KR20080049224A - Iron-vitamins supplememts with enhanced stability and process for preparing thereof - Google Patents

Iron-vitamins supplememts with enhanced stability and process for preparing thereof Download PDF

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KR20080049224A
KR20080049224A KR1020060119566A KR20060119566A KR20080049224A KR 20080049224 A KR20080049224 A KR 20080049224A KR 1020060119566 A KR1020060119566 A KR 1020060119566A KR 20060119566 A KR20060119566 A KR 20060119566A KR 20080049224 A KR20080049224 A KR 20080049224A
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iron
folic acid
vitamin
lipid
cyanocobalamin
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KR100844261B1 (en
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홍재선
이상영
신진하
김지만
민동훈
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일동제약주식회사
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds 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
    • A61K47/50—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
    • A61K47/51—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 non-active ingredient being a modifying agent
    • A61K47/54—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 non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—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 non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A61K47/551—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 non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
    • 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
    • A61K47/6905—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 the form being a colloid or an emulsion
    • A61K47/6907—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 the form being a colloid or an emulsion the form being a microemulsion, nanoemulsion or micelle
    • A61K47/6909—Micelles formed by phospholipids
    • 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
    • A61K9/5015—Organic compounds, e.g. fats, sugars

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Abstract

An iron-vitamin supplement is provided to show very excellent stability compared with a conventional iron-vitamin supplement and excellent content uniformity of main ingredients. A method for preparing the iron-vitamin supplement is provided to reduce the preparation time and simplify a process, thereby increasing convenience and efficiency of the preparation. An iron-vitamin supplement is characterized in that 1 part by weight of a mixture powder of iron, folic acid and vitamin B12 is coated by 0.1-5 parts by weight of a lipid such as wax and fatty acid ester. A method for preparing the iron-vitamin supplement comprises the steps of: (a) after mixing iron, folic acid, vitamin B12 and a lipid through melting, cooling the mixture down to room temperature to coat the iron, folic acid and vitamin B12 with the lipid; and (b) filling a capsule with the coated material obtained from the step(a). Further, the wax is selected from carnauba wax, beeswax, white wax, paraffin and hydrogenated oil.

Description

안정성이 향상된 복합철분제 및 그 제조방법{Iron-vitamins supplememts with enhanced stability and process for preparing thereof}Composite iron powder with improved stability and manufacturing method thereof {Iron-vitamins supplememts with enhanced stability and process for preparing}

도 1은 본 발명의 복합철분제 중의 철의 안정성을 나타낸 것이다.1 shows the stability of iron in the composite iron powder of the present invention.

도 2은 본 발명의 복합철분제 중의 엽산의 안정성을 나타낸 것이다.Figure 2 shows the stability of folic acid in the composite iron powder of the present invention.

도 3는 본 발명의 복합철분제 중의 시아노코발라민의 안정성을 나타낸 것이다.Figure 3 shows the stability of cyanocobalamin in the composite iron powder of the present invention.

본 발명은 안정성이 향상된 엽산 및 비타민 B12를 함유하는 복합철분제 조성물 및 이의 제조방법에 관한 것으로, 더욱 상세하게는 치료학적 유효량의 철분 또는 그의 약제학적으로 허용 가능한 착염과 엽산 및 비타민 B12를 함유하는 복합철분제 및 이의 제조방법에 관한 것이다.The present invention relates to a composite iron powder composition containing folic acid and vitamin B 12 having improved stability, and more particularly, to a method containing the same, and more particularly, to a therapeutically effective amount of iron or a pharmaceutically acceptable complex salt thereof and folic acid and vitamin B 12 . Composite iron And it relates to a manufacturing method thereof.

철분은 필수 영양소로 체내 철분양의 70% 정도는 적혈구에 헤모글로빈 형태로 존재한다. 철분이 부족하게 되면 빈혈이 생기게 되며, 이렇게 발생하는 빈혈이 전체 빈 혈 환자의 대부분을 차지하고 있다. 따라서, 빈혈을 치료하기 위해서는 철분의 공급이 우선적으로 이루어져야 한다. 세계보건기구(WHO)는 12세 이상일 경우 1일 100mg의 철분을 복용할 것을 권장하고 있다.Iron is an essential nutrient and about 70% of iron in the body is present in the form of hemoglobin in red blood cells. An iron deficiency leads to anemia, and this anemia accounts for the majority of patients with anemia. Therefore, in order to treat anemia, the supply of iron should be made first. The World Health Organization (WHO) recommends taking 100mg of iron per day if you are 12 or older.

