KR20050105005A - Composition for injection comprising lansoprazole - Google Patents
Composition for injection comprising lansoprazole Download PDFInfo
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- KR20050105005A KR20050105005A KR1020040030721A KR20040030721A KR20050105005A KR 20050105005 A KR20050105005 A KR 20050105005A KR 1020040030721 A KR1020040030721 A KR 1020040030721A KR 20040030721 A KR20040030721 A KR 20040030721A KR 20050105005 A KR20050105005 A KR 20050105005A
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- lansoprazole
- hpcd
- meglumine
- solubility
- clathrate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Abstract
본 발명은 란소프라졸을 유효성분으로 함유하는 주사제 조성물에 있어서, 2-히드록시프로필-베타-시클로덱스트린에 란소프라졸을 포접시킨 포접화합물을 포함함을 특징으로 하는 주사제 조성물을 제공한다. 또한 안정성의 향상을 위해 메글루민을 추가로 함유하는 주사제 조성물을 제공한다.The present invention provides an injectable composition comprising a clathrate compound in which lansoprazole is included in 2-hydroxypropyl-beta-cyclodextrin in an injectable composition containing lansoprazole as an active ingredient. Also provided is an injectable composition further containing meglumine for improving stability.
Description
본 발명은 란소프라졸을 유효성분으로 함유하는 주사제 조성물에 관한 것으로, 보다 상세하게는 주사제로서 용해도가 매우 높고, 또한 안정성이 크게 증가되어진 란소프라졸을 유효성분으로 함유하는 주사제 조성물에 관한 것이다.The present invention relates to an injectable composition containing lansoprazole as an active ingredient, and more particularly, to an injectable composition containing lansoprazole having an extremely high solubility and greatly increased stability as an injection.
란소프라졸(Lansoprazole)은 벤즈이미다졸 유도체로서 프로톤펌프억제제로 작용하여 위산생성에 관여하는 프로톤 펌프를 불활성화시켜 위산분비를 억제함으로써 위궤양, 십이지장궤양 및 위식도 역류성 질환에 대해 뛰어난 효과를 나타내는 약물이다. 그러나 란소프라졸은 중성내지 산성에서 물에 대해 매우 난용성이고 수분에 민감하여 분해되기 쉬울 뿐 아니라 특히 산성조건하에서 매우 불안정한 화합물로서 쉽게 분해된다는 단점이 있어 제제화에 어려움이 있다.Lansoprazole is a benzimidazole derivative that acts as a proton pump inhibitor and inactivates the proton pump involved in gastric acid production, thereby inhibiting gastric acid secretion and thus exhibiting excellent effects on gastric ulcer, duodenal ulcer and gastroesophageal reflux disease. However, lansoprazole is difficult to formulate because it is very poorly soluble in water and sensitive to water in neutral to acid and easily decomposed as a very unstable compound under acidic conditions.
본 발명은 상기 종래기술이 가지는 문제를 해결하기 위해 안출된 것으로, 그 목적은 란소프라졸의 용해도가 급격하게 상승되고, 또한 안정성이 크게 증가되어진 란소프라졸을 유효성분으로 함유하는 주사제 조성물을 제공함에 있다. The present invention has been made to solve the problems of the prior art, the object of the present invention is to provide an injection composition containing lansoprazole as an active ingredient, solubility of lansoprazole is rapidly increased, and stability is greatly increased.
상기한 목적을 달성하기 위하여 본 발명은 란소프라졸을 유효성분으로 함유하는 주사제 조성물에 있어서, 2-히드록시프로필-베타-시클로덱스트린(이하, HPCD라 한다)에 란소프라졸을 포접시킨 포접화합물을 포함하는 주사제 조성물을 제공한다.In order to achieve the above object, the present invention provides an injectable composition containing a lansoprazole as an active ingredient, comprising an injectable compound containing lansoprazole in 2-hydroxypropyl-beta-cyclodextrin (hereinafter referred to as HPCD). To provide a composition.
본 발명은 바람직하게는 안정화제로 메글루민(MEG)을 포함하는 주사제 조성물을 제공한다.The present invention preferably provides an injectable composition comprising meglumine (MEG) as a stabilizer.
본 발명은 바람직하게는 상기 포접화합물은 란소프라졸 : HPCD가 몰비로 1:1∼1:5인 주사제 조성물을 제공한다.The present invention preferably provides the injection composition wherein the lansoprazole: HPCD is 1: 1 to 1: 5 in a molar ratio.
본 발명은 바람직하게는 상기 메글루민은 란소프라졸의 중량대비 100중량％ 까지 함유되어지는 주사제 조성물을 제공한다.The present invention preferably provides the injection composition wherein the meglumine is contained up to 100% by weight relative to the weight of lansoprazole.
이하, 본 발명의 내용을 보다 상세하게 설명하면 다음과 같다.Hereinafter, the content of the present invention in more detail as follows.
