TW201639559A - Pharmaceutical composition for treating gastrointestinal diseases - Google Patents

Abstract

The present invention provides a pharmaceutical composition for treating gastrointestinal diseases and a preparation method thereof, which comprises ranitidine, sclafi and bismuth subruthenate as active ingredients. According to the present invention, when a combination drug of ranitidine, sclafi and bismuth subruthenate is prepared, it can solve the absorption of ranitidine by controlling the particle size of sclafi and bismuth subruthenium. Wet problems and increased formulation stability and drug bioavailability.

Description

Pharmaceutical composition for treating gastrointestinal diseases

The present invention relates to a pharmaceutical composition for treating gastrointestinal diseases comprising ranitidine, sucralfate and bismuth subcitrate as active ingredients.

Ranitidine is a drug that inhibits the production of gastric acid via H2 receptor blockade, and is used for treating gastric ulcer or reflux esophagitis. In fact, when ranitidine is administered as a mixed treatment with bismuth subcitrate and sclarin, it is known to have an excellent therapeutic effect on gastric ulcer and duodenal ulcer (Patent Document 1: Korean Patent Publication No. 1997-006083) (Korean Laid-open Patent No.)). Therefore, a combination drug of the three drugs as an active ingredient is currently commercially available.

However, ranitidine has a strong hygroscopicity, which causes moisture absorption during storage and causes a change in the weight and characteristics of the tablet (PDA J. Pharm. Sci. Tech. 2009 May-Jun: 63(3) ): 223-33). Therefore, it has a problem of changing the collapse time of the tablet.

Also, when ranitidine is mixed with bismuth subruthenium citrate, it has a problem of changing the physical properties of ranitidine due to bismuth subruthenium citrate.

Therefore, Patent Document 1 discloses a preparation of ranitidine as a core tablet, and mixing a bismuth subruthenium sulphate and a sclarafifine to prepare a tablet in a tablet containing a core tablet (tablet-within-a-tablet) ). Similarly, Patent Document 2 (Korean Patent No. 10-0453179) discloses a method in which it is known that when ranitidine is released in the stomach, ranitidine is adsorbed by sclara and the ranitidine is lowered. The problem of the absorptivity is such that the core tablet containing ranitidine is coated with the film-forming composition, and then mixed with bismuth subruthenium and sclarane to prepare a tablet in the tablet. However, when it has a core tablet coating film containing ranitidine to prepare a tablet in a tablet, the preparation process becomes complicated and the production cost is increased. Furthermore, since the tablet in the tablet has a larger tablet size than the matrix tablet having the same dose, if the amount of the drug is increased, the tablet size is excessively increased and is more swallowed for the patient. uncomfortable.

Therefore, there is a need to prepare a combination drug that solves the following problems: 1) the hygroscopicity of ranitidine itself; 2) the problem of reducing the stability of ranitidine due to mixing with bismuth subcitrate; and 3) When a combination drug of ranitidine, bismuth subcitrate, and sclafi is prepared, the problem of the drug absorption rate is lowered due to the mixing of the three drugs. Further, the preparation of the combination drug requires a simple preparation process, makes the patient swallow more comfortable, and has excellent bioavailability.

[Patent Literature]

(Patent Document 1) Korean Patent Publication No. 1997-006083

(Patent Document 2) Korean Patent No. 10-0453179

[Non-patent literature]

(Non-Patent Document 1) PDA J. Pharm. Sci. Tech. 2009 May-Jun: 63(3): 223-33

The present invention provides a combination drug capable of solving problems in formulation stability and bioavailability of a combination drug of ranitidine, bismuth subcitrate and sclafi, and having a simple preparation process and causing disease Suffering from swallowing is more comfortable.

According to the results of the research of the present invention, in fact, when preparing a combination drug of ranitidine, bismuth subruthenium citrate and sclafi, if the particle size of bismuth subruthenium citrate and sclafi is controlled, it is confirmed that it can be suppressed. The moisture absorption of ranitidine is to achieve formulation stability, and physical interaction between drugs can be avoided to achieve drug bioavailability without the tablet in the preparation of the tablet.

Specifically, in the following examples, each type of grinder or mesh is used to classify and measure the particle size of sclafi and bismuth citrate for each particle size, and to use sclafi and The bismuth citrate was mixed with ranitidine, and then the water content, formulation stability, and bioavailability of ranitidine were observed. As shown by the results, it was confirmed that the water content of ranitidine was suppressed in the specific particle size range of sclafi and bismuth subruthenium, and the stability of the preparation was maintained, and the bioavailability of the drug was good. Next, the size is selected as the preferred particle size.

