KR100396443B1 - Solubilized Felodipine Containing Sustained Release Preparations and it's Manufacturing Process - Google Patents
Solubilized Felodipine Containing Sustained Release Preparations and it's Manufacturing Process Download PDFInfo
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- KR100396443B1 KR100396443B1 KR10-2001-0055305A KR20010055305A KR100396443B1 KR 100396443 B1 KR100396443 B1 KR 100396443B1 KR 20010055305 A KR20010055305 A KR 20010055305A KR 100396443 B1 KR100396443 B1 KR 100396443B1
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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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
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
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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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
Abstract
본 발명은, 가용화된 펠로디핀 함유 지속성 제제의 조성물에 관한 것으로, 수난용성 약물인 펠로디핀을 공통용매인 염화메칠렌과 에탄올 혼합용매에 용해시킨 다음, 분무 건조하여 얻은 수가용성인 고체 분산체를 제조하고, 이를 서방성 기제와 혼합하여 제제화하여 정제 또는 펠렛제형의 가용화된 펠로디핀 함유 지속성 제제의 조성물을 얻을 수 있고, 본 발명의 조성물은 일정시간 동안 지속적으로 약물이 방출됨은 물론 유효농도를 유지하게 하여 치료효과를 상승시킬 수 있다는 특장점이 있다.The present invention relates to a composition of a solubilized felodipine-containing persistent formulation, wherein a water-soluble solid dispersion obtained by dissolving felodipine, a poorly water-soluble drug, in a mixed solvent of methylene chloride and ethanol, which is a common solvent, and then spray drying It can be prepared and mixed with a sustained release base to formulate to obtain a composition of a solubilized felodipine-containing persistent formulation in the form of tablets or pellets, the composition of the present invention to maintain the effective concentration as well as the drug is released for a certain time This can increase the therapeutic effect.
Description
본 발명은 가용화된 펠로디핀(Felodipine)을 함유한 지속성제제의 조성물 및 그의 제조방법에 관한 것으로, 더욱 상세하게는 물에 매우 난용성인 펠로디핀을 수용성고분자와 함께 공통용매인 유기용매에 용해하고 분무건조기나 유동층분무건조코팅기(UniGlatt, GPCG3 등)를 사용하여 분무 건조함으로써 가용화된 고체분산체(Solid-Dispersants)를 제조하고, 서방기제를 사용하여 혼합한 다음 제제화하여 약물이 일정시간 동안 서서히 방출되도록 제조된 펠로디핀 함유 지속방출성 제제의 조성물 및 약제학적 제조방법에 관한 것이다.The present invention relates to a composition of a sustained preparation containing solubilized felodipine (Felodipine) and to a method for preparing the same. More specifically, felodipine, which is very poorly soluble in water, is dissolved in an organic solvent which is a common solvent together with a water-soluble polymer and sprayed. Soluble solid dispersions are prepared by spray drying using a dryer or a fluidized bed spray coating machine (UniGlatt, GPCG3, etc.), mixed using a sustained release agent, and then formulated to release the drug slowly over a period of time. It relates to a composition of the felodipine-containing sustained-release preparation prepared and a pharmaceutical preparation method.
일반적으로 의약품을 복용하였을 경우 인체내에서 신속하게 흡수되고, 높은 약리활성을 나타내려면 약물이 제제로부터 신속하게 용출되어야 하는데, 약물의 용출속도는 체내에서의 흡수속도와 밀접한 관계를 가지고 있으며 혈액중의 약물 농도를 결정하는 중요한 지표로서 이는 약물의 용해도에 의한 영향이 매우 크다.In general, when a drug is taken, it is rapidly absorbed in the human body, and the drug has to be rapidly eluted from the drug to exhibit high pharmacological activity. The dissolution rate of the drug is closely related to the rate of absorption in the body. As an important indicator of drug concentration, it is very influenced by the solubility of the drug.
따라서 본 발명에서는 고혈압치료제로 널리 사용되고 있으나 물에 난용성인 펠로디핀을 각종 수용성 고분자를 이용하여 가용화함으로써 용해도를 증가시키고, 또한 서방기제로 용출율을 조절하여 일정시간 동안 지속적으로 약물이 방출되도록 함으로써 유효농도를 유지하게 하여 치료효과를 상승시키며 환자의 복약순응도를 높이고 삶의 질을 높이는데 그 목적이 있다.Therefore, the present invention is widely used as a treatment for hypertension, but solubilizing soluble in water velodipine using a variety of water-soluble polymers to increase the solubility, and also by controlling the dissolution rate with a sustained-release agent to continuously release the drug for a certain time effective concentration The purpose of the treatment is to increase the therapeutic effect, increase patient compliance and improve the quality of life.
