WO2005058282A1

WO2005058282A1 - Double pellet formulation of proton pump inhibitors and clarithromycin for the treatment of gastrointestinal ulcer, and method for producing the same

Info

Publication number: WO2005058282A1
Application number: PCT/KR2004/001792
Authority: WO
Inventors: Ki-Young Ahn; Young-Sig Gil; Chang-Hun Yu; Hye-Kyeong Kim; Geon-Seok Ahn; Seok-Cheon Hong; Geun-Woo Yang
Original assignee: Korea United Pharm, Inc
Priority date: 2003-12-18
Filing date: 2004-07-19
Publication date: 2005-06-30
Also published as: KR20050061647A; KR100581967B1

Abstract

The present invention relates to a double pellet formulation effective for the treatment of various peptic ulcers, including a peptic ulcer caused by Helicobactor pylori, as well as a preparing method thereof. More particularly, the present invention relates to a double pellet formulation in which layers separated from each other are formed in one pellet, and a proton pump inhibitor and antibiotic clarithromycin are contained in the separated layers, respectively, such that upon administration of the formulation, the drugs can be released in different sites of the living body in a more stable form, thus maximizing a therapeutic effect against various peptic ulcers, including a peptic ulcer caused by Helicobactor pylori, as well as a preparing method thereof.

Description

DOUBLE PELLET FORMULATION OF PROTON PUMP INHIBITORS AND CLARITHROMYCIN FOR THE TREATMENT OF GASTROINTESTINAL ULCER, AND METHOD FOR PRODUCING THE SAME

Technical Field

The present invention relates to a double pellet formulation effective for the treatment of various peptic ulcers, including a peptic ulcer caused by Helicobactor pylori , as well as a preparing method thereof. More particularly, the present invention relates to a double pellet formulation in which layers separated from each other are formed in one pellet, and a proton pump inhibitor and antibiotic clarithromycin are contained in the separated layers, respectively, such that upon administration of the formulation, the drugs can be released in different sites of the living body in a more stable form, thus maximizing a therapeutic effect against various peptic ulcers, including a peptic ulcer caused by Helicobactor pylori , as well as a preparing method thereof.

Background Art For the treatment of peptic ulcers, various therapies are used, and of them, a therapy is mainly used wherein at least two active ingredients are administered at the same time or at some intervals. In the most general administration method, the drugs are formulated separately and administered at the same or different time, thus exhibiting their therapeutic effects. This method has a significant problem in that it causes patients to keep the drug administration time. Of various therapies for the treatment of peptic ulcers, the most generally used therapy may be one associated with a digestive system disease caused by microorganism Helicobactor pylori , and digestive system diseases, such as gastritis and stomach-duodenal ulcer, which can develop into the form of tumors . As known already, Helicobactor pylori , which is a bacterium which had been called Campylobactor pylori , is a classification name changed recently. It is a pathogenic bacterium found in 1983, and is known as a pathogenic factor acting as a background for upper digestive tract diseases, such as peptic ulcers (e.g., stomach ulcer and duodenal ulcer), inflammations (e.g., gastritis) and stomach cancer, mucosa- associated lymphoid tissue (MALT) lymphoma, or chronic heart diseases. At present, studies on the treatment of Helicobactor pylori infection are being actively conducted, and there are many reports of therapeutic methods for removing Helicobactor pylori as well as therapeutic methods for preventing the recurrence of Helicobactor pylori infection. Such therapeutic methods include either the administration of a single formulation, such as bismuth, an antibiotic, a proton pump inhibitor or an anti-ulcer agent, or the administration of a combination of two or three of such substances. However, in such therapeutic methods still have many problems to be solved, in that administration frequency is high, the administration of a larger amount than usual dose may be required, and symptoms, such as diarrhea or constipation, and resistant bacteria, occur due to drug administration. US Patent No. 5,196,205 discloses a method for the treatment of the Helicobactor pylori infection, the method comprising administering a first antibiotic selected from a bismuth compound, penicillin and tetracycline, and a second antibiotic such as metronidazole . Also, this therapeutic method comprises administering three tablets each containing one active ingredient, several times each day. Thus, this therapeutic method has a shortcoming in that it is very complex, thus making patient drug compliance poor. Furthermore, US Patent No. 5,196,205 discloses a therapeutic method using four active ingredients comprising omeprazole which irreversibly inhibits a proton pump to reduce gastric acid secretion, in addition to the above three active ingredients. Of the four active ingredients, omeprazole must be administered at a time different from the remaining three ingredients, and the administration time can be determined depending on disease severity, patient age, and other factors which may influence the effect of omeprazole . The combined therapeutic method requiring a complex posology, disclosed in said patents, has a problem in that a case where a therapeutic effect is not achieved is liable to occur. US Patent Nos . 5,472,695, 5,560,912 and 5,582,837, and WO Nos. 92/11848 and 96/02237 disclose single or combined therapeutic methods for eradicating Helicobactor pylori . However, the therapeutic methods disclosed in such patents did not achieve a satisfactory effect in preparing active ingredients into one formulation while more fundamentally overcoming the problem of interaction between the active ingredients. Korean patent laid-open publication No. 2001-0033244 discloses a method for preparing a double capsule by filling active ingredients for combined therapy into two capsules and filling the smaller capsule of the two capsules into the larger capsule. However, this method has low operation efficiency as well as a very high possibility that the filling operation cannot be smoothly performed due to the already filled capsule or already filled other drugs.

