KR102233986B1 - Solid pharmaceutical composition comprising lafutidine and irsogladin and process for producing thereof - Google Patents

Abstract

The present invention is a solid pharmaceutical composition for the prophylaxis or treatment of peptic ulcer, comprising laputidine or a pharmaceutically acceptable salt thereof, and irsogladin or a pharmaceutically acceptable salt thereof, and It relates to a method of manufacturing the same.
The pharmaceutical composition of the fixed combination single dosage form for the prevention or treatment of peptic ulcer according to the present invention exhibits improved peptic ulcer prevention and treatment effect, has excellent productivity, and excellent dissolution pattern in the entire gastrointestinal tract, and between the two drugs It has the advantage of excellent product stability according to changes over time because the reactivity is minimized.

Description

Solid pharmaceutical composition comprising lafutidine and irsogladin and process for producing thereof TECHNICAL FIELD

The present invention relates to a solid pharmaceutical composition containing raputidine and irsogladin and a method for preparing the same. In more detail, the present invention is a single dosage form of a fixed combination of Lafutidine and Irsogladin, showing improved preventive and therapeutic effects of peptic ulcers, and has excellent productivity, as well as in the entire gastrointestinal tract. The present invention relates to a solid pharmaceutical composition for the prevention or treatment of peptic ulcer, and a method of manufacturing the same, which exhibits an excellent dissolution pattern and has excellent product stability according to changes over time because the reactivity between two drugs is minimized.

Peptic ulcer is a unique mucosal defect that occurs on the wall of the digestive tract and is primarily caused by a breakdown of the balance between the attack and defense factors. Attack factors include gastric acid secreted from parietal cells and pepsin, a digestive factor secreted from main cells. Gastric acid is secreted from parietal cells in the stomach, and factors that promote gastric acid secretion include acetylcholine secreted from the vagus nerve of the stomach, gastrin secreted from the endocrine organ, and histamine secreted from mast cells. On the other hand, defense factors include mucosal resistance and mucus, and prostaglandins present in mucous membranes.

For the treatment of peptic ulcer, it is important to continuously take drugs that can control both attack and defense factors. In fact, several complex drugs for digestive organs have been researched and developed and then marketed.However, due to the lack of development of drug combinations that exhibit excellent anti-ulcer effects, it is possible to develop customized peptic ulcers, especially complex formulations with gastric ulcer treatment, through the development of appropriate complex formulations. There is a need.

Advantages obtained by developing a combination formulation are to show superior disease prevention and treatment effects by using drugs with different mechanisms together, and by reducing the amount of single drugs used in combination administration, which can be caused by long-term drug administration. It has the advantage of reducing side effects. However, the development of a fixed combination dosage form of specific bioactive ingredients is very difficult for several reasons.

First, when formulating a fixed combination dosage composition for the development of a combination formulation, it is difficult to achieve the following goals. It is in the pharmaceutical industry to achieve the goal of providing a combination dosage form of the active ingredients that are biologically equivalent to the corresponding individual free combinations of the same active ingredients, or that are convenient to administer to the patient, or to deliver a better pharmacodynamic effect than the individual ingredients. This is a difficult task that is difficult for companies to solve easily. This is because unexpected difficulties may arise due to various tasks arising from the physiologically active substances to be combined, that is, the pharmacokinetic and pharmaceutical properties of the drug.

For example, there may be a problem of deteriorating stability due to the interaction between different active ingredients. In particular, in the case of compounds that are difficult to handle with each other, it is more difficult to develop a combination formulation having a physicochemically stable form. Moreover, if the solubility of the drug is low, there is a problem that may cause a change in bioavailability because it is highly likely to cause a change in dissolution pattern compared to a single drug due to drug interaction.

[Patent Document 1] Korean Patent Registration No. 10-1641319 (registered on July 14, 2016) [Patent Document 2] Korean Patent Application Publication No. 10-2014-0140353 (published on Dec. 09, 2014)

The present inventors have confirmed that a combination formulation of an attack factor inhibitor, laputidine, and a defense factor enhancer, irsogladin, as a pharmaceutical composition for the prevention or treatment of peptic ulcer can be usefully used for hyperpeptic ulcers. By carrying out a study on the formulation of a combination drug of din and irsogladin, a combination composition of raputidine and irsogladin having optimal physical and chemical properties was developed.

Therefore, the object of the present invention is not only excellent in productivity, but also exhibiting excellent elution patterns of laputidine and irsoglatin at the whole gastrointestinal pH, and digestibility including raputidine and irsogladin having excellent product stability over time. It is to provide a pharmaceutical composition for preventing or treating ulcers.

Another object of the present invention is to provide a method for preparing a solid pharmaceutical composition containing raputidine and irsogladin capable of efficiently preparing the laputidine and irsogladin combination formulation of the present invention.

Other objects and advantages of the present invention will become more apparent by the following detailed description, claims and drawings.

According to one aspect, Lafutidine or a pharmaceutically acceptable salt thereof; And Irsogladin (Irsogladin) or a pharmaceutically acceptable salt thereof; Is separated and granulated, containing a pharmaceutically acceptable additive, there is provided a solid pharmaceutical composition for the prevention or treatment of peptic ulcer.

According to an embodiment, the weight ratio of laputidine or a pharmaceutically acceptable salt thereof and irsogladin or a pharmaceutically acceptable salt thereof may be 1:0.1 to 1:0.8.

According to an embodiment, the pharmaceutically acceptable additive may be at least one selected from excipients, binders, disintegrants, lubricants, and stabilization.

According to an embodiment, the excipient may be 5 to 95% by weight based on the total weight of the solid pharmaceutical composition for preventing or treating peptic ulcer.