본 발명은 난용성인 약물을 수용성 고분자와 함께 공통용매에 녹이고 분무건조(spray drying)하여 고체분산체(solid-dispersion)를 제조함으로써 용해성을 증가시키고, 이를 여러 가지 약제학적 조성물과 함께 혼합하여 제제화함으로써 치료효과를 극대화시키는 기술에 관한 것이다.The present invention increases the solubility by dissolving a poorly soluble drug in a common solvent with a water-soluble polymer and spray drying to produce a solid-dispersion, and then formulated by mixing it with various pharmaceutical compositions It relates to a technique for maximizing the therapeutic effect.
특히, 본 발명에서 사용한 약물인 펠로디핀(Felodipine, Ethylmethyl-4-(2, 3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate, C18H19Cl2NO4, M.W. 384.26)은, 칼슘길항제로서 고혈압치료에 매우 효과적인 약물로 알려져 있으며, 물에는 녹지 않으며 염화메틸렌과 에탄올에는 잘 녹는 특성을 가지고 있다.In particular, the drug used in the present invention (Felodipine, Ethylmethyl-4- (2, 3-dichlorophenyl) -1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate, C 18 H 19 Cl 2 NO 4 , MW 384.26), a calcium antagonist, is known to be a very effective drug for the treatment of hypertension. It is insoluble in water and soluble in methylene chloride and ethanol.
따라서, 펠로디핀을 보다 효과적으로 투여하기 위한 많은 제형이 연구되었는데, 대한민국 특허공고 제93-1803호에는 펠로디핀을 포함한 여러 가지 약물을 폴리비닐피롤리돈, 에칠셀룰로오스, 젤라틴, 히드록시프로필메틸셀룰로오스 등의 고분자를 이용하여 소미립자 및 캡슐화하여 용해도를 증가시키는 방법이 수재되어 있으나 상기 특허방법은 가열 및 강산 등을 사용하여 제조하므로 제조 방법이 복잡하고 산 증기 등에 의한 질병을 유발할 수 있으므로 바람직한 방법이라고 볼 수는 없다. 또한, 대한민국 특허등록번호 제0137731호와 제0162106호에는 삼투압에 의한 방출 조절형 정제에 관한 내용이 개시되어 있는 바, 이러한 제조 방법은 제조 방법이 복잡하고 약물의 방출을 위한 방출구를 별도로 포함해야 하는 등 특허 방법으로 제제를 제조하기 위해서는 별도의 특수 장비가 요구되므로 역시 바람직한 방법이라고 볼 수 없다. 대한민국 특허공고 제95-2147호에는 난용성인 약물의 가용화를 위해 폴리에톡실화지방산, 히드록실지방산 및 지방알콜, 크레모포아(cremophor), Myrj, Polyoxyl 40 stearate 등을 사용하여 친수성겔 시스템을 이용하였는데, 이들 가용화제는 위장관에 독성이 강한 첨가제로 알려져 있기 때문에 최근에는 이의 사용을 자제하고 있다. 또한 인용 특허 방법에서는 가용화된 약물을 친수성 고분자인 히드록시프로필메칠셀룰로오스 등을 이용하여 친수성 겔시스템을 만들고 크산탄검이나 구아검 등의 검 종류를 이용하여 방출 조절을 보조하는 방법을 사용하였는데 이러한 방법은 시험 방법에 따른 재현성이 일정하지 않을 수 있으므로 개선이 요구되는 제조 방법이라 할 수 있다.Therefore, many formulations for more effective administration of felodipine have been studied. Korean Patent Publication No. 93-1803 describes various drugs including felodipine such as polyvinylpyrrolidone, ethylcellulose, gelatin, hydroxypropylmethylcellulose, and the like. The method of increasing the solubility by encapsulating small particles and encapsulation using a polymer of the present invention, but the patented method is manufactured using heating and strong acid, so the manufacturing method is complicated and can cause disease by acid vapor, etc. There is no number. In addition, the Republic of Korea Patent Registration No. 0139731 and 0162106 discloses the content of controlled release tablets by osmotic pressure, such a manufacturing method is a complicated manufacturing method and must include a separate outlet for the release of the drug In order to manufacture the formulation by the patent method, such as a separate special equipment is required it is also not a preferred method. Korean Patent Publication No. 95-2147 uses a hydrophilic gel system using polyethoxylated fatty acid, hydroxyl fatty acid and fatty alcohol, cremophor, Myrj, Polyoxyl 40 stearate, etc. to solubilize poorly soluble drugs. Since these solubilizers are known to be additives that are highly toxic to the gastrointestinal tract, they have recently been refrained from using them. In the cited patent method, a hydrophilic gel system was used for the solubilized drug using hydroxypropylmethylcellulose, which is a hydrophilic polymer, and a method of assisting the release control using a kind of gum such as xanthan gum or guar gum was used. Since the reproducibility may not be constant according to the test method can be said to be a manufacturing method requiring improvement.