Accordingly, the present invention provides a pharmaceutical composition for treating gastrointestinal diseases comprising ranitidine, sclafi and bismuth subcitrate as active ingredients, and satisfying at least one of the following conditions: (a) Carragel has an average particle size of from 1 to 25 mm, and (b) bismuth subruthenium has an average particle size of from 5 to 90 mm.

In the pharmaceutical composition of the present invention, Scolafon may have an average particle size of 1 to 25 mm, such as 1 to 20 mm, 2 to 25 mm, 2 to 20 mm, 2 to 15 mm, 3 to 15 mm, 2 Up to 10 mm, 3 to 10 mm, 3 to 8 mm, 4 to 10 mm or 4 to 8 mm.

In the pharmaceutical composition of the present invention, bismuth subcitrate may have an average particle size of 5 to 90 mm, such as 5 to 80 mm, 5 to 75 mm, 5 to 70 mm, 10 to 75 mm, 10 to 60 mm. 10 to 50 mm, 15 to 75 mm, 20 to 75 mm, 25 to 70 mm, 25 to 65 mm, 25 to 60 mm, 25 to 55 mm or 25 to 50 mm.

In a particular illustration, the Scala can have an average particle size of 2 to 25 mm or 2 to 10 mm.

In a particular illustration, the bismuth subruthenium citrate may have an average particle size of 5 to 75 mm, 25 to 70 mm, or 25 to 50 mm.

In a particular illustration, the scolafon may have an average particle size of from 1 to 25 mm, and the bismuth subruthenium hydride may have an average particle size of from 5 to 90 mm.

In another specific illustration, the Scolafon may have an average particle size of 2 to 25 mm, and the bismuth subruthenium citrate may have an average particle size of 5 to 75 mm.

In a more specific illustration, the Scolafon may have an average particle size of 2 to 10 mm, and the bismuth subruthenium hydride may have an average particle size of 25 to 70 mm.

Although not specified as a specific illustration, the pharmaceutical composition of the present invention can be obtained when a combination of sclara and bismuth subruthenium having an average particle size within the above enumerated ranges is used.

In this specification, the average particle size is the average of volume or mass and refers to the volume weighted Mean D[4,3] value relative to the weight distribution.

When the particle size of the drug needs to be micronized, a conventional grinder for grinding the micronizable particles, such as a Z-mill, a hammer mill, a ball mill, a fluid energy mill, or the like, can be used. Further, when a screening method using a sieve or a size classification such as airflow classification is used, it can subdivide the particle size of the drug. Methods of adjusting the desired particle size are known in the related art. For example, refer to the following literature: Pharmaceutical Formulations: Volume 2, 2nd Edition, edited by: HALieberman, L. Lachman, JB Schwartz (Chapter 3: Particle Size Reduction) [Pharmaceutical dosage forms: volume 2, 2nd edition, Ed .: HALieberman, L. Lachman, JB Schwartz (Chapter 3: SIZE REDUCTION)].

In this specification, the particle size of a drug can be expressed based on a particle size distribution such as d(X) = Y (here, X and Y are positive numbers). d(X) = Y means that when the particle size distribution of the drug obtained by measuring the particle diameter of a part of the drug in the preparation is expressed as a cumulative curve, the particle size accumulated in ascending order and the result reaches X% ( The point where % is based on quantity, volume or weight) has a particle diameter of Y. For example, d(10) represents a point at which the particle diameter is in ascending order of the particle size of the drug and the result reaches 10%. d (50) represents the point at which the particle diameter is in the ascending order of the particle size of the drug and the result reaches 50%. d (90) represents a point at which the particle diameter is in the ascending order of the particle size of the drug and the result reaches 90%.

In this specification, d(X) may alternatively be represented as d(0.X), and d(X) and d(0.X) may be interchangeable. For example, d(50) is represented as d(0.5), and d(10) and ]d(90) are represented as d(0.1) and d(0.9), respectively.

When the particle size distribution d(X) representing the percentage relative to the total accumulated particles is changed according to the method for measuring the particle size distribution, the quantity, volume or weight is used as a reference. Methods for measuring particle size distribution and relative types of % are known in the related art. For example, when the known laser diffraction method is used to measure the particle size distribution, the X value of d(X) represents the percentage calculated based on the volume average. It is known to those skilled in the art that particle size distribution measurements obtained by a particular method based on experience from typical experimentation may have correlations with results obtained from other techniques. For example, in the laser diffraction method, when the density is constant, the volume average particle size is provided to correspond to the volume of particles corresponding to the weight average particle size.