Thus, this method may have many problems upon mass production. Furthermore, US patent Nos. 5,310,555 and 5,501,857 disclose technologies of using the double capsule to administer nutritive components to animals. However, they also have the above-mentioned problems and thus cannot be considered as preferred methods. Of combined therapies for eradicating Helicobactor pylori, active ingredient combinations listed below was clinically tested on the human body, and test methods thereof were already reported. Examples of combinations of more than two drugs are as follows: -amoxicillin, metronidazole and furazolidone; -bismuth subsalicylate, lansoprazole and clarithromycin -bismuth subsalicylate, roxithromycin, metronidazole and ranitidine; -clarithromycin, colloidal bismuth subcitrate and furazolin; -colloidal bismuth subcitrate, amoxicillin and metronidazole; -ebrotidine, amoxicillin and metronidazole; -lansoprazole, amoxicillin and azithromycin; -lansoprazole, amoxicillin and clarithromycin; -lansoprazole, amoxicillin and rebamipide; -lansoprazole, clarithromycin and furazolin; -lansoprazole, azithromycin and metronidazole; -lansoprazole, miconazole and amoxicillin; -lansoprazole and norfloxacin; -metronidazole and dirythromycin; -omeprazole, amoxicillin and azithromycin; -omeprazole, amoxicillin, clarithromycin and metronidazole; -omeprazole, amoxicillin, metronidazole and bismuth; -omeprazole, amoxicillin and rebamipide; -omeprazole, amoxicillin and tinidazole; -omeprazole and amoxicillin; -omeprazole and azithromycin; -omeprazole, bismuth and ciprofloxacin; -omeprazole, bismuth and clarithromycin; -omeprazole, clarithromycin and tinidazole; -omeprazole and dirythromycin; -omeprazole, lansoprazole and rebamipide; -omprazole, metronidazole and amoxicillin; -omeprazole, metronidazole and azithromycin; -omeprazole, metronidazole and clarithromycin; -omeprazole and norfloxacin; -omeprazole, sucralfate, metronidazole and tetracycline; -omeprazole, clarithromycin and tinidazole; -pantoprazole, clarithromycin and amoxicillin; -pantoprazole and clarithromycin; -ranitidine bismuth citrate, clarithromycin and tetracycline; -ranitidine bismuth citrate and clarithromycin; -ranitidine bismuth citrate, metronidazole and clarithromycin; -ranitidine bismuth citrate and cefuroxime; - rifaximin and erythromycin; -omeprazole, bismuth, tetracycline and metronidazole; -omeprazole, bismuth subcitrate, tetracycline and metronidazole; and -bismuth subcitrate, tetracycline and metronidazole.

Disclosure of Invention

The present invention has been made to solve the above-mentioned problems occurring in the prior art, and an object of the present invention is to provide a double pellet formulation in which layers separated from each other are formed in one pellet, and a proton pump inhibitor and antibiotic clarithromycin are contained in the separated layers, respectively, such that upon administration of the formulation, the drugs can be released in different sites of the living body in a more stable form, thus maximizing various peptic ulcers, including a peptic ulcer caused by Helicobactor pylori , as well as a preparing method thereof.