따라서, 본 발명은 상기와 같은 문제점을 해결하기 위한 것으로 난용성인 약물의 가용화를 이룬 다음 서방성기제를 사용하여 장시간 지속적으로 유효 약물을 일정하게 방출할 수 있는 제형을 제공하는데 그 목적이 있다.Accordingly, an object of the present invention is to provide a formulation capable of releasing an effective drug continuously for a long time by using a sustained-release agent after solubilizing a poorly soluble drug to solve the above problems.
도1은 실시예와 비교예에 따른 제제의 각 시간별 약물방출율 비교 그래프이다.1 is a graph comparing the drug release rate for each time of preparations according to Examples and Comparative Examples.
상기의 목적을 달성하기 위한 본 발명은, 난용성인 약물인 펠로디핀(Felodipine)을 수용성고분자와 함께 공용매(또는 공통용매)인 염화메칠렌과 에탄올에 용해한 다음, 분무건조기 또는 유동층분무코팅기를 이용하여 무정형의 고체분산체를 제조하여 가용화함으로써, 물에 대한 용해도를 증가시키는 과정과, 제조된 가용화 혼합물(고체분산체)을 서방성 기제와 혼합하여 습식과립을 제조하거나 건식과립을 형성하고, 제제화하는 공정을 포함한다. 또한 상기의 용해된 가용화 혼합물을 유동층분무코팅기를 이용하여 일정한 입도를 가지는 설탕입자 등에 분무하여 서방형 펠렛을 제조할 수 도 있다.In order to achieve the above object, the present invention dissolves a poorly soluble drug felodipine in water-soluble polymer and co-solvent (or common solvent) methylene chloride and ethanol, and then using a spray dryer or a fluidized bed spray coater. Process to increase the solubility in water, and to prepare wet granules or to form dry granules by formulating a solubilized mixture (solid dispersion) with a sustained-release base. It includes a process to make. In addition, the dissolved solubilization mixture may be sprayed onto a sugar particle having a constant particle size using a fluidized bed spray coating machine to prepare a sustained release pellet.
따라서, 본 발명의 가용화된 텔로디핀 함유 지속성 제제의 조성물은 펠로디핀 유효량을 수용성 고분자 화합물인 폴리비닐피롤리돈 0.5~20 중량%와 함께 염화메칠렌과 에탄올로 구성된 공통용매에 용해시킨 다음, 이를 분무 건조하여 고체 분산체를 제조하고, 얻어진 고체 분산체를 유당 40~70 중량%, 유드라짓 5~40 중량%, 인산일수소칼슘 10~30 중량%, 활택제 0.1~3 중량%, 스테아린산마그네슘 0.1~3 중량%로 구성된 서방성 기제와 혼합하여, 제조된 펠로디핀 함유 지속성 정제 조성물, 또는 펠로디핀 유효량을 수용성 고분자 화합물인 폴리비닐피롤리돈 0.5~20 중량%와 함께 염화메칠렌과 에탄올로 구성된 공통용매에 용해시킨 다음, 여기에 서방성 기제로서유드라짓 5~40 중량%을 가하여 용해시킨 액에 인산일수소칼슘 10~30 중량%, 옥수수전분 10~50 중량%, 활택제 0.1~3 중량%을 가하고 분산시킨 다음, 이 분산액을 설탕 10~30 중량%에 분무 코팅하여 제조된 펠로디핀 함유 지속성 펠렛 조성물로서, 그 제조 방법은, 펠로디핀 유효량을 수용성 고분자 화합물인 폴리비닐피롤리돈 0.5~20 중량%와 함께 염화메칠렌과 에탄올로 구성된 공통용매에 용해시킨 다음, 이를 분무 건조하여 고체 분산체를 제조하고, 얻어진 고체 분산체를 유당 40~70 중량%, 유드라짓 5~40 중량%, 인산일수소칼슘 10~30 중량%, 활택제 0.1~3 중량%, 스테아린산마그네슘 0.1~3 중량%로 구성된 서방성 기제와 혼합하여, 과립으로 한 후 타정함으로서 펠로디핀 함유 지속성 정제 조성물을 얻거나 펠로디핀 유효량을 수용성 고분자 화합물인 폴리비닐피롤리돈 0.5~20 중량%와 함께 염화메칠렌과 에탄올로 구성된 공통용매에 용해시킨 다음, 여기에 서방성 기제로서 유드라짓 5~40 중량%을 가하여 용해시킨 액에 인산일수소칼슘 10~30 중량%, 옥수수전분 10~50 중량%, 활택제 0.1~3 중량%을 가하고 분산시킨 다음, 이 분산액을 설탕 10~30 중량%에 분무 코팅하여 펠로디핀 함유 지속성 펠렛 조성물을 얻는 방법을 