According to an embodiment, the excipient may be at least one selected from starch, lactose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, methyl cellulose, and fructose.

According to an embodiment, the dissolution rate of laputidine and irsogladin in the solid pharmaceutical composition pH 1 to 7 for the prevention or treatment of peptic ulcer of the present application may be 85% or more within 30 minutes of dissolution time.

According to an embodiment, the ratio of fine powder passing through the body eye of 75 μm among the laputidine and irsogladin granules may be less than 50%.

According to another aspect, there is provided a combination formulation for oral administration, which is a fixed combination single dosage form, comprising a solid pharmaceutical composition for the prevention or treatment of peptic ulcer of the present application.

According to one embodiment, the oral combination formulation of the present application may be a tablet or capsule.

According to another aspect, a method for preparing a solid pharmaceutical composition for the prevention or treatment of peptic ulcer of the present application, a) wet granulation of a mixture of raputidine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive Drying by doing; b) drying by wet granulation of a mixture of irsogladine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; And c) mixing the granules obtained in step a) with the granules obtained in step b), and then preparing a composite formulation. Or there is provided a method of preparing a solid pharmaceutical composition for treatment.

According to an embodiment, in the step of preparing the combination formulation in step c) of the preparation method, the weight ratio of laputidine or a pharmaceutically acceptable salt thereof and irsogladine or a pharmaceutically acceptable salt thereof is 1:0.1. ~ 1: Can be mixed with 0.8.

According to an embodiment, the pharmaceutically acceptable additive in the manufacturing method may be at least one selected from excipients, binders, disintegrants, lubricants, and stabilization.

According to an embodiment, in step a) of the preparation method, the excipient may be mixed in an amount of 5 to 95% by weight based on the total weight of laputidine or a pharmaceutically acceptable salt thereof.

According to an embodiment, in step b) of the preparation method, the excipient may be mixed in an amount of 5 to 95% by weight based on the total weight of b) irsogladin or a pharmaceutically acceptable salt thereof.

According to an embodiment, after mixing the granules obtained in step a) and the granules obtained in step b) in step c) of the manufacturing method, a step of mixing a pharmaceutically acceptable additive may be further included.

According to an embodiment, in step c) of the manufacturing method, the step of mixing the granules obtained in step a) and the granules obtained in step b) and then coating the granules may be further included.

According to one embodiment, the pharmaceutical composition of laputidine and irsogladin is a fixed combination single dosage form, has excellent adherence to medication, and exhibits improved peptic ulcer prevention and treatment effects than conventional single formulations.

According to one embodiment, the pharmaceutical composition of Laputidine and Irsogladin dissolves rapidly in the entire gastrointestinal pH range, so that the bioavailability is excellent, and the reactivity between the two drugs is minimized, so that the product stability according to the time change is excellent. This has the advantage of greatly improving storage stability.

According to one embodiment, it is possible to efficiently prepare a combination formulation of laputidine and irsogladin of the present application.

FIG. 1 is a graph showing results of evaluating suitability by comparing laputidine, irsogladine, and mixed powders thereof according to Experimental Example 1 using differential scanning calorimetry, respectively.
2 is a liquid chromatograph analysis chart for a two-week storage sample of severe stability of Comparative Example 1 according to Experimental Example 2. FIG.
3A is a graph showing the dissolution rate of laputidine obtained from a single commercially available agent of Examples 1 and 4 and Comparative Examples 1 and 3 and each component in purified water according to Experimental Example 3. FIG.
3B is a graph showing the dissolution rate of irsogladin obtained from Examples 1 and 4 and Comparative Examples 1 and 3 and a single commercially available agent of each component in purified water according to Experimental Example 3. FIG.
4A is a graph showing the dissolution rate of laputidine for Example 1 performed by varying the pH of the eluate according to Experimental Example 4. FIG.
FIG. 4B is a graph showing the dissolution rate of irsogladine for Example 1 performed by varying the pH of the eluate according to Experimental Example 4. FIG.

Since the present invention can apply various transformations and can have various embodiments, specific embodiments will be described in detail. However, this is not intended to limit the present invention to a specific embodiment, it should be understood to include all conversions, equivalents, and substitutes included in the spirit and scope of the present invention. In describing the present invention, when it is determined that a detailed description of a related known technology may obscure the subject matter of the present invention, a detailed description thereof will be omitted.

Certain terms are defined herein for convenience in order to make the present invention easier to understand. Unless otherwise defined herein, scientific and technical terms used herein will have the meanings generally understood by one of ordinary skill in the art. The term "comprising" as used in the present specification does not exclude other components unless specifically stated to the contrary, but means that other components may be further included.

According to one aspect, Lafutidine or a pharmaceutically acceptable salt thereof; And Irsogladin (Irsogladin) or a pharmaceutically acceptable salt thereof; Is separated and granulated, containing a pharmaceutically acceptable additive, there is provided a solid pharmaceutical composition for the prevention or treatment of peptic ulcer.

Raputidine used herein is (± furfurylsulfinyl)-N-[4-[4-(piperidinomethyl)-2-pyridyl]oxy-(Z)-2-butenyl]acetoamide It is a general name of (following formula 1) and is a known compound.

The method for preparing the laputidine may be prepared according to the method described in, for example, European patents EP0282077 and EP0582304. Laputidine is commonly known as a histamine 2 receptor antagonist, and exhibits an inhibitory effect on attack factors through gastric acid secretion, and is a drug that is marketed as a treatment for patients with peptic ulcer (gastric ulcer, duodenal ulcer) and gastritis.