Brief Description of Drawings

FIG. 1 is a schematic diagram showing a double pellet formulation containing a proton pump inhibitor and antibiotic clarithromycin, according to an embodiment of the present invention.

Best Mode for Carrying Out the Invention

The inventive double pellet formulation with a spherical pellet shape is characterized in that it is prepared by the steps of: dissolving a proton pump inhibitor, an alkalinizing agent together with a coating base in a solvent, to prepare a coating solution; coating the coating solution on an inert sugar particle; subjecting the coated particle to protective coating and then to enteric coating, so as to prepare a formulation capable of protecting the proton pump inhibitor, an acid-unstable drug; and coating the outer layer of the formulation with an antibiotic together with a coating base. The inventive double pellet formulation contains two or three active ingredients. In other words, the inventive formulation contains one proton pump inhibitor selected from the group consisting of omeprazole, lansoprazole, pantoprazole and rabeprazole, and one or two antibiotics selected from the group consisting of erythromycin, clarithromycin, azithromycin, tetracycline, tinidazole and metronidazole selectively. In the present invention, a formulation may be prepared in the form of a double pellet which can be filled into a hard capsule. Namely, it can be prepared either in the form of a multi-layer composite pellet by forming a layer containing a proton pump inhibitor, such as omeprazole, on an inert core, subjecting the coated core to protective coating and enteric coating, and then forming a layer containing an antibiotic, such as clarithromycin, on the enteric coating layer, or in the form of a composite tablet having different layers. Alternatively, it may also be prepared in the form of a double core tablet, such that one or two drugs are contained in a core tablet, and one or two other drugs are contained in an outer layer. It is preferably prepared in the double pellet or double core tablet form, and particularly preferably the double pellet form. The inventive double pellet formulation is prepared by dissolving a proton pump inhibitor and an alkalizing agent together with a coating base in a solvent, and then coating the solution on an inert sugar particle. The innermost part of the inventive double pellet formulation preferably contains one proton pump inhibitor selected from the group consisting of omeprazole, lansoprazole, pantoprazole and rabeprazole. At this time, it is very important in view of the stability of the formulation that an alkalizing agent is also contained in the innermost part. The alkalizing agent is preferably selected from the group consisting of meglumine, eglumine, diethanolamine, monoethanolamine, triethanolamine, talc, magnesium hydroxide, magnesium oxide, sodium monohydrogen phosphate, potassium monohydrogen phosphate, arginine, lysine, histidine and a mixture of two thereof. After the inert sugar particle is coated with the solution of the proton pump inhibitor, the alkalizing agent and the coating base, the coated sugar particle is subjected to protective coating in order to protect the acid-unstable drugs. The protective coating base, which can be used in the protective coating, is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone and a mixture of two thereof. Also, the inventive double pellet formulation may be prepared by coating the coated core material with at least one enteric coating layer as a separate layer using a suitable coating technique. Examples of an enteric coating base which is used in the enteric coating include methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate butylate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylcellulose, shellac, and other suitable enteric coating bases. One or a mixture of two of such enteric coating bases is used as a solution or dispersion in water or any suitable organic solvent. In view of environmental factors such as environmental pollution prevention, a water-based coating process is preferably performed. In this water-based coating process, a water dispersion containing methacrylic acid copolymer is most preferably used as a solvent . In order to impart preferred mechanical properties and soft and hard properties to the enteric coating layer, the enteric coating layer may contain a pharmaceutically acceptable plasticizer. Examples of such a plasticizer include triacetin, citric acid, ester, phthalic acid ester, dibutyl sebacate, cetyl alcohol, polyethylene glycol, and polysorbate. The amount of the plasticizer can be suitably selected depending on the kind and amount of the enteric coating layer polymer selected and the kind of the plasticizer selected. Also, an increase in the thickness of the coating layer can make acid-sensitive active ingredients resistant against acidic gastric juice. In order to protect the acid-sensitive active ingredients from the acidic gastric juice, the thickness of the enteric coating layer is preferably at least about 10 μm. The pellet or tablet core coated with the enteric coating layer may be further coated with at least one upper coating layer. However, unless a great problem in the stability of the formulation is not caused, the additional coating layer does not need to be formed. The outer layer of the enteric-coated formulation is coated with an antibiotic together with a coating base, so as to prepare a double pellet formulation with a spherical pellet shape. At this time, the antibiotic may be added as either a solution completely dissolved in a suitable solvent, or a dispersion containing fine particles. The antibiotic which can be contained in the inventive double pellet formulation is selected from the group consisting of a macrolide