In the present invention, in order to measure the average particle size and particle size distribution of the particles of bismuth subruthenium citrate and sclafifil, a commercially available device using a laser diffraction and scattering method based on the Mie theory can be used. For example, a commercially available device such as the Mastersizer laser diffraction device of the Malvern instrument can be used for measurement. The device is used to obtain a particle diameter distribution such that when a helium-neon laser beam emits light to a particle or a blue light emitting diode emits light to a particle, scattering is caused, and a light scattering pattern is displayed in the detection. And the light scattering pattern is analyzed according to the Mie theory. Any of the dry method or the wet method can be used as the measuring method, but the results measured by the wet method are shown in the following examples.

In a particular illustration, the pharmaceutical composition of the present invention may have a particle size distribution of sclafi that additionally satisfies at least one of the following conditions: 1) d(10) is 1 to 10 mm, 2) d(50) It is 3 to 25 mm, 3) d (90) is 5 to 50 mm.

In a specific illustration, the pharmaceutical composition of the present invention may have a particle size distribution of bismuth subcitrate additionally satisfying at least one of the following conditions: 1) d(10) is 5 to 17 mm, 2) d ( 50) is 20 to 70 mm, 3) d (90) is 40 to 130 mm.

In another specific illustration, the pharmaceutical composition of the present invention may have a particle size distribution of sclafi that additionally satisfies at least one of the following conditions: 1) d(10) is 1 to 10 mm, 2) d ( 50) is 3 to 25 mm, 3) d (90) is 5 to 50 mm; and the particle size distribution of bismuth niobate which satisfies at least one of the following conditions: 1) d(10) is 5 to 17 mm, 2) d (50) is 20 to 70 mm, 3) d (90) is 40 to 130 mm.

The average particle size or particle size distribution different from sclafi and bismuth subruthenium is preferably in a specific range, and the particle size of ranitidine contained in the pharmaceutical composition of the present invention is not particularly limited.

The present invention also provides a pharmaceutical composition wherein the average particle size or particle size distribution of sclafi and bismuth subruthenium citrate is in the above range, and the dissolution rate of sclafi with the sclafi of the AlbisTM tablet is equivalent. The rate of dissolution in the horizontal. Here, the drug equivalence test control guidelines can be used to define whether the dissolution rate shows an equivalent level.

The present invention also provides a pharmaceutical composition wherein the average particle size or particle size distribution of sclare and bismuth subcitrate is in the above range, and ranitidine and bismuth subruthenium citrate are shown to have the same active ingredient. The area under the concentration-time curve (AUC) and the observed maximum plasma concentration (Cmax) of the dose equivalent of the AlbisTM lozenge. Here, the drug equivalent standard can be used to define whether the area under the concentration-time curve (AUC) and the observed maximum plasma concentration (Cmax) indicate the level of bioequivalence. For example, when the area under the concentration-time curve (AUC) of the reference drug and the test drug and the observed maximum plasma concentration (Cmax) are logarithmically converted according to the bioequivalence test of the drug equivalent test standard of the drug-related regulations. (log-transformed) and statistical processing, if the two items are in the log 0.8 to log 1.25 in the 90% confidence interval of the mean difference of the logarithmic transformation, the definition of the drug equivalent test is equivalent. However, as a guide for bioequivalence exceptions, when 1) the mean value of the logarithmic conversion of the comparative evaluation item values of the reference drug and the test drug is in the log 0.9 to log 1.11, and 2) when according to the drug Equivalent test criteria are defined as equivalent when the two conditions of the dissolution test are satisfied, and the results are equivalent under all defined conditions.

Meanwhile, the components of ranitidine, sclafi and bismuth subcitrate which are active ingredients of the pharmaceutical composition of the present invention may be contained in an amount of 1 to 2 parts by weight of ranitidine, 6 to 12 parts by weight. The composition ratio of sclafi and 2 to 4 parts by weight of bismuth subcitrate is effective pharmacologically.

In particular, the pharmaceutical composition of the present invention is preferably prepared to contain 50 to 300 mg of ranitidine, 240 to 1200 mg of sclafi and 80 to 400 mg of bismuth subcitrate, and particularly preferably It is prepared to contain 50 to 150 mg of ranitidine, 240 to 600 mg of sclafi and 80 to 200 mg of bismuth subcitrate.

The pharmaceutical composition of the present invention comprises at least one excipient in addition to the active ingredient.

The diluent increases the amount of the solid pharmaceutical composition and can be a pharmaceutical dosage form comprising the composition that is easier to treat for the patient and caregiver. Exemplary diluents for solid compositions include microcrystalline cellulose (e.g., Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate ( Calcium carbonate), calcium sulfate, sugar, dextrate, dextrin, dextrose, dibasic calcium phosphate dehydrate, tricalcium phosphate Tribasic calcium phosphate), kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylate (eg, Eudragit ®), calcium chloride, powdered cellulose, sodium chloride, sorbitol and talc.