Laputidine as used herein is in the form of a laputidine free base or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable salts of raputidine are, for example, hydrochloride, hydrobromide, sulfate, phosphate, acetate. , Malate, fumarate, lactate, tartrate, citrate, gluconate, besylate, camsylate, salicylate and nicotinate, and the like, but is not limited thereto. The most preferred of these is the free base of raputidine. The daily dosage of laputidine or a pharmaceutically acceptable salt thereof is 2.5 to 80 mg, preferably 5 to 40 mg, and more preferably 10 to 20 mg.

The irsogladine is a known compound known by the general name of 2,4-diamino-6-[2,5-dichlorophenyl]-s-triazine (Formula 2 below).

Irsogladin is used as a therapeutic agent for gastric ulcers or gastric mucosal lesions in Japan and Korea, and its mechanism is known to enhance the mucosal protective effect by improving the defense function of the mucous membrane (M. Akagi et al . , Curr. Pharm . Des. 19: 106-114, 2013).

Irsogladin as used herein is in the form of an irsogladin free base or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable salts of irsogladin include, for example, hydrochloride, hydrobromide, sulfate, Phosphate, acetate, malate, fumarate, lactate, tartrate, citrate, gluconate, besylate, camsylate, salicylate, nicotinate, and the like, but are not limited thereto. The most preferred of these is the irsogladine malate salt. The daily dosage of irsogladin or a pharmaceutically acceptable salt thereof is 1 to 32 mg, preferably 2 to 16 mg, more preferably 4 to 8 mg.

In the composition of the present application, the weight ratio of laputidine or a pharmaceutically acceptable salt thereof and irsogladin or a pharmaceutically acceptable salt thereof is 1: 0.1 to 1: 0.8, preferably 1: 0.2 to 1: 0.4, More preferably, it may be 1:0.3 to 1:0.4. Although not limited thereto, if the weight ratio of laputidine and irsogladin provided herein is specifically expressed as a fixed drug combination, raputidine 10 mg: irsogladin 2 mg to 4 mg or raputidine 20 mg: It may be 4mg to 8mg irsogladin.

A preferred method of administration of the solid pharmaceutical composition of the present application is once to twice a day, more preferably twice a day.

The solid pharmaceutical composition containing laputidine or a pharmaceutically acceptable salt thereof and irsogladin or a pharmaceutically acceptable salt thereof of the present application is ideally suited for the imbalance between an attack factor and a defense factor occurring in the gastrointestinal wall of a patient with peptic ulcer. As a controllable drug combination, it can exhibit excellent anti-ulcer effect. In addition, there is an advantage in that side effects that may be caused by long-term drug administration can be reduced by reducing the amount of use of a single drug by co-administration of an attack factor inhibitor and a defense factor enhancer. However, it is very difficult to develop a fixed combination dosage form between the two drugs due to properties such as thermodynamic instability and low solubility that occur between the two drugs.

For example, both laputidine and irsogladin have low solubility and are known as drugs corresponding to BCS Class II (low solubility, high biopermeability) (A.Ono et al., ADMET & DMPK 4(4): 335 -360, 2016) Even when administered as an individual unit, it is difficult to develop a fixed combination dosage form with other drugs because the bioavailability varies greatly depending on the dissolution pattern.

In addition, as a result of confirming by the present inventors, in the case of laputidine and irsogladin, when the two drugs are mixed, a eutectic mixture is formed to show a eutectic point lower than the melting point of each drug (see Fig. 1). In the case of developing a fixed-combination single-dose formulation using two drugs, it is very difficult to develop a formulation with excellent stability because it may cause unexpected decomposition products or lower dissolution rate during the manufacturing process or storage conditions after manufacturing. .

In order to overcome the problem of stability change due to the change in dissolution rate and the formation of a eutectic mixture between the two drugs in the composite composition of laputidine and irsogladin, laputidine and irsogladin may be formulated separately from each other. For example, laputidine may be tableted as a first tablet portion, and irsogladin may be tableted as a second tablet portion to prepare a complex two-layer tablet. However, in order to separately tablet the laputidine moiety and the irsogladin moiety, not only a special tablet press capable of producing a double-layer tablet is required, but it is highly likely to cause a double mass deviation compared to a single-layer tablet, and due to a decrease in the tableting speed. There are many disadvantages such as decreased productivity. Therefore, there is a need for a study on a solid pharmaceutical composition that can be tableted even in a general tableting machine and a method of manufacturing the same.

Accordingly, the present application provides a solid pharmaceutical composition in which laputidine and irsogladin are physically separated to prepare separate granules to reduce their contact surface area as much as possible. Accordingly, as a preferred embodiment, the present application provides a solid pharmaceutical composition containing laputidine and irsogladin in which laputidine and irsogladin are separated by wet granulation. In the formulation of the present application, since each drug component is substantially separated, there is an advantage that there is little change in dissolution rate due to physical and chemical interactions of the drug, and because each component is separated and granulated, there is an advantage between the two drugs during the granulation process. Since the mutual reactivity can be completely eliminated, the reactivity between the two drugs can be reduced, and thus, bioavailability equal to or higher than that of each single product can be obtained through securing an excellent dissolution rate, and product stability according to changes over time is excellent. In addition, since it is manufactured as a single dosage form, there is an advantage of being very excellent in medication compliance compared to individual administration of the existing single formulation, and there is an advantage of reducing side effects that may occur when taking the existing single formulation for a long period of time.

