KR20080000121A - Methods and compositions of stabilizing sod. rabeprazole - Google Patents
Methods and compositions of stabilizing sod. rabeprazole Download PDFInfo
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- KR20080000121A KR20080000121A KR1020060057442A KR20060057442A KR20080000121A KR 20080000121 A KR20080000121 A KR 20080000121A KR 1020060057442 A KR1020060057442 A KR 1020060057442A KR 20060057442 A KR20060057442 A KR 20060057442A KR 20080000121 A KR20080000121 A KR 20080000121A
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- coating
- calcium hydroxide
- sodium
- rabeprazole
- labeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- 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
- A61K9/5005—Wall or coating material
- A61K9/501—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- 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
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- 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
- A61K9/5073—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 having two or more different coatings optionally including drug-containing subcoatings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- 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
- A61K9/5089—Processes
Abstract
Description
벤즈이미다졸계 화합물 또는 그 염은 프로톤펌프 저해 작용을 가진 소화성궤양 치료제로 오메프라졸, 란소프라졸, 라베프라졸, 판토프라졸 등이 현재 사용되고 있다. 하지만 이들 약물은 공통적으로 산에 불안정하여 제형화 할 경우 알칼리성물질을 포함해야 안정화가 가능한 단점이 있다. 특히 라베프라졸은 H2 수용체 길항제와 비교하여 강력하고, 현재 나트륨염으로 파리에트정이라는 상품명으로 시판중에 있으며 1일 1회 복용제제이다. 하지만 라베프라졸나트륨 역시 제제 중의 첨가제에 의해 안정성에 많은 영향을 받으며, 특히 알칼리성 물질의 첨가로 인한 pH의 영향을 많이 받는 것으로 알려져 있다. 또한 흡습성이 있어 이를 개선할 수 있는 첨가제의 선택이 중요하다.Benzimidazole-based compounds or salts thereof are currently used omeprazole, lansoprazole, rabeprazole, pantoprazole and the like as a therapeutic agent for peptic ulcer having a proton pump inhibitory action. However, these drugs have a disadvantage that can be stabilized to include an alkaline substance when formulated in common because the acid is unstable. In particular, rabeprazole is more potent than the H2 receptor antagonist, and is currently marketed under the trade name Pariset tablet as sodium salt and is a once-daily dosage. However, rabeprazole sodium is also affected by the stability of the additives in the formulation, especially the pH due to the addition of alkaline substances are known. In addition, it is important to select an additive that can improve hygroscopicity.
국제공개번호 WO 2001/28559에는 라베프라졸을 크로스포비돈, 수산화나트륨 또는/및 수산화칼륨과 함께 제조하여 안정화한 방법이 소개되어 있다. 그러나 이들 제형의 경우 장기보존시에 붕해가 지연되는 단점이 보고 되었다.International Publication No. WO 2001/28559 discloses a process by which rabeprazole is prepared and stabilized with crospovidone, sodium hydroxide and / or potassium hydroxide. However, these formulations have been reported to have a delay in disintegration upon long-term preservation.
일본국 특개소62-258320에는 벤즈이미다졸계 화합물을 포함하는 핵 부분에 알칼리 화합물을 배합하고, 수용성이거나 또는 물에서 급속히 분해되는 정제의 부형제 또는 중합체이고 수용성인 필름 형성 화합물 등으로 피복하고, 추가하여 장용성 피막으로 피복하는 경구 의약제제가 소개되어 있으나 구체적인 첨가제을 한정하고 있지 않다.In Japanese Patent Laid-Open No. 62-258320, an alkali compound is added to a nucleus portion containing a benzimidazole compound, and coated with an excipient or polymer which is water-soluble or rapidly decomposed in water, and a film-forming compound which is water-soluble. Oral pharmaceutical preparations that are coated with an enteric coating have been introduced, but do not limit specific additives.
