with the drug Preparing an intermediate layer comprising an additive, preparing a second drug layer comprising ranitidine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, and a second drug layer comprising the first drug layer, And then compressing the drug layer to contact in order to produce a multi-layer formulation.

In one aspect, the present invention provides a pharmaceutical composition comprising a first drug layer comprising ecabet or a pharmaceutically acceptable salt thereof, a stabilizer (alkalizing agent) and a pharmaceutically acceptable additive, A second drug layer comprising ranitidine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. ≪ Desc / Clms Page number 2 >

The pharmaceutically acceptable salt of ecarbate may be ecarbad sodium. Also preferably, the pharmaceutically acceptable salt of ranitidine may be ranitidine hydrochloride.

The total content of the ecarbette or a pharmaceutically acceptable salt thereof and the lanitidine or a pharmaceutically acceptable salt thereof may be 40 to 90% by weight with respect to the whole preparation. The total content of the ecarbine or a pharmaceutically acceptable salt thereof and the lanitidine or a pharmaceutically acceptable salt thereof may be 50 to 85% by weight based on the total amount of the preparation.

Also preferably, the weight ratio of ecarbette or a pharmaceutically acceptable salt thereof and ranitidine or a pharmaceutically acceptable salt thereof may be from 20: 1 to 2: 1.

Also preferably, the content of the ecarbette or a pharmaceutically acceptable salt thereof is from 250 mg to 1000 mg. Also preferably, the content of the ranitidine or a pharmaceutically acceptable salt thereof may be 30 mg to 200 mg.

Also preferably, the stabilizer is selected from the group consisting of magnesium oxide, meglumine, calcium carbonate, magnesium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium citrate and potassium citrate And the like. The content of the stabilizer may be 1 to 10% by weight with respect to the whole preparation. More preferably, the stabilizer may be magnesium oxide.

The pharmaceutically acceptable excipient contained in the first drug layer may be at least one selected from the group consisting of disintegrants, excipients, and glidants.

The disintegrant may be at least one selected from the group consisting of starch glycolic acid sodium, carboxymethylcellulose sodium, croscarmellose sodium, low-substituted-hydroxypropylcellulose, pregelatinized starch and crospovidone.

The sliding motif may be at least one selected from the group consisting of colloidal silicon dioxide and magnesium metasilicate aluminate. The lubricant may be at least one selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate, and glycerol palmitostearic acid.

The first drug layer may comprise from 70 to 95% by weight of ecarbette or a pharmaceutically acceptable salt thereof, from 1 to 8% by weight of an alkalizing agent, from 4 to 15% by weight of a disintegrant and from 0.1 to 3% by weight of a lubricant .

Also preferably, the first drug layer may not contain a binder.

The pharmaceutically acceptable excipient contained in the second drug layer may be at least one selected from the group consisting of a binder or a sustained release agent, an excipient and a glidant.

The binder may be selected from the group consisting of ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, and polyethylene oxide And the like. More preferably, the binder may be ethylcellulose.

More preferably, the excipient may be at least one selected from the group consisting of microcrystalline cellulose, low substituted hydroxypropylcellulose, cellulose derivatives such as methylcellulose, potato starch and corn starch, lactose, and fructose.

The lubricant may be at least one selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate, and glycerol palmitostearic acid.

The second drug layer may comprise from 20 to 50% by weight of ranitidine or a pharmaceutically acceptable salt thereof, from 20 to 60% by weight of an excipient, from 5 to 40% by weight of a binder and from 0.5 to 5% by weight of a lubricant.

And an intermediate layer comprising an additive which is pharmaceutically acceptable between the first drug layer and the second drug layer and does not react with the drug.

Additives which are pharmaceutically acceptable and which do not react with the drug include lactose, lactose, sugar, glucose, mannitol, sorbitol, sugar derivatives, corn starch, potato starch, sweet potato starch, dextrin, starch derivatives, microcrystalline cellulose, microcrystalline cellulose, Wherein the inorganic filler is selected from the group consisting of anhydrous silicic acid spray dried foam, cellulose derivative, gum arabic, dextran, pullulan, organic excipient, light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium aluminate metasilicate, calcium silicate, calcium hydrogenphosphate, At least one selected from the group consisting of calcium carbonate, calcium sulfate, calcium sulfate, magnesium stearate, calcium stearate, sodium stearate fumarate, stearic acid derivatives, talc, sucrose fatty acid esters and fatty acid derivatives.

Also preferably, the first drug layer may not contain a binder.

Also preferably, the multi-layer solid preparation can be a multi-layer tablet. Also, the content of the ranitidine may preferably be maintained at 85% or more after 5 days at 60 ° C, 75% relative humidity and sealing conditions. Also preferably, the formulation may have a dissolution rate of at least 85% after 30 minutes in water.

In another aspect, the present invention relates to a method for preparing a multi-layered solid preparation having improved stability. Specifically, the present invention relates to a pharmaceutical composition comprising a first drug layer comprising ecabeat or a pharmaceutically acceptable salt thereof, an alkalizing agent and a pharmaceutically acceptable additive, a second drug layer comprising ranitidine or a pharmaceutically acceptable salt thereof, The method comprising the steps of: preparing a second drug layer comprising a pharmaceutically acceptable additive and compressing the first drug layer and the second drug layer to produce a multi-layer formulation; will be.

Preferably, the second drug layer is firstly tableted and the first drug layer is later tableted.

In another embodiment, there is provided a method of making a pharmaceutical composition comprising the steps of: preparing a first drug layer comprising ecarbette or a pharmaceutically acceptable salt thereof, an alkalizing agent and a pharmaceutically acceptable additive, Preparing a second drug layer comprising ranitidine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, and forming a second drug layer comprising the first drug layer, the intermediate layer and the second drug layer In turn, to contact so as to produce a multi-layer formulation.

Preferably, the second drug layer is firstly tableted, the intermediate layer is tableted, and the first drug layer is later tableted.

Preferably, the first drug layer, the intermediate layer and the second drug layer may be prepared by direct compression, wet granulation or dry granulation, respectively, .

Also preferably, the step of coating the multi-layer formulation may be further included.

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

The present invention provides a pharmaceutical composition comprising a first drug layer comprising ecabet or a pharmaceutically acceptable salt thereof, a stabilizing agent (alkalizing agent) and a pharmaceutically acceptable additive, in order to prepare a multi-layer solid preparation with improved stability, Layered solid preparation comprising a second drug layer comprising ranitidine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

In a specific example of the present invention, the degree of decomposition of lanitidine was confirmed in the case of simple mixing of ranitidine and ecarbet and in the case of adding magnesium oxide. As a result, when ranitidine and ecarbet were simply mixed, the stability of ranitidine was rapidly degraded, but it was confirmed that the decomposition of lanitidine can be suppressed by adding magnesium oxide (Test Example 2).