As a specific embodiment, in the present application, laputidine and irsogladin were separated from each other to prepare a wet granulated raputidine-irsogladin solid pharmaceutical composition, respectively. That is, a granule part of laputidine or a pharmaceutically acceptable salt thereof was prepared, a granule part of irsogladin or a pharmaceutically acceptable salt thereof was prepared, and then the two granules were mixed to prepare a combination formulation. When prepared in this way, it is not necessary to prepare a two-layer tablet to separate the laputidine and the irsogladin part, and even if the two granular parts are mixed and used, there is little deterioration in stability. The reason is that laputidine and irsogladin are granulated separately and the particle size is larger than when the raw materials are simply mixed, so not only the specific surface area decreases, but also the main component is enclosed by excipients, so that the contact area between the main components This is because it exhibits a very diminishing effect. The composite formulations of the examples below prepared in this way were compared to the composite formulations of Comparative Example 1, which is a simple mixed direct tablet of laputidine and irsogladin, Comparative Example 2 which is a mixed granule tablet, and Comparative Example 3 which is a dry granule tablet. It was excellent in terms of the stability of the active substance (see Table 2), and showed further improved dissolution rates of laputidine and irsogladin (see FIGS. 3A and 3B).

In the present application, the pharmaceutically acceptable additive may be one or more selected from excipients, binders, disintegrants, fluidizing agents, and lubricants.

The solid composition from which laputidine and irsogladin are substantially separated may include a pharmaceutically acceptable granulation excipient in the granules of raputidine and the granules of irsogladin, respectively. As the granulation excipients according to the present application, any excipients commonly used in the pharmaceutical field may be used, but excipients sold for wet granulation are preferred. Specific examples of pharmaceutically acceptable granulation excipients may be selected from the group consisting of starch, lactose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, methyl cellulose, fructose, and mixtures thereof, most preferably starch. This is because starch, lactose and microcrystalline cellulose maintain the moisture content of the wet granulated raputidine or irsogladin granules at a certain level, thereby improving tabletting properties during formulation and improving stability over time. Because. Since the laputidine granule part and the irsogladin granule part of the present application have improved fluidity and compression properties, a granulation excipient for improving tabletting properties may be required in a relatively small amount, and thus a small size containing a high concentration of the active ingredient It is possible to manufacture tablets. The pharmaceutical composition of the present invention has the advantage of increasing patient compliance because it can be easily swallowed due to its small size. A specific amount of the granulation excipient may be used in an amount ranging from about 5 to about 95% by weight, preferably from about 10 to about 85% by weight, based on the total weight of the composition.

The tablet for oral administration of the present application provides a binder as a pharmaceutically acceptable additive in order to maintain an appropriate hardness. The binder according to the present invention binds the active ingredient and tableting excipient while dissolving in a solvent. The binder may be appropriately selected according to the type and amount of the solvent, active ingredient, and tableting excipient. Specifically, for example, polyvinylpyrrolidone (PVP), hydroxypropylcellulose (HPMC), hydroxypropylmethylcellulose (HPC), hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, poly It may be selected from the group consisting of vinyl alcohol, dextrin, polyacrylic acid, polymethacrylic acid, gum arabic, gelatin, agar, and mixtures thereof. Preferably, it may be selected from polyvinylpyrrolidone, hydroxypropylmethylcellulose, and hydroxypropylcellulose, more preferably hydroxypropylcellulose. In the present invention, the granulation binder increases the specific gravity of the granules and increases the binding force, thereby facilitating the formation of tablets, so that when compressed into tablets, tablets can be formed well even at low tableting pressure. The amount of the granulated binder may be used in an amount ranging from about 1 to about 10% by weight, preferably from about 2 to about 5% by weight, based on the total weight of the composition.

Other pharmaceutically acceptable additives provide a disintegrant for proper drug absorption when administered orally. Disintegrant refers to a substance that helps to achieve a sufficient dissolution rate by promoting the disintegration of the solid composition in the digestive solution.In order to improve the solubility of the solid preparation, especially the tablet, an appropriate type of disintegrant is selected and an appropriate amount of disintegrant is used. It is important to do. If there is a decrease in dissolution due to a delay in disintegration, the dissolution decrease can be improved by increasing the amount of disintegrant, but if the disintegrant is used excessively, the properties of the tablet are sufficiently maintained during the manufacturing and packaging process of the solid preparation or during transport and storage. The tablets will not be able to exhibit the strength as strong as possible. Therefore, selection of an appropriate disintegrant is very important, and there is also a limit to the amount of disintegrant. As the disintegrant used in the pharmaceutical composition of the present invention, sodium starch glycolate, croscarmellose sodium, light anhydrous silicic acid, crospovidone, low-substituted hydroxypropyl cellulose, starch, alginic acid or sodium salt thereof, and mixtures thereof It may be selected from the group consisting of, and preferably sodium starch glycolate, croscarmellose sodium, light anhydrous silicic acid and low-substituted hydroxypropyl cellulose. The disintegrant may be used in an amount ranging from about 1 to about 20% by weight, preferably from about 2 to about 10% by weight, based on the total weight of the composition.

Another pharmaceutically acceptable additive provides a lubricant. Specific examples of lubricants include talc, stearic acid, stearic acid metal salts such as calcium stearate or magnesium stearate, sucrose fatty acid esters, hydrogenated vegetable oils, waxes of high melting point, glyceryl fatty acid esters, glycerol dibehenate. And mixtures thereof, and may be preferably selected from magnesium stearate and talc.

In addition, a stabilizer may be included as an additive to the composition provided by the present invention. Antioxidants are the best stabilizers, and the use of antioxidants is a decomposition product of the active ingredient as the time changes when laputidine or irsogladin is mixed with other pharmaceutically acceptable excipients. It increases the stability by reducing the speed of making. Antioxidants usable in the present invention are butylated hydroxy toluene (BHT), butyrate hydroxy anisole (BHA), ascorbic acid, ascorbyl palmitic acid, ethylenediaminetetraacetic acid (EDTA), and sodium pyrosulfite. It may be selected from the group consisting of. In particular, butylated hydroxy toluene is most preferred.