최근에 공개된 대한민국 공개특허 10-2005-0044545에는 벤즈이미다졸계 화합물을 수불용성고분자 및 장용성고분자와 함께 피복하여 서방화하는 기술이 소개되어 있으나 여전히 알칼리성 물질을 수산화나트륨, 수산화칼륨, 탄산나트륨, 및 탄산칼륨을 한정하고 있다.Recently disclosed Korean Patent Publication No. 10-2005-0044545 discloses a technique of sustained-release by coating a benzimidazole-based compound with a water-insoluble polymer and an enteric polymer, but still maintains an alkaline substance with sodium hydroxide, potassium hydroxide, sodium carbonate, and Potassium carbonate is defined.
본 발명에서는 기존에 소개된 라베프라졸나트륨의 안정화제로서 새로운 알칼리성물질을 적용하여 새로운 안정화 방법을 제공하고자 한다.The present invention is to provide a new stabilization method by applying a new alkaline material as a stabilizer of the introduced labeprazole sodium.
본 발명의 구성은 라베프라졸나트륨과 수산화칼슘을 포함하는 핵을 만들고 그 외층에 수산화칼슘을 포함하는 중간피막 및 장용성 피막을 피복함으로써 라베프라졸나트륨의 안정화가 가능한 조성물 및 제조방법에 관한 것이다.The composition of the present invention relates to a composition and a method for producing a stabilizer of labeprazole sodium by making a nucleus containing labeprazole sodium and calcium hydroxide and coating the intermediate layer and the enteric coating containing calcium hydroxide on the outer layer.
이하 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명자들은 라베프라졸나트륨을 수산화칼슘 및 기타의 첨가제와 함께 성형하여 핵으로 한 다음, 외층에 장용성 고분자를 피복하는 공정을 확립하였다. 이 때 핵은 알칼리성 물질로 수산화칼슘을 포함하고 2% 수용액의 pH가 11 이상인 것이 바람직하다. 핵정과 외층 사이의 중간피막 또한 알칼리성물질로 수산화칼슘을 포함하며 경우에 따라 가소제의 첨가가 가능하다. 최외층의 피막은 장용성피막으로 통상의 장용성 고분자를 사용하여 제조가 가능하다The inventors have established a process of shaping labeprazole sodium together with calcium hydroxide and other additives to make a nucleus and then coating the enteric polymer on the outer layer. At this time, it is preferable that the nucleus contains calcium hydroxide as an alkaline substance and the pH of 2% aqueous solution is 11 or more. The intermediate film between the core and the outer layer also contains calcium hydroxide as an alkaline substance, and in some cases plasticizers can be added. The outermost coating is an enteric coating, which can be manufactured using a conventional enteric polymer.
실시예1Example 1
라베프라졸나트륨 30g, 만니톨 237g, 수산화칼슘 3g, 저치환도히드록시프로필셀룰로오스 30g, 카르복시메칠셀룰로오스칼슘 20.4g 및 히드록시프로필셀룰로오스 36g을 혼합한 다음 에탄올 25mL을 넣어 연합하고 14호체로 제립하였다. 제립한 과립을 40도에서 5시간 건조한 다음 16호체로 정립하고 스테아린산마그네슘 0.36g을 넣어 혼합하였다. 혼합한 과립을 지름 7mm의 원형펀치로 타정하여 1정당 중량이 120mg인 정제를 얻었다. Labeprazole sodium 30g, mannitol 237g, calcium hydroxide 3g, low-substituted hydroxypropyl cellulose 30g, carboxymethyl cellulose calcium 20.4g and hydroxypropyl cellulose 36g were mixed and 25mL ethanol was combined and granulated into No. 14 sieve. The granulated granules were dried at 40 ° C. for 5 hours, sieved to No. 16, and mixed with 0.36 g of magnesium stearate. The mixed granules were compressed into circular punches having a diameter of 7 mm to obtain tablets having a weight of 120 mg per tablet.