antibiotic, an imidazole antibiotic, a tetracycline antibiotic and a mixture of two thereof . Examples of the macrolide antibiotic include erythromycin, clarithromycin, azithromycin, and roxithromycin. Examples of the imidazole antibiotic include metronidazole, apronidazole, azomycin, benzonidazole, carnidazole, demetridazole, etanidazole, flunidazole, misonidazole, nimorazole, ornidazole, panidazole, ronidazole, and tinidazole. Examples of the tetracycline antibiotic include tetracycline, chlorotetracycline, doxycycline, glycocycline, guamecycline, lymecycline, metacycline, and sancycline. When the double pellet or double tablet prepared by the above method is administered to a patient, the outermost layer of the formulation is first disintegrated to release the antibiotic present therein. The released drug acts on Helicobactor pylori of gastrointestinal tract mucosa to kill it, and as the formulation reaches the upper portion of the small intestines some time after its administration, the proton pump inhibitor contained in the innermost layer is released to perform anti-ulcer action such as the inhibition of gastric acid secretion. In other words, the prior formulation for the treatment of peptic ulcers had inconvenience resulting from several administrations, since the proton pump inhibitor and the antibiotics were administered separately. On the other hand, the inventive double pellet formulation can be administered to a patient in a more convenient manner and exhibits an excellent therapeutic effect against peptic ulcers . In a preferred embodiment of the present invention, the inventive double pellet formulation may comprise 1-4% by weight, based on the total weight of the formulation, of the proton pump inhibitor, 30-70% by weight of the antibiotic, 5-15% by weight of hydroxypropylcellulose or a derivative thereof, 0.1-7% by weight of the alkalizing agent, 0.1-2% by weight of polyethylene glycol , 2-7% by weight of the enteric coating base, and 15-30% by weight of the inert sugar particle. In another preferred embodiment of the present invention, the inventive double pellet formulation may comprise 1-4% by weight, based on the total weight of the formulation, of the proton pump inhibitor, 30-70% by weight of the antibiotic, 5-15% by weight of hydroxypropylcellulose or a derivative thereof, 0.1-7% by weight of the alkalizing agent, 0.1-2% by weight of polyethylene glycol, 2-7% by weight of the enteric coating base, and 15-30% by weight of various excipients. In the present invention, although the proton pump inhibitor may also be dissolved and used at the amount of 1-10% by weight relative to the total weight of the formulation, it is preferably dissolved and used at the amount of 1-4% by weight in view of the stability and expression of optimal effect of the drug. Examples of a suitable solvent which can be used for the dissolution of the proton pump inhibitor include acetone, ethanol, dichloromethane, isopropyl alcohol, purified water and a mixture of two or more thereof . The most preferred solvent is acetone, and it is used at the amount of 30-100 times the proton pump inhibitor, a main drug. If the solvent is used at the amount of less than 30 times the main drug, complete dissolution of the drug cannot be achieved, and if it is used at the amount of more than 100 times, a delay in operation time and the instability of the drug can be caused. As the alkalizing agent to increase the stability of the proton pump inhibitor, all kinds of alkali substances may be used, bit it was confirmed that sodium monohydrogen phosphate, potassium monohydrogen phosphate, sodium hydrogen carbonate, meglumine and ethanolamines are preferred, and mono-, di-, tri-ethanolamine and meglumine are most preferred in the preparation of the inventive double pellet formulation. The alkalizing agent is preferably added in such an amount that the ratio of the proton pump inhibitor : the alkalizing agent is at least about 1:0.1-1:5, and more preferably 1:0.5-1:3. At a ratio of less than 1:0.1, it will not exhibit a function as an alkalizing agent to increase the stability of the proton pump inhibitor, and at a ratio of more than 1:5, the alkalizing agent added will cause a delay in the drying time of a film, resulting in the phenomenon of adhesion between granules or even a lumping phenomenon. In the present invention, protective coating is carried out since the proton pump inhibitor, a main drug, is very unstable in acidic conditions like gastric juice. The protective coating is required to protect the drug against the enteric coating base which is added to ensure the acid stability of the drug. Examples of a protective coating base which can be used in this protective coating include hydroxypropylmethylcellulose and derivatives thereof, polyvinyl alcohol and polyvinyl pyrrolidone. The protective coating base may be used at the amount of about 0.5-4% by weight relative to the total weight of the formulation. At the amount of less than 0.5% by weight, the protective coating base cannot have perfect protective function, and at the amount of more than 4% by weight, it can cause a delay in operation time and a delay in drug dissolution time. It is most important in the preparation of the inventive double pellet formulation to form an enteric coating layer. This enteric coating layer has a very important effect on the stability of the proton pump inhibitor, an acid-unstable drug, which is contained in the innermost part of the formulation. In the preparation of the inventive double pellet formulation, enteric coating must be performed in such a manner that the enteric coating base may be used at the amount of about 2-7% by weight of the total weight of the formulation. If this enteric coating is performed, an enteric coating layer with a thickness