포함한다.Therefore, the composition of the solubilized telodipine-containing persistent preparation of the present invention is dissolved in a common solvent consisting of methylene chloride and ethanol with an effective amount of felodipine 0.5 to 20% by weight of the water-soluble polymer compound polyvinylpyrrolidone, Spray drying it to prepare a solid dispersion, the obtained solid dispersion is 40 to 70% by weight of lactose, 5 to 40% by weight of Eudragit, 10 to 30% by weight of calcium dihydrogen phosphate, 0.1 to 3% by weight of lubricant, Pelodipine-containing sustained-release tablet composition prepared by mixing with a sustained-release base composed of 0.1 to 3% by weight of magnesium stearate, or effective amount of felodipine with 0.5 to 20% by weight of polyvinylpyrrolidone as a water-soluble high molecular compound and After dissolving in a common solvent composed of ethanol, 5-40 wt% of Eudragit was added as a sustained-release base, and 10-30 wt% of calcium dihydrogen phosphate, 10-50 wt% of corn starch, and a lubricant. 0.1 ~ 3 Pelodipine-containing sustained pellet composition prepared by adding and dispersing in an amount of% by weight, and then spraying the dispersion onto 10 to 30% by weight of sugar, and the method for preparing the same comprises polyvinylpyrrolidone 0.5, which is a water-soluble high molecular compound. It was dissolved in a common solvent composed of methylene chloride and ethanol together with ˜20% by weight, and then spray dried to prepare a solid dispersion, and the obtained solid dispersion was 40 to 70% by weight of lactose and 5 to 40% by weight of Eudragit. %, Calcium monohydrogen phosphate, 10-30% by weight, 0.1-3% by weight of lubricant, 0.1-3% by weight of magnesium stearate, mixed with a sustained-release base to obtain granules and tableting to obtain a sustained tablet composition containing felodipine Or an effective amount of felodipine is dissolved in a common solvent composed of methylene chloride and ethanol together with 0.5 to 20% by weight of polyvinylpyrrolidone, a water-soluble high molecular compound, and then eudragit as a sustained-release base. 10-40 wt% of calcium dihydrogen phosphate, 10-50 wt% of corn starch, 0.1-3 wt% of lubricant, and disperse this dispersion were added to 10-40 wt% of sugar. Spray coating to% to obtain a felodipine-containing persistent pellet composition.
이하 상기와 같은 기술적 특징을 가지는 본 발명을 상세하게 설명하기로 한다.Hereinafter, the present invention having the technical features as described above will be described in detail.
