KR100592511B1 - Release Controlled type Formulation Comprising Benzimidazole Derivatives and There Pharmaceutically Acceptable Salt with Increased Stability and Manufacturing Method thereof - Google Patents

Release Controlled type Formulation Comprising Benzimidazole Derivatives and There Pharmaceutically Acceptable Salt with Increased Stability and Manufacturing Method thereof Download PDF

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KR100592511B1
KR100592511B1 KR1020020087300A KR20020087300A KR100592511B1 KR 100592511 B1 KR100592511 B1 KR 100592511B1 KR 1020020087300 A KR1020020087300 A KR 1020020087300A KR 20020087300 A KR20020087300 A KR 20020087300A KR 100592511 B1 KR100592511 B1 KR 100592511B1
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지웅길
황성주
박진규
박경래
문영걸
권용진
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안경섭
노영한
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    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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Abstract

본 발명은 적어도 활성물질로 벤즈이미다졸 유도체 또는 약리학적으로 허용되는 이의 염과, 양이온성 폴리머를 포함하는 펠렛: 상기 펠렛의 외피층으로 중간피막, 방습피막, 장용성 피막의 적어도 하나 이상의 피막층이 형성된 안정성이 강화된 방출제어형 제제 및 그 제조방법을 개시한다.The present invention provides a pellet comprising at least one benzimidazole derivative or a pharmacologically acceptable salt thereof as an active substance and a cationic polymer: Stability in which at least one coating layer of an intermediate coating, a moisture barrier coating, and an enteric coating is formed as an outer coating layer of the pellet. This enhanced release controlled formulation and method for preparing the same are disclosed.

상기 구성에 의하면 벤즈이미다졸 유도체 또는 약리학적으로 허용되는 이의 염을 정전기적으로 안정화시켜 산성환경과 수성환경에서도 뛰어난 내성을 가질 수 있도록 한다. According to the above constitution, the benzimidazole derivative or pharmacologically acceptable salt thereof is electrostatically stabilized to have excellent resistance in an acidic environment and an aqueous environment.

Description

벤즈이미다졸 유도체 또는 약리학적으로 허용되는 이의 염을 활성물질로 하는 안정성이 강화된 방출제어형 제제 및 그 제조방법{Release Controlled type Formulation Comprising Benzimidazole Derivatives and There Pharmaceutically Acceptable Salt with Increased Stability and Manufacturing Method thereof} Release Controlled Type Formulation Comprising Benzimidazole Derivatives and There Pharmaceutically Acceptable Salt with Increased Stability and Manufacturing Method According to Benzimidazole Derivatives or Pharmacologically Acceptable Salts thereof as Active Material             

도 1은 본 발명의 실시예에 사용된 압출성형기의 개략적인 구조도1 is a schematic structural diagram of an extruder used in an embodiment of the present invention

도 2a는 본 발명에서 이용가능한 펠렛타이저의 사시도2A is a perspective view of a pelletizer usable in the present invention

도 2b는 본 발명에서 이용가능한 펠렛타이저의 좌측면도Figure 2b is a left side view of the pelletizer usable in the present invention

도 2c는 본 발명에서 이용가능한 펠렛타이저의 A-A 단면도2C is a cross-sectional view A-A of a pelletizer usable in the present invention.

도 3은 본 발명에 의한 제제를 대상으로 약물의 함량을 측정한 결과그래프Figure 3 is a result of measuring the content of the drug in the formulation according to the present invention

도 4는 본 발명에 의한 제제를 대상으로 하는 용출 실험의 결과 그래프4 is a result graph of the dissolution test for the preparation according to the present invention

본 발명은 벤즈이미다졸 유도체 또는 약리학적으로 허용되는 이의 염을 활성물질로 하는 안정성이 강화된 방출제어형 제제 및 그 제조방법에 관한 것이다.The present invention relates to a stability-controlled controlled release formulation having a benzimidazole derivative or a pharmacologically acceptable salt thereof as an active substance and a method for producing the same.

벤즈이미다졸 유도체는 H+,K+-ATPase 억제제로서, 항궤양 활성을 가진다. 이러한 유도체의 예로는 란소프라졸(2-[[[3-메틸-4(2,2,2-트리플로로에톡시)-2-피리딜]메틸]설피닐]벤즈이미다졸)과, 현재 많이 사용되는 오메프라졸(5-메톡시-3,5-디메틸-2피리디닐)메틸)설피닐)-1H-벤즈이미다졸) 등이 있다. 이들 화합물은 위 및 십이지장 궤양의 치료에 사용되어진다.Benzimidazole derivatives are H + , K + -ATPase inhibitors and have antiulcer activity. Examples of such derivatives include lansoprazole (2-[[[3-methyl-4 (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole) and are currently widely used. Omeprazole (5-methoxy-3,5-dimethyl-2pyridinyl) methyl) sulfinyl) -1H-benzimidazole). These compounds are used for the treatment of gastric and duodenal ulcers.

란소프라졸, 오메프라졸 등을 포함하는 벤즈이미다졸 유도체는 물에 대한 용해도가 낮지만 음전하를 띈 이온을 함유하는 알카리 용액에는 매우 용해도가 높다. 벤즈이미다졸 유도체는 수용액 상태에서 불안정하며, 특히 pH가 감소함에 따라 더욱 불안정해지는 특성을 보인다.Benzimidazole derivatives, including lansoprazole, omeprazole, and the like, have low solubility in water but are highly soluble in alkaline solutions containing negatively charged ions. Benzimidazole derivatives are unstable in aqueous solution, especially as pH decreases.

따라서 이들 벤즈이미다졸 유도체를 제형화함에 있어서는 위산과 접촉하는 것을 피하기 위해 장용코팅제 등으로 코팅처리될 것이 요구된다. 그러나 통상의 장용코팅물질은 산성이기 때문에 그대로 코팅하여 사용할 수 없는 문제가 있다. 이를 위해 중앙코어에 알칼리 물질을 넣어 pH를 높이거나, 중성 또는 알칼리성의 코팅을 1차적으로 수행한 후 2차적으로 장용코팅을 수행하는 방법이 이용되고 있다.Therefore, in formulating these benzimidazole derivatives, it is required to be coated with an enteric coating agent or the like to avoid contact with gastric acid. However, since the conventional enteric coating material is acidic, there is a problem that can not be used as it is coated. To this end, an alkali material is added to the central core to increase the pH, or a method of performing enteric coating secondarily after performing neutral or alkaline coating firstly.

예를 들어 상품명 Losec(아스트라사)은 안정화제로 무기알칼리화제를 도입하여 코어를 형성하고, 이 코어를 수용성 내피층으로 피복시킨 후 최종적으로 장용성 피복을 수행한 것이다. 하지만 이러한 방법은 활성물질을 안정화시키기 위해 제피공정의 정확성이 요구되며, 많은 양의 나트륨을 사용하므로 고혈압 환자와 같이 나트륨 섭취에 제한을 받는 환자에게는 적합하지 않다. 또한 알칼리화제에 의해 장용 성 피막이 손상되어 장기 안정성에 영향을 주는 문제도 있다.For example, the trade name Losec (Astrasa) is to introduce an inorganic alkalizing agent as a stabilizer to form a core, the core is coated with a water-soluble endothelial layer and finally enteric coating. However, this method requires the accuracy of the epidermal process to stabilize the active substance, and because it uses a large amount of sodium, it is not suitable for patients with limited sodium intake such as hypertension patients. There is also a problem that enteric coating is damaged by alkalizing agent and affects long-term stability.

한편, 대한민국 특허공보 91-4579, 87-1005에는 알칼리화제로 NaHPO4와 같은 염의 형태가 개시되어 있으나, 활성물질의 안정화에 방해가 되는 음이온도 함께 공급되므로 오히려 안정화에 저해가 될 수 있다.On the other hand, the Republic of Korea Patent Publications 91-4579, 87-1005 discloses the form of a salt such as NaHPO 4 as an alkalizing agent, but also supplied with anions that interfere with the stabilization of the active material may be inhibited rather than stabilization.

본 발명자는 상기 종래 방출제어형 제제가 지니는 문제에 대한 대안으로서, 활성물질을 안정화시키며, 함량이 균일하며 약물을 완전히 방출할 수 있는 새로운 제제를 연구하여 오던 중 본 발명을 완성하게 되었다.As an alternative to the problem of the conventional controlled release formulation, the inventors have completed the present invention while studying a new formulation that stabilizes the active substance, has a uniform content, and can completely release the drug.

이에 의한 본 발명의 목적은 수성환경 내지는 산성환경에서도 안정하며, 제제의 생산과정 중에 초래되는 약물 소실의 위험을 현저히 감소시키고, 약물이 균일하게 함유된 경구투여용 제제 및 그 제조방법을 제공함에 있다.
It is an object of the present invention to be stable in an aqueous environment or an acidic environment, to significantly reduce the risk of drug loss caused during the production of the preparation, and to provide a formulation for oral administration containing the drug uniformly and a method for preparing the same. .

상기한 목적을 달성하기 위한 본 발명은 적어도 활성물질로 벤즈이미다졸 유도체 또는 약리학적으로 허용되는 이의 염과, 양이온성 다당류를 포함하는 펠렛: 상기 펠렛의 외피층으로 중간피막, 방습피막, 장용성 피막의 적어도 하나 이상의 피막층이 형성된 안정성이 강화된 방출제어형 제제를 포함한다.The present invention for achieving the above object is a pellet containing at least a benzimidazole derivative or a pharmacologically acceptable salt thereof as an active substance, and a cationic polysaccharide: the outer layer of the pellet as an intermediate film, moisture-proof film, enteric coating And controlled release controlled formulations having at least one coating layer formed thereon.