본 발명은 시클로덱스트린(CD)류의 일종인 HPCD를 란소프라졸의 포접화합물로 사용한다. 시클로덱스트린(CD)류는 글루코오스 분자가 알파-1-4 결합에 의해 연결된 시클릭 올리고당으로서 그 외부표면은 친수성이고 내부에 소수성 공동이 원통형의 구조를 하고 있어서 많은 유기화합물과 단분자성 포접화합물을 형성한다. 난용성 약물의 포접현상에 의하여 주로 약물의 용해성, 안정성 및 생체이용률 향상, 액상 약물의 분말화, 약물간의 상호작용방지, 불쾌한 냄새나 맛의 은폐 및 약물송달 등에 이용된다. 베타-시클로덱스트린은 여러 약물제제에 널리 응용되고 있지만, 주사제에의 이용은 그 자체의 제한된 용해성 및 신장독성으로 인해서 사용에 제한이 있다. 이러한 난점을 극복하고자 많은 CD 유도체 들이 보고되어 왔는데 그 중에서도 HPCD가 보다 안전하고 그 자체의 용해성이 높다. HPCD는 베타-CD의 히드록실기의 일부에 프로필렌옥시드를 첨가시켜 만든 것으로서 물에서의 자체 용해성은 높고 포접능은 베타-CD에 비견할만 하며, 액상 및 고형제제에 응용되어 고농도의 가용화와 신속한 용출을 기대할 수 있다.The present invention uses HPCD, a kind of cyclodextrin (CD), as an inclusion compound of lansoprazole. Cyclodextrins (CD) are cyclic oligosaccharides in which glucose molecules are linked by alpha-1-4 bonds. Their outer surfaces are hydrophilic and hydrophobic cavities have a cylindrical structure. Many organic and monomolecular clathrate compounds Form. The inclusion phenomenon of poorly soluble drugs is mainly used to improve the solubility, stability and bioavailability of drugs, powdering of liquid drugs, preventing interaction between drugs, hiding of unpleasant smells or tastes, and drug delivery. Beta-cyclodextrins are widely used in many drug formulations, but their use in injections is limited due to their limited solubility and nephrotoxicity. Many CD derivatives have been reported to overcome this difficulty, among which HPCD is safer and more soluble in itself. HPCD is made by adding propylene oxide to a part of hydroxyl group of beta-CD. It has high self-solubility in water and comparable ability to beta-CD. It is applied to liquid and solid preparations, so that it has high concentration of solubilization and Rapid dissolution can be expected.
본 발명에 따른 포접화합물은 특별한 한정을 요하는 것은 아니나, 바람직하게는 란소프라졸 : HPCD가 몰비로서 1:1∼1:10으로 구성함이 좋다. 란소프라졸은 HPCD의 공동속으로 포접되어 AL형의 복합체를 형성하고, 이때 란소프라졸과 HPCD의 결합조성비는 1:1로 나타나며, 안정도 상수는 41.557-1M 로 나타났다.The clathrate compound according to the present invention does not require any particular limitation, but preferably, lansoprazole: HPCD is comprised in a molar ratio of 1: 1 to 1:10. Lansoprazole was entrapped into the cavity of HPCD to form an A L complex, wherein the ratio of lansoprazole to HPCD was 1: 1 and the stability constant was 41.557 -1 M.
포접비에 따른 포접화합물의 최대포화용해도는 란소프라졸대 HPCD의 몰비가 증가함에 따라 란소프라졸의 용해도가 급격히 상승하며, 1:5 란소프라졸-HPCD 포접화합물은 실온에서의 용해도가 2.904mg/㎖±0.100로 란소프라졸의 용해도인 0.027mg/㎖±0.001보다 100배 이상으로 증가함이 확인되었다.The maximum saturation solubility of the clathrate compound according to the clathrate ratio increased rapidly with the increase in the molar ratio of lansoprazole to HPCD. It was confirmed that the solubility of 100% or more increased from 0.027 mg / ml ± 0.001.
본 발명의 주사제 조성물은 란소프라졸의 안정성을 증가시키기 위하여 바람직하게는 메글루민을 사용한다. 메글루민(1-데옥시-1-(메틸아미노)-D-글루시톨, C7H17NO5)은 pH가 10.5(1％)이며, 산과 염을 형성하고 금속과는 착화합물을 형성하는 성질을 가진 염기성 물질로서 인체에 무독하여 엔티프로토졸의 안티모네이트(antimonate)로 사용되는 약물이다. 또한, 이는 디아트리조에이트 메글루민 인젝션, 아이오다마이드 메글루민 인젝션 및 아이오도탈라메이트 메글루민 인젝션 등 약물의 분자화합물을 형성하는데 사용되는 염기성 물질이기도 하다. 메글루민의 첨가량이 증가할수록 란소프라졸의 안정성은 증가됨이 관찰되었으며, 특별한 한정을 요하는 것은 아니나, 바람직하게는 란소프라졸의 중량대비 100중량％ 까지 첨가하는 것이 좋다.Injectable compositions of the present invention preferably use meglumine to increase the stability of lansoprazole. Meglumine (1-deoxy-1- (methylamino) -D-glucitol, C 7 H 17 NO 5 ) has a pH of 10.5 (1%), forms salts with acids and complexes with metals As a basic substance having the property of being toxic to the human body, it is a drug used as an antimonate of entiprotosol. It is also a basic substance used to form molecular compounds of drugs such as diatrizoate meglumine injection, iodide meglumine injection and iodotalamate meglumine injection. It was observed that the stability of the lansoprazole increases as the amount of meglumine added increases, although not particularly limited, it is preferable to add up to 100% by weight of the lansoprazole.