1) 고체분산체의 제조1) Preparation of Solid Dispersion
고체분산체는 난용성인 약물과 친수성 내지는 수용성 고분자인 폴리비닐피롤리돈, 히드록시프로필메칠셀룰로오스 등과 혼합하여 공통용매 등으로 완전 용해하고 분무 건조기, 유동층분무코팅기 또는 감압 농축기를 사용하여 용매를 휘발시킴으로써 고체분산체 또는 공침 혼합물을 얻을 수 있다. 이렇게 얻어진 공침 혼합물은 그 형태가 무정형으로 전환되어 매우 미세한 입자로 변화하는데 이러한 입자는 용해도가 크게 증가된다. 더구나 수용성 고분자에 의해 미세캡슐이 형성되므로 용해시 고분자의 팽윤과 함께 약물의 용해가 이루어져 더욱 용해도가 증가된 제형을 얻을 수 있다.The solid dispersion is mixed with a poorly soluble drug and a hydrophilic or water-soluble polymer such as polyvinylpyrrolidone, hydroxypropylmethylcellulose, and the like completely dissolved in a common solvent, and then volatilized the solvent using a spray dryer, a fluidized bed spray coater or a vacuum concentrator. Solid dispersions or coprecipitation mixtures can be obtained. The coprecipitation mixture thus obtained is converted into amorphous form and converted into very fine particles, which greatly increase the solubility. Moreover, since the microcapsules are formed by the water-soluble polymer, the dissolution of the drug is performed along with the swelling of the polymer during dissolution, thereby obtaining a formulation having increased solubility.
2) 지속방출성 정제의 제조2) Preparation of Sustained-Release Tablets
가용화된 약물을 함유한 고체분산체를 서방성 기제인 유드라짓RS, 유드라짓RL, 유드라짓RSPO, 유드라짓RLPO, 유드라짓S, 유드라짓L, 유드라짓NE30D 등과 혼합하여 습식 또는 건식으로 과립화하고 일정한 크기로 정립한 다음 타정하여 지속적으로 유효약물을 방출하는 제형을 얻을 수 있다.The solid dispersion containing the solubilized drug is mixed with the sustained-release bases Eudragit RS, Eudragit RL, Eudragit RSPO, Eudragit RLPO, Eudragit S, Eudragit L, Eudragit NE30D, etc. It can be granulated by wet or dry, sizing to a constant size and then tableted to obtain a formulation that continuously releases the effective drug.
3) 지속방출성 펠렛의 제조3) Preparation of sustained release pellets
난용성 약물과 수용성 고분자를 공통용매에 함께 녹인 다음 일정한 입도를 가지는 설탕입자 또는 논파레일에 분무하여 코팅하고, 서방성 기제를 사용하여 코팅함으로써 일정한 시간동안 지속적으로 유효약물을 방출하는 제형을 얻을 수 있다. 또한 보다 공정을 간단하게 하기 위해 약물과 수용성 고분자 및 서방성 기제를 함께 공통용매에 용해하고 앞서의 방법과 동일하게 설탕입자나 논파레일에 분무, 코팅하여 동일한 효과를 나타내는 지속성 펠렛을 제조할 수 있다.By dissolving the poorly soluble drug and the water-soluble polymer together in a common solvent, and then sprayed onto sugar particles or non-pareils having a constant particle size, and using a sustained-release base, a dosage form that continuously releases the effective drug for a certain time can be obtained. have. In addition, in order to simplify the process, the drug, the water-soluble polymer, and the sustained-release base may be dissolved together in a common solvent and sprayed and coated on the sugar particles or the non-pareil in the same manner as in the previous method to prepare a sustained pellet having the same effect. .
본 발명을 수행함에 있어서, 수용성 고분자의 양이 전체 중량대비 0.5% 보다 적으면 가용화가 부족하고 한계점을 지나 전체 중량대비 20% 보다 많으면 용해도 증가율은 오히려 감소하며 제제는 상대적으로 커지게 된다. 유드라짓의 양이 전체 중량대비 5% 보다 적으면 서방성이 확보가 안되고 40% 보다 많으면 너무 방출이 지연된다. 인산일수소칼슘도 전체 중량대비 2% 보다 적게 함유되면 용출이 빨라지고, 50% 보다 많으면 제제가 너무 커진다. 활택제의 양이 0.1% 보다 적으면 제조시 sticking 현상이 발생하고 유동성이 불량하여 제조하는데 어려움이 있으며 스테아린산마그네슘은 전체 중량대비 3% 보다 많으면 제제의 약물 용출이 안되고 복용시 설사 증상을 나타낼 수 도 있다.In carrying out the present invention, when the amount of the water-soluble polymer is less than 0.5% by weight, solubilization is insufficient, and when the amount exceeds 20% by weight, the solubility increase rate is rather decreased and the formulation becomes relatively large. If the amount of Eudragit is less than 5% of the total weight, the sustained release is not secured, and if it is more than 40%, the release is delayed too much. Calcium dihydrogen phosphate also contains less than 2% of the total weight, the elution is faster, more than 50% the formulation is too large. If the amount of lubricant is less than 0.1%, sticking phenomenon occurs during manufacturing, and fluidity is difficult to prepare, and if magnesium stearate is more than 3% of the total weight, drug dissolution of the preparation may not occur and diarrhea may occur when taken. have.