또한 본 발명은 적어도 활성물질로 벤즈이미다졸 유도체 또는 약리학적으로 허용되는 이의 염과, 양이온성 다당류를 포함하는 연합물을 압출하여 필라멘트로 성형하는 단계: 상기 필라멘트를 펠렛으로 성형하는 단계; 및 상기 펠렛에 중간피막, 방습피막, 장용성 피막의 적어도 하나 이상의 피막층을 형성하는 단계를 포함하는 안정성이 강화된 방출제어형 제제의 제조방법을 포함한다.In another aspect, the present invention comprises the steps of extruding a combination comprising a benzimidazole derivative or a pharmacologically acceptable salt thereof as an active material and a cationic polysaccharide to form a filament: forming the filament into pellets; And a method for preparing a stable release controlled formulation comprising forming at least one coating layer of an intermediate coating, a moistureproof coating, or an enteric coating on the pellet.

활성물질은 벤즈이미다졸 유도체 또는 약학적으로 허용되는 이들의 염을 포함한다. 이들은 프로톤 펌프 억제제로서 기능하며, pH변화에 매우 민감하게 영향을 받는 특징이 있다. 이러한 벤즈이미다졸계 화합물로는 현재 란소프라졸, 오메프라졸, 판토프라졸, 라베프라졸 등의 관용명칭으로 불리우는 화합물들이 있다.Active substances include benzimidazole derivatives or pharmaceutically acceptable salts thereof. They function as proton pump inhibitors and are characterized by being very sensitive to pH changes. Such benzimidazole-based compounds include compounds commonly referred to as conventional names such as lansoprazole, omeprazole, pantoprazole, and rabeprazole.

상기에서 '연합물'은 펠렛으로 성형되기 이전의 미성형단계의 조성물로서 압출하기에 적합한 강도 및 연성을 가지도록 각종 보조성분과 함께 조성된 혼합물을 의미한다. 필라멘트로 압출하기에 적합한 강도 및 연성은 구체적으로는 실험을 통해 경험적으로 얻어질 수 있으나, 1000∼4000N의 압출력을 가해 압출하는 경우 바람직하게는 연합물의 응집력은 3.0∼45 N인 것으로 충분하다.As used herein, the term "conjugate" refers to a mixture formulated with various auxiliary components to have strength and ductility suitable for extruding as a composition of an unmolded step prior to molding into pellets. Although strength and ductility suitable for extruding into filaments can be obtained empirically specifically through experiments, when extruding with an extrusion force of 1000 to 4000 N, preferably the cohesion of the coalescence is preferably 3.0 to 45 N.

연합물에 포함되는 성분 중 양이온성 다당류는 수분환경에서 벤즈이미다졸계 화합물의 분해를 촉진하는 -SO 치환기와의 흡착에 의해 활성물질의 정전기적 안정성을 제공한다. 또한 산성 환경에서는 구조적인 차폐 등의 효과를 통해 활성물질의 안정성을 제공한다.Cationic polysaccharides among the components included in the association provide electrostatic stability of the active material by adsorption with -SO substituents that promote the decomposition of benzimidazole compounds in a water environment. In addition, the acidic environment provides the stability of the active material through the effect of structural shielding.

이러한 양이온성 다당류의 예를 들면, 수용성 키토산, 올리고 키토산을 들 수 있다.Examples of such cationic polysaccharides include water-soluble chitosan and oligo chitosan.

연합물에 포함될 수 있는 기타 성분에는 알칼리화제, 계면활성제, 부형제 등이 있다.Other components that may be included in the combination include alkalizing agents, surfactants, excipients, and the like.

알칼리화제는 활성성분의 안정화에 요구되는 적정한 pH 환경을 조성하기 위해 유효량 첨가될 수 있다. 따라서 산에 불안정한 활성성분의 주위환경이 중성 내지는 알칼리성인 경우 사용이 제한될 수 있다. 상기 알칼리화제의 종류로는 예를 들면, 산화마그네슘, 인산일수소나트륨, 인산일수소칼륨, 수산화마그네슘, 탄산마그네슘, 수산화알루미늄, 탄산알루미늄, 탄산칼슘, 탄산나트륨, 탄산수소나트륨, 탄산칼륨, 탄산수소칼륨, 인산알루미늄, 인산칼슘, 인산나트륨, 인산칼륨, 시트르산알루미늄, 시트르산칼슘, 시트르산나트륨, 시트르산칼륨, 아르기닌, 라이신, 히스티딘, 에글루민, 메글루민의 군에서 선택되는 단일성분 또는 2이상의 혼합성분이 있다.Alkalizing agents can be added in an effective amount to create the proper pH environment required for stabilization of the active ingredient. Therefore, the use may be limited when the environment of the acid-stable active ingredient is neutral or alkaline. Examples of the alkalizing agent include magnesium oxide, sodium monohydrogen phosphate, potassium monohydrogen phosphate, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, aluminum carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, hydrogen carbonate Potassium, aluminum phosphate, calcium phosphate, sodium phosphate, potassium phosphate, aluminum citrate, calcium citrate, sodium citrate, potassium citrate, arginine, lysine, histidine, eglumine, meglumine There is this.

계면활성제는 약제학적으로 허용되며, 약물의 용해 및 용출을 보조하기 위해 사용되는 어떠한 종류의 물질도 여기에 포함된다. 이들 계면활성제의 예로는 소듐라우릴설페이트, 폴리솔베이트, 스테아린산트리에탄올아민, 알킬설폰산염, 알킬아릴설폰산염, 솔비탄에스테르류, 플루론류 등의 이온성 및 비이온성 계면활성제의 군에서 선택되는 하나 이상의 물질이 있다. 상기 계면활성제의 첨가량은 적용되는 활성물질의 용출 양상에 따라 다르지만 활성물질의 중량에 대해 0.5 ~ 100 중량% 정도가 바람직하다.Surfactants are pharmaceutically acceptable and include any kind of material used to aid in the dissolution and dissolution of the drug. Examples of these surfactants include one selected from the group of ionic and nonionic surfactants such as sodium lauryl sulfate, polysorbate, triethanolamine stearic acid, alkyl sulfonate, alkylaryl sulfonate, sorbitan esters, and flulons. There is more than one substance. The amount of the surfactant added varies depending on the dissolution pattern of the active material, but is preferably about 0.5 to 100% by weight based on the weight of the active material.

본 발명의 연합물을 형성하기 위해 사용가능한 부형제의 예로는 미세결정성셀룰로오스, 셀룰로오스분말, 저치환히드록시프로필셀룰로오스, 셀룰로오스아세테이트, 크로스카멜로오스나트륨, 칼슘포스페이트, 칼슘설페이트, 콘 스타치, 락토오스, 만니톨, 솔비톨, 폴리비닐피롤리돈, 탈크, 덱스트레이트, 덱스트린, 글루코오스, 프럭토스, 말토오스, 수크로오스, 카올린, 마스네슘카보네이트, 마그네슘옥사이드, 폴리메타크릴레이트, 히드록시프로필메틸셀룰로오스, 에틸셀룰로오스, 젤라틴, 구아검, 잔탄검, 아크릴레이트 중합체 또는 공중합체의 군에서 선택되는 단독 또는 2종이상의 혼합성분이 있다.Examples of excipients that can be used to form the present invention include microcrystalline cellulose, cellulose powder, low substituted hydroxypropyl cellulose, cellulose acetate, croscarmellose sodium, calcium phosphate, calcium sulfate, corn starch, lactose, Mannitol, sorbitol, polyvinylpyrrolidone, talc, dexrate, dextrin, glucose, fructose, maltose, sucrose, kaolin, magnesium carbonate, magnesium oxide, polymethacrylate, hydroxypropylmethylcellulose, ethylcellulose, gelatin , Guar gum, xanthan gum, acrylate polymers or copolymers, or a mixture of two or more kinds.

이하 펠렛으로의 성형을 위한 연합물의 조성과정 및 성형과정에 대해 설명하기로 한다.Hereinafter, the composition process and the molding process of the association for molding into pellets will be described.

먼저 활성성분을 용매 바람직하게는 물, 에탄올 또는 물과 에탄올의 혼합용매에 알칼리화제, 계면활성제 등과 함께 현탁시키고, 여기에 양이온성 다당류가 용해된 용액을 혼합한다. 상기 혼합액에 부형제를 첨가하여 소정의 강도와 연성을 가지도록 연합한다.First, the active ingredient is suspended in a solvent, preferably water, ethanol or a mixed solvent of water and ethanol together with an alkalizing agent, a surfactant, and the like, and a solution in which a cationic polysaccharide is dissolved is mixed. An excipient is added to the mixed solution so as to have a predetermined strength and ductility.

도 1에는 본 발명에서 이용가능한 압출성형기의 개략적인 구조도가 도시되어 있다.1 shows a schematic structural diagram of an extrusion machine usable in the present invention.

압출성형공정은 저면에 일정한 내경을 가지는 다수개의 구멍(2)이 형성된 유압식 압출성형기(1)가 이용될 수 있다. 상기 적당한 강도와 연성을 가지도록 조성된 연합물은 압출성형기(1)에 투입되어 실린더형의 필라멘트로서 성형된다.In the extrusion process, a hydraulic extruder 1 having a plurality of holes 2 having a predetermined inner diameter on its bottom may be used. The union formed to have the appropriate strength and ductility is introduced into the extruder 1 to be molded as a cylindrical filament.

도 2a 내지 2c에는 상기 연합물로부터 압출공정에 의해 얻어진 필라멘트를 펠렛으로 성형하기 위한 펠렛타이저의 사시도, 좌측면도 및 A-A 단면도가 도시되어 있다.2A to 2C show a perspective view, a left side view and an A-A cross sectional view of a pelletizer for molding the filament obtained by the extrusion process from the union into pellets.