특히, 란소프라졸(LAN)-HPCD-메글루민(MEG) 포접화합물은 생리식염수와 5％ 포도당 용액에 용해시켰을 때 실온에서 안정하였으며, 40℃에서는 24시간 후 약 10∼15％ 함량의 감소만을 보여 주사제 조성물로서 매우 적합함을 확인할 수 있다.In particular, the lansoprazole (LAN) -HPCD-meglumine (MEG) clathrate compound was stable at room temperature when dissolved in physiological saline and 5% glucose solution, and showed only a decrease of about 10-15% after 24 hours at 40 ° C. It can be confirmed that it is very suitable as an injection composition.
본 발명의 주사제 조성물은 특히, 분말주사제로서 제형화되어질 수 있다. 분말주사제로서 제형화하고자 하는 경우, 동결건조법에 의해 포접화합물을 얻을 수 있다. 예를 들어, HPCD를 적당량의 증류수에 녹인 다음 란소프라졸을 적량 넣고 교반하면서 28∼30％ 암모니아수를 조금씩 첨가하면서 란소프라졸을 완전히 녹인 다음, 충분한 교반을 거친 후 딥프리저(deep freezer)에서 하루동안 냉동시키고 2일 동안 동결건조한 후 이를 감압건조하는 과정을 통해 분말화된 포접화합물을 얻는 것이 가능하다.Injectable compositions of the invention may in particular be formulated as powder injections. When formulated as a powder injection, a clathrate compound can be obtained by lyophilization. For example, after dissolving HPCD in an appropriate amount of distilled water, lansoprazole is dissolved in a proper amount with 28 to 30% ammonia water in a small amount, and then thoroughly dissolved, lansoprazole is sufficiently stirred, then frozen in a deep freezer for 1 day. It is possible to obtain a powdered clathrate compound by freeze drying for one day and then drying under reduced pressure.
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><Example>
재료 및 시약Materials and reagents
란소프라졸(한미약품), HPCD(Nihon Shokuhin kako Co., 일본), 메글루민(Sigma사, 미국), 포타슘 포스페이트 모노베이식(Sigma사, 미국), 암모늄 하이드록사이드(DC Chemical Co.,Ltd), 아세토니트릴(HPLC용, J.T.Baker사, 미국) 기타 다른 시약들은 시판 특급 혹은 일급을 사용하였다.Lansoprazole (Hanmi Pharm.), HPCD (Nihon Shokuhin kako Co., Japan), Meglumine (Sigma, USA), Potassium Phosphate Monobasic (Sigma, USA), Ammonium Hydroxide (DC Chemical Co., Ltd) , Acetonitrile (for HPLC, JTBaker, USA) and other reagents used commercial express or first class.
기기 및 장치Devices and devices
동결건조기(FDU-506, EYELA, 일본), Deep freezer(BIO FREEZER, Model OPR-DFC-566C, OPERON ENG. Co.), 액체크로마토그래피(Waters 510 pump, WatersTM 486 Tunable Absorbance Detector), 시차주사열량분석기(Shimadzu DSC 50), X선 회절분석기(Shimadzu SALD-301) 등을 사용하였다.Freeze dryer (FDU-506, EYELA, Japan), Deep freezer (BIO FREEZER, Model OPR-DFC-566C, OPERON ENG. Co.), Liquid chromatography (Waters 510 pump, WatersTM 486 Tunable Absorbance Detector), Differential scanning calorie An analyzer (Shimadzu DSC 50), an X-ray diffractometer (Shimadzu SALD-301), and the like were used.