이하 상기의 재료 및 방법을 이용한 본 발명의 바람직한 실시예를 설명하기로 한다.Hereinafter, a preferred embodiment of the present invention using the above materials and methods will be described.
실시예 1Example 1
펠로디핀 5.0 그람, 폴리비닐피롤리돈 5.0 그람을 공용매인 염화메칠렌 50.0 그람, 에탄올 50.0 그람에 완전히 용해하고 유동층분무코팅기(UniGlatt, GPCG3)를 사용하여 분무건조하고 고체 분산체를 얻는다. 고체분산체 10.0 그람과 유당(lactose) 130.0 그람, 유드라짓 RSPO 45.0 그람, 인산일수소칼슘 30.0 그람을 잘 혼합하고, 스테아린산마그네슘 3.0 그람, 탈크 2.0 그람을 최종적으로다음 10분간 잘 섞어 준 후 타정한다.5.0 grams of felodipine, 5.0 grams of polyvinylpyrrolidone are completely dissolved in 50.0 grams of methylene chloride and 50.0 grams of co-solvent and spray dried using a fluidized bed spray coater (UniGlatt, GPCG3) to obtain a solid dispersion. 10.0 grams of solid dispersion and 130.0 grams of lactose, 40.0 grams of Eudragit RSPO, 30.0 grams of calcium dihydrogen phosphate are mixed well, and 3.0 grams of magnesium stearate and 2.0 grams of talc are finally mixed well for 10 minutes. do.
실시예 2Example 2
고체 분산체는 실시예 1과 동일한 방법으로 얻는다. 고체분산체 10.0그람과 유당 135.0 그람, 유드라짓 RSPO 50.0 그람, 인산일수소칼슘 20.0 그람을 잘 혼합하고, 스테아린산마그네슘 3.0 그람, 탈크 2.0 그람을 최종적으로 혼합한 다음 10분간 잘 섞어 준 후 타정한다.The solid dispersion is obtained in the same manner as in Example 1. Mix 10.0 grams of solid dispersion, 135.0 grams of lactose, 50.0 grams of Eudragit RSPO, 20.0 grams of calcium dihydrogen phosphate, finally mix 3.0 grams of magnesium stearate, 2.0 grams of talc, and then mix well for 10 minutes. .
실시예 3Example 3
펠로디핀 5.0 그람, 폴리비닐피롤리돈 10.0 그람을 공용매인 염화메칠렌 60.0 그람, 에탄올 50.0 그람에 완전히 용해하고 유동층분무코팅기(UniGlatt, GPCG3)를 사용하여 분무건조하고 고체 분산체를 얻는다. 고체분산체 15.0그람과 유당 105.0 그람, 유드라짓 RSPO 45.0 그람, 인산일수소칼슘 50.0 그람을 잘 혼합하고, 스테아린산마그네슘 3.0 그람, 탈크 2.0 그람을 최종적으로 혼합한 다음 10분간 잘 섞어 준 후 타정한다.5.0 grams of felodipine, 10.0 grams of polyvinylpyrrolidone are completely dissolved in 60.0 grams of methylene chloride and 50.0 grams of co-solvent and spray dried using a fluidized bed spray coater (UniGlatt, GPCG3) to obtain a solid dispersion. Mix 15.0 grams of solid dispersion, 105.0 grams of lactose, 45.0 grams of Eudragit RSPO, 50.0 grams of calcium dihydrogen phosphate, finally mix 3.0 grams of magnesium stearate, 2.0 grams of talc, and then mix well for 10 minutes. .