상기 펠렛타이저에는 필라멘트를 원형의 환으로 성형하는데 요구되는 1조의 성형롤러(4,5)가 구비된다. 상기 성형롤러는 롤러면을 따라 회전축에 수직으로 일정한 내경을 가지는 반원형 홈(6)이 압출물을 절단하는 돌출면(7)을 사이로 연속하여 형성되어 있다. 상기 1조의 성형롤러(4,5)는 반원형 홈과 돌출면끼리 상호 대응접촉하여 상하에서 역으로 회전한다. 이때 상하 두 롤러의 접촉면 사이에 긴 실린더형의 필라멘트(3)를 회전축과 평행하게 올려놓으면 상하에서 각기 다른 속도로 회전하는 두 롤러에 의해 압출물이 회전하면서 롤러의 돌출면(7)에 의해 절단되고 반원형 홈에 의해 압축되어 일정한 내경을 갖는 환으로 성형된다.The pelletizer is provided with a set of forming rollers 4 and 5 required for forming the filament into a circular ring. The shaping roller is formed with a semicircular groove 6 having a constant inner diameter perpendicular to the rotational axis along the roller surface between the protruding surface 7 for cutting the extrudate. The pair of forming rollers 4 and 5 rotate in the up and down direction by making the semicircular grooves and the protruding surfaces correspond to each other. At this time, if the long cylindrical filament 3 is placed in parallel between the contact surfaces of the upper and lower rollers, the extrudate is rotated by two rollers rotating at different speeds from the upper and lower sides, and is cut by the protruding surface 7 of the roller. And compressed by a semicircular groove to form a ring having a constant inner diameter.

최종 펠렛의 크기는 압출성형기에 형성된 다수개의 구멍(2)의 내경 또는 펠렛타이저의 성형롤러에 형성된 돌출면사이의 홈(6)의 크기를 조절하는 방법으로 제 어가 가능하다.The size of the final pellets can be controlled by adjusting the inner diameter of the plurality of holes 2 formed in the extruder or the size of the grooves 6 between the protruding surfaces formed in the forming roller of the pelletizer.

본 발명은 상기 과정으로 제조되는 펠렛의 크기가 바람직하게는 1∼5mm, 보다 바람직하게는 1.5∼2.5mm 정도인 제제를 포함한다.The present invention includes formulations wherein the pellets produced by the above process have a size of preferably 1 to 5 mm, more preferably about 1.5 to 2.5 mm.

또한 펠렛에는 중간피막, 방습피막, 장용성 피막의 적어도 하나 이상의 피막층이 형성된다. 이러한 피막층의 형성물질로는 다음의 것 중 1종 이상의 중합체를 단독 또는 2종 이상 함께 용해시켜 사용되며, 반드시 이들에 제한되는 것은 아니다: 메틸셀룰로오스, 히드록시에틸셀룰로오스, 히드록시부틸셀룰로오스, 히드록시프로필메틸셀룰로오스, 히드록시메틸셀룰로오스, 폴리옥시에틸렌글리콜셀룰로오스, 히드록시메틸셀룰로오스프탈레이트, 히드록시프로필메틸셀룰로오스프탈레이트, 셀룰로스아세테이트프탈레이트, 키토산, 알긴산, 갈락토만노스, 트라가간트, 셀락, 한천, 아라비아고무, 구아 고무 및 크산탄 고무, 폴리아크릴산공중합체, 메타크릴공중합체, 폴리비닐아세테이트프탈레이트, 폴리에틸렌옥사이드, 폴리프로필렌옥사이드 또는 당업계에 공지되어 있는 기타 적합한 장용 제피층 중합체In addition, the pellet is formed with at least one coating layer of an intermediate coating, a moisture barrier coating, and an enteric coating. As the material for forming the coating layer, one or more of the following polymers are used alone or in combination of two or more thereof, and are not necessarily limited thereto: methyl cellulose, hydroxyethyl cellulose, hydroxybutyl cellulose, and hydroxy. Propyl methyl cellulose, hydroxymethyl cellulose, polyoxyethylene glycol cellulose, hydroxymethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, chitosan, alginic acid, galactomannose, tragaganth, shellac, agar, gum arabic , Guar rubber and xanthan rubber, polyacrylic acid copolymer, methacryl copolymer, polyvinylacetate phthalate, polyethylene oxide, polypropylene oxide or other suitable enteric coating film polymers known in the art.

상기 피막층 물질은 특별한 한정을 요하는 것은 아니나 알콜, 아세톤, 메틸렌클로라이드 등의 유기 용매 또는 물과 이들 용매와의 혼합 용매에 용해 또는 희석되며 통상적으로는 점도의 고저에 따라 1.5∼30중량% 범위로 첨가된다.The coating layer material does not require any particular limitation, but is dissolved or diluted in an organic solvent such as alcohol, acetone, methylene chloride, or a mixed solvent of water and these solvents, and is usually in the range of 1.5 to 30% by weight depending on the height of the viscosity. Is added.

이하 본 발명의 내용을 실시예에 의해 보다 상세하게 설명하기로 한다. 다만 이들 실시예는 본 발명의 내용을 이해하기 위해 제시되는 것일 뿐 본 발명의 권리범위가 이들 실시예에 한정되어지는 것으로 해석되어져서는 아니된다.Hereinafter, the content of the present invention will be described in more detail with reference to Examples. However, these examples are only presented to understand the content of the present invention, and the scope of the present invention should not be construed as being limited to these embodiments.

<실시예 1∼2><Examples 1 and 2>

하기 표 1의 조성과 같이 양이온을 띄는 글루코사민으로 중합되어진 수용성 키토산(평균분자량 20만)을 적당량의 증류수(란소프라졸 30mg에 해당하는 몰당량)에 녹이고, 위 용액을 란소프라졸과 계면활성제인 SLS, 알칼리화제인 인산일수소나트륨(Na2HPO4)을 녹인 수용액에 더하였다. 이때 키토산과 구조적으로 음이온을 띄는 란소프라졸은 정전기적 안정성으로 수용액 상태에서 탁월한 안정성을 지니게 된다. 이후 위 용액을 충분한 시간동안 초음파 처리하였다. As shown in Table 1, the water-soluble chitosan (average molecular weight 200,000) polymerized with glucosamine having a cation was dissolved in an appropriate amount of distilled water (molar equivalent of 30 mg of lansoprazole), and the solution was lansoprazole and SLS, an alkalizing agent. Sodium dihydrogen phosphate (Na 2 HPO 4 ) was added to the dissolved aqueous solution. In this case, lansoprazole having a structural anion with chitosan has excellent stability in aqueous solution due to electrostatic stability. The solution was then sonicated for a sufficient time.

이와는 별도로 미세결정셀룰로오스(Avicel PH102)와 저치환 히드록시프로필 셀룰로오스(L-HPC), 만니톨을 각각 하기 표 1과 같이 측량하여 미리 혼합 및 연합한 후 상기 용액과 혼합하였다.Separately, microcrystalline cellulose (Avicel PH102), low-substituted hydroxypropyl cellulose (L-HPC), and mannitol were measured as shown in Table 1 below, mixed and fed in advance, and then mixed with the solution.

충분히 연합한 후 위 연합물을 내경 2.00mm의 구멍을 다수개 가지는 압출성형기에 넣고 긴 실린더형의 필라멘트로 성형한 후 펠렛타이저를 이용해 펠렛으로 최종 성형하였다. 이후 서늘하고 통풍이 잘되는 그늘에서 위 펠렛을 1∼2일 정도 건조시켰다. 건조 후 코팅펜에서 증류수에 용해시킨 4중량%의 히드록시프로필메틸셀룰로오스(HPMC) 코팅액으로 1차 코팅처리한 후, 아세톤, 에탄올, 세틸알콜에 녹 인 12중량%의 히드록시프로필메틸셀룰로오스프탈레이트(HPMCP) 코팅액으로 장용피층을 형성시켰다.After sufficient union, the above union was put into an extruder having a plurality of holes having an inner diameter of 2.00 mm, molded into a long cylindrical filament, and finally formed into pellets using a pelletizer. The pellets were then dried for 1 to 2 days in a cool, airy shade. After drying, the first coating treatment with 4% by weight of hydroxypropyl methyl cellulose (HPMC) coating solution dissolved in distilled water in a coating pen, and 12% by weight of hydroxypropyl methyl cellulose phthalate dissolved in acetone, ethanol, cetyl alcohol ( Enteric coating layer was formed with HPMCP) coating solution.