In the present application, there is also provided a solid pharmaceutical composition in which the ratio of fine powder passing through the body of 75 μm in the granules of laputidine and irsogladin is less than 50%, preferably less than 25%, and more preferably less than 10%. do. This is because the discovery of an unexpected phenomenon that the dissolution pattern and the stability with time change remarkably vary depending on the particle size of the granular part containing the excipient. The present inventors have confirmed that the particle size of the wet granulation part should be adjusted in order to reduce the variation of the dissolution rate according to the particle size of the granule part and improve the stability over time, and the fraction of fine particles of the raputidine and irsogladin granule parts It was found that the stability improved as the value decreased. Accordingly, in another embodiment of the present invention, laputidine and irsogladin are separated and granulated raputidine and irsogladin, characterized in that the proportion of fine powder passing through the body of 75 μm in the wet granulation part is less than 50%. It provides a solid pharmaceutical composition containing sogladin.

As used herein, the "solid pharmaceutical composition" refers to a combination of raputidine and irsogladin present in a single dosage unit having a solid form such as a tablet or capsule. The composition of the present invention is more preferably a tablet in the form of a fixed combination dosage form composition. Laputidine and Irsogladin are prepared after being separated from each other and granulated together with a wet granulation excipient, so that they not only have excellent tabletting properties, but also exhibit excellent dissolution patterns in the entire gastrointestinal tract, and have excellent product stability over time.

The pharmaceutical composition of laputidine and irsogladin according to the present invention is a fixed combination single-dose formulation, has excellent adherence to medication, and exhibits improved peptic ulcer prevention and treatment effects than conventional single formulations. In addition, it exhibits high dissolution rates of laputidine and irsogladin in the entire gastrointestinal pH range, and has the advantage of greatly improving storage stability. More specifically, the dissolution rate of laputidine and irsogladin in the range of pH 1 to 7 may be 85% or more within 30 minutes of the elution time.

According to another aspect, there is provided a method comprising: a) drying by wet granulation of a mixture of laputidine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; b) drying by wet granulation of a mixture of irsogladine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; And c) mixing the granules obtained in step a) with the granules obtained in step b), and then preparing a composite formulation. Or there is provided a method of preparing a solid pharmaceutical composition for treatment.

In the above production method, granulation may be performed using a conventional wet granulation method.

In the above manufacturing method, the pharmaceutically acceptable additive may be at least one selected from excipients, binders, disintegrants, lubricants, and stabilization.

In step a), the excipient may be mixed in an amount of 5 to 95% by weight based on the total weight of laputidine or a pharmaceutically acceptable salt thereof.

In step b), the excipient may be mixed in an amount of 5 to 95% by weight based on the total weight of b) irsogladine or a pharmaceutically acceptable salt thereof.

In the step of preparing the combination formulation in step c), a weight ratio of laputidine or a pharmaceutically acceptable salt thereof and irsogladine or a pharmaceutically acceptable salt thereof may be mixed in a ratio of 1:0.1 to 1:0.8. .

In step c), after mixing the granules obtained in step a) and the granules obtained in step b), the step of mixing a pharmaceutically acceptable additive may be further included.

The solid pharmaceutical composition of the present invention may be formulated in the form of tablets, capsules, multi-particles, etc. according to a conventional formulation method and administered by oral, oral, sublingual, or the like. The method of administration will be determined by the physician after evaluation of the subject's symptoms and needs. The composition of the present invention may be preferably formulated in the form of a tablet, and it is preferable to form a film coating layer on the prepared tablet. The polymer used herein may be a conventional polymer capable of forming a film coating, and the amount is preferably kept to a minimum in order to provide an optimal formulation size and to make an effective formulation, based on the total weight of the formulation. About 1 to 10% by weight, preferably about 2 to 5% by weight is good. The coating may be performed according to a conventional coating method, but it is preferable to coat using a general method used for tablet coating. Tablets prepared by the above composition and preparation method are very stable under normal storage conditions and very stable to temperature and moisture.

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are for illustrative purposes only, and the scope of the present invention is not limited thereto.

Example 1: Preparation I of complex tablets

-Raputidine wet granulation part-

10.0mg raputidine

Microcrystalline cellulose 47.0mg

8.0mg corn starch

2.0mg light anhydrous silicic acid

Croscarmellose Sodium 4.0mg

Hydroxypropylcellulose 2.0mg

Purified water (30.0mg)

-Irsogladin wet granulation part-

Irsogladin malate 2.0mg

Microcrystalline cellulose 50.0mg

Corn starch 21.0mg

1.0mg light anhydrous silicic acid

5.0 mg of low-substituted hydroxypropyl cellulose

Hydroxypropyl cellulose 1.5mg

Purified water (30.0mg)

-Lubricants-

4.5mg talc

2.0mg magnesium stearate

Laputidine, microcrystalline cellulose, corn starch, croscarmellose sodium, and light anhydrous silicic acid were passed through a No. 16 sieve, placed in a high-speed stirrer, mixed for 3 minutes, and then a solution of hydroxypropyl cellulose dissolved in purified water was added and kneaded for 5 minutes. Assembled. After opening a high-speed stirrer, scraping the wall, kneading for an additional 2 minutes, drying in a dryer at 60°C, and sizing to prepare raputidine wet granules. Separately, irsogladine malate, microcrystalline cellulose, corn starch, low-substituted hydroxypropyl cellulose and light anhydrous silicic acid were passed through a sieve No. 16, placed in a high-speed stirrer, mixed for 3 minutes, and then hydroxypropyl cellulose was added to purified water. The dissolved solution was added, and the mixture was assembled by combining for 5 minutes. After opening a high-speed stirrer, scraping the wall, kneading for an additional 2 minutes, drying in a dryer at 60°C, and sizing to prepare irsogladin wet granules. Put the sieved raputidine granules and irsogladin granules into a mixer, mix them for 30 minutes, add talc and magnesium stearate as lubricants, mix for 5 minutes, and tablet to make a total mass of 160 mg, and raputidine 10 mg-ir A combination tablet containing 2 mg of sogladin was prepared.