실시예 4Example 4
펠로디핀 5.0 그람, 폴리비닐피롤리돈 10.0 그람을 공용매인 염화메칠렌 60.0 그람, 에탄올 60.0 그람에 완전히 용해하고 유동층분무코팅기(UniGlatt, GPCG3)를 사용하여 분무건조하고 고체 분산체를 얻는다. 고체분산체 15.0그람과 유당 105.0 그람, 유드라짓 RSPO 40.0 그람, 인산일수소칼슘 55.0 그람을 잘 혼합하고, 스테아린산마그네슘 3.0 그람, 탈크 2.0 그람을 최종적으로 혼합한 다음 10분간 잘 섞어 준 후 타정한다.5.0 grams of felodipine, 10.0 grams of polyvinylpyrrolidone are completely dissolved in 60.0 grams of methylene chloride and 60.0 grams of co-solvent and spray dried using a fluidized bed spray coater (UniGlatt, GPCG3) to obtain a solid dispersion. Mix 15.0 grams of solid dispersion, 105.0 grams of lactose, 40.0 grams of Eudragit RSPO, 55.0 grams of calcium dihydrogen phosphate, finally mix 3.0 grams of magnesium stearate, 2.0 grams of talc, and mix well for 10 minutes .
실시예 5Example 5
펠로디핀 5.0 그람, 폴리비닐피롤리돈 5.0 그람을 공용매인 염화메칠렌 60.0 그람, 아세톤 30.0 그람, 에탄올 30.0 그람에 완전히 용해하고, 유드라짓 RS100 22.0 그람과 유드라짓 RL100 4.4 그람을 넣고 완전히 용해한다. 인산일수소칼슘 50.0 그람과 옥수수전분80.0 그람, 탈크 3.6 그람을 넣고 고르게 분산시킨 다음 유동층분무코팅기(UniGlatt, GPCG3)를 사용하여 355∼710㎛ 크기의 설탕입자에 분무하여 최종 500∼1,500 ㎛ 직경을 가지는 구형의 펠렛을 제조한다.Dissolve 5.0 grams of felodipine, 5.0 grams of polyvinylpyrrolidone, completely dissolved in 60.0 grams of methylene chloride, 30.0 grams of acetone, and 30.0 grams of ethanol, and completely dissolve Eudragit RS100 22.0 grams and Eudragit RL100 4.4 grams. do. Add 50.0 grams of calcium dihydrogen phosphate, 80.0 grams of corn starch, 3.6 grams of talc, and disperse evenly. Spray the 355-710 ㎛ size sugar particles with a fluidized bed spray coating machine (UniGlatt, GPCG3). Eggplants produce spherical pellets.
실시예 6Example 6
펠로디핀 5.0그람, 폴리비닐피롤리돈 5.0그람을 HPMC 3.0그람이 용해되어 있는 염화메칠렌 60.0그람, 아세톤 30.0그람, 에탄올 30.0그람에 넣고 완전히 용해한 다음 유동층분무코팅기(UniGlatt, GPCG3)를 사용하여 355~710㎛크기의 설탕입자에 분무하여 약 400~1,500㎛ 직경을 가지는 구형의 펠렛을 제조한다. 이어서 유드라짓 RS100 22.0그람과 유드라짓 RL100 4.4그람을 염화메칠렌 500그람과 아세톤 300그람의 혼합용매에 넣고 완전히 용해한다. 인산일수소칼슘 50.0그람과 옥수수전분 77.0그람, 탈크 3.6그람을 넣고 고르게 분산시킨 다음 유동층분무코팅기(UniGlatt, GPCG3)를 사용하여 앞서 제조된 약물 함유 입자에 분무하여 최종 500~1,500㎛직경을 가지는 구형의 필름 코팅된 서방형 펠렛을 제조한다.5.0 grams of felodipine and 5.0 grams of polyvinylpyrrolidone were added to 60.0 grams of methylene chloride, 30.0 grams of acetone, and 30.0 grams of ethanol in which HPMC 3.0 grams were dissolved, and then completely dissolved. 355 using a fluidized bed spray coater (UniGlatt, GPCG3) A spherical pellet having a diameter of about 400 to 1500 μm is prepared by spraying sugar particles having a size of ˜710 μm. Subsequently, 22.0 grams of Eudragit RS100 and 4.4 grams of Eudragit RL100 are added to a mixed solvent of 500 grams of methylene chloride and 300 grams of acetone and completely dissolved. 50.0 grams of calcium dihydrogen phosphate, 77.0 grams of corn starch, 3.6 grams of talc, and evenly dispersed, sprayed onto the drug-containing particles prepared previously by using a fluidized bed spray coating machine (UniGlatt, GPCG3) to have a final diameter of 500 ~ 1,500㎛ Film-coated sustained release pellets were prepared.