of about 10 μm will be formed on the surface of the formulation. If the enteric coating layer has a thickness of less than 10 μm, the proton pump inhibitor will not show resistance to acidic solution, and if it has a thickness of more than 10 μm, a delay in operation time will be caused. On the outer layer of the enteric-coated formulation, an antibiotic-containing layer is formed such that the antibiotic is preferably contained at the amount of 30-70% by weight relative to the total weight of the formulation. In the preparation of the inventive double pellet formulation, a GPCG3 fluidized bed processor (Glatt, Germany) was used and similar equipment may also be used to prepare the inventive formulation. The operation conditions of the fluidized bed processor are adjusted to an inlet air temperature of 50 °C, an outlet air temperature of 40 °C, an air flow rate of 7 m/sec, a nozzle diameter of 1.0 mm, an injection pressure of 1.3 bar and an inlet rate of coating solution of 25 g/min, and then each step was performed. The present invention will hereinafter be described in further detail by examples. It is to be understood that these examples are presented for illustrative purpose only and not intended to limit the scope of the present invention. Example 1 Coating with main drug 1 221 g of inert sugar particles are placed into a fluidized bed processor, and then the processor is operated to fluidize the particles to be coated. Meanwhile, 10 g of meglumine, an alkalizing agent, is dissolved in 1000 g of acetone, jafterj which 20 g of omeprazole is added and dissolved completely in the solution, and then 25 g of hydroxypropylcellulose and 2.5 g of polyethylene glycol 6000 are added and dissolved completely in the solution. The resulting main drug-containing coating solution is injected through the fluidized bed coater to coat the sugar particles with the drug. Protective coating After performing the main drug coating, a protective coating solution consisting of 20 g of hydroxypropylmethylcellulose and 2 g of polyethylene glycol 600 dissolved in a mixture of 400 g of ethanol and 400 g of dichloromethane is continuously injected onto the main drug-coated pellets to form a protective coating layer. Enteric coating 30 g of Eudragit LI00 and 3 g of triethyl citrate are added and dissolved completely in a mixture of 450 g of acetone and 450 g of isopropyl alcohol, and then injected to the protective-coated pellets to form an enteric coating layer. Coating with main drug 2 500 g of clarithromycin is added and dissolved completely in a mixture of 1000 g of ethanol and 3000 g of dichloromethane, to which 30 g of hydroxypropylmethylcellulose and 3 g of polyethylene glycol 6000 are then added and dissolved, thus preparing a transparent coating solution of the main drug 2. The coating solution is injected onto the enteric-coated pellets to obtain main drug 2-coated pellets. Final coating with film 30 g of hydroxypropylmethylcellulose and 3 g of polyethylene glycol 6000 are added and dissolved in a mixture of 300 g of ethanol and 300 g of dichloromethane, and then coated on the main drug 1- and main drug 2-coated pellets finally, thus preparing a double pellet formulation. Example 2 Coating with main drug 1 221 g of inert sugar particles are placed into a fluidized bed processor, and then the processor is operated to fluidize the particles to be coated. Meanwhile, 10 g of diethanolamine, an alkalizing agent, is dissolved in 1000 g of acetone, after which 20 g of omeprazole is added and dissolved completely in the solution, and then 25 g of hydroxypropylcellulose and 2.5 g of polyethylene glycol 6000 are added and dissolved completely in the solution. The resulting main drug 1-containing coating solution is injected through the fluidized bed coater to coat the sugar particles with the drug. A protective coating step and subsequent steps are carried out in the same manner as in Example 1. Example 3 Coating with main drug 1 221 g of inert sugar particles are placed into a fluidized bed processor, and then the processor is operated to fluidize the particles to be coated. Meanwhile, 10 g of sodium monohydrogen phosphate is dissolved in 100 g of purified water and then in 900 g of acetone, after which 20 g of omeprazole is added and dissolved completely in the solution, and then 25 g of hydroxypropylcellulose and 2.5 g of polyethylene glycol 6000 are added and dissolved completely in the solution. The resulting main drug 1- containing coating solution is injected through the fluidized bed coater to coat the sugar particles with the drug. A protective coating step and subsequent steps are carried out in the same manner as in Example 1. Example 4 Coating with main drug 1 221 g of inert sugar particles are placed into a fluidized bed processor, and then the processor is operated to fluidize the particles to be coated. Meanwhile, 10 g of talc is suspended in 1000 g of acetone, after which 20 g of omeprazole is added and dissolved completely in the- suspension, and then 25 g of hydroxypropylcellulose and 2.5 g of polyethylene glycol 6000 are added and dissolved completely in the solution. The resulting main drug 1- containing coating solution is injected through the fluidized bed coater to coat the sugar particles with the drug. A protective coating step and subsequent steps are carried out in the same manner as in Example 1. Example 5 Coating with main drug 1 211 g of inert sugar particles are placed into a fluidized bed processor, and then the processor is operated to fluidize the particles to be coated. Meanwhile, 15 g of meglumine, an alkalizing agent, is dissolved in 1000 g of acetone, after which 30 g of lansoprazole is added and dissolved completely in the solution, and then 25 g of hydroxypropylcellulose and 2.5 g of polyethylene glycol