<표 1>TABLE 1

처방Prescription 실시예 1Example 1 실시예 2Example 2 키토산(AMW=20만)Chitosan (AMW = 20 only) 1313 1313 D.WD.W q.sq.s q.sq.s 란소프라졸Lansoprazole 3030 3030 소듐라우릴설페이트Sodium lauryl sulfate 0.80.8 0.50.5 인산일수소나트륨Sodium hydrogen phosphate 1414 1212 D.WD.W q.sq.s q.sq.s Avicel PH-102Avicel PH-102 5252 5252 L-HPC LH-11L-HPC LH-11 5252 5252 만니톨Mannitol 148148 150150 HPMC 6cpHPMC 6cp appr.12.4appr.12.4 appr. 12.4appr. 12.4 D.WD.W q.sq.s q.sq.s HPMCPHPMCP appr. 37.2appr. 37.2 appr. 37.2appr. 37.2 아세톤Acetone q.sq.s q.sq.s 에탄올ethanol q.sq.s q.sq.s 세틸알콜Cetyl alcohol q.sq.s q.sq.s 총계sum 359.4359.4 359.4359.4 단위: mgUnit: mg

<실시예 3∼8><Examples 3 to 8>

하기 표 2의 조성과 같이 란소프라졸 펠렛의 붕해속도의 향상을 위해 수용성 키토산(평균분자량 20만 이하, 1만 이하), 부형제로서 특히 크로스카멜로오스(Ac-di-sol), 미세결정성셀룰로오스(Avecel PH102), 저치환히드록시프로필셀룰로오스 (L-HPC) 및 만니톨의 함량을 변화시키고 상기 실시예 1∼2의 경우와 동일한 방법으로 연합시켰다.In order to improve the disintegration rate of lansoprazole pellets as shown in Table 2, water-soluble chitosan (average molecular weight 200,000 or less, 10,000 or less), as an excipient, especially croscarmellose (Ac-di-sol), microcrystalline cellulose (Avecel PH102), low-substituted hydroxypropylcellulose (L-HPC) and mannitol contents were varied and associated in the same manner as in Examples 1-2 above.

충분히 연합한 후 위 연합물을 내경 2.00mm의 구멍을 다수개 가지는 압출성 형기에 넣고 긴 실린더형의 필라멘트로 성형한 후 펠렛타이저를 이용해 펠렛으로 최종 성형하였다. 이후 서늘하고 통풍이 잘되는 그늘에서 위 펠렛을 1∼2일 정도 건조시켰다. 건조 후 코팅펜에서 증류수에 용해시킨 4중량%의 히드록시프로필메틸셀룰로오스(HPMC) 코팅액으로 1차 코팅처리한 후, 아세톤, 에탄올, 세틸알콜에 녹인 12중량%의 히드록시프로필메틸셀룰로오스프탈레이트(HPMCP) 코팅액으로 장용피층을 형성시켰다.After sufficient union, the above union was put into an extruder having a plurality of holes having an inner diameter of 2.00 mm, molded into a long cylindrical filament, and finally formed into pellets using a pelletizer. The pellets were then dried for 1 to 2 days in a cool, airy shade. After drying, the coating was first coated with 4% by weight of hydroxypropylmethylcellulose (HPMC) coating solution dissolved in distilled water in a coating pen, and then 12% by weight of hydroxypropylmethylcellulose phthalate (HPMCP) dissolved in acetone, ethanol, and cetyl alcohol. ) The enteric coating layer was formed from the coating liquid.

<표 2>TABLE 2

처방Prescription 실시예 3Example 3 실시예 4Example 4 실시예 5Example 5 실시예 6Example 6 실시예 7Example 7 실시예 8Example 8 키토산(AMW=20만)Chitosan (AMW = 20 only) 1010 -- -- -- -- -- 키토산 (AMW=1만 이하)Chitosan (AMW = 1 only or less) -- 1010 1010 1010 1010 1010 D.WD.W q.sq.s q.sq.s q.sq.s q.sq.s q.sq.s q.sq.s 란소프라졸Lansoprazole 3030 3030 3030 3030 3030 3030 소듐라우릴설페이트Sodium lauryl sulfate 0.80.8 0.80.8 0.80.8 0.80.8 0.80.8 0.80.8 인산일수소나트륨Sodium hydrogen phosphate 1414 1414 1414 1414 1414 1414 D.WD.W q.sq.s q.sq.s q.sq.s q.sq.s q.sq.s q.sq.s Ac-di-solAc-di-sol 2020 2020 -- 2020 2020 2020 Avicel PH-102Avicel PH-102 -- -- 2020 250250 -- -- L-HPC LH-11L-HPC LH-11 100100 100100 100100 -- 250250 -- 만니톨Mannitol 150150 150150 150150 -- -- 250250 HPMC 6cpHPMC 6cp appr.12.4appr.12.4 appr. 12.4appr. 12.4 appr. 12.4appr. 12.4 appr. 12.4appr. 12.4 appr. 12.4appr. 12.4 appr. 12.4appr. 12.4 D.WD.W q.sq.s q.sq.s q.sq.s q.sq.s q.sq.s q.sq.s HPMCPHPMCP appr. 37.2appr. 37.2 appr. 37.2appr. 37.2 appr. 37.2appr. 37.2 appr. 37.2appr. 37.2 appr. 37.2appr. 37.2 appr. 37.2appr. 37.2 아세톤Acetone q.sq.s q.sq.s q.sq.s q.sq.s q.sq.s q.sq.s 에탄올ethanol q.sq.s q.sq.s q.sq.s q.sq.s q.sq.s q.sq.s 세틸알콜Cetyl alcohol q.sq.s q.sq.s q.sq.s q.sq.s q.sq.s q.sq.s 총계sum 374.4374.4 374.4374.4 374.4374.4 374.4374.4 374.4374.4 374.4374.4 단위: mgUnit: mg

<실시예 9∼12><Examples 9-12>

하기 표 3의 조성과 같이 키토산(1만 이하) 10mg을 증류수에 녹인 뒤, 별도 로 란소프라졸과 계면활성제인 폴록사머 F127, 알칼리화제로서 메글루민을 증류수에 녹인 현탁액에 혼합하였다. 여기에 부형제로서 크로스카멜로오스(Ac-di-sol), 저치환히드록시프로필셀룰로오스(L-HPC) 및 만니톨을 첨가하였다.10 mg of chitosan (less than 10,000) was dissolved in distilled water as shown in Table 3, and then lansoprazole and poloxamer F127 as a surfactant and meglumine as an alkalizing agent were mixed in a suspension dissolved in distilled water. To this was added croscarmellose (Ac-di-sol), low substituted hydroxypropyl cellulose (L-HPC) and mannitol as excipients.

충분히 연합한 후 위 연합물을 실시예 1∼2에서와 동일한 과정에 의해 펠렛을 제조하고 코팅처리하였다.After sufficient coalescing, the pellets were prepared and coated by the same process as in Examples 1 and 2 above.

<표 3>TABLE 3

처방Prescription 실시예 9Example 9 실시예 10Example 10 실시예 11Example 11 실시예 12Example 12 키토산 (AMW=1만 이하)Chitosan (AMW = 1 only or less) 1010 1010 1010 1010 D.WD.W q.sq.s q.sq.s q.sq.s q.sq.s 란소프라졸Lansoprazole 3030 3030 3030 3030 폴록사머 F127Poloxamer F127 22 22 22 22 메글루민Meglumine 1616 1616 1616 1616 D.WD.W q.sq.s q.sq.s q.sq.s q.sq.s Ac-di-solAc-di-sol -- 1010 3030 4040 L-HPC LH-11L-HPC LH-11 140140 140140 140140 140140 만니톨Mannitol 100100 100100 100100 100100 HPMC 6cpHPMC 6cp appr.12.4appr.12.4 appr. 12.4appr. 12.4 appr. 12.4appr. 12.4 appr. 12.4appr. 12.4 D.WD.W q.sq.s q.sq.s q.sq.s q.sq.s HPMCPHPMCP appr. 37.2appr. 37.2 appr. 37.2appr. 37.2 appr. 37.2appr. 37.2 appr. 37.2appr. 37.2 아세톤Acetone q.sq.s q.sq.s q.sq.s q.sq.s 에탄올ethanol q.sq.s q.sq.s q.sq.s q.sq.s 세틸알콜Cetyl alcohol q.sq.s q.sq.s q.sq.s q.sq.s 총계sum 347.6347.6 357.6357.6 377.6377.6 387.6387.6 단위: mgUnit: mg

<실시예 13∼14><Examples 13-14>

하기 표 4의 조성과 같이 키토산(1만 이하) 10mg을 증류수에 녹인 뒤, 별도로 란소프라졸과 계면활성제인 폴록사머 F127, 알칼리화제로서 메글루민을 증류수 에 녹인 현탁액에 혼합하였다. 여기에 부형제로서 크로스카멜로오스(Ac-di-sol), 저치환히드록시프로필셀룰로오스(L-HPC) 및 만니톨을 첨가하였다.10 mg of chitosan (less than 10,000) was dissolved in distilled water as shown in Table 4, and then lansoprazole, poloxamer F127 as a surfactant, and meglumine as an alkalizing agent were mixed in a suspension dissolved in distilled water. To this was added croscarmellose (Ac-di-sol), low substituted hydroxypropyl cellulose (L-HPC) and mannitol as excipients.

충분히 연합한 후 위 연합물을 실시예 1∼2에서와 동일한 과정에 의해 펠렛을 제조하고 코팅처리하였다.After sufficient coalescing, the pellets were prepared and coated by the same process as in Examples 1 and 2 above.

<표 4>TABLE 4

처방Prescription 실시예 13Example 13 실시예 14Example 14 키토산 (AMW=1만 이하)Chitosan (AMW = 1 only or less) 1010 1010 D.WD.W q.sq.s q.sq.s 란소프라졸Lansoprazole 3030 3030 폴록사머 F127Poloxamer F127 44 66 메글루민Meglumine 1616 1616 D.WD.W q.sq.s q.sq.s Ac-di-solAc-di-sol 3030 3030 L-HPC LH-11L-HPC LH-11 140140 140140 만니톨Mannitol 100100 100100 HPMC 6cpHPMC 6cp appr.12.4appr.12.4 appr. 12.4appr. 12.4 D.WD.W q.sq.s q.sq.s HPMCPHPMCP appr. 37.2appr. 37.2 appr. 37.2appr. 37.2 아세톤Acetone q.sq.s q.sq.s 에탄올ethanol q.sq.s q.sq.s 세틸알콜Cetyl alcohol q.sq.s q.sq.s 총계sum 379.6379.6 381.6381.6 단위: mgUnit: mg

<실시예 15∼16><Examples 15-16>

하기 표 5의 조성과 같이 키토산(1만 이하) 10mg을 증류수에 녹인 뒤, 별도로 란소프라졸과 계면활성제인 폴록사머 F127, 알칼리화제로서 메글루민을 증류수에 녹인 현탁액에 혼합하였다. 여기에 부형제로서 크로스카멜로오스(Ac-di-sol), 저치환히드록시프로필셀룰로오스(L-HPC) 및 만니톨을 첨가하였다.10 mg of chitosan (10,000 or less) was dissolved in distilled water as in the composition of Table 5, and then lansoprazole, poloxamer F127 as a surfactant, and meglumine as an alkalizing agent were mixed in a suspension dissolved in distilled water. To this was added croscarmellose (Ac-di-sol), low substituted hydroxypropyl cellulose (L-HPC) and mannitol as excipients.