<실험예 1> 용해도 상도 및 안정도 상수Experimental Example 1 Solubility Phase and Stability Constants
Higuchi and Lach(T. Higuchi and K.A. Connors,Phase solubility techniques. Acv.Anal.Chem.Instrum., 4, 117-212(1965).)에 의한 용해도 상도에 따라 0.005, 0.01, 0.015, 0.02, 0.025, 0.03M의 각종 농도의 HPCD 용액을 pH 11.0의 인산염 완충액을 사용하여 제조하고 20㎖ 마개달린 바이알에 10㎖씩을 취한 다음 각각의 바이알에 일정 과량의 란소프라졸(100mg)을 정확하게 칭량하여 넣고 25℃의 항온진탕기에서 7일간 반응시켜 평형에 도달하게 하였다. 각 용액을 0.45㎛ 막필터로 여과하고 pH 10.0의 인산염 완충액으로 적절히 희석하여 하기 조건의 HPLC로 용해량을 정량하였다.0.005, 0.01, 0.015, 0.02, 0.025, depending on solubility phase by Higuchi and Lach (T. Higuchi and KA Connors, Phase solubility techniques. Acv. Anal. Chem. Instrum., 4, 117-212 (1965).) HPCD solutions of various concentrations of 0.03M were prepared using a phosphate buffer solution of pH 11.0, 10 ml each of 20 ml stoppered vials, and an appropriate amount of lansoprazole (100 mg) was accurately weighed into each vial, and the temperature was maintained at 25 ° C. The shaker was allowed to react for 7 days to reach equilibrium. Each solution was filtered through a 0.45 μm membrane filter and appropriately diluted with a phosphate buffer of pH 10.0 to quantify the amount of dissolution by HPLC under the following conditions.
HPLC 조건HPLC conditions
액체크로마토그래피장치로 Waters 510 pump를, 검출기로는 WatersTM 486 Tunable Absorbance Detector, 데이터처리장치로 Autochro-Win ver 2.0을 사용하였다. 칼럼으로는 guard 칼럼(uBondapakTM C18)이 부착된 XTerra C18(5㎛, 4.6×250mm)을 사용하고 이동상으로는 아세토니트틸과 인산염완충액의 혼합액(1:1 v/v)을 사용하여 유속 1.0㎖/min으로 유출시켜 파장 270nm에서 검출하였다. 검량선은 란소프라졸을 메탄올에 녹여 1mg/㎖ 농도의 스톡 용액을 제조한 후 적절히 희석하여 작성하였다.Waters 510 pump was used as a liquid chromatography device, WatersTM 486 Tunable Absorbance Detector was used as a detector, and Autochro-Win ver 2.0 was used as a data processing device. The flow rate was 1.0 ml using XTerra C18 (5 μm, 4.6 × 250 mm) with guard column (uBondapak TM C18) attached, and a mixture of acetonitrile and phosphate buffer solution (1: 1 v / v) as a mobile phase. Flow out at / min was detected at wavelength 270nm. The calibration curve was prepared by dissolving lansoprazole in methanol to prepare a stock solution at a concentration of 1 mg / ml, and then diluting it appropriately.
Higuchi와 connors의 용해도 분석법에 따라 HPCD의 첨가에 따른 란소프라졸의 용해도를 시험하여 용해도 상수를 작성한 결과 도 1과 같이 HPCD의 농도가 증가함에 따라 란소프라졸의 용해도가 직선적으로 증가하는 AL형을 나타나었다. 이는 호스트 화합물인 HPCD와 게스트 화합물인 란소프라졸이 포접화합물을 형성함에 기인한다고 할 수 있다.As the concentration of HPCD increased as a result create a solubility constant by testing the solubility of lansoprazole according to the addition of HPCD in accordance with the solubility method of Higuchi and connors Figure 1 are shown the A L-shaped to the solubility of lansoprazole increased linearly. This can be attributed to the formation of a clathrate compound between the host compound HPCD and the guest compound lansoprazole.
또한, 용해도 상도로부터 최소자승법으로 직선의 식을 얻고 다음식에 따라 겉보기 안정도 정수 K를 산출하였다.Moreover, the formula of a straight line was obtained from the solubility phase by the least square method, and the apparent stability constant K was computed according to following Formula.
K=slope/intercept(1-slope)K = slope / intercept (1-slope)
그 결과 란소프라졸-HPCD 포접화합물의 안정도 정수는 41.557-1M 이었다.As a result, the stability constant of the lansoprazole-HPCD clathrate was 41.557 -1 M.
<실험예 2> 포접화합물의 결합조성비 결정Experimental Example 2 Determination of Binding Composition Ratio of Inclusion Compound
란소프라졸 37.4mg을 적당량의 증류수에 분산시켜 28∼30％ 암모니아수를 소량씩 가하면서 완전히 용해시킨 후 증류수를 가해 100㎖로 맞추어 란소프라졸 용액(1×10-3M)을 만들고 HPCD 150mg을 증류수 100㎖에 녹여 HPCD 용액(1×10-3M)을 만들었다. 이들 HPCD와 란소프라졸 용액을 사용하여 연속변화법에 따라 란소프라졸과 HPCD의 몰비가 2:8, 4:6, 5:5, 6:4, 8:2가 되도록 혼합한 후 딥프리저에서 하루동안 냉동시키고 2일동안 동결건조하였다. 각각의 몰비로부터 얻어진 포접화합물을 증류수 10㎖에 녹여 30분간 교반하고 0.45㎛ 막필터를 사용하여 여과한 후 HPLC로 란소프라졸의 용해도를 측정하였다.37.4 mg of lansoprazole was dispersed in an appropriate amount of distilled water, completely dissolved in a small amount of 28-30% ammonia water, and then distilled water was added to make 100 ml of lansoprazole solution (1 × 10 -3 M), and 150 mg of HPCD was added to 100 ml of distilled water. It melted to make HPCD solution (1 × 10 −3 M). Using these HPCD and lansoprazole solutions, the molar ratio of lansoprazole and HPCD was 2: 8, 4: 6, 5: 5, 6: 4, 8: 2 according to the continuous change method, and then frozen in a deep freezer for one day. Lyophilization for 2 days. The clathrate obtained from each molar ratio was dissolved in 10 ml of distilled water, stirred for 30 minutes, filtered using a 0.45 μm membrane filter, and the solubility of lansoprazole was measured by HPLC.