A solid pharmaceutical composition that is compressed into a dosage form, such as a lozenge, can contain excipients that facilitate the incorporation of the active ingredient into another excipient after compression. Adhesives for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g., carbopol), sodium carboxymethylcellulose. , dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxy ethylcellulose, hydroxypropyl Hydroxypropyl cellulose (eg, Klucel®), hydroxypropylmethylcellulose (eg, Methocel®), liquid glucose, magnesium aluminum silicate, malt paste Maltodextrin, methylcellulose, polymethacrylate, povidone (eg, Kollidon® and Plasdone®), pregelatinized starch, sodium alginate ) and starch.

When a disintegrant is added to the composition, it can increase the rate of dissolution of the compressed solid pharmaceutical composition in the stomach of the patient. The disintegrant comprises hydroxypropylcellulose, carboxymethylcellulose calcium, sodium carboxymethylcellulose (for example, Ac-Di-Sol® and Primellose®), microcrystalline cellulose, methylcellulose. , powdered cellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone (for example, Kollidon ® and Polyplasdone ® ), Guan Huadou Gum, magnesium aluminum silicate, polacrilin potassium, pregelatinized starch, alginic acid, sodium alginate, sodium starch glycolate (eg, Explotab®), and starch.

When the powdered composition is compressed to prepare a dosage form such as a tablet, the composition receives pressure from a punch and a dye. Some excipients and active ingredients tend to adhere to the surface of the stamper and dye, which may cause pitting and other surface irregularities of the product. In order to reduce the adhesion and easily extract the product material from the dye, a lubricant may be added to the composition. Lubricants include, for example, magnesium stearate, calcium stearate, aluminum stearate, and zinc stearate, glyceryl monostearate. , glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate (sodium lauryl sulfate), sodium stearate fumarate, talc, etc.

In order to increase storage stability, for example, ethanol, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole and ethylenediaminetetraacetic acid may be added at a safe intake level. Store and sequester the formulation.

The pharmaceutical composition of the present invention is not limited thereto, but may be formulated into a tablet.

In an embodiment, the pharmaceutical compositions of the invention may be formulated as a matrix lozenge. According to the following exemplification, the pharmaceutical composition of the present invention is not formulated as a tablet in a tablet containing a core tablet, but can be formulated into a matrix tablet after controlling the particle size of sclafi and bismuth subruthenium. However, it can be confirmed that all the problems of the combined preparation in the related art have been solved.

Tablets comprising a pharmaceutical composition according to the invention may additionally be coated with a coating agent.

An embodiment of the present invention provides a tablet in which an uncoated tablet containing ranitidine, sclafi and bismuth subruthenium as an active ingredient is coated with a polyvinyl alcohol.

In the following examples, it was confirmed that coating with polyvinyl alcohol as a coating agent ensures better stability.

The formulation process of the pharmaceutical composition according to the present invention will be exemplified as follows.

The granules were prepared at a mixing ratio of ranitidine, sclara and sine at a ratio of 150:600:200. Here, as the binder, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone or the like can be used as the other binder. Further, in the production method of the present invention, the drying is preferably carried out at a temperature of from 30 to 60 ° C so that the water content of the granular composition is 11% or less with respect to the total weight, and the drying is preferably carried out at 50%. The temperature is °C.

The present invention provides a method for treating a gastrointestinal disease, comprising: administering to a pharmaceutical composition comprising ranitidine, sclafi and bismuth subruthenium having the above-exemplified particle size range as an active ingredient A subject, and a composition comprising ranitidine, sclafi and bismuth subcitrate as active ingredients for the preparation of a medicament for treating gastrointestinal diseases.

In the present invention, the term "gastrointestinal diseases" includes, for example, symptoms or diseases of inflammation and ulceration occurring in a digestive organ. For example, gastrointestinal diseases include gastric ulcer, gastritis, duodenal ulcer, Zollinger-Ellison syndrome, reflux esophagitis, pre-anesthetic medication (avoiding Mendelson's syndrome), postoperative ulceration (post- Oxygen duodenal ulcer caused by op ulcer) and non-steroidal anti-inflammatory drugs (NSAIDs), but the invention is not limited thereto.

In the present invention, the term "subject" means a warm-blooded animal, such as a mammal having a specific disease, disorder or disease, and includes, for example, human, orangutan, chimpanzee, mouse, large. Rat, dog, cow, chicken, pig, goat, sheep, etc., but the invention is not limited thereto.

In the present invention, the term "treatment" or "treating" includes alleviating symptoms, temporarily or permanently removing the cause of the symptoms, avoiding or slowing the occurrence of symptoms, and progress of the disease, disorder or discomfort, but The invention is not limited to this.