엽산은 핵단백질 합성과 정상적인 적혈구 생성에 필수적이다. 엽산은 태아 척수의 기형을 막을 수 있다고 알려져 있고 하루 권장량은 400~1000㎍이다Folic acid is essential for nucleoprotein synthesis and normal red blood cell production. Folic acid is known to prevent malformations of the fetal spinal cord and the recommended daily dose is 400 to 1000 µg.

비타민 B12는 신경기능과 밀접한 관계가 있으며, 신경통이나 관절염, 말초신경염 등의 신경증상의 개선에 효과가 있다. Vitamin B 12 is closely related to nerve function and is effective in improving neurological symptoms such as neuralgia, arthritis and peripheral neuritis.

본 발명에 있어서 철 공급 목적으로 사용되는 철 성분으로는 카르보닐철, 황산철, 푸마르산철, 헵토글루콘산제일철, 아미노초산황산제일철착염, 수산화제이철폴리말토오스복염, 폴리삭카리드철착염, 글루콘산제이철 등을 예로 들 수 있으며 본 제제 중에 철로서 100~200mg 배합하는 것이 바람직하다.In the present invention, the iron component used for iron supply purposes is carbonyl iron, iron sulfate, iron fumarate, heptogluconate ferrous salt, amino acetate ferrous sulfate complex, ferric hydroxide polymaltose double salt, polysaccharide iron complex salt, ferric gluconate Etc. are mentioned, It is preferable to mix | blend 100-200 mg as iron in this formulation.

본 발명에 있어서, 비타민 B12로서는 시아노코발라민, 히드록소코발라민, 염산히드록소코발라민, 초산히드록소코발라민을 예로 들 수 있으며 본 제제 중에 1~1,000㎍ 배합하는 것이 바람직하다In the present invention, examples of vitamin B 12 include cyanocobalamin, hydroxylcobalamin, hydroxylcobalaline hydrochloride and hydroxylcobalaline acetate, and preferably 1 to 1,000 µg of the present formulation.

통상적으로 시판되고 있는 복합철분제는 철분 및 함께 첨가되는 주성분을 분말 상 태로 캡슐에 충진하거나 통상의 정제 형태로 제조하는 것이 일반적이다. Commercially available complex iron powders are generally filled in powder or capsules of iron and the main ingredients added together, or prepared in conventional tablet form.

이러한 복합철분제의 제조방법에 있어서 일반적으로는 철, 엽산 및 비타민 B12등을 건식 혼합하여 캡슐에 충진하는 방법으로 제조하는데 이 방법으로 제조시에는 각 성분간의 밀도차로 인하여 함량 편차가 심하게 되어 제조된 제품의 함량 균일성을 확보할 수 없다는 문제점이 있다.In the manufacturing method of such complex iron powder, iron, folic acid, and vitamin B 12 are generally prepared by dry mixing and filling in capsules. There is a problem that the content uniformity of the product cannot be secured.

또한, 철분, 엽산 및 비타민 B12를 약제학적으로 통상적으로 사용되는 부형제, 결합제, 붕해제, 활택제 등을 첨가하여 과립의 제조 및 정립을 통하여 얻어진 분말을 캡슐에 충진하는 방법으로 제조하기도 하는데 이러한 방법으로 제조시, 결합액 제조에 사용되는 정제수나 주정에 의해 주성분인 철의 산화가 가속되어 함께 첨가된 엽산 및 비타민 B12의 안정성이 떨어지게 된다는 단점이 있다.In addition, iron, folic acid, and vitamin B 12 may be prepared by adding the excipients, binders, disintegrants, glidants, etc., which are commonly used in the pharmaceutical industry, to fill the capsule with powder obtained through the preparation and formulation of granules. When manufacturing by the method, there is a disadvantage in that the oxidation of iron as a main component is accelerated by purified water or alcohol used in the preparation of the binder solution, thereby decreasing the stability of folic acid and vitamin B 12 added together.

더욱이 이러한 제조 방법은, 제조시에 결합제를 용매에 녹이는 단계, 과립을 제조하는 단계, 과립을 정립하는 단계 및 캡슐에 충진하는 단계를 포함하는 공정으로 제조되므로 그 제조에 걸리는 시간이 길고 복잡하다.Moreover, such a manufacturing method is manufactured by a process including dissolving a binder in a solvent, preparing granules, establishing granules, and filling a capsule during preparation, and thus the time taken for preparing the preparation is long and complicated.