In another embodiment, the coagulation phenomenon during the elution of a single mixed tablet of lanitidine and ecarbet and a magnesium-added multi-layer tablet was compared. As a result, in the case of the multi-layer tablet of the present invention, there was no entanglement phenomenon, but in the case of a single mixed tablet, entanglement phenomenon occurred and it was confirmed that the dissolution rate was very poor (Test Example 3).

In another embodiment of the present invention, in order to confirm the stability of the tablets to which magnesium oxide was added, the content of ranitidine and tablets to which no magnesium oxide was added were compared (Test Example 4). As a result, it was confirmed that the stability of the tablets to which magnesium oxide was added was significantly higher than that of the tablets to which magnesium oxide was not added (Test Example 4).

Further, the stability of the multi-layer tablets of the present invention was compared with tablets to which magnesium oxide was not added. As a result, it was confirmed that the stability of ranitidine was maintained for up to 3 months in the present invention, but the stability of the tablets not containing magnesium oxide was not maintained (Test Example 5).

Accordingly, the present invention relates to a pharmaceutical composition comprising a multilayer solid preparation comprising a first drug layer comprising ecarbette or a pharmaceutically acceptable salt thereof, a stabilizer (alkalizing agent) and a pharmaceutically acceptable additive, and a second drug layer comprising ranitidine or a pharmaceutically acceptable salt thereof The present invention provides a formulation which can inhibit the decomposition of ranitidine to improve stability, which can be used in various formulations, and can be easily administered, by containing a second drug layer containing an acceptable salt and a pharmaceutically acceptable additive. .

Ectavid is an antiulcer and protease inhibitor of sulfodehydroabietic acid · sodium · pentahydrate and is the first substance extracted from the pine tree rosin. Specifically, the compound of the ecarbette is (4bS, 8R, 8aR) -8-methoxycarbonyl-4b-methyl-2-propan-2-yl-6,7,8,8a, 9,10-hexahydro- (4bS, 8R, 8aR) -8-methoxycarbonyl-4b-methyl-2-propan-2-yl-6,7,8,8a, 9,10- hexahydro-5H-phenanthrene -3-sulfonate), and has a structure represented by the following formula (1).

[Chemical Formula 1]

In the present invention, ecocet can be used as a free base or a pharmaceutically acceptable salt thereof, a racemate, an enantiomer, a polymorph, a hydrate and a solvate thereof, etc., as long as the equivalent pharmacological activity is maintained It can be used in various forms.

The pharmaceutically acceptable salts include salts derived from pharmaceutically acceptable bases. For example, salts derived from suitable bases may include alkali metals such as sodium, potassium, alkaline earth metals such as magnesium, and ammonium. Preferably, but not limited to, ecarbad sodium in the present invention.

Ranitidine is a drug that acts as an antagonist of the H2 receptor and inhibits gastric acid production. More specifically, the name of the compound of the lanthidine is N- (2 - [(5- [(dimethylamino) methyl] furan-2-yl) methylthio] ethyl) 2-nitroethene-1,1-diamine)), and a compound represented by the following general formula (1): < EMI ID = (2).

(2)

In the present invention, as long as the equivalent pharmacological activity is maintained, the ranitidine can be in various forms such as a free base or a pharmaceutically acceptable salt thereof, a racemate thereof, an enantiomer, a polymorph, a hydrate and a solvate thereof Can be used as.

The pharmaceutically acceptable salt includes a pharmaceutically acceptable inorganic or organic acid. Examples of suitable acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, Sulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid and the like. Preferably, in the present invention, it is not limited to ranitidine hydrochloride.

Eucavet is a stable form containing a large amount of water in an amount of 15 to 20% (wt / wt), and when the raw material is dried and left under normal conditions, moisture in the air until 17 to 18% (wt / . ≪ / RTI > On the other hand, lanitidine has hygroscopicity. Therefore, when mixing a large amount of water-containing eczacet with hygroscopic ranitidine in one preparation, it is obvious that ranitidine absorbs moisture of the eczac to decompose lanitidine and the stability of eczac is also inferior. In addition, ecarvette exhibits a pH of about 4.2 in aqueous solution and contains a large amount of water, and since ranitidine has an acidity of less than pH 5 or a poor stability in a strong base state, when lecithin is mixed with a single preparation of erucate and lanitidine, . In addition, when mixing ranitidine and erucate at the same time, the uniformity of the content becomes poor, and the coagulation phenomenon occurs due to the interaction of the two components, so that the dissolution rate of the drug may decrease and the absorption and bioavailability may be lowered. Therefore, it is very difficult to produce erbat and ranitidine in one preparation.

Thus, the present inventors continued their research to add a stabilizer that inhibits the decomposition of ranitidine to the first drug layer containing ecabat and a pharmaceutically acceptable additive, and to add a stabilizer that inhibits the decomposition of ranitidine and a pharmaceutically acceptable excipient 2 drug layer has been confirmed through experimentation that the stability is improved and the coagulation phenomenon does not occur due to the inhibition of the decomposition of ranitidine and the dissolution rate of the drug is excellent, and the invention is completed.

In one embodiment of the invention there is provided a pharmaceutical composition comprising a first drug layer comprising ecabet or a pharmaceutically acceptable salt thereof, a stabilizing agent (alkalizing agent) and a pharmaceutically acceptable additive, ranitidine or its There can be provided a multi-layered solid preparation with improved stability comprising a second drug layer comprising a pharmaceutically acceptable salt, and a pharmaceutically acceptable additive.

In a specific embodiment of the present invention, the total content of ecarbette or a pharmaceutically acceptable salt thereof and lanitidine or a pharmaceutically acceptable salt thereof may be 40 to 90% by weight based on the whole preparation. Preferably, it may be from 50 to 85% by weight, based on the total formulation.

In another embodiment of the present invention, the weight ratio of ecarbette or a pharmaceutically acceptable salt thereof and lanitidine or a pharmaceutically acceptable salt thereof may be from 20: 1 to 2: 1, preferably from 15: 1 to 3: 1 , More preferably from 10: 1 to 3: 1. As a specific example, the content of ecarbette or a pharmaceutically acceptable salt thereof may be from 250 mg to 1000 mg, and preferably from 250 mg to 800 mg. The content of ranitidine or a pharmaceutically acceptable salt thereof may be from 30 mg to 200 mg, and preferably from 35 mg to 180 mg.

In one preferred embodiment, the content of ecarbette or a pharmaceutically acceptable salt thereof is 250 mg and the content of ranitidine or a pharmaceutically acceptable salt thereof is 42 mg. In another embodiment, the content of ecarbette or a pharmaceutically acceptable salt thereof is 500 mg and the content of ranitidine or a pharmaceutically acceptable salt thereof is 84 mg.