6000 are added and dissolved completely in the solution.

The resulting main drug 1-containing coating solution is injected through the fluidized bed coater to coat the sugar particles with the drug. A protective coating step and subsequent steps are carried out in the same manner as in Example 1. Example 6 Coating with main drug 1 211 g of inert sugar particles are placed into a fluidized bed processor, and then the processor is operated to fluidize the particles to be coated. Meanwhile, 15 g of diethanolamine, an alkalizing agent, is dissolved in 1000 g of acetone, after which 30 g of lansoprazole is added and dissolved completely in the solution, and then 25 g of hydroxypropylcellulose and 2.5 g of polyethylene glycol 6000 are added and dissolved completely in the solution. The resulting main drug 1-containing coating solution is injected through the fluidized bed coater to coat the sugar particles with the drug. A protective coating step and subsequent steps are carried out in the same manner as in Example 1. Example 7 Coating with main drug 1 211 g of inert sugar particles are placed into a fluidized bed processor, and then the processor is operated to fluidize the particles to be coated. Meanwhile, 15 g of sodium monohydrogen phosphate is dissolved in 150 g of purified water and then in 900 g of acetone, after which 30 g of lansoprazole is added and dissolved completely in the solution, and then 25 g of hydroxypropylcellulose and 2.5 g of polyethylene glycol 6000 are added and dissolved completely in the solution. The resulting main drug 1- containing coating solution is injected through the fluidized bed coater to coat the sugar particles with the drug. A protective coating step and subsequent steps are carried out in the same manner as in Example 1. Example 8 Coating with main drug 1 211 g of inert sugar particles are placed into a fluidized bed processor, and then the processor is operated to fluidize the particles to be coated. Meanwhile, 10 g of talc is suspended in 1000 g of acetone, after which 30 g of lansoprazole is added and dissolved completely in the suspension, and then 25 g of hydroxypropylcellulose and 2.5 g of polyethylene glycol 6000 are added and dissolved completely in the solution. The resulting main drug 1- containing coating solution is injected through the fluidized bed coater to coat the sugar particles with the drug. A protective coating step and subsequent steps are carried out in the same manner as in Example 1. Example 9 Coating with main drug 1 221 g of inert sugar particles are placed into a fluidized bed processor, and then the processor is operated to fluidize the particles to be coated. Meanwhile, 10 g of meglumine, an alkalizing agent, is dissolved in 1000 g of acetone, after which 20 g of pantoprazole is added and dissolved completely in the solution, and then 25 g of hydroxypropylcellulose and 2.5 g of polyethylene glycol 6000 are added and dissolved completely in the solution. The resulting main drug 1-containing coating solution is injected through the fluidized bed coater to coat the sugar particles with the drug. A protective coating step and subsequent steps are carried out in the same manner as in Example 1. Example 10 Coating with main drug 1 221 g of inert sugar particles are placed into a fluidized bed processor, and then the processor is operated to fluidize the particles to be coated. Meanwhile, 10 g of diethanolamine, an alkalizing agent, is dissolved in 1000 g of acetone, after which 20 g of pantoprazole is added and dissolved completely in the solution, and then 25 g of hydroxypropylcellulose and 2.5 g of polyethylene glycol 6000 are added and dissolved