위 정제 300g을 코팅 팬에 넣고 아래의 처방으로 코팅액을 제조하고 분무 건조하여 1정당 중간피막 12mg을 입힌 정제를 얻었다.300 g of the above tablets were put in a coating pan, and a coating solution was prepared according to the following formulation and spray-dried to obtain a tablet coated with 12 mg of the intermediate coating per tablet.
[코팅액 조성][Coating Liquid Composition]
에칠셀룰로오스 24gEthyl Cellulose 24g
수산화칼슘 6gCalcium Hydroxide 6g
에탄올 480mL480 mL of ethanol
실시예2Example 2
실시예1에서 얻어진 정제 330g을 실시예1과 마찬가지로 팬코팅기에서 아래의 처방으로 분무하여 1정당 12mg의 장용코팅막을 입혔다. 330 g of the tablet obtained in Example 1 was sprayed in the same manner as in Example 1 in a pan coater to coat 12 mg of enteric coating film per tablet.
[코팅액 조성][Coating Liquid Composition]
히드록시프로필메칠셀룰로오스프탈레이트 23g23 g of hydroxypropyl methyl cellulose phthalate
글리세린지방산에스테르 2.3gGlycerine Fatty Acid Ester 2.3g
수산화칼슘 2.3gCalcium Hydroxide 2.3g
탈크 1.2gTalc 1.2 g
산화티탄 1.2gTitanium Oxide 1.2g
에탄올 450mLEthanol 450mL
실시예3Example 3
실시예1에서 얻어진 정제 330g을 실시예1과 마찬가지로 팬코팅기에서 아래의 처방으로 분무하여 1정당 18mg의 장용코팅막을 입혔다. 330 g of the tablet obtained in Example 1 was sprayed in the same manner as in Example 1 in the pan coater to coat an enteric coating film of 18 mg per tablet.
[코팅액 조성][Coating Liquid Composition]
히드록시프로필메칠셀룰로오스프탈레이트 34.5gHydroxypropylmethylcellulose phthalate 34.5g
글리세린지방산에스테르 3.45gGlycerin Fatty Acid Ester 3.45g
수산화칼슘 3.45gCalcium Hydroxide 3.45g
탈크 1.8gTalc 1.8 g
산화티탄 1.8gTitanium Oxide 1.8g
에탄올 675mLEthanol 675mL
실시예4Example 4
실시예1에서 얻어진 정제 330g을 실시예1과 마찬가지로 팬코팅기에서 아래의 처방으로 분무하여 1정당 24mg의 장용코팅막을 입혔다. 330 g of the tablet obtained in Example 1 was sprayed in the same manner as in Example 1 in a pan coater to coat an enteric coating membrane of 24 mg per tablet.
[코팅액 조성][Coating Liquid Composition]
히드록시프로필메칠셀룰로오스프탈레이트 46gHydroxypropylmethylcellulose phthalate 46g
글리세린지방산에스테르 4.6gGlycerine Fatty Acid Ester 4.6g
수산화칼슘 4.6gCalcium Hydroxide 4.6g
탈크 2.4gTalc 2.4g
산화티탄 2.4gTitanium oxide 2.4g
에탄올 900mLEthanol 900mL
위 실시예1의 정제를 곱게 갈아 수용액에 현탁시켜 2%의 농도가 되게 하였을 때의 pH는 약 12.3이었다.When the tablet of Example 1 was finely ground and suspended in an aqueous solution to have a concentration of 2%, the pH was about 12.3.