Example 2: Preparation of complex tablet II

-Raputidine wet granulation part-

10.0mg raputidine

Microcrystalline cellulose 47.0mg

8.0mg corn starch

2.0mg light anhydrous silicic acid

Croscarmellose Sodium 4.0mg

Hydroxypropylcellulose 2.0mg

Purified water (30.0mg)

-Irsogladin wet granulation part-

4.0mg irsogladin malate

Microcrystalline cellulose 48.0mg

Corn starch 21.0mg

1.0mg light anhydrous silicic acid

5.0 mg of low-substituted hydroxypropyl cellulose

Hydroxypropyl cellulose 1.5mg

Purified water (30.0mg)

-Lubricants-

4.5mg talc

2.0mg magnesium stearate

A composite tablet containing a total mass of 160 mg and 10 mg of irsogladin-4 mg of irsogladin was prepared through the same procedure as in Example 1, except that the composition ratio of the irsogladin wet granules was changed.

Example 3: Preparation of complex tablet III

-Raputidine wet granulation part-

20.0mg raputidine

Microcrystalline cellulose 37.0mg

8.0mg corn starch

2.0mg light anhydrous silicic acid

Croscarmellose Sodium 4.0mg

Hydroxypropylcellulose 2.0mg

Purified water (30.0mg)

-Irsogladin wet granulation part-

4.0mg irsogladin malate

Microcrystalline cellulose 48.0mg

Corn starch 21.0mg

1.0mg light anhydrous silicic acid

5.0 mg of low-substituted hydroxypropyl cellulose

Hydroxypropyl cellulose 1.5mg

Purified water (30.0mg)

-Lubricants-

4.5mg talc

2.0mg magnesium stearate

The total mass was 160 mg, and a combined tablet containing 20 mg of raputidine and 4 mg of irsogladin was prepared through the same procedure as in Example 1, except that the amount of raputidine and irsogladin was increased by 2 times. .

Example 4: Preparation of complex tablet IV

-Raputidine wet granulation part-

10.0mg raputidine

Microcrystalline cellulose 20.0mg

5.0mg corn starch

2.0mg light anhydrous silicic acid

Croscarmellose Sodium 3.0mg

Hydroxypropylcellulose 2.0mg

Purified water (20.0mg)

-Irsogladin wet granulation part-

Irsogladin malate 2.0mg

Microcrystalline cellulose 30.0mg

Corn starch 15.0mg

1.0mg light anhydrous silicic acid

4.0mg of low-substituted hydroxypropyl cellulose

Hydroxypropyl cellulose 1.5mg

Purified water (30.0mg)

-Lubricants-

3.0mg talc

1.5mg magnesium stearate

A composite tablet containing a total mass of 100 mg and 10 mg of raputidine-2 mg of irsogladin was prepared through the same procedure as in Example 1 in the composition ratio as shown in the table above.

Example 5: Preparation V of complex tablets

-Raputidine wet granulation part-

10.0mg raputidine

25.0mg lactose

Corn starch 11.0mg

2.0mg light anhydrous silicic acid

Croscarmellose Sodium 4.0mg

Hydroxypropylcellulose 2.0mg

Purified water (20.0mg)

-Irsogladin wet granulation part-

Irsogladin malate 2.0mg

50.0mg lactose

Corn starch 30.0mg

1.0mg light anhydrous silicic acid

5.0 mg of low-substituted hydroxypropyl cellulose

Hydroxypropyl cellulose 1.5mg

Purified water (20.0mg)

-Lubricants-

4.5mg talc

2.0mg magnesium stearate

A composite tablet containing a total mass of 150 mg and 10 mg of raputidine-2 mg of irsogladin was prepared through the same procedure as in Example 1 in the composition ratio as shown in the table above.

Comparative Example 1: Preparation of simple mixed direct tablets of raputidine and irsogladin

-Mixed part-

10.0mg raputidine

Irsogladin malate 2.0mg

100.0mg lactose

Microcrystalline cellulose 50.0mg

Mannitol 30.0mg

6.0mg crospovidone

-Lubricants-

2.0mg magnesium stearate

In the composition of Comparative Example 1, laputidine, irsogladin, and excipients were mixed and compressed at one time to prepare a simple mixed composite tablet containing 10 mg of raputidine-2 mg of irsogladin.

Comparative Example 2: Preparation of mixed wet granule tablets of raputidine and irsogladin

-Wet granulation part-

10.0mg raputidine

Irsogladin malate 2.0mg

30.0mg lactose

Microcrystalline cellulose 50.0mg

3.0mg crospovidone

3.0mg polyvinylpyrrolidone

Purified water (30.0mg)

-Lubricants-

2.0mg magnesium stearate

Put laputidine, irsogladin, lactose, microcrystalline cellulose, and crospovidone through a sieve No. 16, put in a high-speed stirrer, mix for 3 minutes, add a solution of polyvinylpyrrolidone dissolved in purified water, and combine for 5 minutes to assemble. I did. After opening a high-speed stirrer, scraping the wall, kneading for an additional 2 minutes, drying in a dryer at 60℃ and sizing to prepare wet granules of raputidine and irsogladin, add magnesium stearate, and mix for 5 minutes. A mixed wet granule composite tablet containing a total mass of 100 mg and 10 mg of raputidine and 2 mg of irsogladin was prepared by tableting.