As used herein, the term "stabilizer" means a substance that inhibits decomposition of ranitidine. In the present invention, an alkalizing agent is used as a stabilizer contained in the ecabat containing layer. Specifically, the stabilizer means a substance that inhibits the decomposition of ranitidine to accelerate by reaction with ecabet. For example, it may be a substance that inhibits the decomposition of lanitidine when lanitidine is decomposed by reacting lanitidine and ecarbet, which are components of the formulation of the present invention. In addition, the stability of ranitidine in an acidic or strong base state at pH 5 or lower is poor, and it may be a substance inhibiting the decomposition of ranitidine in such an environment. Specific examples of the stabilizer include magnesium oxide, meglumine, calcium carbonate, magnesium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium citrate, and potassium citrate And the like, but it is not limited thereto, as long as it corresponds to a substance capable of inhibiting the decomposition of ranitidine. Preferably, the content of the stabilizer in the present invention may be 1 to 10% by weight with respect to the whole preparation.

Meanwhile, the first drug layer of the present invention may further include a pharmaceutically acceptable additive. The additive is used for improving the preparation, compressibility and appearance of the preparation, and can be prepared by conventional additives known to those skilled in the art within a range that does not cause interaction with the ecarbette and does not cause adverse effects on the efficacy.

The pharmaceutically acceptable excipients further included in the first drug layer may include, but are not limited to, disintegrants, excipients, lubricants, and the like.

The term "disintegrating " as used herein generally refers to a material that is used to accelerate the disintegration of a solid formulation so that the active agent exhibiting drug efficacy in the formulation is released within a short time. In a specific example, the multi-layered solid preparation of the present invention may be a substance that dissolves in vivo to allow rapid release of the eczacbet.

Examples of disintegrants include alginic acid, sodium alginate, maize starch, pregelatinised starch, low-substituted hydroxypropyl cellulose (L- HPC), sodium carboxymethyl starch, calcium carboxymethyl starch, cross-linked carboxymethylcellulose sodium [croscarmellose sodium], cross-linked polyvinylpyrrolidone [ Crospovidone], sodium starch glycolate, and the like can be used. Preferably, it may be, but is not limited to, sodium starch glycolate, carboxymethylcellulose sodium, croscarmellose sodium, low substituted hydroxypropylcellulose, pregelatinized starch and crospovidone.

As used herein, the term "active theme" refers to a material added to enhance the flowability of the powder mixture. One example that can be applied to the present invention may be a substance which promotes the flowability of the ecarbet and facilitates the release of the ecarbet when the ecarbet is released from the living body. Examples of the sliding theme include colloidal silicon dioxide (silicon dioxide), talc, magnesium metasilicate aluminate. Preferably, it may be colloidal silicon dioxide, magnesium metasilicate aluminate, but is not limited thereto.

As used herein, the term "lubricant" is a material that imparts improved flow properties to pharmaceutical compositions. As an example, it may be a substance that facilitates the release of ecarbets or ranitidine by reducing the friction between ecarbets or ranitidine and other additives when ecarbets or ranitidine are released. Examples of glidants include magnesium stearate, stearic acid, sodium stearyl fumarate, glycerol palmitostearic acid, stearyl alcohol, glycerol monostearate, talc, and combinations or mixtures thereof. But is not limited to, magnesium stearate, stearic acid, sodium stearyl fumarate, and glycerol palmitostearic acid.

Further, the shape of the first drug layer is not limited, but may be a spherical or a spherical shape. Preferably, the content of components in the first drug layer is between 70 and 95% by weight of ecarbette or a pharmaceutically acceptable salt thereof, between 1 and 8% by weight of a stabilizer, between 4 and 15% by weight of a disintegrant, and between 0.1 and 0.1% To 3% by weight. More preferably from 80 to 90% by weight of ecarbette or a pharmaceutically acceptable salt thereof, from 2 to 6% by weight of a stabilizer, from 6 to 15% by weight of a disintegrant and from 0.5 to 3% by weight of a lubricant .

On the other hand, in the first drug layer containing ecarbette, there is a problem that the size of the tablets becomes large when complex tablets are formed because the ecarbette dose is very large at 1 g per dose. Thus, the present inventors have found that ecarbet has its own binding ability, and it has been confirmed that the size of tablets can be minimized by not adding a binder to the first drug layer containing ecarbette. In this regard, in one preferred embodiment of the present invention, the first drug layer comprising ecarbette may not contain a binding agent, but is not limited thereto.

The second drug layer of the present invention may further comprise a pharmaceutically acceptable additive. The additive is used for improving the preparation, compressibility, appearance, and delay of release of the preparation. The additive may be any conventional additive known in the art within the range that does not cause interaction with ranitidine and does not adversely affect the drug efficacy. .

 The pharmaceutically acceptable excipients included in the second drug layer may include, but are not limited to, binders or sustained release agents, excipients, diluents, lubricants, and the like.

As used herein, the term "binder" in the term "binder " means a material capable of imparting elasticity and tackiness to increase the strength of the formed formulation, especially the strength of the formed tablet. In addition, the binder may impart elasticity and tackiness to the formulation, thereby delaying release of the active agent from the formulation. Specifically, the present invention may be a substance that delays the release of ranitidine in vivo. Examples of the binder include ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), hydroxyethylmethyl cellulose ), Polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, polyethylene oxide, polyvinyl alcohol, polyacrylic acid, polymethacrylic acid, and the like. Preferably, the hydrophilic polymer is selected from the group consisting of ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, and polyethylene oxide But is not limited thereto.

As used herein, the term "diluent " refers to a substance that is added to increase the volume of the drug or to dilute the concentration. For example, lactose, mannitol, glucose, sucrose, calcium sulfate, calcium phosphate, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch, polyvinylpyrrolidone, magnesium metasilicate aluminate But is not limited thereto.

As used herein, the term "excipient " refers to a material added to impart a suitable hardness or shape to a drug, or to be of a size that is easy to handle given a constant dose weight when the amount of the active ingredient is low. For example, it may be a sugar derivative such as mannitol or sorbitol, an inorganic excipient such as corn starch, potato starch, microcrystalline cellulose, low substituted hydroxypropylcellulose, a cellulose derivative such as methylcellulose, and carbonate such as calcium carbonate. It is not limited.

In addition, the shape of the second drug layer is not limited, but may be a spherical or spherical shape. Preferably, the content between the components contained in the second drug layer is 20 to 50% by weight of ranitidine or a pharmaceutically acceptable salt thereof, 20 to 60% by weight of an excipient, 5 to 40% by weight of a binder and 0.5 to 5% %. ≪ / RTI > More preferably, it is not limited to 25 to 40% by weight of ranitidine or a pharmaceutically acceptable salt thereof, 30 to 50% by weight of an excipient, 10 to 25% by weight of a binder and 0.5 to 3% by weight of a lubricant.

In a preferred embodiment of the present invention, the intermediate layer may include an additive that is pharmaceutically acceptable between the first drug layer and the second drug layer and does not react with the drug.