도 2는 연속변화법으로 제조된 란소프라졸-HPCD 시스템에서 란소프라졸과 HPCD의 몰비변화에 따른 란소프라졸의 용해도를 HPLC로 측정하여 나타낸 것이다. 몰비가 1:1인 시스템에서 란소프라졸의 용해도가 최대로 나타났다. 이는 란소프라졸과 HPCD간의 결합조성비가 몰비로 1:1임을 보여준다. Figure 2 shows the solubility of the lansoprazole in accordance with the change in the molar ratio of the lansoprazole and HPCD in the lansoprazole-HPCD system prepared by the continuous change method measured by HPLC. The solubility of lansoprazole was maximal in a system with a molar ratio of 1: 1. This shows that the bonding composition ratio between lansoprazole and HPCD is 1: 1 in molar ratio.
<실시예 1> 포접화합물의 제조Example 1 Preparation of Inclusion Compound
란소프라졸과 HPCD의 몰비가 1:1, 1:2, 1:3, 1:4 및 1:5가 되도록 칭량하였다. 먼저 HPCD를 적당량의 증류수에 녹인 다음 란소프라졸을 넣고 교반하면서 28∼30％ 암모니아수를 조금씩 첨가하면서 란소프라졸을 완전히 녹였다. 이를 2시간 동안 더 교반한 후 딥프리저에서 하루동안 냉동시키고 2일 동안 동결건조하였다. 이후 얻어진 포접화합물들을 감압건조하여 란소프라졸-HPCD 포접화합물들을 제조하였다.The molar ratios of lansoprazole and HPCD were weighed to be 1: 1, 1: 2, 1: 3, 1: 4 and 1: 5. First, HPCD was dissolved in an appropriate amount of distilled water, and then lansoprazole was completely dissolved by adding 28-30% ammonia water little by little with stirring. It was further stirred for 2 hours and then frozen in a deep freezer for 1 day and lyophilized for 2 days. The clathrate compounds thus obtained were dried under reduced pressure to prepare lansoprazole-HPCD clathrate compounds.
<실험예 3> 용해도 비교Experimental Example 3 Solubility Comparison
란소프라졸, 물리적 혼합물(몰비 1:1, 1:2, 1:3, 1:4, 1:5) 그리고 포접화합물들을 (몰비 1:1, 1:2, 1:3, 1:4, 1:5) 일정과량씩 취하여 증류수 2㎖에 넣고 1시간 동안 교반한 후 여과하고 적절히 희석하여 용해도를 측정하였다.Lansoprazole, physical mixture (molar ratio 1: 1, 1: 2, 1: 3, 1: 4, 1: 5) and clathrate compounds (molar ratio 1: 1, 1: 2, 1: 3, 1: 4, 1: 5) After taking a predetermined excess amount into 2ml of distilled water, stirred for 1 hour, filtered and diluted properly to measure the solubility.
표 1은 실온에서 란소프라졸, 란소프라졸과 HPCD의 물리적 혼합물 및 포접화합물들의 실온에서의 증류수에 대한 용해도를 보여주고 있다.Table 1 shows the solubility of lansoprazole, physical mixtures of lansoprazole and HPCD, and clathrate compounds in distilled water at room temperature.
<표 1>TABLE 1
* 평균±S.D.(n=3)* ± S.D. (N = 3)
실온에서 란소프라졸의 용해도는 0.027mg/㎖±0.001이고, 물리적 혼합물의 용해도는 란소프라졸보다 3∼13배 정도 증가하였고, 포접화합물들의 경우에는 17배∼107배 정도 증가했음을 볼 수 있다. 그리고, 란소프라졸에 대한 HPCD의 몰수가 증가함에 따라 용해도 증가폭이 물리적 혼합물에서는 작은 반면에 포접화합물들에서는 매우 큼을 볼 수 있었다.The solubility of lansoprazole at room temperature was 0.027 mg / ml ± 0.001, and the solubility of the physical mixture was increased by 3 to 13 times than that of lansoprazole, and 17 to 107 times increased for clathrate compounds. And as the number of moles of HPCD to lansoprazole increased, the solubility increase was small in the physical mixture while very large in the clathrate compounds.