본 발명에 있어서는 약제학적으로 사용되는 통상의 결합제, 부형제 및 활택제로서 리피드(lipid)만을 첨가하여 제조하는 방법을 고안함으로써 제조 시간을 줄이고 공정을 단순화 하였으며, 특히 철, 엽산 및 비타민 B12의 안정성을 높이고 동시에 함량의 균일성 또한 우수한 복합철분제에 대한 발명을 완성하였다.In the present invention, by devising a method of preparing by adding only lipid (lipid) as a conventional binder, excipient, and glidant used in pharmaceuticals, the manufacturing time is shortened and the process is simplified, in particular, the stability of iron, folic acid and vitamin B 12 The invention for composite iron powder with high content uniformity is also achieved.

본 발명은 안정성이 향상된 엽산 및 비타민 B12를 함유하는 복합철분제 제제 조성물 및 이의 제조방법을 제공하기 위한 것이다.The present invention is to provide a composite iron preparation formulation containing folic acid and vitamin B 12 with improved stability and a method for producing the same.

본 발명은 안정성이 향상된 엽산 및 비타민 B12를 포함하는 복합철분제 및 그 제조방법에 관한 것이다.The present invention improves the stability of folic acid and vitamin B 12 It relates to a composite iron powder containing and a method for producing the same.

본 발명의 복합철분제는 철, 엽산 및 비타민 B12를 리피드(lipid)층으로 코팅하는 공정으로 제조된 복합철분제 및 이의 제조 방법에 관한 것이다.The composite iron powder of the present invention relates to a composite iron powder produced by a process of coating iron, folic acid and vitamin B 12 with a lipid layer (lipid) and a method for producing the same.

본 발명의 복합철분제는 철, 엽산 및 비타민 B12 의 혼합 분말 1 중량부에 리피드 0.1~5 중량부가 코팅되어 있는 것을 특징으로 한다.Composite iron powder of the present invention is characterized in that the lipid is coated 0.1 to 5 parts by weight of 1 part by weight of the mixed powder of iron, folic acid and vitamin B 12 .

본 발명에 사용되는 리피드는 왁스류 및 지방산에스테르류로 이루어진 군 중에서 선택된 하나 이상이 될 수 있다.The lipid used in the present invention may be at least one selected from the group consisting of waxes and fatty acid esters.

리피드 중 왁스류는 구체적으로 카르나우바 납, 밀납, 백납, 파라핀, 경화유등이 될 수 있다.Among the lipids, waxes may be specifically carnauba lead, beeswax, white lead, paraffin, or hardened oil.

리피드 중 지방산에스테르류는 구체적으로 글리세릴 팔미토스테아레이트(glyceryl palmitostearate), 글리세릴 베헤네이트(glyceryl behenate), 글리세릴 스테아레이 트(glyceryl stearate), 글리세릴 올레이트(glyceryl oleate), 글리세릴 미리스테이트(glyceryl myristate), 세틸 팔미테이트(cetyl palmitate), 세틸 카프레이트(cetyl caprate), 스테아릴 팔미테이트(stearyl palmitate), 스테아릴 스테아레이트(stearyl stearate) 등이 될 수 있다.The fatty acid esters in the lipid are specifically glyceryl palmitostearate, glyceryl behenate, glyceryl stearate, glyceryl oleate, and glyceryl myriline. Glyceryl myristate, cetyl palmitate, cetyl caprate, stearyl palmitate, stearyl stearate, and the like.

본 발명에서는 상기의 리피드 중에서 글리세릴 팔미토스테아레이트를 사용하는 것이 가장 바람직하다.In this invention, it is most preferable to use glyceryl palmitostearate among said lipids.

본 발명에 있어서 철 공급 목적으로 사용되는 철 성분으로는 카르보닐철, 황산철, 푸마르산철, 헵토글루콘산제일철, 아미노초산황산제일철착염, 수산화제이철폴리말토오스복염, 폴리삭카리드철착염, 글루콘산제이철 등을 예로 들 수 있으며 폴리삭카리드철착염이 바람직하다. 본 제제 중에 철로서 100~200mg 배합하는 것이 바람직하다In the present invention, the iron component used for iron supply purposes is carbonyl iron, iron sulfate, iron fumarate, heptogluconate ferrous salt, amino acetate ferrous sulfate complex, ferric hydroxide polymaltose double salt, polysaccharide iron complex salt, ferric gluconate And the like, and polysaccharide iron salts are preferable. It is preferable to mix | blend 100-200 mg as iron in this formulation.