The intermediate layer may physically prevent contact between the first drug layer and the second drug layer, and specifically may be a layer that prevents interaction of erbidine included in the first drug layer and ranitidine contained in the second drug layer . In addition, by this intermediate layer, the dissolution rate can be improved by preventing the interaction of the erbatide contained in the first drug layer and the ranitidine contained in the second drug layer.

Preferably, the intermediate layer may comprise an additive that does not react with the drug. Specifically, the additive may not react with the drug contained in the first drug layer or the drug contained in the second drug layer. The term "unresponsive" may include not only a case where no reaction occurs between drugs, but also a reaction that does not interfere with the effect of the drug due to a small reaction between the drugs.

Pharmaceutically acceptable and drug-free additives that may be included in the intermediate layer may be additives commonly used as excipients and include, for example, sugar derivatives such as lactose, milk powder for direct use, white sugar, glucose, mannitol or sorbitol, Starch derivatives such as corn starch, potato starch, sweet potato starch or dextrin, organic excipients such as microcrystalline cellulose, microcrystalline cellulose and light anhydrous silicic acid spray dry foam, gum arabic, dextran, or pullulan, Aluminum, silicate derivatives such as calcium silicate or magnesium metasilicate aluminate, phosphates such as calcium hydrogen phosphate, carbonates such as calcium carbonate, or sulfates such as calcium sulfate. A lubricant may be used for the intermediate layer. The lubricant may be, for example, stearic acid derivatives such as magnesium stearate, stearic acid, sodium stearyl fumarate and glycerol palmitostearic acid, mineral resources such as talc, fatty acid derivatives such as sucrose fatty acid esters, But are not limited thereto.

In one preferred embodiment of the present invention, the multi-layer solid preparation of the present invention may be a multi-layer tablet. It may be a two-layer tablet, and preferably it may be a three-layer tablet. Specifically, the two-ply tablet comprises a first drug layer comprising, from the inside to the outside, ecarvet or a pharmaceutically acceptable salt thereof, an alkalizing agent and a pharmaceutically acceptable additive, and at least one of ranitidine or a pharmaceutically acceptable salt thereof, Or a tablet comprising a second drug layer comprising a pharmaceutically acceptable additive. Also, the two-ply tablet comprises a second drug layer comprising ranitidine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive from the inside to the outside, and a second drug layer comprising ecarbet or a pharmaceutically acceptable salt thereof, an alkalizing agent, A tablet comprising a first drug layer comprising an admixable admixture. The three-layer tablet comprises a first drug layer comprising, from the inside to the outside, ecavet or a pharmaceutically acceptable salt thereof, an alkalizing agent and a pharmaceutically acceptable additive, a pharmaceutically acceptable excipient which is not reactive with the drug An intermediate layer and a second drug layer comprising ranitidine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. In another embodiment, the three-ply tablet comprises a second drug layer comprising, from the inside to the outside, ranitidine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, a pharmaceutically acceptable excipient And a first drug layer comprising an ecarbet or a pharmaceutically acceptable salt thereof, an alkalizing agent and a pharmaceutically acceptable additive.

As a specific example, the multilayered preparation of the present invention can maintain the content of ranitidine at 85% or more after 5 days at 60 ° C, 75% relative humidity and sealing conditions. As a result of the present invention which solves the problem of ranitidine which is easily decomposed under moisture, it is preferable that the content of ranitidine is maintained at 85% or more after 5 days at 60 ° C, 75% relative humidity and sealing condition.

As another example, the multi-layered preparation of the present invention may have a dissolution rate of not less than 85% after 30 minutes in an aqueous solution. This satisfies the dissolution rate similar to that of the existing commercial formulation while maintaining the stability of the ranitidine, and thus it is possible to provide multi-layered tablets of ecavet and ranitidine excellent in dissolution rate in vivo.

In another aspect of the present invention, the present invention provides a method for preparing a multi-layered solid preparation with improved stability. The multi-layered solid preparation of the present invention can be produced by a production method known in the art.

Preferably, the method further comprises:

Preparing a first drug layer comprising ecarbet or a pharmaceutically acceptable salt thereof, an alkalizing agent and a pharmaceutically acceptable additive,

Preparing a second drug layer comprising ranitidine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, and

Compressing the first drug layer and the second drug layer to produce a multi-layer formulation

And a method for producing a multilayer solid preparation having improved stability.

More preferably, the first drug layer and the second drug layer can be produced by direct compression molding, wet granulation or dry granulation, respectively. Specifically, the first drug layer and the second drug layer may be prepared by direct compression molding, or by conventional wet granulation or dry granulation techniques, respectively, followed by compression molding each layer. In one example, when the multilayered solid preparation of the present invention is embodied as a two-layer tablet, the first drug layer and the second drug layer are each prepared by conventional wet granulation or dry granulation techniques, and then the first drug Compressing the layer and the second drug layer, and combining both layers using a conventional two-layer molding machine.

The method may further comprise coating the multi-layer formulation with one of the manufacturing methods of the multi-layer formulation.

The present invention provides another method for producing a multilayer solid preparation having improved stability. The preparation method can be carried out by using a production method known in the art, but preferably,

Preparing a first drug layer comprising ecarbet or a pharmaceutically acceptable salt thereof, an alkalizing agent and a pharmaceutically acceptable additive,

Preparing an intermediate layer comprising a pharmaceutically acceptable additive that does not react with the drug,

Preparing a second drug layer comprising ranitidine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, and

Compressing the first drug layer, the intermediate layer and the second drug layer so as to contact one another in order to produce a multilayer preparation

And a method for producing a multilayer solid preparation having improved stability.

More preferably, the first drug layer, the intermediate layer and the second drug layer can be produced by direct compression molding, wet granulation or dry granulation, respectively. Specifically, the first drug layer, the intermediate layer and the second drug layer may be directly compression-molded, or may be prepared by conventional wet granulation or dry granulation techniques, respectively, followed by compression molding each layer. As an example, when the multi-layered solid preparation of the present invention is embodied as a three-layered tablet, the first drug layer, the intermediate layer and the second drug layer may each be prepared by conventional direct tableting granules or by wet granulation or dry granulation techniques And then compressing the first drug layer, the middle layer and the second drug layer, and combining the two layers using a conventional three-layer molding machine.

And then coating the multi-layer formulation after preparation of the multi-layer formulation.

In the method for producing a multi-layered solid preparation having improved stability according to the present invention, it can be produced by considering the interaction between the saccharides and the ranitidine so that the stability of the ranitidine is not degraded.

The dosage form of the multilayered solid preparation prepared by the multilayered solid preparation having improved stability or the improved multilayered solid preparation of the present invention may be an oral, parenteral (muscle, subcutaneous, intravenous, etc.) administration form. Formulations for oral administration may be tablets, capsules, troches, dispersants, suspensions, etc., and may be, but not limited to, tablets.