<실험예 4> 포접화합물의 안정성Experimental Example 4 Stability of Inclusion Compound
메글루민의 첨가에 따른 포접화합물의 안정성Stability of Inclusion Compound with Addition of Meglumine
메글루민 150mg을 증류수 100㎖에 녹여 메글루민 용액(1.5mg/㎖)을 제조한 후 이를 계열희석하여 농도가 0.75mg/㎖, 0.325mg/㎖인 메글루민 용액들을 제조하였다. 그리고 대조용으로는 증류수를 사용하였다. 이 용액들을 각각 10㎖바이알에 4㎖씩 분주하고 란소프라졸 6mg이 함유되도록 1:4 포접화합물 103.5mg과 1:5 포접화합물 127.8mg을 정확하게 칭량하여 넣고 용해시켰다. (이때 각각의 용액 4㎖에는 메글루민이 0mg, 1.5mg, 3mg, 6mg가 함유되어 있어 이를 란소프라졸 6mg에 대한 w/w％로 0％, 25％, 50％, 100％로 표시한다.) 이들을 실온에 방치하면서 0h, 3h, 6h 후에 함량을 측정하였다. 그리고, 6시간 후에는 침전여부와 착색을 관찰하고 pH를 측정하였다.150 mg of meglumine was dissolved in 100 ml of distilled water to prepare a meglumine solution (1.5 mg / ml), followed by serial dilution to prepare meglumine solutions having a concentration of 0.75 mg / ml and 0.325 mg / ml. Distilled water was used as a control. Each of these solutions was dispensed in 10 ml vials 4 ml and accurately weighed and dissolved in 103.5 mg of 1: 4 clathrate compound and 127.8 mg of 1: 5 clathrate compound to contain 6 mg of lansoprazole. (At this time, 4 ml of each solution contained 0 mg, 1.5 mg, 3 mg, and 6 mg of meglumine, which was expressed as 0%, 25%, 50%, and 100% in w / w% for 6 mg of lansoprazole.) The content was measured after 0h, 3h, 6h while standing at room temperature. After 6 hours, the precipitate was observed for coloration and the pH was measured.
도 3 및 도 4는 1:4 란소프라졸-HPCD 포접화합물과 1:5 란소프라졸-HPCD 포접화합물을 메글루민 0％, 25％, 50％, 100％ 용액에 용해시켜 실온에 방치하면서 시간경과에 따른 란소프라졸의 함량(％)을 나타낸 것이다. 메글루민을 함유하지 않은 용액(메글루민 0％)에서는 6시간 후에 1:5 란소프라졸-HPCD 포접화합물의 함량(％)이 1:4 란소프라졸-HPCD 포접화합물보다 15％ 정도 더 높음을 볼 수 있었고, 1:4 포접화합물은 6시간 후에 노란색으로 착색되면서 적갈색의 침전이 형성되었으나 1:5 포접화합물의 경우에는 약간의 착색은 보였지만 침전은 형성되지 않았다. 이는 란소프라졸과 HPCD간의 포접비에 따른 안정성을 보여주는 것이라 사료된다. 또한, 란소프라졸 용액내의 메글루민 ％(w/w)가 증가함에 따라 1:4, 1:5 포접화합물들의 안정성이 증가되었음을 알 수 있었다. 용액내 메글루민의 함유량이 란소프라졸의 양과 같은 메글루민 100％의 경우에는 6시간 후 1:4 란소프라졸-HPCD 포접화합물의 경우에는 함량이 5％ 감소하였으나 1:5 포접화합물의 경우에는 란소프라졸의 함량이 거의 감소하지 않았고, 착색과 침전도 보이지 않음을 확인하였다. 이는 표 2에서와 같이 유기알칼리화제인 메글루민의 양이 증가함에 따라 란소프라졸 용액의 pH가 증가하면서 란소프라졸의 안정성이 점차 증가한 것이라 사료된다.FIG. 3 and FIG. 4 show that 1: 4 lansoprazole-HPCD clathrate compound and 1: 5 lansoprazole-HPCD clathrate compound were dissolved in 0%, 25%, 50%, and 100% solution of meglumine and left at room temperature. The content (%) of lansoprazole is shown. In the solution containing no meglumine (0% meglumine), after 6 hours, the content of 1: 5 lansoprazole-HPCD clathrate was 15% higher than 1: 4 lansoprazole-HPCD clathrate. In the case of the 1: 5 clathrate, reddish brown precipitate was formed after 6 hours, but the color of the 1: 4 clathrate compound was slightly colored, but no precipitate was formed. This suggests that stability of lansoprazole and HPCD depends on inclusion ratio. In addition, it was found that the stability of the 1: 4 and 1: 5 clathrates increased as the% meglumine% (w / w) in the lansoprazole solution increased. After 6 hours, the content of meglumine in the solution was 100% meglumine equal to the amount of lansoprazole, and the content of lansoprazole was decreased by 5% for the 1: 4 lansoprazole-HPCD clathrate compound after 6 hours. It was confirmed that there was almost no reduction and no coloring and precipitation were found. As shown in Table 2, the stability of lansoprazole was gradually increased as the pH of the lansoprazole solution increased as the amount of meglumine, an organic alkalizing agent, increased.