completely in the solution. The resulting main drug 1-containing coating solution is injected through the fluidized bed coater to coat the sugar particles with the drug. A protective coating step and subsequent steps are carried out in the same manner as in Example 1. Example 11 Coating with main drug 1 221 g of inert sugar particles are placed into a fluidized bed processor, and then the processor is operated to fluidize the particles to be coated. Meanwhile, 10 g of sodium monohydrogen phosphate is dissolved in 100 g of purified water and then in 900 g of acetone, after which 20 g of pantoprazole is added and dissolved completely in the solution, and then 25 g of hydroxypropylcellulose and 2.5 g of polyethylene glycol 6000 are added and dissolved completely in the solution. The resulting main drug 1- containing coating solution is injected through the fluidized bed coater to coat the sugar particles with the drug. A protective coating step and subsequent steps are carried out in the same manner as in Example 1. Example 12 Coating with main drug 1 221 g of inert sugar particles are placed into a fluidized bed processor, and then the processor is operated to fluidize the particles to be coated. Meanwhile, 10 g of talc is suspended in 1000 g of acetone, after which 20 g of pantoprazole is added and dissolved completely in the suspension, and then 25 g of hydroxypropylcellulose and 2.5 g of polyethylene glycol 6000 are added and dissolved completely in the solution. The resulting main drug 1- containing coating solution is injected through the fluidized bed coater to coat the sugar particles with the drug. A protective coating step and subsequent steps are carried out in the same manner as in Example 1. Comparative Example 1 Coating with main drug 1 231 g of inert sugar particles are placed into a fluidized bed processor, and the processor is operated to fluidize the particles to be coated. Meanwhile, 20 g of omeprazole is added and dissolved completely in 1000 g of acetone, and then 25 g of hydroxypropylcellulose and 2.5 g of polyethylene glycol 6000 are added and dissolved completely in the solution. The resulting main drug 1- containing coating solution is injected through the fluidized bed coater to coat the sugar particles with the drug. A protective coating step and subsequent steps are carried out in the same manner as in Example 1. Comparative Example 2 Coating with main drug 1 221 g of inert sugar particles are placed into a fluidized bed processor, and the processor is operated to fluidize the particles to be coated. Meanwhile, 30 g of lansoprazole is added and dissolved completely in 1000 g of acetone, and then 25 g of hydroxypropylcellulose and 2.5 g of polyethylene glycol 6000 are added and dissolved completely in the solution. The resulting main drug 1- containing coating solution is injected through the fluidized bed coater to coat the sugar particles with the drug. A protective coating step and subsequent steps are carried out in the same manner as in Example 1. Comparative Example 3 Coating with main drug 1 231 g of inert sugar particles are placed into a fluidized bed processor, and the processor is operated to fluidize the particles to be coated. Meanwhile, 20 g of pantoprazole is added and dissolved completely in 1000 g of acetone, and then 25 g of hydroxypropylcellulose and 2.5 g of polyethylene glycol 6000 are added and dissolved completely in the solution. The resulting main drug 1- containing coating solution is injected through the fluidized bed coater to coat the sugar particles with the drug. A protective coating step and subsequent steps are carried out in the same manner as in Example 1.