An effective dose of the active ingredient of the pharmaceutical composition of the present invention means the amount required to treat the disease. Thus, the effective dose can be based on various factors such as the type of disease, the severity of the disease, the type and amount of active ingredient, and the other ingredients included in the composition, the type of the dosage form, the age, weight, general health and gender of the patient. Adjusted by diet, time of administration, route of administration, release rate of ingredients, treatment cycle, and concurrent use of the drug. For example, the pharmaceutical composition of the present invention can be administered once a day to three times a day, and a dose of 50 to 150 mg based on ranitidine can be administered at a time, but the present invention is not limited thereto.

According to the present invention, when a combination drug of ranitidine, sclafi and bismuth subruthenium is prepared, it can prepare a ranitidine by controlling the particle size of sclafi and bismuth subruthenium citrate. A combination of hygroscopicity and stability of the formulation, and a simple preparation process and excellent bioavailability.

The advantages and features of the present invention and the method of practicing the same are apparent from the following detailed description. However, the invention is not limited to the examples disclosed below, but may be embodied in various different forms. The illustrations are provided to fully explain the present invention and fully explain the scope of the present invention to those skilled in the art. The scope of the invention is defined by the scope of the appended claims. [Illustrates] Example 1 illustrates: a non-adjusted Sklar and bismuth subcitrate particle size

The ranitidine, sclafi and bismuth subruthenates of the raw material particle size before the microparticulation of Table 1 were used for the experiment.

[Table 1] Raw material particle size before micronization

The particle size of the raw material was measured by a wet method under the following conditions using a particle size measuring device (Malvern Mastersizer 2000/Hydro S).

<Measurement conditions for particle size distribution> Device: Laser diffraction particle size distribution measuring device Malvern Mastersizer 2000/Hydro S (Malvern) Wet unit: Hydro 2000S Sample size: 1 g Sample refractive index: 1.520 Sample measurement time: 10 seconds Background measurement time: 10 seconds Analysis mode: General purpose calculation sensitivity: Normal particle shape: Irregular analysis range: 0.020 to 2000 mm

Ranitidine was used directly in experiments without specific particle size specifications.

Sclafi and bismuth citrate are micronized by Z-grinding and grinders or by meshing in order to adjust the particle size.

After microparticulation according to the average particle size and particle size distribution, the raw materials of sclafi and bismuth subsulphonate are classified into Skra non 1 to 6 and bismuth subsulphate 1 to 5, and are listed in Tables 2 and 3 below. description.

[Table 2] Particle size distribution of sclafi before and after micronization

[Table 3] Particle size distribution of bismuth subruthenium citrate before and after microparticulation

Formulations containing ranitidine, sclafi and bismuth subruthenium having different combinations of raw material particle sizes are prepared to select particle sizes of the drug that ensures formulation stability, proper drug dissolution rate, and bioavailability.

Therefore, in the following experimental examples, materials having different particle size combinations were used and formulated according to the composition of Table 4 and then experiments were conducted.

[Table 4] Composition of lozenges containing ranitidine, sclafi and bismuth subruthenium (wt%) Experimental Example 1: Adjustment of particle size of sclafi

In order to identify the change in the dissolution rate of sclafi according to the particle size adjustment of sclafi, as shown in Table 5, the materials having the particle size combination were used and formulated according to the composition of Table 4, wherein only the particle size of the sclafi was changed, At the same time, the particle size of ranitidine and bismuth subruthenium citrate was fixed, and then experiments were carried out.

[Table 5] Particle size combination of ranitidine, sclafi and bismuth subruthenium

In addition to the different particle sizes of the raw materials, according to the same composition as shown in Table 4, pure water (or a mixed solvent of pure water and ethanol) was used according to the usual method, dried at 50 ° C and then established with 18 mesh openings. The way to prepare dry or wet granules. Next, the prepared granules were subjected to tableting and coating to prepare a matrix troche. Coated with 3% PVA. Finally, a yellow-green rectangular film coated lozenge was obtained.

The tablets of Preparations 1 to 6 were used for the comparative dissolution test of sclafi. Since sclafi is not absorbed in vivo, the bioequivalence test is not performed, but the comparative dissolution results are used instead. Albis ^(TM) tablets were used as reference drugs (available from Daewoong Pharmaceutical Co., Ltd.). A comparative dissolution test was carried out according to Section 3, Section 1, Section 1, No. 1 (the guidelines for drug equivalence test control). A dissolution solution having a pH of 1.2 was used. According to the dissolution test of the Korean Pharmacopeia Guideline (second method (paddle method)), the HPLC method was carried out at a temperature of 37 ± 0.5 ° C and a dissolution solution of 50 rpm for 2 hours.