본 발명에 있어서, 비타민 B12로서는 시아노코발라민, 히드록소코발라민, 염산히드록소코발라민, 초산히드록소코발라민을 예로 들 수 있으며 시아노코발라민이 바람직하다.In the present invention, examples of the vitamin B 12 include cyanocobalamin, hydroxylcobalamin, hydroxylcobalaline hydrochloride and hydroxylcobalaline acetate, and cyanocobalamin is preferable.

본 제제 중에 1~1,000㎍ 배합하는 것이 바람직하다.It is preferable to mix | blend 1-1,000 micrograms in this formulation.

또한 본 발명의 복합철분제는 필요에 따라 약제학적으로 사용되는 통상적인 부형제, 결합제, 붕해제, 활택제 등의 첨가물을 추가로 함유할 수 있다.In addition, the composite iron powder of the present invention may further contain additives such as conventional excipients, binders, disintegrating agents, lubricants, etc., which are used pharmaceutically as necessary.

부형제는 유당, 전분, 미결정셀룰로오스, 만니톨, 소르비톨 등이 될 수 있다.Excipients can be lactose, starch, microcrystalline cellulose, mannitol, sorbitol and the like.

결합제는 히드록시프로필메틸셀룰로오스, 에틸셀룰로오스, 메틸셀룰로오스, 카르복시메틸셀룰로오스 나트륨과 같은 셀룰로오스 유도체, 전분, 젤라틴, 포비돈 등이 될 수 있다.The binder may be hydroxypropylmethylcellulose, ethylcellulose, methylcellulose, cellulose derivatives such as carboxymethylcellulose sodium, starch, gelatin, povidone and the like.

붕해제는 전분 및 전분 유도체, 카르복시메틸셀룰로오스 칼슘, 가교 카르복시메틸셀룰로오스 유도체, 미결정셀룰로오스, 가교 포비돈 등이 될 수 있다.Disintegrants can be starch and starch derivatives, carboxymethylcellulose calcium, crosslinked carboxymethylcellulose derivatives, microcrystalline cellulose, crosslinked povidone, and the like.

활택제는 스테아린산과 이의 알칼리금속염이나 아민염, 콜로이드성 이산화규소, 규산염류, 탈크 등이 될 수 있다.The lubricant may be stearic acid and its alkali metal salts or amine salts, colloidal silicon dioxide, silicates, talc and the like.

본 발명의 복합철분제는 기존의 복합철분제에 비해 비흡습성 등의 안정성이 월등하여 장기간 보관시에도 안정성이 우수하다.The composite iron powder of the present invention is superior in stability, such as non-hygroscopicity, compared to the conventional composite iron powder is excellent even in long-term storage.

본 발명의 복합철분제는 기존의 복합철분제에 비해 주성분의 함량 균일성 또한 뛰어나다.The composite iron powder of the present invention is also excellent in content uniformity of the main components compared to the conventional composite iron powder.

본 발명의 복합철분제는 주로 서방출성 제제에 사용되는 리피드를 코팅 물질로 사 용하였음에도 불구하고 기존의 복합철분제 캡슐과 비슷한 정도의 우수한 용출율을 나타낸다.The composite iron powder of the present invention shows an excellent dissolution rate similar to that of the conventional composite iron powder capsule, although the lipid used in the sustained-release preparation is used as a coating material.

즉, 본 발명은 기존의 복합철분제의 문제점이었던 저장 안정성(기존의 습식제조방법에 따른 문제점)과 함량 균일성(기존의 건식제조방법에 따른 문제점)의 문제를 동시에 개선하면서 아울러 용출율 또한 우수한 복합철분제를 제공한다.That is, the present invention simultaneously improves the problems of storage stability (problem with the existing wet manufacturing method) and content uniformity (problem with the existing dry manufacturing method), which are the problems of the conventional composite iron powder, and also has an excellent dissolution rate. To provide.

또한, 본 발명은 상기 복합철분제 제제의 제조방법을 함께 제공한다.In addition, the present invention provides a method for producing the complex iron powder formulation.