충분히 연합한 후 위 연합물을 실시예 1∼2에서와 동일한 과정에 의해 펠렛을 제조하고 코팅처리하였다.After sufficient coalescing, the pellets were prepared and coated by the same process as in Examples 1 and 2 above.

<표 5>TABLE 5

처방Prescription 실시예 15Example 15 실시예 16Example 16 키토산 (AMW=1만 이하)Chitosan (AMW = 1 only or less) 1010 66 D.WD.W q.sq.s q.sq.s 란소프라졸Lansoprazole 3030 3030 폴록사머 F127Poloxamer F127 22 22 메글루민Meglumine 99 3030 D.WD.W q.sq.s q.sq.s Ac-di-solAc-di-sol 4040 4040 L-HPC LH-11L-HPC LH-11 140140 140140 만니톨Mannitol 100100 100100 HPMC 6cpHPMC 6cp appr.12.4appr.12.4 appr. 12.4appr. 12.4 D.WD.W q.sq.s q.sq.s HPMCPHPMCP appr. 37.2appr. 37.2 appr. 37.2appr. 37.2 아세톤Acetone q.sq.s q.sq.s 에탄올ethanol q.sq.s q.sq.s 세틸알콜Cetyl alcohol q.sq.s q.sq.s 총계sum 378.6378.6 397.6397.6 단위: mgUnit: mg

<실시예 17∼19><Examples 17-19>

하기 표 6의 조성과 같이 키토산(1만 이하) 10mg을 증류수에 녹인 뒤, 별도로 란소프라졸과 계면활성제인 폴록사머 F127, 알칼리화제로서 메글루민을 증류수에 녹인 현탁액에 혼합하였다. 여기에 부형제로서 크로스카멜로오스(Ac-di-sol), 저치환히드록시프로필셀룰로오스(L-HPC) 및 만니톨을 첨가하였다.10 mg of chitosan (10,000 or less) was dissolved in distilled water as in the composition of Table 6, and then lansoprazole, poloxamer F127 as a surfactant, and meglumine as an alkalizing agent were mixed in a suspension dissolved in distilled water. To this was added croscarmellose (Ac-di-sol), low substituted hydroxypropyl cellulose (L-HPC) and mannitol as excipients.

충분히 연합한 후 위 연합물을 실시예 1∼2에서와 동일한 과정에 의해 펠렛을 제조하고 코팅처리하였다. After sufficient coalescing, the pellets were prepared and coated by the same process as in Examples 1 and 2 above.

또한 표 6의 실시예 19에서, 키토산(1만 이하) 10mg을 증류수에 녹인 뒤, 별도로 란소프라졸은 넣지 않고 계면활성제인 폴록사머 F127, 알칼리화제로서 메글루민을 증류수에 녹인 현탁액에 혼합하였다. 여기에 부형제로서 크로스카멜로오스 (Ac-di-sol), 저치환히드록시프로필셀룰로오스(L-HPC) 및 만니톨을 첨가하였다.In Example 19 of Table 6, 10 mg of chitosan (up to 10,000) was dissolved in distilled water, and then lanoxprazole was added to the poloxamer F127 as a surfactant and meglumine as an alkalizing agent was mixed in a suspension dissolved in distilled water. To this was added croscarmellose (Ac-di-sol), low substituted hydroxypropyl cellulose (L-HPC) and mannitol as excipients.

충분히 연합한 후 위 연합물을 실시예 1∼2에서와 동일한 과정에 의해 펠렛을 제조하고 코팅처리하였다.After sufficient coalescing, the pellets were prepared and coated by the same process as in Examples 1 and 2 above.

<표 6>TABLE 6

처방Prescription 실시예 17Example 17 실시예 18Example 18 실시예 19Example 19 키토산 (AMW=1만 이하)Chitosan (AMW = 1 only or less) 1010 1010 1010 D.WD.W q.sq.s q.sq.s q.sq.s 란소프라졸Lansoprazole 3030 3030 00 폴록사머 F127Poloxamer F127 22 22 22 메글루민Meglumine 1212 1616 1616 D.WD.W q.sq.s q.sq.s q.sq.s 에탄올ethanol q.sq.s q.sq.s q.sq.s Ac-di-solAc-di-sol 4040 4040 4040 L-HPC LH-11L-HPC LH-11 140140 140140 140140 만니톨Mannitol 100100 100100 100100 HPMC 6cpHPMC 6cp appr.12.4appr.12.4 appr. 12.4appr. 12.4 appr. 12.4appr. 12.4 D.WD.W q.sq.s q.sq.s q.sq.s HPMCPHPMCP appr. 37.2appr. 37.2 appr. 37.2appr. 37.2 appr. 37.2appr. 37.2 아세톤Acetone q.sq.s q.sq.s q.sq.s 에탄올ethanol q.sq.s q.sq.s q.sq.s 세틸알콜Cetyl alcohol q.sq.s q.sq.s q.sq.s 총계sum 379.6379.6 381.6381.6 357.6357.6 단위: mgUnit: mg

<실시예 20∼22><Examples 20-22>

하기 표 7의 조성과 같이 키토산(1만 이하) 10mg을 증류수에 녹인 뒤, 별도 로 란소프라졸과 계면활성제인 폴록사머 F127, 알칼리화제로서 메글루민의 함량을 각각 변화시켜 증류수에 녹인 현탁액에 혼합하였다. 여기에 부형제로서 크로스카멜로오스(Ac-di-sol), 저치환히드록시프로필셀룰로오스(L-HPC) 및 만니톨을 첨가하였다.10 mg of chitosan (less than 10,000) was dissolved in distilled water as shown in the following Table 7, and then the lansoprazole and poloxamer F127, a surfactant, and meglumine were respectively changed and mixed in a suspension dissolved in distilled water. To this was added croscarmellose (Ac-di-sol), low substituted hydroxypropyl cellulose (L-HPC) and mannitol as excipients.

충분히 연합한 후 위 연합물을 실시예 1∼2에서와 동일한 과정에 의해 펠렛을 제조하고 코팅처리하였다.After sufficient coalescing, the pellets were prepared and coated by the same process as in Examples 1 and 2 above.

<표 7>TABLE 7

처방Prescription 실시예 20Example 20 실시예 21Example 21 실시예 22Example 22 키토산 (AMW=1만 이하)Chitosan (AMW = 1 only or less) 1010 1010 1010 D.WD.W q.sq.s q.sq.s q.sq.s 란소프라졸Lansoprazole 3030 3030 3030 폴록사머 F127Poloxamer F127 22 22 22 메글루민Meglumine 00 3232 6464 D.WD.W q.sq.s q.sq.s q.sq.s 에탄올ethanol q.sq.s q.sq.s q.sq.s Ac-di-solAc-di-sol 4040 4040 4040 L-HPC LH-11L-HPC LH-11 140140 140140 140140 만니톨Mannitol 100100 100100 100100 HPMC 6cpHPMC 6cp appr.12.4appr.12.4 appr. 12.4appr. 12.4 appr. 12.4appr. 12.4 D.WD.W q.sq.s q.sq.s q.sq.s HPMCPHPMCP appr. 37.2appr. 37.2 appr. 37.2appr. 37.2 appr. 37.2appr. 37.2 아세톤Acetone q.sq.s q.sq.s q.sq.s 에탄올ethanol q.sq.s q.sq.s q.sq.s 세틸알콜Cetyl alcohol q.sq.s q.sq.s q.sq.s 총계sum 381.6381.6 403.6403.6 435.6435.6 단위: mgUnit: mg

<실시예 23∼25><Examples 23-25>

하기 표 8의 조성과 같이 란소프라졸 30mg을 폴록사머 F127 2mg, 메글루민 24mg과 함께 증류수와 동량의 에탄올에 용해시킨 뒤, 적당량의 증류수에 용해시킨 글루코사민과 혼합하였다. 여기에 부형제로서 크로스카멜로오스(Ac-di-sol), 저치환히드록시프로필셀룰로오스(L-HPC) 및 만니톨을 첨가하였다.As shown in the composition of Table 8, 30 mg of lansoprazole was dissolved in distilled water and the same amount of ethanol together with 2 mg of poloxamer F127 and 24 mg of meglumine, and then mixed with glucosamine dissolved in an appropriate amount of distilled water. To this was added croscarmellose (Ac-di-sol), low substituted hydroxypropyl cellulose (L-HPC) and mannitol as excipients.

충분히 연합한 후 위 연합물을 실시예 1∼2에서와 동일한 과정에 의해 펠렛을 제조하고 코팅처리하였다.After sufficient coalescing, the pellets were prepared and coated by the same process as in Examples 1 and 2 above.