The multi-layered solid preparation having improved stability of the present invention or the multi-layer solid preparation having improved stability prepared by the production method of the present invention contains two active ingredients of ecarbette and ranitidine in one preparation, It is possible to increase the convenience of taking. In addition, the coagulation phenomenon due to the interaction of ranitidine and erucate can be suppressed, the dissolution rate of each component can be secured, and decomposition of ranitidine can be suppressed. In addition, it has excellent effects as compared with a pharmaceutical composition composed of a single component, thereby maximizing therapeutic and prophylactic effects.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the results of dissolution of ecabet in a mixed tablet of Example 1 and Example 7 of the present invention and a commercially available Gastrex granule (Cheil Pharmaceutical).
Fig. 2 shows the results of the dissolution of ranitidine in the complex tablets of Example 1 and Example 7 of the present invention and the commercial product, Kuran Chung (Ildong Pharmaceutical).

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

Example  1. Magnesium The oxide (stabilizer)  Manufacture of formulations containing

Rinitidine hydrochloride, anhydrous lactose, microcrystalline cellulose, ethyl cellulose and magnesium stearate were weighed, respectively, and the mixture was passed through a mesh of 35 sieves, mixed using a high speed mixer, and ecarbad sodium The tablet layer contained was obtained by weighing ecarbad sodium, starch sodium glycolate, magnesium oxide, colloidal silicon dioxide, and magnesium stearate, passing through 35 mesh sieves and mixing using a high-speed mixer. The contents of each component are shown in Table 1.

The bulk density of the ranitidine hydrochloride containing layer was 0.58 g / ml, the tapped density was 0.70 g / ml, and the Carr's index was 17.6%. The bulk density of the ecarbad sodium-containing layer was 0.59 g / ml, the tap density was 0.75 g / ml, and the Kaf Index was 21.5%.

The final mixtures thus obtained were compression-pressed with 224.5 mg of ranitidine hydrochloric acid-containing layer on a two-layer tablet press compression tablet machine using a 17.45 * 7.10 mm rectangular punch, and an ecarbad sodium layer as an upper layer composition was compressed and titrated by 575.5 mg 800 mg of a two-pack tablet was obtained. 4% of the total tablet weight was coated with the coating, and the weight of the final two-layer tablet was 832 mg.

Floor classification ingredient Total amount
(g) Party weight ( mg ) Weight% (w / w) Ranitidine layer Ranitidine hydrochloride 1,260.0 84.0 10.5 Anhydrous lactose 855.5 57.0 7.1 Microcrystalline cellulose 600.0 40.0 5.0 Ethyl cellulose 600.0 40.0 5.0 Magnesium stearate 52.5 3.5 0.4 sub Total 3,367.5 224.5 28.0 Ekavet floor Ecarbad sodium 5,000.0 500.0 62.5 Magnesium oxide 230.0 23.0 2.9 Starch glycolic acid sodium 455.0 45.5 5.7 Colloidal silicon dioxide 10.0 1.0 0.1 Magnesium stearate 60.0 6.0 0.8 sub Total 5,755.0 575.5 72.0 final  Sum 800.0 100.0

Example  2. Polyvinylpyrrolidone  Manufacture of formulations containing

Rinitidine hydrochloride, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, and magnesium stearate were each weighed and passed through 35 mesh sieves, shaken and mixed in a plastic bag, mixed with ecarbad sodium A tablet layer was obtained by weighing ecarbad sodium, starch sodium glycolate, magnesium oxide, colloidal silicon dioxide, and magnesium stearate, passing through 35 mesh sieves, shaking them in a plastic bag and mixing them. The content of each component is shown in Table 2.

The final mixtures thus obtained were compression-pressed with 224.5 mg of a ranitidine hydrochloric acid-containing layer on a two-layer tablet-compression tableting machine using a 17.45 * 7.10 mm rectangular punch, and an ecarbad sodium layer as an upper layer composition was compressed by 575.5 mg 800 mg of a two-layer tablet was obtained. 4% of the total tablet weight was coated with the coating, and the weight of the final two-layer tablet was 832 mg.

Floor classification ingredient Total amount
(g) Party weight ( mg ) Weight% (w / w) Ranitidine layer Ranitidine hydrochloride 252.0 84.0 10.5 Anhydrous lactose 171.0 57.0 7.1 Microcrystalline cellulose 120.0 40.0 5.0 Polyvinylpyrrolidone 120.0 40.0 5.0 Magnesium stearate 10.5 3.5 0.4 sub Total 673.5 224.5 28.0 Ekavet floor Ecarbad sodium 1000.0 500.0 62.5 Magnesium oxide 46.0 23.0 2.9 Starch glycolic acid sodium 91.0 45.5 5.7 Colloidal silicon dioxide 2.0 1.0 0.1 Magnesium stearate 12.0 6.0 0.8 sub Total 1151.0 575.5 72.0 final  Sum 800.0 100.0

Example  3. Crospovidone  Manufacture of formulations containing

A two-layer tablet was prepared in the same manner as in Example 2. The contents of each component are shown in Table 3.

Floor classification ingredient Total amount
(g) Party weight ( mg ) Weight% (w / w) Ranitidine layer Ranitidine hydrochloride 252.0 84.0 10.5 Anhydrous lactose 171.0 57.0 7.1 Microcrystalline cellulose 120.0 40.0 5.0 Ethyl cellulose 120.0 40.0 5.0 Magnesium stearate 10.5 3.5 0.4 sub Total 673.5 224.5 28.0 Ekavet floor Ecarbad sodium 1000.0 500.0 62.5 Magnesium oxide 46.0 23.0 2.9 Crospovidone 91.0 45.5 5.7 Colloidal silicon dioxide 2.0 1.0 0.1 Magnesium stearate 12.0 6.0 0.8 sub Total 1151.0 575.5 72.0 final  Sum 800.0 100.0

Example  4. Cross camelose  Manufacture of preparations containing sodium

A two-layer tablet was prepared in the same manner as in Example 2. The contents of each component are shown in Table 4.

Floor classification ingredient Total amount (g) Party weight ( mg ) Weight% (w / w) Ranitidine layer Ranitidine hydrochloride 252.0 84.0 10.5 Anhydrous lactose 171.0 57.0 7.1 Microcrystalline cellulose 120.0 40.0 5.0 Ethyl cellulose 120.0 40.0 5.0 Magnesium stearate 10.5 3.5 0.4 sub Total 673.5 224.5 28.0 Ekavet floor Ecarbad sodium 1000.0 500.0 62.5 Magnesium oxide 46.0 23.0 2.9 Cross camelose sodium 91.0 45.5 5.7 Colloidal silicon dioxide 2.0 1.0 0.1 Magnesium stearate 12.0 6.0 0.8 sub Total 1151.0 575.5 72.0 final  Sum 800.0 100.0

Example  5. Polyethylene oxide  Manufacture of formulations containing

A two-layer tablet was prepared in the same manner as in Example 2. The content of each component is shown in Table 5.