비교예 1Comparative Example 1
펠로디핀 5.0 그람, 폴리비닐피롤리돈 5.0 그람을 잘 혼합하고 유당 135.0 그람, 유드라짓 RSPO 50.0 그람, 인산일수소칼슘 20.0 그람을 잘 혼합하고, 스테아린산마그네슘 3.0 그람, 탈크 2.0 그람을 최종적으로 혼합한 다음 10분간 잘 섞어 준 후 타정한다.Mix well 5.0 grams of felodipine, 5.0 grams of polyvinylpyrrolidone, 135.0 grams of lactose, 50.0 grams of Eudragit RSPO, 20.0 grams of calcium dihydrogen phosphate, 3.0 grams of magnesium stearate, 2.0 grams of talc 2.0 Mix well for 10 minutes and tablet.
실험예 1Experimental Example 1
본 발명에서 제조된 고체분산체와 단순혼합물의 물에 대한 용해도 %를 측정하기 위해 20 mg 함유 정제를 이용하여 비교하였다.In order to measure the solubility in water of the solid dispersion prepared in the present invention and the simple mixture in water, 20 mg-containing tablets were compared.
물에 대한 용해도는 약물의 가용화도를 쉽게 판단할 수 있는 척도가 되며, 상기의 도표에 나타난 결과에서 본 발명의 고체분산체는 단순혼합물에 비해 적어도 4배이상 용해도가 증가하였음을 알 수 있다.Solubility in water is a measure that can be easily determined the solubility of the drug, the results shown in the above table can be seen that the solubility of the solid dispersion of the present invention increased at least four times compared to the simple mixture.
실험예 2Experimental Example 2
실시예와 비교예에서 제조된 제형을 이용하여 각 시간별 약물 방출율%을 비교하였다.Using the formulations prepared in Examples and Comparative Examples, the percent drug release rate was compared for each hour.
상기의 도표에 나타난 결과를 살펴보면 7시간째 용출율 비교시 실시예1~실시예5 모두 비교예에 비해 약 1.6배 이상 증가 하였으며, 특히 실시예 1과 실시예 5는 본 발명의 목적에 부합하는 가장 적절한 제형이라 할 수 있다.Looking at the results shown in the above chart, when compared to the dissolution rate at 7 hours, all of Examples 1 to 5 increased by about 1.6 times or more, especially Example 1 and Example 5 were the most suitable for the purpose of the present invention. It may be referred to as a suitable formulation.
수난용성 약물인 펠로디핀을 공통용매인 염화메틸렌과 에탄올 홍합용매에 용해시킨 다음, 분무건조하여 얻은 수가용성인 고체분산체를 제조하고, 이를 서방성 기제와 혼합하여 제제화하여 정제 도는 펠렛제형의 가용화된 펠로디핀 함유 지속성 제제의 조성을 얻을 수 있고, 본 발명의 조성물은 일정시간 동안 지속적으로 약물이 방출됨은 물은 유효농도를 유지하게 하여 치료효과는 상승시킬 수 있다는 특장점이 있다.Pelodipine, a poorly water-soluble drug, was dissolved in a common solvent of methylene chloride and an ethanol mussel solvent, and then a water-soluble solid dispersion obtained by spray drying was prepared, and then mixed with a sustained-release base to be formulated to solubilize tablets or pellets. It is possible to obtain the composition of the pelodipine-containing persistent preparation, and the composition of the present invention has the advantage that the drug is released for a certain time to maintain the effective concentration of water to increase the therapeutic effect.
Claims (4)
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0274176A2 (en) * | 1987-01-09 | 1988-07-13 | ELAN CORPORATION, Plc | Sustained release capsule or tablet formulation |
| KR20010073461A (en) * | 2000-01-15 | 2001-08-01 | 최현식 | Methods of enhancement of solubility of felodipine of poorly soluble dryg and sustained release systems |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0274176A2 (en) * | 1987-01-09 | 1988-07-13 | ELAN CORPORATION, Plc | Sustained release capsule or tablet formulation |
| KR20010073461A (en) * | 2000-01-15 | 2001-08-01 | 최현식 | Methods of enhancement of solubility of felodipine of poorly soluble dryg and sustained release systems |
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