<표 8>TABLE 8

처방Prescription 실시예 23Example 23 실시예 24Example 24 실시예 25Example 25 글루코사민Glucosamine 88 1010 1414 D.WD.W q.sq.s q.sq.s q.sq.s 란소프라졸Lansoprazole 3030 3030 3030 폴록사머 F127Poloxamer F127 22 22 22 메글루민Meglumine 2424 2424 2424 D.WD.W q.sq.s q.sq.s q.sq.s 에탄올ethanol q.sq.s q.sq.s q.sq.s Ac-di-solAc-di-sol 4040 4040 4040 L-HPC LH-11L-HPC LH-11 140140 140140 140140 만니톨Mannitol 100100 100100 100100 HPMC 6cpHPMC 6cp appr.12.4appr.12.4 appr. 12.4appr. 12.4 appr. 12.4appr. 12.4 D.WD.W q.sq.s q.sq.s q.sq.s HPMCPHPMCP appr. 37.2appr. 37.2 appr. 37.2appr. 37.2 appr. 37.2appr. 37.2 아세톤Acetone q.sq.s q.sq.s q.sq.s 에탄올ethanol q.sq.s q.sq.s q.sq.s 세틸알콜Cetyl alcohol q.sq.s q.sq.s q.sq.s 총계sum 387.6387.6 389.6389.6 393.6393.6 단위: mgUnit: mg

<실시예 26∼28><Examples 26-28>

하기 표 9의 조성과 같이 란소프라졸 30mg을 폴록사머 F127, 메글루민과 함께 증류수와 동량의 에탄올에 용해시킨 뒤, 미리 용해시켜 놓은 올리고키토산 14mg을 혼합하였다. 여기에 부형제로서 크로스카멜로오스(Ac-di-sol), 저치환히드록시 프로필셀룰로오스(L-HPC) 및 만니톨을 첨가하였다.As shown in Table 9, 30 mg of lansoprazole was dissolved in distilled water and the same amount of ethanol together with poloxamer F127 and meglumine, followed by mixing 14 mg of oligochitosan previously dissolved. To this was added croscarmellose (Ac-di-sol), low substituted hydroxy propyl cellulose (L-HPC) and mannitol as excipients.

충분히 연합한 후 위 연합물을 실시예 1∼2에서와 동일한 과정에 의해 펠렛을 제조하고 코팅처리하였다.After sufficient coalescing, the pellets were prepared and coated by the same process as in Examples 1 and 2 above.

<표 9>TABLE 9

처방Prescription 실시예 26Example 26 실시예 27Example 27 실시예 28Example 28 올리고키토산Oligochitosan 1414 1414 1414 D.WD.W q.sq.s q.sq.s q.sq.s 란소프라졸Lansoprazole 3030 3030 3030 폴록사머 F127Poloxamer F127 22 44 66 메글루민Meglumine 2424 2424 2424 D.WD.W q.sq.s q.sq.s q.sq.s 에탄올ethanol q.sq.s q.sq.s q.sq.s Ac-di-solAc-di-sol 4040 4040 4040 L-HPC LH-11L-HPC LH-11 140140 140140 140140 만니톨Mannitol 100100 100100 100100 HPMC 6cpHPMC 6cp appr.12.4appr.12.4 appr. 12.4appr. 12.4 appr. 12.4appr. 12.4 D.WD.W q.sq.s q.sq.s q.sq.s HPMCPHPMCP appr. 37.2appr. 37.2 appr. 37.2appr. 37.2 appr. 37.2appr. 37.2 아세톤Acetone q.sq.s q.sq.s q.sq.s 에탄올ethanol q.sq.s q.sq.s q.sq.s 세틸알콜Cetyl alcohol q.sq.s q.sq.s q.sq.s 총계sum 393.6393.6 395.6395.6 397.6397.6 단위: mgUnit: mg

<실시예 29∼31><Examples 29-31>

하기 표 10의 조성과 같이 란소프라졸 30mg을 폴록사머 F127, 메글루민과 함께 증류수와 동량의 에탄올에 용해시킨 뒤, 미리 용해시켜 놓은 각기 다른 중량의 올리고키토산을 혼합하였다. 여기에 부형제로서 크로스카멜로오스(Ac-di-sol), 저치환히드록시프로필셀룰로오스(L-HPC) 및 만니톨을 첨가하였다.As shown in the composition of Table 10, 30 mg of lansoprazole was dissolved in distilled water and the same amount of ethanol together with poloxamer F127 and meglumine, followed by mixing different weights of oligochitosan. To this was added croscarmellose (Ac-di-sol), low substituted hydroxypropyl cellulose (L-HPC) and mannitol as excipients.

충분히 연합한 후 위 연합물을 실시예 1∼2에서와 동일한 과정에 의해 펠렛 을 제조하고 코팅처리하였다.After sufficient association, the pellets were prepared and coated by the same procedure as in Examples 1-2.

<표 10>TABLE 10

처방Prescription 실시예 29Example 29 실시예 30Example 30 실시예 31Example 31 올리고키토산Oligochitosan 88 1010 1414 D.WD.W q.sq.s q.sq.s q.sq.s 란소프라졸Lansoprazole 3030 3030 3030 폴록사머 F127Poloxamer F127 22 22 22 메글루민Meglumine 1212 1616 2424 D.WD.W q.sq.s q.sq.s q.sq.s 에탄올ethanol q.sq.s q.sq.s q.sq.s Ac-di-solAc-di-sol 4040 4040 4040 L-HPC LH-11L-HPC LH-11 140140 140140 140140 만니톨Mannitol 100100 100100 100100 HPMC 6cpHPMC 6cp appr.12.4appr.12.4 appr. 12.4appr. 12.4 appr. 12.4appr. 12.4 D.WD.W q.sq.s q.sq.s q.sq.s HPMCPHPMCP appr. 37.2appr. 37.2 appr. 37.2appr. 37.2 appr. 37.2appr. 37.2 아세톤Acetone q.sq.s q.sq.s q.sq.s 에탄올ethanol q.sq.s q.sq.s q.sq.s 세틸알콜Cetyl alcohol q.sq.s q.sq.s q.sq.s 총계sum 381.6381.6 385.6385.6 393.6393.6 단위: mgUnit: mg

<실험예 1> 함량 측정Experimental Example 1 Content Measurement

상기 각 실시예에 따라 제조된 펠렛 중에서 20캅셀 분량(란소프라졸 0.6g에 해당하는 분량)을 정밀하게 달아 내용물을 잘 혼합했다. 그 다음, 상기 혼합물로부터 란소프라졸 30mg 해당량을 정밀하게 측량하였다. 여기에 0.25mol/L 수산화나트륨 25mL를 가하여 초음파 진탕하여 녹인 후 에탄올 25.0mL 및 0.235mol/L인산수소나트륨 약 150mL를 더 가하여 초음파 추출하였다. 이 액에 0.235mol/L 인산수소나트륨을 더 가하여 정확하게 250mL로 하여 섞은 다음 여과하였다. 이 여액 25.0mL를 정확하게 취해 100mL 용량 플라스크에 넣고 0.235mol/L 인산수소나트륨을 가하여 총량이 100ml가 되도록 하였다. 이것을 여과하여 검액으로 하였다.The amount of 20 capsules (corresponding to 0.6 g of lansoprazole) was precisely weighed in the pellets prepared according to the above examples, and the contents were mixed well. Then, 30 mg of the corresponding amount of lansoprazole was precisely weighed from the mixture. 25 mL of 0.25 mol / L sodium hydroxide was added thereto, followed by ultrasonic shaking, followed by dissolution of 25.0 mL of ethanol and about 150 mL of 0.235 mol / L sodium hydrogen phosphate. 0.235 mol / L sodium hydrogen phosphate was further added to this solution to make an exact 250 mL, followed by filtration. 25.0 mL of this filtrate was accurately taken into a 100 mL volumetric flask and 0.235 mol / L sodium hydrogen phosphate was added to make a total amount of 100 mL. This was filtered and used as the sample liquid.

이와는 별도로 란소프라졸 표준품 30mg을 정밀하게 측량하였다. 여기에 0.25mol/L 수산화나트륨 25mL, 에탄올 25.0mL 및 0.235mol/L 인산수소나트륨 약 150mL를 가하여 초음파 추출하였다. 이 액에 0.235mol/L 인산수소나트륨을 더 가하여 정확하게 250ml하여 섞은 다음 여과하였다. 이 여액 25mL를 정확하게 취해 100mL 용량플라스크에 넣고 0.235mol/L 인산수소나트륨을 가하여 총량이 100ml가 되도록 하였다. 이것을 여과하여 표준액으로 하였다.Separately, 30 mg of lansoprazole standard was precisely weighed. 25 mL of 0.25 mol / L sodium hydroxide, 25.0 mL of ethanol, and about 150 mL of 0.235 mol / L sodium hydrogen phosphate were added thereto, followed by ultrasonic extraction. 0.235 mol / L sodium hydrogen phosphate was further added to the solution, followed by 250 ml, followed by filtration. 25 mL of this filtrate was accurately taken into a 100 mL volumetric flask and 0.235 mol / L sodium hydrogen phosphate was added to make a total amount of 100 mL. This was filtered to give a standard solution.

검액 및 표준액 20㎕를 가지고 다음의 조건으로 대한약전 일반시험법 액체크로마토그래피법에 따라 실험하였고 란소프라졸의 피크면적 Ar 및 As를 구한 다음 펠렛에 포함된 란소프라졸의 양을 계산하고 그 결과를 도 3에 나타내었다.20 μl of the sample solution and the standard solution were tested according to the Pharmacopoeia General Test Liquid Chromatography method under the following conditions, and the peak areas Ar and As of lansoprazole were calculated, and then the amount of lansoprazole contained in the pellet was calculated. Indicated.