Floor classification ingredient Total amount
(g) Party weight ( mg ) Weight% (w / w) Ranitidine layer Ranitidine hydrochloride 252.0 84.0 10.8 Anhydrous lactose 171.0 57.0 7.3 Microcrystalline cellulose 120.0 40.0 5.1 Polyethylene oxide 100.0 20.0 2.6 Magnesium stearate 10.5 3.5 0.4 sub Total 673.5 204.5 26.2 Ekavet floor Ecarbad sodium 1000.0 500.0 64.2 Magnesium oxide 46.0 23.0 2.9 Starch glycolic acid sodium 91.0 45.5 5.8 Colloidal silicon dioxide 2.0 1.0 0.1 Magnesium stearate 12.0 6.0 0.8 sub Total 1151.0 575.5 73.8 final  Sum 780.0 100.0

Example  6. The meglumine (stabilizer)  Manufacture of formulations containing

A two-layer tablet was prepared in the same manner as in Example 2. The content of each component is shown in Table 6.

Floor classification ingredient Total amount
(g) Party weight ( mg ) Weight% (w / w) Ranitidine layer Ranitidine hydrochloride 252.0 84.0 10.5 Anhydrous lactose 171.0 57.0 7.1 Microcrystalline cellulose 120.0 40.0 5.0 Ethyl cellulose 120.0 40.0 5.0 Magnesium stearate 10.5 3.5 0.4 sub Total 673.5 224.5 28.0 Ekavet floor Ecarbad sodium 1000.0 500.0 62.5 Meglumine 46.0 23.0 2.9 Crospovidone 91.0 45.5 5.7 Colloidal silicon dioxide 2.0 1.0 0.1 Magnesium stearate 12.0 6.0 0.8 sub Total 1151.0 575.5 72.0 final  Sum 800.0 100.0

Example  7. Manufacture of 3-layer tablet

A two-layer tablet was prepared in the same manner as in Example 2. The content of each component is shown in Table 7.

Floor classification ingredient Total amount
(g) Party weight ( mg ) Weight% (w / w) Ranitidine layer Ranitidine hydrochloride 252.0 84.0 9.3 Anhydrous lactose 171.0 57.0 6.3 Microcrystalline cellulose 120.0 40.0 4.4 Ethyl cellulose 120.0 40.0 4.4 Magnesium stearate 10.5 3.5 0.4 sub Total 673.5 224.5 24.8 Middle layer Microcrystalline cellulose 350.0 70.0 7.8 Anhydrous lactose 127.5 25.5 2.8 Hydroxypropylcellulose 15.0 3.0 0.3 Magnesium stearate 7.5 1.5 0.2 sub Total 500.0 61.0 11.1 Ekavet floor Ecarbad sodium 1000.0 500.0 55.6 Magnesium oxide 46.0 23.0 2.6 Crospovidone 91.0 45.5 5.1 Colloidal silicon dioxide 2.0 1.0 0.1 Magnesium stearate 12.0 6.0 0.7 sub Total 1151.0 575.5 64.1 final  Sum 900.0 100.0

Example  8. Manufacture of 3-layer tablet

A two-layer tablet was prepared in the same manner as in Example 2. The content of each component is shown in Table 7.

Floor classification ingredient Total amount
(g) Party weight ( mg ) Weight% (w / w) Ranitidine layer Ranitidine hydrochloride 252.0 84.0 9.3 Anhydrous lactose 171.0 57.0 6.3 Microcrystalline cellulose 120.0 40.0 4.4 Ethyl cellulose 120.0 40.0 4.4 Magnesium stearate 10.5 3.5 0.4 sub Total 673.5 224.5 24.8 Middle layer Microcrystalline cellulose 350.0 70.0 7.8 Mannitol 127.5 25.5 2.8 Hydroxypropylcellulose 15.0 3.0 0.3 Magnesium stearate 7.5 1.5 0.2 sub Total 500.0 100.0 11.1 Ekavet floor Ecarbad sodium 1000.0 500.0 55.6 Magnesium oxide 46.0 23.0 2.6 Crospovidone 91.0 45.5 5.1 Colloidal silicon dioxide 2.0 1.0 0.1 Magnesium stearate 12.0 6.0 0.7 sub Total 1151.0 575.5 64.1 final  Sum 900.0 100.0

Comparative Example  1. Magnesium The oxide (stabilizer)  Manufacture of non-contained two-layer tablet

Rinitidine hydrochloride, anhydrous lactose, microcrystalline cellulose, crospovidone, sodium starch glycolate, and magnesium stearate were each weighed and passed through 35 mesh sieves, shaken and mixed in a plastic bag.

The purified layer containing ecarbad sodium was obtained by weighing ecarbad sodium, anhydrous lactose, microcrystalline cellulose, crospovidone, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate, passing through 35 mesh sieves, Shaken and mixed.

The final mixtures thus obtained were compression-pressed with 114.0 mg of ranitidine hydrochloric acid-containing layer on a two-layer tablet-compressed tablet press using a 17.45 * 7.10 mm rectangular punch, and 566.0 mg of an erbat sodium layer as an upper layer composition was compressed on the lower layer tablet 680 mg of two-layer tablet was obtained. 4% of the total tablet weight was coated with the coating, and the weight of the final two-layer tablets was 707.2 mg. The content of each component is shown in Table 9.

layer ingredient Total amount (g) party mg Weight% (w / w) Ranitidine layer Ranitidine hydrochloride 252.0 84.00 12.4 Anhydrous lactose 16.5 5.50 0.8 Microcrystalline cellulose 60.0 20.00 2.9 Crospovidone 3.0 1.00 0.1 Starch glycolic acid sodium 9.0 3.00 0.4 Magnesium stearate 1.5 0.50 0.1 sub Total 342.0 114.0 16.7 Ekavet floor Ecarbad sodium 1000.0 500.00 73.6 Anhydrous lactose 50.0 25.00 3.7 Microcrystalline cellulose 30.0 15.00 2.2 Crospovidone 10.0 5.00 0.7 Starch glycolic acid sodium 28.0 14.00 2.1 Colloidal silicon dioxide 2.0 1.00 0.1 Magnesium stearate 12.0 6.00 0.9 sub Total 1,132.0 566.0 83.3 final  Sum 680.0 100.0

Comparative Example  2. Manufacture of a single mixed tablet

According to the ingredients and contents in Table 10 below, a single mixed tablet was prepared by the following production method.

Ranitidine, microcrystalline cellulose and low-substituted hydroxypropylcellulose were weighed, placed in a plastic bag, shaken for 3 minutes, mixed, passed through a 30-mesh sieve, and shaken for 30 seconds for re-mixing. Eka bat was further added and mixed for 5 minutes. Further, magnesium stearate was passed through a 35-mesh sieve and re-mixed for 1 minute. The tablet was tableted.