Dissolution device -Manufacturer:VARIAN -Model name:VK7025 Vk8000

HPLC Analytical-HPLC equipment: Waters - Analytical column: Aminopropylsilyl silica gel (4.6 x 250 mm, 5 mm) - Mobile phase: Buffer solution: acetonitrile = 9 : (filter using 0.45 mm membrane filtration) (buffer solution: obtain 79.3 g of ammonium sulfate, input 1000 mL of water and then adjust the pH to 3.5 with phosphoric acid) - column temperature : 25 °C - Flow rate: 1.0 ml / min - Detector: Differential refractometer - Injection volume: 50 ml

[Table 6] Comparative test results of sclafi

Comparative dissolution tests were performed as described above. The results are shown in Table 6, which can be determined as the tablets of Preparation Examples 4 to 6, in which the use of a sclafi having a particle size such as sclaletium 4 to 6 indicates that the dissolution rate of the sclafi is equivalent. Refer to the dissolution rate of the drug. As an equivalent definition standard, when comparing according to Section 21 (Guidelines for Drug Equivalent Test Control), if the average dissolution rate of the reference drug is 85% or more within the defined test time, and in the reference drug When the average dissolution rate of the test drug at an average dissolution rate of about 40% and 85% at both time points is within ±15% of the average dissolution rate of the reference drug, it is defined as equivalent. Experimental Example 2 : Adjustment of particle size of bismuth subruthenium citrate

Based on the results of Experimental Example 1, a raw material having a particle size defined by Scraza 4 to 6 of Table 2 was preferably used as Skrafi. Therefore, the particle size of the sclafi is fixed to the particle size of "Sclafi 6", and then the particle size of the bismuth subruthenium hydride is adjusted to evaluate the stability of the tablet according to the particle size of the ruthenium.

The materials having the particle size combinations of Table 7 were used and formulated according to the composition of Table 4, and then experiments were conducted.

[Table 7]

Particle size combination of ranitidine, sclafi and bismuth subruthenium

In addition to the different particle sizes of the raw materials, according to the same composition as shown in Table 4, pure water (or a mixed solvent of pure water and ethanol) was used according to the usual method, dried at 50 ° C and then established with 18 mesh openings. Ranitidine, sclafi and bismuth subruthenium are prepared as dry granules or wet granules. Next, the prepared granules were tableted and prepared as a matrix troche and the room temperature stability was evaluated.

The results are shown in Table 8, which was confirmed to have satisfactory characteristics and water content at specific particle sizes as Preparation Examples 8, 9, and 10. This indicates that when ranitidine is mixed with bismuth subruthenium, the problem of changing the physical properties of ranitidine due to bismuth subruthenium is solved, which is considered to inhibit the drug by specific particle size. The reason for the physical interaction is achieved.

[Table 8] Results of room temperature stability test of combination drugs of ranitidine, sclafi and bismuth subcitrate

It was observed that the particle size combination of the preparations of Preparation Examples 8, 9, and 10 solved the problem of changing the physical properties of ranitidine due to bismuth subruthenium citrate. In order to additionally confirm whether the combination is suitable in terms of formulation stability, moisture absorption, and bioavailability, an experiment was conducted. Experimental Example 3 : Comparative stability test for selecting a coating agent

Based on the uncoated tablet of Preparation Example 9, in order to avoid the additional water content of ranitidine, a test for selecting a coating agent was performed. The uncoated tablet of Preparation Example 9 was coated with polyvinyl alcohol (PVA) (Preparation Example 12) and HPMC (Preparation Example 13) (3 wt% for uncoated tablets). Next, the room temperature stability test of the coated tablet was carried out. As shown by the results, it was confirmed that the two samples had preferable characteristics, but the tablet of Preparation Example 12 coated with PVA showed no significant change in the water content test to exhibit an excellent moisture-proof effect.

[Table 9] Comparative stability test results for selecting a coating agent

Based on the tests conducted above, PVA was selected as a coating agent, and the uncoated tablets of Preparation Examples 7, 8, 10 and 11 were coated with 3 wt% PVA to prepare packages of Preparation Examples 14, 15, 16 and 17. Overfilling agent. Next, the coated tablet was used to carry out the following experimental examples. Experimental Example 4 : Evaluation of formulation stability

The coated tablets of Preparations 12, 14, 15, 16 and 17 were subjected to a room temperature/acceleration stability test. The results are shown in Table 10. It has been observed that the properties and contents of the tablets of Preparations 12, 15 and 16 and the disintegration test have better results with respect to the standard. In Preparation Examples 14 and 17, the characteristics were not good, and thus the content of the joint and the disintegration test were suspended.