란소프라졸의 양(mg)=란소프라졸 표준품의 양(mg)×

Figure 112002043882461-pat00001
Amount of lansoprazole (mg) = Amount of lansoprazole standard (mg) x
Figure 112002043882461-pat00001

At는 실시예 샘플의 피크면적, As는 표준품의 피크면적을 나타낸다.A t is the peak area of the example sample and A s is the peak area of the standard product.

[조작조건][Operation Conditions]

칼럼: 안지름 4.6mm, 길이 15cm인 스테엔레스관에 5㎛의 옥타데실실릴화한 실리카겔을 충진한 칼럼Column: A column filled with 5 μm octadecylsilylated silica gel in a stainless steel tube having a diameter of 4.6 mm and a length of 15 cm.

검출기: 자외부흡광광도계(측정파장 270nm)Detector: ultraviolet absorbance photometer (wavelength 270 nm)

이동상: 아세토니트릴:0.1M KH2PO4(40:60)Mobile phase: Acetonitrile: 0.1M KH 2 PO 4 (40:60)

유속: 1mL/분Flow rate: 1mL / min

<실험예 2> 용출실험Experimental Example 2 Dissolution Test

란소프라졸 30mg에 해당하는 펠렛을 정확하게 취하였다. pH 6.8 인산완충액(약전)에 폴리솔베이트80(Tween80)을 1%w/v 첨가한 용출액 900mL를 써서 대한약전 일반시험법 용출시험법 중 제 2법에 따라 매분 100회전으로 시험하였다. 30분 동안 용출시험한 다음에 용출액 10mL를 취하여 여과하였다. 이 여액 5.0mL를 취한 뒤, 여기에 0.25mol/L 수산화나트륨시액 1.0mL를 가하고, 잘 혼합하여 검액으로 하였다.Pellets corresponding to 30 mg of lansoprazole were correctly taken. Using eluate 900mL of 1% w / v of polysorbate 80 (Tween80) in pH 6.8 phosphate buffer (Pharmacopoeia) was tested at 100 revolutions per minute in accordance with the second method of the General Test Methods elution test. After elution test for 30 minutes, 10 mL of eluate was taken and filtered. 5.0 mL of this filtrate was taken, and then 1.0 mL of 0.25 mol / L sodium hydroxide solution was added thereto, mixed well to obtain a sample solution.

이와는 별도로 란소프라졸 표준품 30mg을 정밀하게 달아 에탄올 10.0mL를 넣어 녹인후, 이 액에 용출액을 가하여 정확하게 100mL로 하였다. 이액 5.0mL를 취하여, 여기에 용출액을 넣어 정확하게 50mL가 되게 한 뒤 여과하였다. 이 여액 5.0mL를 취한 뒤, 여기에 0.25mol/L 수산화나트륨 시액 1.0mL를 가하고, 잘 혼합하여 검액으로 하였다.Separately, 30 mg of lansoprazole standard was precisely weighed and dissolved in 10.0 mL of ethanol, and then eluent was added to the solution to make 100 mL accurately. 5.0 mL of this solution was taken, and the eluate was added to exactly 50 mL, followed by filtration. 5.0 mL of this filtrate was taken, and then 1.0 mL of 0.25 mol / L sodium hydroxide solution was added thereto, mixed well to obtain a sample solution.

1정 중 란소프라졸(C16H14F3N3O2S)의 용출율(%)=

Figure 112002043882461-pat00002
Dissolution rate of lansoprazole (C 16 H 14 F 3 N 3 O 2 S) in 1 tablet =
Figure 112002043882461-pat00002

Ws:란소프라졸 표준품의 취한량(mg)W s : Taken amount of lansoprazole standard (mg)

Wt: 검체 1정 중의 란소프라졸의 해당량(mg)W t : Corresponding amount of lansoprazole in one tablet (mg)

C: 란소프라졸 표준품의 함량(%)C: content of lansoprazole standard (%)

실험결과 거의 모든 활성약물이 용출되어 나오는 것을 확인하였다. Experimental results showed that almost all active drugs were eluted.

<실험예 3> 안정성 시험Experimental Example 3 Stability Test

상기 실시예 31로 얻은 키토산 펠렛을 25℃, 37℃, 50℃ 상대습도 66%, 0%로 1개월간 보존 후에 고속액체크로마토그래피에 의해 측정한 펠렛 중의 란소프라졸 함량을 표 11에 표시하였다.The lansoprazole content in the pellets measured by high performance liquid chromatography after storing the chitosan pellets obtained in Example 31 at 25 ° C., 37 ° C., 50 ° C., 66% and 0% for one month is shown in Table 11.

<표 11>TABLE 11

구분division 초기함량Initial content 25℃25 ℃ 37℃37 ℃ 50℃50 ℃ (1개월간)(For 1 month) 66%RH66% RH 99.799.7 96.8396.83 91.6791.67 22.7122.71 0%RH0% RH 100.1100.1 99.9199.91 98.2498.24 96.3296.32 단위(%)unit(%)

상기 표 11을 통해 본 발명의 제제가 가혹한 조건에서도 유효성분의 충분한 안정화를 나타낸다는 것을 알 수 있다. 또한, 본 제제를 낮은 습도에서 보관하였을 때, 안정화에 보다 상승적으로 기여함을 알 수 있다. 따라서 본 발명에 따른 유효성분을 산업적으로 이용하는 과정에서 예를 들어, PTP포장 등으로 실온에 보관하거나 유통시킬 시에는 유효성분의 안정화에 보다 상승적으로 기여할 것임을 기대할 수 있다.It can be seen from Table 11 that the formulation of the present invention exhibits sufficient stabilization of the active ingredient even in harsh conditions. It can also be seen that when the formulation is stored at low humidity, it contributes more synergistically to stabilization. Therefore, in the process of industrially using the active ingredient according to the present invention, for example, it can be expected to contribute more synergistically to the stabilization of the active ingredient when stored or distributed at room temperature in PTP packaging or the like.

본 발명에 의하면 벤즈이미다졸 유도체 또는 약리학적으로 허용되는 이의 염을 정전기적으로 안정화시켜 산성환경과 수성환경에서도 뛰어난 내성을 가질 수 있도록 한다. According to the present invention, the benzimidazole derivatives or pharmacologically acceptable salts thereof are electrostatically stabilized to have excellent resistance in acidic and aqueous environments.                     

또한 펠렛으로 가공함으로써 제제의 생산과정 중에 초래되는 약물 손실의 위험을 현저히 감소시키며, 약물의 균일한 함량을 가지는 제제의 생산을 가능하게 한다.Processing into pellets also significantly reduces the risk of drug loss incurred during the production of the formulation and enables the production of formulations with a uniform content of the drug.

Claims (16)