<표 2>TABLE 2
메글루민을 함유하는 1:5 포접화합물의 제조 및 안정성 시험Preparation and Stability Test of 1: 5 Inclusion Compound Containing Meglumine
약물과 동량의 메글루민을 함유하는 1:5 포접화합물은 다음과 같이 제조되었다. HPCD 6.091g과 메글루민 300mg을 증류수 40㎖에 녹인 후 란소프라졸 300mg을 칭량하여 용액에 넣고 28∼30％ 암모니아수를 소량씩 가하면서 란소프라졸을 완전히 용해시킨 후 증류수로 50㎖로 맞추었다. 이를 하루동안 냉동시킨 후 2일동안 동결건조하여 얻어진 분말을 감압건조시켜 제조하였다. 위에서 제조된 메글루민을 함유하는 1:5 포접화합물 133.8mg을 칭량하여 0.9％ NaCl 용액과 5％ 포도당 용액에 각각 용해시켜 란소프라졸의 농도가 1.5mg/㎖가 되도록 제조하여 실온과 40℃에서 방치하면서 0, 3, 6, 24시간 후에 란소프라졸의 함량을 측정하였다.A 1: 5 clathrate compound containing the same amount of drug as meglumine was prepared as follows. After dissolving 6.091 g of HPCD and 300 mg of meglumine in 40 ml of distilled water, 300 mg of lansoprazole was weighed into a solution, and the lansoprazole was completely dissolved in a small amount of 28-30% ammonia and then adjusted to 50 ml with distilled water. After freezing for one day it was prepared by drying under reduced pressure the powder obtained by lyophilization for two days. 133.8 mg of a 1: 5 clathrate compound containing meglumine prepared above was weighed and dissolved in a 0.9% NaCl solution and a 5% glucose solution, respectively, so that the concentration of lansoprazole was 1.5 mg / ml and left at room temperature and 40 ° C. The content of lansoprazole was measured after 0, 3, 6 and 24 hours.
도 5와 도 6은 실온과 40℃에서 0.9％ NaCl 용액과 5％ 포도당 용액에서의 메글루민이 란소프라졸과 동량으로 함유하는 1:5 란소프라졸-HPCD 포접화합물의 시간에 따른 함량변화를 보여주고 있다. 실온에서 0.9％ NaCl과 5％ 포도당 용액에서는 증류수에서와 비슷한 안정성을 보였으나 40℃에서는 24시간 후 10∼15％ 정도 함량이 감소하였다.5 and 6 show the change in the content of the 1: 5 lansoprazole-HPCD clathrate containing meglumine in the same amount with lansoprazole in 0.9% NaCl solution and 5% glucose solution at room temperature and 40 ℃. At room temperature, 0.9% NaCl and 5% glucose solution showed similar stability as distilled water, but the content decreased after 10 hours at 40 ℃.
<실험예 5> 포접화합물의 확인Experimental Example 5 Identification of Inclusion Compound
시차주사열량분석Differential Scanning Calorimetry
란소프라졸, HPCD, 물리적 혼합물(몰비 1:1) 및 포접화합물(몰비 1:1)들을 DSC로 측정하였다. 시료의 측정조건은 다음과 같다. 각각의 시료들을 약 1∼2mg 취해서 알루미늄 접시에 넣은 후 가온 속도를 10℃/min으로 하여 0∼300℃의 범위에서 측정하였다.Lansoprazole, HPCD, physical mixture (molar ratio 1: 1) and clathrate compounds (molar ratio 1: 1) were measured by DSC. The measurement conditions of the sample are as follows. About 1 to 2 mg of each sample was taken into an aluminum dish, and the heating rate was measured at a range of 0 to 300 ° C. at a temperature of 10 ° C./min.
도 7을 보면 란소프라졸은 183.99℃와 207.18℃ 부근에서 흡열과 발열피크가 나타난 반면에 HPCD에서는 흡열, 발열 피크가 나타나지 않음을 볼 수 있다. 그리고, 란소프라졸과 HPCD의 물리적 혼합물에서는 란소프라졸의 흡열, 발열 피크가 나타난 반면에, 포접화합물에서는 두 개의 흡열, 발열 패턴이 사라졌음을 확인할 수 있었다. 이는 결정형인 란소프라졸이 HPCD의 공동안으로 포접되면서 란소프라졸의 결정형이 가려져 나타나지 않고 무정형으로 나타나는 것으로 사료된다.7 shows that lansoprazole showed endothermic and exothermic peaks at around 183.99 ° C. and 207.18 ° C., whereas HPCD did not show endothermic and exothermic peaks. In addition, the endothermic and exothermic peaks of lansoprazole appeared in the physical mixture of lansoprazole and HPCD, whereas the two endothermic and exothermic patterns disappeared in the clathrate compound. It is thought that the crystalline form of lansoprazole is entrapped into the cavity of HPCD.