The resulting final mixtures were compressed by using a 17.45 * 7.10 mm rectangular punch to obtain 680 mg of a single mixed tablet. 4% of the total tablet weight was coated with the coating, and the weight of the final two-layer tablets was 707.2 mg.

ingredient Total amount (g) party ( mg ) Weight% (w / w) Ekavet  Sodium 300.0 500.0 73.5 Hydrochloric acid Lanitidine 50.4 84.0 12.4 Microcrystalline cellulose 27.0 45.0 6.6 Low substitution Hydroxypropylcellulose 24.0 40.0 5.9 Colloidal  Silicon dioxide 0.6 1.0 0.1 Stearic acid  magnesium 6.0 10.0 1.5 sub Total 408.0 680.0 100.0

Test Example  1. Dissolution test of compound

Example 1 and Example 7 were subjected to a dissolution test. Gastrex granules (Cheil Pharmaceuticals) were used for the Ekaabt treaty and Kuran Jung (Ildong Pharmaceuticals) was used for the lanitidine treaty. The elution test was carried out by using a 900 ml volume of the aqueous solution with the eluent at 37 ° C for 50 revolutions per minute in accordance with the dissolution test method (paddle method) described in Korean Pharmacopoeia. The test solution was sampled at a predetermined time from the start of the test and filtered using a 0.45 um membrane filter. The filtrate was packed with a stainless steel tube having an inner diameter of about 4.6 mm and a length of 15 cm and containing 5 탆 of octadecylsilylated silica gel And the components were quantified using liquid chromatography at a flow rate of about 1.0 ml / min.

As a result, as shown in Fig. 1 and Fig. 2, the combined preparation of Example 1 and Example 7 exhibited a dissolution rate similar to that of the commercial formulation of each ingredient.

Test Example  2. Lanitidine  Hydrochloride, Ekavet  When mixing sodium and magnesium oxide pH  And stability

In order to confirm whether or not such problems can be solved in the case of adding magnesium oxide, a test group was constructed as shown in Table 11, and ranitidine, ecarbet and magnesium oxide were mixed in a volume of 30 ml , And the mixture was shaken. The mixture was allowed to stand in a stability tester at 60 ° C and 75% relative humidity for 20 hours, and the wet state and color change were observed at each time point (Table 12).

The color change process of the composition of the mixture of ranitidine hydrochloride and ecarbad sodium is in the order of yellow, orange, white brown and dark brown in the initial beige, while ranitidine begins to be decomposed.

Test group Furtherance ( mg ) Lanitidine
Hydrochloride Ekavet
Sodium Oxidation
magnesium Test group  One 1,000 0 0 Test group  2 1,000 0 10 Test group  3 1,000 500 0 Test group  4 1,000 500 10

Test group Wetting and color change over time (time) 0 2 4 6 8 20 One Wet state - Low Low Low middle plenty Color change beige beige beige beige White Brown Orange 2 Wet state - middle middle Somewhat more Somewhat more plenty Color change beige beige yellow yellow yellow yellow 3 Wet state - plenty plenty plenty plenty plenty Color change beige White Brown Brown Brown Brown dark brown 4 Wet state - plenty plenty plenty plenty plenty Color change beige beige yellow yellow yellow Orange

Beige: Original color of the composition containing lanitidine

Yellow: ranitidine slightly degraded in composition

Orange: slightly more degraded than yellow

White Brown: Orange and dark brown intermediate state

Dark Brown: Many ranitidine breakdowns in composition

As a result of the test, it was found that when the mixture of only ranitidine and ecarbette was mixed, the wettability was increased and the color change rapidly changed from 2 hours to brown. However, it was confirmed that the addition of magnesium oxide slowed the color change, and it was confirmed that the addition of magnesium oxide could inhibit the decomposition of lanitidine.

Test Example  3. Coagulation

The tablets of Example 1 and the tablets of Comparative Example 2 which were single mixed tablets were placed in a pH 1.2 eluate under the same conditions as those of the elution test (Test Example 1), and each of the tablets was placed in a dissolution tester at 37 DEG C and 50 rpm for 5 minutes, After 15 minutes, the entanglement of the tablets was observed.

time Example  One Comparative Example  2 refine One 2 3 4 One 2 3 4 5 minutes - - - - ++ ++ ++ ++ 15 minutes - - - - ++ + ++ ++

+++: Severely tangled

++: moderate tangle

+: Slightly tangled

-: No entanglement

It was confirmed that the two-layered tablet preparation of Example 1 had no entanglement phenomenon, disintegrated and eluted well, and the tablets of Comparative Example 2 had a moderate entanglement phenomenon, resulting in a very poor dissolution rate.

Test Example  4. Ekavet  And Lanitidine  Multilayer Tablet Accelerated Stability Test - 2nd floor definition  magnesium Oxide  Comparison of stability of addition

In the case of adding magnesium oxide, in order to confirm whether the stability of the tablets containing the lanitidine was increased, it was confirmed that when the container was sealed at 40 캜 and 60 캜 and when the container was opened (opened) Over the course of time, the contents of ranitidine in Example 1 containing magnesium oxide and Comparative Example 1 not containing magnesium oxide were tested by liquid chromatography and compared.

Storage conditions Control group ( Kyurang Jeong ) Example  One Comparative Example  One Early 1 day 5 days Early 1 day 5 days Early 1 day 5 days 40 <
RH  75%, unopened 99.6 101.0 97.8 100.1 98.9 95.2 101.1 99.1 94.3 40 <
RH  75%, sealing 99.6 101.1 98.7 100.1 96.3 99.7 101.1 103.2 100.9 60 ° C,
RH  75%, unopened 99.6 88.5 77.6 100.1 94.4 60.4 101.1 77.7 29.6 60 ° C,
RH  75%, sealing 99.6 100.5 94.3 100.1 97.3 90.7 101.1 101.4 79.0

As a result of the test, in Example 3 and Comparative Example 1 at 40 ° C and 75% RH, the same stability as that of the control (Kurean) was observed, but magnesium oxide was added to the ranitidine hydrochloride purification at 60 ° C and RH 75% The stability of the tablet was remarkably increased. In addition, it was confirmed that Example 1 containing magnesium oxide at 60 ° C and RH 75% was more stable than Comparative Example 1.

Test Example  5. Ekavet  And Lanitidine  Multilayer Tablet Stability Test - 2nd floor definition  Comparison of Stability of Magnesium Oxide Addition

The tablets of Example 1, which is a tablet containing magnesium oxide as a stabilizer, and the tablets of Comparative Example 1, which does not contain magnesium oxide, were subjected to a content test for 5 tablets per predetermined period while being stored at 25 캜 for long term storage test conditions Respectively.