Comparative Example 3: Preparation of dry granular tablets of raputidine and irsogladin

-Wet granulation part-

10.0mg raputidine

Irsogladin malate 2.0mg

30.0mg lactose

Microcrystalline cellulose 50.0mg

3.0mg crospovidone

3.0mg polyvinylpyrrolidone

Purified water (30.0mg)

-Lubricants-

2.0mg magnesium stearate

In the composition of Comparative Example 3, laputidine, irsogladin, and excipients were dry granulated at once using a roller compactor, magnesium stearate was added, mixed for 5 minutes, and tableted to have a total mass of 100 mg, and raputidine 10 mg. -A dry granule complex tablet containing 2 mg of irsogladin was prepared.

The characteristics of the formulations of Examples 1 to 5 and Comparative Examples 1 to 3 are compared and summarized in Table 1 below.

Tablet weight
(mg) Raputidine content
(mg) Irsogladin content
(mg) Formulation form Example 1 160 10 2 Separated granule and tablet Example 2 160 10 4 Separated granule and tablet Example 3 160 20 4 Separated granule and tablet Example 4 100 10 2 Separated granule and tablet Example 5 150 10 2 Separated granule and tablet Comparative Example 1 200 10 2 Simple mixed tablet Comparative Example 2 100 10 2 Mixed Wet Granule Tablet Comparative Example 3 100 10 2 Dry Granule Tablet

room Experience One: Laputidine and Irsogladin's Differential scanning calorimeter (Differential scanning calorimeter, DSC ) Through conformity assessment.

In order to analyze the compatibility between the two biologically active substances, Laputidine and Irsogladin, to make the solid pharmaceutical composition for the prevention or treatment of peptic ulcer of the present application, analysis of each drug and drug mixture is conducted by differential scanning calorimetry. I did. Differential scanning calorimetry is a method of heating a reference material and a sample at a constant rate of increase in temperature at the same time to analyze the temperature difference between the phase change of the sample and endotherm due to thermal decomposition or heat generation. This is an analysis method that can be used. As a result, referring to FIG. 1, it was possible to confirm a peak in which an endothermic reaction occurred near about 95° C., which is known as a melting point, in the case of raputidine and about 185° C. in the case of irsogladin. However, in the case of the mixture of the two drugs, the endothermic peak of irsogladin completely disappeared in all samples, and the start temperature of the endothermic peak of raputidine was lower. Moreover, it was confirmed that as the ratio of irsogladin increased, the starting temperature of the endothermic peak of laputidine gradually decreased and disappeared completely. Through this, it was found that a eutectic mixture was formed between the two drugs, and this phenomenon was expected to affect the stability of the two drugs.

Experimental Example 2: Severe Stability Test of Formulations Containing Laputidine and Irsogladin

A harsh stability test was conducted under the following conditions using the combination formulations of laputidine and irsogladin obtained in Examples 1 and 2 and Comparative Examples 1 to 3 to compare the total content of the resulting decomposition products. . The total content of decomposition products was calculated by adding the sum of (a), (b) and (c) peak area% when the total peak area of the sample analyzed by the liquid chromatography method below was 100% (Fig. 2).

Storage conditions-Stored in HDPE bottle packaging in a drying oven controlled at 60℃

Test Time-Initial, 1 week, 2 weeks, 4 weeks

Analytical Targets-Raputidine, Irsogladin and Degradation Products

Analysis condition-

Column: A column filled with octadecylylated silica gel for liquid chromatography with a particle diameter of 5 μm in a stainless steel tube with an inner diameter of about 4.6 mm and a length of 25 cm.

Mobile phase: 1% ammonium acetate buffer: acetonitrile (75: 25, v/v)

Detector: Ultraviolet absorption photometer (measurement wavelength 220nm)

Flow rate: 1.0 mL/min

Injection volume: 10 uL

The results are shown in Table 2 below.

Formulation Early 1 week 2 weeks 4 weeks Example 1 0.00% 0.00% 0.00% 0.08% Example 2 0.02% 0.02% 0.02% 0.05% Comparative Example 1 0.05% 0.18% 0.51% 1.25% Comparative Example 2 0.15% 0.34% 0.65% 1.56% Comparative Example 3 0.21% 0.41% 0.69% 2.01%

As can be seen from Table 2, the combination formulations of Examples 1 and 2 prepared by physically separating laputidine and irsogladin to prepare granules and tablets were simple mixed direct tablets of laputidine and irsogladin. Phosphorus Comparative Example 1, compared to the composite formulation of Comparative Example 2, which is a mixed granule tablet, and Comparative Example 3, which is a dry granule tablet, the rate of increase of the decomposition product was significantly slower, and only a small amount of decomposition products was produced every week within 0.1% during the severe stability period. Could. Therefore, in terms of the stability of the two bioactive substances, it can be seen that the storage stability of the solid pharmaceutical composition prepared according to the method of Examples of the present invention is very superior compared to Comparative Examples 1 to 3.

Experimental Example 3: Dissolution test of the composite formulations of Examples 1 and 4 and Comparative Examples 1 and 3

A dissolution test was conducted using the composite tablets obtained in Examples 1 and 4 and Comparative Examples 1 and 3 and a commercially available single agent of each component. The dissolution test conditions were as follows, and the analysis conditions were the same as in Experimental Example 2.