[Table 10] Room temperature / accelerated stability test results Experimental Example 5 : Change in water content in a preparation according to particle size of a drug

The coated tablets of Preparation Examples 12, 14, 15, 16 and 17 were used to carry out the following water content test. The test was carried out for 6 months at room temperature. In order to measure the water content, the Karl Fisher method in the usual test method according to the Korean Drug Guide is used as the moisture measurement method. In practice, it is utilized to quantitatively react water with iodine and sulfur dioxide in the presence of a lower alcohol such as methanol and an organic base such as pyridine, for use in moisture determination. Methanol is used as a reagent for moisture measurement. A sample was obtained by grinding the tablet and about 200 mg thereof was used for the test.

[Table 11] Water content test results of coated tablets

As shown in the results of Table 11, the tablets of Preparation Examples 12, 15 and 16 were preferred for the water content standard. However, the tablets of Preparations 14 and 17 had poor characteristics under the 6 month room temperature stability test, and thus no additional moisture test was performed. Based on this result, it was confirmed that the particle size of sclafi and bismuth subruthenium inhibited the water content of ranitidine, and the PVA coating ensured better stability of the product. Experimental Example 6 : PK test results based on differences in particle size

The coated tablets of Preparations 12, 14, 15, 16 and 17 were used for PK testing of healthy individuals. The analysis of the variance number was performed with barium citrate and ranitidine relative to the logarithmic conversion values of AUC and _Cmax for the two comparative evaluation items.

As a drug equivalent standard, the area under the concentration-time curve (AUC) of the reference drug and the test drug and the observed maximum plasma concentration (Cmax) are equal to the standard of the drug equivalent test according to the drug-related regulations. When the logarithmic conversion and statistical processing are performed in the sex test, if the two items are log 0.8 to log 1.25 in the 90% confidence interval of the mean difference of the logarithmic transformation, the definition of the drug equivalent test is equivalent. However, as a guide for bioequivalence exceptions, when 1) the mean value of the logarithmic conversion of the comparative evaluation item values of the reference drug and the test drug is in the log 0.9 to log 1.11, and 2) when according to the drug The equivalent test criteria are defined as equivalent when the two conditions of the comparative dissolution test are satisfied, and the results are equivalent under all defined conditions.

Albis ^(TM) tablets (available from Daewoong Pharmaceutical Co., Ltd.) were used as reference drugs.

Fig. 1 and Fig. 2 are comprehensive charts showing statistics on the concentration-time of bismuth citrate obtained from the blood drug concentration data of the individual administered to the tablets of Preparations 12, 14, 15, 16 and 17. Bioavailability parameters for the area under the curve (AUC) and the observed maximum plasma concentration (Cmax). Figures 3 to 5 are graphs showing statistically below the concentration-time curve (AUC) of ranitidine from blood drug concentration data for individuals administered the tablets of Preparations 12, 15 and 16. Bioavailability parameters for the area and observed maximum plasma concentration (Cmax). In the tablets of Preparation Examples 12, 15 and 16, and the tablets of Preparations 14 and 17, the particle sizes of ranitidine and sclara were the same, and the excipients and coating agents were the same, but only after The particle size of bismuth citrate is different. Based on the PK test results of Figs. 1 and 2, it was confirmed that the bioavailability according to the particle size of the bismuth citrate was different. That is, it can determine the particle size interval in which the bismuth citrate has better bioavailability, and it can confirm that the bioavailability of the additionally tested ranitidine is also equivalent.

The PK test result of the tablet of Preparation Example 12 was compared with the PK test result of the reference drug. As shown by the results, in the bismuth subcitrate, the AUC was 0.8749 to 1.1967, and the C _max was 0.8681 to 1.12342. Therefore, it can be determined that PK is equivalent. In ranitidine, the AUC is from 0.9282 to 1.1213 and the _Cmax is from 0.9282 to 1.1539, so it is also equivalent.

Based on the PK test results of the tablet of Preparation Example 15, in the bismuth subcitrate, the AUC was 0.7672 to 1.1624 and the _Cmax was 0.7717 to 1.1633. Since the lower limit is not good, PK is non-equivalent. However, the equivalence is confirmed according to the guidelines for equivalent exceptions. In ranitidine, the AUC is from 0.9029 to 1.0108 and the _Cmax is from 0.8151 to 1.0280, so it is equivalent.

Based on the PK test results of the tablet of Preparation Example 16, in the bismuth subcitrate, the AUC was 1.1058 to 1.2785 and the _Cmax was 1.0545 to 1.3188. Since the upper limit is not good, PK is non-equivalent. However, equivalence is confirmed according to guidelines for bioequivalence exceptions. In ranitidine, the AUC is from 0.9085 to 1.0084 and the _Cmax is from 0.8912 to 1.0411, so it is equivalent.