Yes ingredient Duration (months) Early 0.5 One 1.5 2 3 Example  One Lanitidine 100.1 99.7 99.2 99.0 99.2 99.5 Ekavet 100.3 99.5 99.8 99.9 98.8 99.2 Comparative Example  One Lanitidine 99.8 99.5 99.3 98.7 95.4 91.3 Ekavet 99.6 99.2 99.3 99.5 99.0 99.2

As a result of the test, the tablets of Example 1 contained magnesium oxide as a stabilizer, so that the stability of the ranitidine was maintained for up to 3 months, but the tablets of Comparative Example 1 were not stable. Ecarbott was stable in both Example 1 and Comparative Example 1.

Claims (33)

A first drug layer comprising ecabet or a pharmaceutically acceptable salt thereof, an alkalizing agent and a pharmaceutically acceptable additive,
A second drug layer comprising ranitidine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive,
Wherein the alkalizing agent is selected from the group consisting of magnesium oxide, meglumine, calcium carbonate, magnesium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium citrate, However,
A multi-layered solid preparation having improved stability.
The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of ecarbate is ecarbad sodium,
A multi-layered solid preparation having improved stability.
The method of claim 1, wherein the pharmaceutically acceptable salt of lanitidine is lanitidine hydrochloride,
A multi-layered solid preparation having improved stability.
The pharmaceutical composition according to claim 1, wherein the total content of ecarbette or a pharmaceutically acceptable salt thereof and ranitidine or a pharmaceutically acceptable salt thereof is 40 to 90 wt%
A multi-layered solid preparation having improved stability.
5. The pharmaceutical composition according to claim 4, wherein the total content of ecarbette or a pharmaceutically acceptable salt thereof and lanitidine or a pharmaceutically acceptable salt thereof is 50 to 85% by weight,
A multi-layered solid preparation having improved stability.
2. The method of claim 1 wherein the weight ratio of ecarbette or a pharmaceutically acceptable salt thereof and ranitidine or a pharmaceutically acceptable salt thereof is from 20: 1 to 2: 1,
A multi-layered solid preparation having improved stability.
The pharmaceutical composition according to claim 1, wherein the content of said saccharide or its pharmaceutically acceptable salt is 250 mg to 1000 mg,
A multi-layered solid preparation having improved stability.
The pharmaceutical composition according to claim 1, wherein the content of the lanitidine or a pharmaceutically acceptable salt thereof is 30 mg to 200 mg,
A multi-layered solid preparation having improved stability.
delete The composition according to claim 1, wherein the content of the alkalizing agent is 1 to 10 wt%
A multi-layered solid preparation having improved stability.
The method of claim 1, wherein the alkalizing agent is magnesium oxide,
A multi-layered solid preparation having improved stability.
The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable excipient contained in the first drug layer is at least one selected from the group consisting of a disintegrant,
A multi-layered solid preparation having improved stability.
The method of claim 1, wherein the first drug layer does not comprise a binder.
A multi-layered solid preparation having improved stability.
13. The method of claim 12, wherein the disintegrant is at least one selected from the group consisting of starch glycolic acid sodium, carboxymethylcellulose sodium, croscarmellose sodium, low substituted hydroxypropylcellulose, pregelatinized starch and crospovidone.
A multi-layered solid preparation having improved stability.
delete The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable excipient contained in the second drug layer is at least one selected from the group consisting of a binder, an excipient,
A multi-layered solid preparation having improved stability.
17. The method of claim 16, wherein the binder is selected from the group consisting of ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, polyvinylpyrrolidone, vinylpyrrolidone- And at least one member selected from the group consisting of polyethylene oxide,
A multi-layered solid preparation having improved stability.
17. The method of claim 16, wherein the binder is ethyl cellulose.
A multi-layered solid preparation having improved stability.
The pharmaceutical composition according to claim 16, wherein the excipient is at least one selected from the group consisting of microcrystalline cellulose, low substituted hydroxypropyl cellulose, cellulose derivatives such as methyl cellulose, potato starch and corn starch, lactose,
A multi-layered solid preparation having improved stability.
18. The composition of claim 16, wherein the second drug layer comprises 20-50 wt% of ranitidine or a pharmaceutically acceptable salt thereof, 20-60 wt% excipient, 5-40 wt% binder or sustained release agent, and 0.5-5 ≪ / RTI > by weight,
A multi-layered solid preparation having improved stability.
2. The pharmaceutical composition of claim 1, further comprising an intermediate layer comprising a pharmaceutically acceptable additive between the first drug layer and the second drug layer,
A multi-layered solid preparation having improved stability.
22. The method of claim 21, wherein the first drug layer does not comprise a binder.
A multi-layered solid preparation having improved stability.
The method according to claim 1, wherein the multi-layered solid preparation is a multilayered tablet
A multi-layered solid preparation having improved stability.
The method according to claim 1, wherein the content of the ranitidine is maintained at 60 占 폚, 75% relative humidity, and 85% or more after 5 days of sealing.
A multi-layered solid preparation having improved stability.
The pharmaceutical composition according to claim 1, wherein the preparation has a dissolution rate of 85% or more after 30 minutes in water.
A multi-layered solid preparation having improved stability.
Preparing a first drug layer comprising ecarbet or a pharmaceutically acceptable salt thereof, an alkalizing agent and a pharmaceutically acceptable additive,
Preparing a second drug layer comprising ranitidine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, and
Compressing the first drug layer and the second drug layer to produce a multi-layer formulation.
A method for preparing the multilayered solid preparation of claim 1.
27. The method of claim 26, wherein the first drug layer is tableted after tableting the second drug layer.
A method for preparing a multilayer solid formulation.
27. The method of claim 26, wherein the first drug layer and the second drug layer are each prepared by direct compression, wet granulation, or dry granulation sign,
A method for preparing a multilayer solid formulation.
28. The method of claim 26, further comprising coating the multi-layer formulation.
A method for preparing a multilayer solid formulation.
Preparing a first drug layer comprising ecarbet or a pharmaceutically acceptable salt thereof, an alkalizing agent and a pharmaceutically acceptable additive,
Preparing an intermediate layer comprising a pharmaceutically acceptable additive that does not react with the drug,
Preparing a second drug layer comprising ranitidine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, and
Compressing the first drug layer, the intermediate layer and the second drug layer so as to be in contact with one another,
A method for preparing the multilayered solid preparation of claim 1.
31. The method of claim 30, wherein after the second drug layer is tableted, the intermediate layer is tableted and the first drug layer is tableted.
A method for preparing a multilayer solid formulation.
31. The method of claim 30, wherein the first drug layer, the intermediate layer and the second drug layer are each prepared by compression molding, wet granulation or dry granulation.
A method for preparing a multilayer solid formulation.
31. The method of claim 30, further comprising coating the multi-layer formulation.
A method for preparing a multilayer solid formulation.

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