실시예5Example 5
라베프라졸나트륨 30g, 만니톨 150g, 수산화칼슘 90g, 저치환도히드록시프로필셀룰로오스 30g, 카르복시메칠셀룰로오스칼슘 20.4g 및 히드록시프로필셀룰로오스 36g을 혼합한 다음 에탄올 25mL을 넣어 연합하고 14호체로 제립하였다. 제립한 과립을 40도에서 5시간 건조한 다음 16호체로 정립하고 스테아린산마그네슘 0.36g을 넣어 혼합하였다. 혼합한 과립을 지름 7mm의 원형펀치로 타정하여 1정당 중량이 120mg인 정제를 얻었다. Rabeprazole sodium 30g, mannitol 150g, calcium hydroxide 90g, low-substituted hydroxypropyl cellulose 30g, carboxymethyl cellulose calcium 20.4g and hydroxypropyl cellulose 36g were mixed and 25mL ethanol was combined and granulated into No. 14 sieve. The granulated granules were dried at 40 ° C. for 5 hours, sieved to No. 16, and mixed with 0.36 g of magnesium stearate. The mixed granules were compressed into circular punches having a diameter of 7 mm to obtain tablets having a weight of 120 mg per tablet.
위 정제 300g을 코팅 팬에 넣고 아래의 처방으로 코팅액을 제조하고 분무 건조하여 1정당 중간피막 12mg을 입힌 정제를 얻었다.300 g of the above tablets were put in a coating pan, and a coating solution was prepared according to the following formulation and spray-dried to obtain a tablet coated with 12 mg of the intermediate coating per tablet.
[코팅액 조성][Coating Liquid Composition]
에칠셀룰로오스 24gEthyl Cellulose 24g
수산화칼슘 6gCalcium Hydroxide 6g
에탄올 480mL480 mL of ethanol
위 실시예2~실시예4의 정제를 가지고 PTP 포장하고, 냉소 및 40도 75% RH에서 1주일간 보존한 결과 함량 및 유연물질의 양은 두가지 보존 조건 하에서 차이가 없이 안정적이었다.PTP packaging with the tablets of Examples 2 to 4 above, and stored for 1 week in the cold and 40 degrees 75% RH content and amount of the flexible material was stable without difference between the two storage conditions.
본 발명에 따르면 라베프라졸나트륨 1중량부에 대하여 수산화칼슘의 양이 0.1 중량부 미만이 되면 알칼리화의 역할이 충분하지 못하고, 3중량부 이상이 되면 정제의 붕해가 지연되는 현상이 관찰되었다. 따라서 라베프라졸나트륨에 대한 알칼리화제의 비율이 정제의 물성 및 안정성에 영향을 주는 주요한 원인이 됨이 밝혀졌다.According to the present invention, when the amount of calcium hydroxide is less than 0.1 part by weight based on 1 part by weight of labeprazole sodium, the role of alkalizing is not sufficient, and when the amount is more than 3 parts by weight, disintegration of the tablets is observed. Therefore, it was found that the ratio of alkalizing agent to rabeprazole sodium is a major factor affecting the physical properties and stability of the tablet.
본 발명에 따른 라베프라졸나트륨 및 수산화칼슘을 포함한 핵정과 알칼리성 물질을 포함하는 중간층 및 그 외층에 장용성피막을 피복하는 방법은 산성하에서 불안정한 라베프라졸나트륨의 안정성을 확보하여 상업화가 가능한 조성물 및 그 제 조방법을 제공한다The method of coating the enteric coating on the intermediate layer and the outer layer containing the core tablet and the alkaline substance including the labeprazole sodium and calcium hydroxide according to the present invention and the composition and commercially available to ensure the stability of the labile plabazole sodium unstable under acid Provide a method of preparation
Claims (4)
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| KR1020060057442A KR20080000121A (en) | 2006-06-26 | 2006-06-26 | Methods and compositions of stabilizing sod. rabeprazole |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20220126426A (en) * | 2021-03-09 | 2022-09-16 | 주식회사한국파마 | Immediate release oral formulation with enhenced stability comprising Rabeprazole and method for preparing the same |
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| KR20220126426A (en) * | 2021-03-09 | 2022-09-16 | 주식회사한국파마 | Immediate release oral formulation with enhenced stability comprising Rabeprazole and method for preparing the same |
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