-Elution condition-

Eluent: Purified water, 900mL

Analysis subject: Laputidine and Irsogladin

Device: USP paddle method, 50rpm

Temperature: 37℃

The results are shown in FIGS. 3A and 3B.

In general, the paddle method, which is the dissolution test condition most tested in oral formulations, was tested for dissolution of laputidine and irsogladin by selecting purified water as the elution solution at 50 rpm, as shown in FIGS. 3A and 3B. It can be seen that in the case of the composite tablets of Examples 1 and 4, the elution patterns of laputidine and irsogladin were significantly higher than those of the tablets of Comparative Examples 1 and 3. In other words, it was confirmed that the solid composite formulation was separated and granulated using an excipient for wet granulation using laputidine and irsogladin, and then tableted to show a significantly faster and higher dissolution pattern compared to Comparative Examples 1 or 3. .

Experimental example 4: Example 1 Dissolution test of complex formulation

The composite tablet obtained in Example 1 was subjected to a dissolution test using an eluate corresponding to a range representing the pH of the gastrointestinal tract in vivo. The dissolution test conditions were as follows, and the analysis conditions were the same as in Experimental Example 2.

-Elution condition-

Eluent: pH1.2, pH 4.0 and pH 6.8 buffer solution, 900mL each

Analysis subject: Laputidine and Irsogladin

Device: USP paddle method, 50rpm

Temperature: 37℃

The results are shown in FIGS. 4A and 4B.

Dissolution test results for each eluate solution As shown in FIGS. 4A and 4B, in the case of Example 1 composite tablet, the dissolution rate of both laputidine and irsogladin was 85% or more within 30 minutes in the eluate range of pH 1.2 to 6.8. Achieved. That is, it was confirmed that the solid composite formulation of the present invention, which was separated and granulated using an optimized excipient using laputidine and irsogladin, and then tableted, exhibited a fast and high dissolution pattern in the entire gastrointestinal range.

Claims (16)

Lafutidine or a pharmaceutically acceptable salt thereof; And Irsogladin or a pharmaceutically acceptable salt thereof; is separated and granulated,
The pharmaceutically acceptable additive is at least one selected from excipients, binders, disintegrants, lubricants, and stabilizers,
The excipient is at least one selected from starch, lactose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, methyl cellulose, and fructose,
A solid pharmaceutical composition for the prevention or treatment of peptic ulcer, wherein the dissolution rate of laputidine and irsogladin in the range of pH 1 to 7 is 85% or more within 30 minutes of dissolution time. The method of claim 1,
The weight ratio of laputidine or a pharmaceutically acceptable salt thereof and irsogladin or a pharmaceutically acceptable salt thereof is 1:0.1 to 1:0.8, a solid pharmaceutical composition for the prevention or treatment of peptic ulcer. delete The method of claim 1,
The excipient is 5 to 95% by weight based on the total weight of the solid pharmaceutical composition for preventing or treating peptic ulcer, a solid pharmaceutical composition for preventing or treating peptic ulcer. delete delete The method of claim 1,
A solid pharmaceutical composition for the prevention or treatment of peptic ulcer, wherein the ratio of fine powder passing through the body eye of 75㎛ among the laputidine and irsogladin granules is less than 50%. A combination formulation for oral administration comprising a solid pharmaceutical composition for preventing or treating peptic ulcer according to any one of claims 1, 2, 4, and 7 in a fixed combination single dosage form. The method of claim 8,
Tablets or capsules, oral combination formulation. A method for preparing a solid pharmaceutical composition for preventing or treating peptic ulcer according to any one of claims 1, 2, 4, and 7,
a) drying by wet granulation of a mixture of laputidine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive;
b) wet granulating and drying irsogladine or a mixture of a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; And
c) comprising the step of preparing a composite formulation after mixing the granules obtained in step a) with the granules obtained in step b), and containing separately granulated laputidine and irsogladine,
The pharmaceutically acceptable additive is at least one selected from excipients, binders, disintegrants, lubricants, and stabilizers,
The excipient is at least one selected from starch, lactose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, methyl cellulose, and fructose,
A method of preparing a solid pharmaceutical composition for preventing or treating peptic ulcer, wherein the dissolution rate of laputidine and irsogladin in the range of pH 1 to 7 is 85% or more within 30 minutes of dissolution time. The method of claim 10,
peptic ulcer, in which the weight ratio of laputidine or a pharmaceutically acceptable salt thereof and irsogladin or a pharmaceutically acceptable salt thereof is mixed in a ratio of 1: 0.1 to 1: 0.8 in the step of preparing the combination preparation in step c). Method for producing a solid pharmaceutical composition for the prevention or treatment of. delete The method of claim 10,
In step a), the excipient is mixed in an amount of 5 to 95% by weight based on the total weight of laputidine or a pharmaceutically acceptable salt thereof. A method for preparing a solid pharmaceutical composition for the prevention or treatment of peptic ulcer. The method of claim 10,
In step b), the excipient is mixed in an amount of 5 to 95% by weight based on the total weight of b) irsogladin or a pharmaceutically acceptable salt thereof. The method of claim 10,
A method for preparing a solid pharmaceutical composition for the prevention or treatment of peptic ulcer further comprising the step of mixing the granules obtained in step a) and the granules obtained in step b) in step c) and then mixing a pharmaceutically acceptable additive. . The method of claim 10,
In step c), a method for preparing a solid pharmaceutical composition for preventing or treating peptic ulcer further comprising the step of mixing and then coating the granules obtained in step a) and the granules obtained in step b).

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