X선 회절분석X-ray diffraction analysis
란소프라졸, HPCD, 물리적 혼합물(몰비 1:1) 및 포접화합물(몰비 1:1)에 대해서 분말법으로 회절각(2θ) 0∼60°범위에서 주사속도 10°/min으로 측정하였다.The lansoprazole, HPCD, physical mixture (molar ratio 1: 1) and clathrate compound (molar ratio 1: 1) were measured at a scanning speed of 10 ° / min in a diffraction angle (2θ) of 0 to 60 ° by powder method.
도 8에서와 같이 란소프라졸과 물리적 혼합물에서는 결정형이 관찰되었으나 HPCD와 포접화합물에서는 이와는 달리 무정형을 보여주고 있다.As shown in FIG. 8, the crystalline form was observed in the lansoprazole and the physical mixture, but the amorphous form was different from the HPCD and the clathrate compound.
본 발명에 의하면 란소프라졸과 HPCD는 AL형의 복합체를 형성하여 란소프라졸의 용해도를 급격하게 상승시키며, 포접비가 증가할수록 그리고, 메글루민의 함량이 증가할수록 란소프라졸의 안정성이 증가되어진다. 또한, 상기 본 발명에 따른 포접화합물을 생리식염수와 5％포도당 용액에 용해시켰을 때 실온에서 안정하고, 40℃에서 24시간 후 약 10∼15％ 함량이 감소되는 정도에 불과하여 분말주사제로서의 활용이 가능함을 확인할 수 있다.According to the present invention, lansoprazole and HPCD form an A L- type complex to rapidly increase the solubility of lansoprazole, and increase the stability of lansoprazole as the inclusion ratio increases and as the content of meglumine increases. In addition, when the clathrate compound according to the present invention is dissolved in physiological saline solution and 5% glucose solution, it is stable at room temperature, and only about 10 to 15% content decreases after 24 hours at 40 ° C. It can be confirmed.
도 1은 본 발명에 따른 포접화합물 시스템의 용해도 다이아그램1 is a solubility diagram of a clathrate compound system according to the present invention
도 2는 본 발명에 따른 포접화합물의 구성 몰비에 따른 농도변화그래프2 is a concentration change graph according to the molar ratio of the inclusion compound according to the present invention
도 3은 본 발명에 따른 메글루민(MEG) 농도별 포접화합물(1:4 LAN-HPCD)의 안정성그래프 [0％(◆), 25％(□), 50％(▲), 100％(×), 실온(n=3, 평균±S.D)]3 is stability graph of clathrate compound (1: 4 LAN-HPCD) according to the concentration of meglumine (MEG) according to the present invention [0% (◆), 25% (□), 50% (▲), 100% ( ×), room temperature (n = 3, mean ± SD)]
도 4는 본 발명에 따른 메글루민(MEG) 농도별 포접화합물(1:5 LAN-HPCD)의 안정성그래프 [0％(◆), 25％(□), 50％(▲), 100％(×), 실온(n=3, 평균±S.D)]4 is a stability graph of clathrate compound (1: 5 LAN-HPCD) according to the concentration of meglumine (MEG) according to the present invention [0% (◆), 25% (□), 50% (▲), 100% ( ×), room temperature (n = 3, mean ± SD)]
도 5는 본 발명에 따른 포접화합물(1:5 LAN-HPCD-MEG)의 0.9％ NaCl 용액에서의 안정성그래프 [실온(◇), 40℃(■), (n=3, 평균±S.D)]Figure 5 is stability graph of 0.9% NaCl solution of clathrate compound (1: 5 LAN-HPCD-MEG) according to the present invention [room temperature (◇), 40 ℃ (■), (n = 3, average ± S.D)]
도 6은 본 발명에 따른 포접화합물(1:5 LAN-HPCD-MEG)의 5％ 덱스트로스 용액에서의 안정성그래프 [실온(◇), 40℃(■), (n=3, 평균±S.D)]6 is stability graph of 5% dextrose solution of clathrate compound (1: 5 LAN-HPCD-MEG) according to the present invention [room temperature (◇), 40 ℃ (■), (n = 3, average ± SD) ]
도 7은 본 발명에 따른 포접화합물을 대상으로 하는 시차주사열량분석결과도 [1: LAN 단독, 2: HPCD 단독, 3: LAN과 HPCD의 물리적 혼합물, 4: 포접화합물]7 is a differential scanning calorimetry result of clathrate compound according to the present invention [1: LAN alone, 2: HPCD alone, 3: physical mixture of LAN and HPCD, 4: clathrate compound]
도 8은 본 발명에 따른 포접화합물을 대상으로 하는 분말 ×선 분석 결과도 [1: LAN 단독, 2: HPCD 단독, 3: LAN과 HPCD의 물리적 혼합물, 4: 포접화합물] 8 is a powder x-ray analysis of the inclusion compound according to the present invention [1: LAN alone, 2: HPCD alone, 3: physical mixture of LAN and HPCD, 4: clathrate compound]
Claims (4)
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