Test Example 1: Stability test and comparative evaluation of omeprazole/clarithromycin composite formulation

content Test example 2 : Stability test and comparative evaluation of lansoprazole/clarithromycin composite formulation

content

Test Example 3 : Stability test and comparative evaluation of pantoprazole/clarithromycin composite formulation

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Test Example 4 : Dissolution test of formulation

Industrial Applicability

As described above, the present invention provides the double pellet formulation in which layers separated from each other are formed in one pellet, and a proton pump inhibitor and antibiotic clarithromycin are contained in the separated layers, respectively, such that upon administration of the formulation, the drugs can be released in different sites of the living body in a more stable form, thus maximizing a therapeutic effect against various peptic ulcers, including a peptic ulcer caused by Helicobactor pylori . Furthermore, the present invention provides a simple posology for the administration of two or more active ingredients. In addition, the present invention provides a double pellet formulation effective for the treatment of various peptic ulcers,, including a peptic ulcer caused by Helicobactor pylori , which allows active ingredients to be activated at suitable time intervals and suitable amounts, thus preventing the interaction between the active ingredients, as well as a preparing method thereof.

Claims

What Is Claimed Is:

1. A method for preparing a double pellet formulation with a spherical pellet shape, the method comprising the steps of : dissolving a proton pump inhibitor and an alkalizing agent together with a coating base in a solvent, to prepare a coating solution; coating an inert sugar particle with the coating solution; subjecting the coated sugar particle to protective coating and then to enteric coating, to prepare a formulation capable of protecting the proton pump inhibitor, an acid-unstable drug; and coating the outer layer of the enteric coated particle with an antibiotic together with a coating base.

2. A method for preparing a double pellet formulation with a spherical pellet shape, the method comprising the steps of: dissolving 1-4% by weight, based on the total weight of the formulation, of a proton pump inhibitor and 0.1-7% by weight of an alkalizing agent, together with a coating base in a solvent, to prepare a coating solution; coating 15-30% by weight of an inert sugar particle with the coating solution; subjecting the coated sugar particle to protective coating and then to enteric coating, to prepare a formulation capable of protecting the proton pump inhibitor, an acid-unstable drug; and coating the outer layer of the enteric-coated particle with 30-70% by weight of an antibiotic together with a coating base.

3. The method of Claim 1 or 2 , wherein the proton pump inhibitor is selected from the group consisting of omeprazole, lansoprazole, pantoprazole and rabeprazole.

4. The method of Claim 1 or 2 , wherein the alkalizing agent is selected from the group consisting of meglumine, eglumine, diethanolamine, monoethanolamine, triethanolamine, talc, magnesium hydroxide, magnesium oxide, sodium monohydrogen phosphate, potassium monohydrogen phosphate, arginine, lysine, histidine, and a mixture of two thereof.

5. The method of Claim 1 or 2 , wherein a protective coating base used in the protective coating step is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, and a mixture of two thereof .

6. The method of Claim 1 or 2 , wherein an enteric coating base used in the enteric coating step is selected from the group consisting of methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate butylate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylcellulose, shellac and a mixture of two thereof.

7. The method of Claim 1 or 2 , wherein the antibiotic is selected from the group consisting of a macrolide antibiotic, an imidazole antibiotic, a tetracycline antibiotic and a mixture of two thereof.

8. The method of Claim 7, wherein the macrolide antibiotic is selected from the group consisting of erythromycin, clarithromycin, azithromycin, and roxithromycin.

9. The method of Claim 7, wherein the imidazole antibiotic is selected from the group consisting of metronidazole, apronidazole, azomycin, benzonidazole, carnidazole, demetridazole, etanidazole, flunidazole, misonidazole, nimorazole, ornidazole, panidazole, ronidazole, and tinidazole.

10. The method of Claim 7, wherein the tetracycline antibiotic is selected from the group consisting of tetracycline, chlorotetracycline, doxycycline, glycocycline, guamecycline, lymecycline, metacycline, and sancycline.

11. A double pellet formulation prepared by the method of any one of Claims 1 to 10.