Meanwhile, based on the PK test result of the tablet of Preparation Example 14, in the bismuth subcitrate, the AUC was 0.5906 to 0.7805, and the C _max was 0.4538 to 0.6794. Since the lower limit is not good, PK is non-equivalent.

Meanwhile, based on the PK test result of the tablet of Preparation Example 17, in the bismuth subcitrate, the AUC was 1.8565 to 2.7649, and the C _max was 2.0868 to 3.1544. Since the upper limit is not good, PK is non-equivalent.

As shown by the results, it was confirmed that the tablets of Preparation Examples 12, 15 and 16 suppressed the water content of ranitidine by appropriately adjusting the particle size of sclafi and bismuth subruthenium, and were applicable to It provides excellent bioavailability as a combination drug that inhibits changes in physical properties due to drug mixing.

no.

Fig. 1 and Fig. 2 show changes in the average concentration of bismuth subcitrate in the plasma of the individual administered to the tablets of Preparations 12, 15 and 16 and Preparations 14 and 17. Fig. 2 shows an enlargement of Fig. 1.

Figures 3 to 5 show the change in the average concentration of ranitidine in the plasma of the individual administered to the tablets of Preparations 12, 15 and 16.

Claims (19)

A pharmaceutical composition for treating gastrointestinal diseases, comprising as an active ingredient a ranitidine, a sclafi and a bismuth citrate, and satisfying at least one of the following conditions: (a) the skra It does not have an average particle size of 1 to 25 mm; (b) The bismuth ruthenate has an average particle size of 5 to 90 mm. The pharmaceutical composition according to claim 1, wherein the sclafi has an average particle size of from 2 to 25 mm. The pharmaceutical composition of claim 1, wherein the sclafi has an average particle size of from 2 to 10 mm. The pharmaceutical composition according to claim 1, wherein the bismuth ruthenate has an average particle size of from 5 to 75 mm. The pharmaceutical composition according to claim 1, wherein the bismuth ruthenate has an average particle size of 25 to 70 mm. The pharmaceutical composition according to claim 1, wherein the bismuth ruthenate has an average particle size of 25 to 50 mm. The pharmaceutical composition according to claim 1, wherein the sclara has an average particle size of from 1 to 25 mm, and the bismuth citrate has an average particle size of from 5 to 90 mm. The pharmaceutical composition according to claim 1, wherein the sclara has an average particle size of from 2 to 25 mm, and the bismuth citrate has an average particle size of from 5 to 75 mm. The pharmaceutical composition according to claim 1, wherein the sclara has an average particle size of from 2 to 10 mm, and the bismuth citrate has an average particle size of from 25 to 70 mm. The pharmaceutical composition according to claim 1, wherein the sclafi has a particle size distribution satisfying at least one of the following conditions: 1) d(10) is 1 to 10 mm, 2) d (50) ) is 3 to 25 mm, 3) d (90) is 5 to 50 mm. The pharmaceutical composition according to claim 1, wherein the bismuth ruthenate has a particle size distribution satisfying at least one of the following conditions: 1) d(10) is 5 to 17 mm, 2) d (50) is 20 to 70 mm, 3) d (90) is 40 to 130 mm. The pharmaceutical composition according to claim 1, wherein the sclafi has a particle size distribution satisfying at least one of the following conditions: 1) d(10) is 1 to 10 mm, 2) d (50) ) is 3 to 25 mm, 3) d (90) is 5 to 50 mm, and wherein the bismuth ruthenate has a particle size distribution that satisfies at least one of the following conditions: 1) d(10) is 5 to 17 mm, 2) d (50) is 20 to 70 mm, and 3) d (90) is 40 to 130 mm. The application of the pharmaceutical composition according to item 1 patentable scope, wherein the non Sklar having a dissolution rate level equivalent to the rate of dissolution of lozenges Albis ^TM Sklar Africa. The pharmaceutical composition according to claim 1, wherein the ranitidine and the bismuth citrate in the pharmaceutical composition are equal to the equivalent of the Albis ^(TM) tablet having the same active ingredient dose. The area under the concentration-time curve (AUC) of the sex level and the observed maximum plasma concentration ( _Cmax ). The pharmaceutical composition according to any one of claims 1 to 14, wherein the pharmaceutical composition comprises 50 to 300 mg of the ranitidine, 240 to 1200 mg of the sclara And 80 to 400 mg of this bismuth citrate. The pharmaceutical composition according to any one of claims 1 to 14, wherein the pharmaceutical composition is formulated in the form of a tablet. The pharmaceutical composition according to any one of claims 1 to 14, wherein the pharmaceutical composition is formulated in the form of a matrix lozenge. The pharmaceutical composition according to claim 17, wherein the matrix tablet is coated with a coating agent. The pharmaceutical composition according to claim 18, wherein the coating agent is polyvinyl alcohol.