적어도 활성물질로 벤즈이미다졸 유도체 또는 약리학적으로 허용되는 이의 염과, 양이온성 다당류를 포함하는 펠렛:Pellets comprising at least benzimidazole derivatives or pharmacologically acceptable salts thereof as the active substance and cationic polysaccharides: 상기 펠렛의 외피층으로 중간피막, 방습피막, 장용성 피막의 적어도 하나 이상의 피막층이 형성된 안정성이 강화된 방출제어형 제제Stability-enhanced release-formulated formulation in which at least one coating layer of an intermediate coating, a moistureproof coating, and an enteric coating is formed as an outer coating layer of the pellet. 제 1항에 있어서,The method of claim 1, 상기 펠렛은 활성성분의 안정화에 요구되는 적정한 pH환경을 조성하기 위한 유효량의 알칼리화제를 더 포함하는 제제The pellet further comprises an effective amount of an alkalizing agent to create an appropriate pH environment required for stabilization of the active ingredient. 제 1항에 있어서,The method of claim 1, 활성성분은 란소프라졸, 판토프라졸, 라베프라졸에서 선택됨을 특징으로 하는 제제The active ingredient is selected from lansoprazole, pantoprazole and rabeprazole. 제 1항에 있어서,The method of claim 1, 양이온성 다당류는 수용성 키토산, 올리고 키토산에서 선택되는 제제Cationic polysaccharides are agents selected from water soluble chitosan, oligo chitosan 제 2항에 있어서,The method of claim 2, 알칼리화제는 산화마그네슘, 인산일수소나트륨, 인산일수소칼륨, 수산화마그네슘, 탄산마그네슘, 수산화알루미늄, 탄산알루미늄, 탄산칼슘, 탄산나트륨, 탄산수소나트륨, 탄산칼륨, 탄산수소칼륨, 인산알루미늄, 인산칼슘, 인산나트륨, 인산칼륨, 시트르산알루미늄, 시트르산칼슘, 시트르산나트륨, 시트르산칼륨, 아르기닌, 라이신, 히스티딘, 에글루민, 메글루민의 군에서 선택되는 단독 또는 2종 이상의 혼합성분인 제제 The alkalizing agent is magnesium oxide, sodium dihydrogen phosphate, potassium monohydrogen phosphate, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, aluminum carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydrogen carbonate, aluminum phosphate, calcium phosphate, Sodium Phosphate, Potassium Phosphate, Aluminum Citrate, Calcium Citrate, Sodium Citrate, Potassium Citrate, Arginine, Lysine, Histidine, Eglumin, Meglumine 제 1항에 있어서, 펠렛은The method of claim 1 wherein the pellets 계면활성제로서 소듐라우릴설페이트, 폴리솔베이트, 스테아린산트리에탄올아민, 알킬설폰산염, 알킬아릴설폰산염, 솔비탄에스테르류, 플루론류 등의 이온성 및 비이온성 계면활성제의 군에서 선택되는 단독 또는 2종 이상의 혼합성분을 포함하는 제제Single or two type selected from the group of ionic and nonionic surfactants such as sodium lauryl sulfate, polysorbate, stearic acid triethanolamine, alkyl sulfonate, alkylaryl sulfonate, sorbitan esters, and fluorones as surfactants Formulations containing the above mixed ingredients 제 1항에 있어서, 펠렛은The method of claim 1 wherein the pellets 부형제로서 미세결정성셀룰로오스, 셀룰로오스분말, 저치환히드록시프로필셀룰로오스, 셀룰로오스아세테이트, 크로스카멜로오스나트륨, 칼슘포스페이트, 칼슘설페이트, 콘 스타치, 락토오스, 만니톨, 솔비톨, 폴리비닐피롤리돈, 탈크, 덱스트레이트, 덱스트린, 글루코오스, 프럭토스, 말토오스, 수크로오스, 카올린, 마스네슘카보네이트, 마그네슘옥사이드, 폴리메타크릴레이트, 히드록시프로필메틸셀룰로오스, 에틸셀룰로오스, 젤라틴, 구아검, 잔탄검, 아크릴레이트 중합체 또는 공중합 체의 군에서 선택되는 단독 또는 2종 이상의 혼합성분을 포함하는 제제 As an excipient, microcrystalline cellulose, cellulose powder, low substituted hydroxypropyl cellulose, cellulose acetate, croscarmellose sodium, calcium phosphate, calcium sulfate, corn starch, lactose, mannitol, sorbitol, polyvinylpyrrolidone, talc, deck Straight, dextrin, glucose, fructose, maltose, sucrose, kaolin, magnesium carbonate, magnesium oxide, polymethacrylate, hydroxypropylmethylcellulose, ethylcellulose, gelatin, guar gum, xanthan gum, acrylate polymer or copolymer Formulations comprising one or more mixed ingredients selected from the group of 제 1항에 있어서,The method of claim 1, 피막층은 메틸셀룰로오스, 히드록시에틸셀룰로오스, 히드록시부틸셀룰로오스, 히드록시프로필메틸셀룰로오스, 히드록시메틸셀룰로오스, 폴리옥시에틸렌글리콜셀룰로오스, 히드록시메틸셀룰로오스프탈레이트, 히드록시프로필메틸셀룰로오스프탈레이트, 셀룰로스아세테이트프탈레이트, 키토산, 알긴산, 갈락토만노스, 트라가간트, 셀락, 한천, 아라비아고무, 구아 고무 및 크산탄 고무, 폴리아크릴산공중합체, 메타크릴공중합체, 폴리비닐아세테이트프탈레이트, 폴리에틸렌옥사이드, 폴리프로필렌옥사이드의 군에서 선택되는 단독 또는 2종 이상의 혼합성분을 포함하는 제제The coating layer is methyl cellulose, hydroxyethyl cellulose, hydroxybutyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, polyoxyethylene glycol cellulose, hydroxymethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, chitosan Alginic acid, galactomannose, tragaganth, shellac, agar, gum arabic, guar rubber and xanthan rubber, polyacrylic acid copolymer, methacryl copolymer, polyvinylacetate phthalate, polyethylene oxide, polypropylene oxide Formulations comprising only one or two or more mixed ingredients 적어도 활성물질로 벤즈이미다졸 유도체 또는 약리학적으로 허용되는 이의 염과, 양이온성 다당류를 포함하는 연합물을 압출하여 필라멘트로 성형하는 단계:Extruding an association comprising a benzimidazole derivative or pharmacologically acceptable salt thereof with at least an active substance and a cationic polysaccharide to form a filament: 상기 필라멘트를 펠렛으로 성형하는 단계; 및Shaping the filament into pellets; And 상기 펠렛에 중간피막, 방습피막, 장용성 피막의 적어도 하나 이상의 피막층을 형성하는 단계를 포함하는 안정성이 강화된 방출제어형 제제의 제조방법 Method for producing a stable release controlled formulation comprising the step of forming at least one coating layer of the intermediate film, moisture-proof film, enteric coating film in the pellet 제 9항에 있어서,The method of claim 9, 연합물은 활성성분의 안정화에 요구되는 적정한 pH환경을 조성하기 위한 유 효량의 알칼리화제를 더 포함하는 제조방법 The combination further comprises an effective amount of alkalizing agent to create an appropriate pH environment required for stabilization of the active ingredient. 제 9항에 있어서,The method of claim 9, 활성성분은 란소프라졸, 오메프라졸, 판토프라졸, 라베프라졸에서 선택되는 제조방법Active ingredient is selected from lansoprazole, omeprazole, pantoprazole, and labeprazole 제 9항에 있어서,The method of claim 9, 양이온성 다당류는 수용성 키토산, 올리고 키토산에서 선택되는 제조방법Cationic polysaccharide is a production method selected from water-soluble chitosan, oligo chitosan 제 10항에 있어서,The method of claim 10, 알칼리화제는 산화마그네슘, 인산일수소나트륨, 인산일수소칼륨, 수산화마그네슘, 탄산마그네슘, 수산화알루미늄, 탄산알루미늄, 탄산칼슘, 탄산나트륨, 탄산수소나트륨, 탄산칼륨, 탄산수소칼륨, 인산알루미늄, 인산칼슘, 인산나트륨, 인산칼륨, 시트르산알루미늄, 시트르산칼슘, 시트르산나트륨, 시트르산칼륨, 아르기닌, 라이신, 히스티딘, 에글루민, 메글루민의 군에서 선택되는 단독 또는 2종이상의 혼합성분임을 특징으로 하는 제조방법 The alkalizing agent is magnesium oxide, sodium dihydrogen phosphate, potassium monohydrogen phosphate, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, aluminum carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydrogen carbonate, aluminum phosphate, calcium phosphate, Sodium Phosphate, Potassium Phosphate, Aluminum Citrate, Calcium Citrate, Sodium Citrate, Potassium Citrate, Arginine, Lysine, Histidine, Eglumin, Meglumine, a method for producing a mixture characterized in that it is single or two or more selected from the group 제 9항에 있어서, 연합물은The method of claim 9, wherein the association is 계면활성제로서 소듐라우릴설페이트, 폴리솔베이트, 스테아린산트리에탄올아 민, 알킬설폰산염, 알킬아릴설폰산염, 솔비탄에스테르류, 플루론류 등의 이온성 및 비이온성 계면활성제의 군에서 선택되는 단독 또는 2종 이상의 혼합성분임을 특징으로 하는 제조방법 Single or two selected from the group of ionic and nonionic surfactants such as sodium lauryl sulfate, polysorbate, triethanolamine stearic acid, alkyl sulfonate, alkylaryl sulfonate, sorbitan esters, and fluorones as surfactants Method for producing a mixture of more than one species 제 9항에 있어서, 연합물은The method of claim 9, wherein the association is 부형제로서 미세결정성셀룰로오스, 셀룰로오스분말, 저치환히드록시프로필셀룰로오스, 셀룰로오스아세테이트, 크로스카멜로오스나트륨, 칼슘포스페이트, 칼슘설페이트, 콘 스타치, 락토오스, 만니톨, 솔비톨, 폴리비닐피롤리돈, 탈크, 덱스트레이트, 덱스트린, 글루코오스, 프럭토스, 말토오스, 수크로오스, 카올린, 마스네슘카보네이트, 마그네슘옥사이드, 폴리메타크릴레이트, 히드록시프로필메틸셀룰로오스, 에틸셀룰로오스, 젤라틴, 구아검, 잔탄검, 아크릴레이트 중합체 또는 공중합체의 군에서 선택되는 단독 또는 2종 이상의 혼합성분임을 특징으로 하는 제조방법 As an excipient, microcrystalline cellulose, cellulose powder, low substituted hydroxypropyl cellulose, cellulose acetate, croscarmellose sodium, calcium phosphate, calcium sulfate, corn starch, lactose, mannitol, sorbitol, polyvinylpyrrolidone, talc, deck Straight, dextrin, glucose, fructose, maltose, sucrose, kaolin, magnesium carbonate, magnesium oxide, polymethacrylate, hydroxypropylmethylcellulose, ethylcellulose, gelatin, guar gum, xanthan gum, acrylate polymer or copolymer Manufacturing method characterized in that the single or mixed components of two or more selected from the group of 제 9항에 있어서,The method of claim 9, 피막층은 메틸셀룰로오스, 히드록시에틸셀룰로오스, 히드록시부틸셀룰로오스, 히드록시프로필메틸셀룰로오스, 히드록시메틸셀룰로오스, 폴리옥시에틸렌글리콜셀룰로오스, 히드록시메틸셀룰로오스프탈레이트, 히드록시프로필메틸셀룰로오스프탈레이트, 셀룰로스아세테이트프탈레이트, 키토산, 알긴산, 갈락토만노스, 트라가간트, 셀락, 한천, 아라비아고무, 구아 고무 및 크산탄 고무, 폴리아크릴산공중합체, 메타크릴공중합체, 폴리비닐아세테이트프탈레이트, 폴리에틸렌옥사이드, The coating layer is methyl cellulose, hydroxyethyl cellulose, hydroxybutyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, polyoxyethylene glycol cellulose, hydroxymethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, chitosan , Alginic acid, galactomannose, tragaganth, shellac, agar, gum arabic, guar rubber and xanthan rubber, polyacrylic acid copolymer, methacrylic copolymer, polyvinylacetate phthalate, polyethylene oxide, 폴리프로필렌옥사이드의 군에서 선택되는 단독 또는 2종 이상의 혼합성분을 포함하는 제조방법.Method for producing a single or a mixture of two or more selected from the group of polypropylene oxide.
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