본 발명의 제조 방법은 1) 철, 엽산 및 비타민 B12에 리피드를 혼합하고 가열하여 리피드를 용융시킨 후 실온에서 냉각하여 철, 엽산 및 비타민 B12를 리피드로 한 번에 코팅하는 단계, 2) 제조한 코팅물을 정립하여 캡슐에 충진하는 단계로 이루어진다.The preparation method of the present invention comprises the steps of 1) mixing lipids with iron, folic acid and vitamin B 12 and heating them to melt the lipids, and then cooling them at room temperature to coat iron, folic acid and vitamin B 12 with lipids at once, 2) Formulating the prepared coating consists of a step of filling the capsule.

이하 본 발명의 제조방법에 대해 상세하게 설명한다.Hereinafter, the manufacturing method of the present invention will be described in detail.

본 발명의 제조방법의 1)단계에서는 철, 엽산 및 비타민 B12에 리피드를 적절한 비율로 혼합하며, 철, 엽산 및 비타민 B12 의 혼합 분말 1 중량부에 리피드 0.1~5 중량부를 첨가하는 것이 바람직하다.In step 1) of the preparation method of the present invention, it is preferable to mix lipids with iron, folic acid and vitamin B 12 in an appropriate ratio, and add 0.1 to 5 parts by weight of lipid to 1 part by weight of the mixed powder of iron, folic acid and vitamin B 12 . Do.

혼합 분말에 대한 리피드의 함량이 상기 비율보다 너무 낮으면 코팅이 완전히 이루어지지 못하며, 리피드의 함량이 상기 비율보다 너무 높으면 주성분의 용출이 늦어 진다.If the content of the lipid in the mixed powder is too lower than the ratio, the coating is not completely made. If the content of the lipid is too high, the dissolution of the main component is delayed.

상기의 혼합 분말을 리피드의 융점보다 0~10℃ 높은 온도를 5~15분간 유지하여 리피드를 완전히 용융시킨다.The mixed powder is kept at a temperature of 0 to 10 ° C. higher than the melting point of the lipid for 5 to 15 minutes to completely melt the lipid.

본 발명에서 사용하는 리피드는 그 융점이 대체로 40~90℃의 범위에 속한다. 구체적으로 글리세릴 팔미토스테아레이트를 사용할 경우, 글리세릴 팔미토스테아레이트의 융점인 53~57℃보다 약간 높은 온도인 65℃에서 혼합 분말을 용융, 혼합하였다.The lipid used in the present invention generally falls in the range of 40 to 90 ° C. Specifically, in the case of using glyceryl palmitostearate, the mixed powder was melted and mixed at 65 ° C., which is slightly higher than the melting point of glyceryl palmitostearate, 53 to 57 ° C.

상기의 용융 혼합물을 실온에서 서서히 냉각하여 얇은 리피드 막으로 코팅된 코팅물을 얻어, 체망으로 정립하여 적당한 크기의 과립을 얻는다. The molten mixture is slowly cooled at room temperature to obtain a coating coated with a thin lipid film, which is sieved to a sieve to obtain granules of a suitable size.

체망의 크기는 14~30호체가 바람직하며 더욱 바람직하게는 16~24호체가 바람직하다. The size of the body mesh is preferably No. 14 to 30, more preferably No. 16 to 24.

본 발명의 2)단계에서는 상기의 리피드로 코팅된 코팅물에 추가적인 첨가제를 가하지 않고In step 2) of the present invention, an additional additive is not added to the coating coated with lipids.

바로 캡슐에 충진하는 방법으로 제조한다.It is prepared by filling the capsule directly.

이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것으로 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.

[[ 실시예Example 1]  One] 폴리삭카리드철착염Polysaccharide Ferric Salt , 엽산 및 , Folic acid and 시아노코발라민의Cyanocobalamin 글리세릴Glyceryl 팔미토스테아레이트Palmitostearate 코팅 - 1 Coating-1

본 발명의 제조방법에 의해 폴리삭카리드철착염, 엽산 및 시아노코발라민을 글리세릴 팔미토스테아레이트로 코팅하였다.Polysaccharide ferric salt, folic acid and cyanocobalamin were coated with glyceryl palmitostearate by the preparation method of the present invention.

폴리삭카리드철착염, 엽산 및 시아노코발라민과 글리세릴 팔미토스테아레이트의 혼합비는 다음과 같다.The mixing ratio of polysaccharide ferric salt, folic acid and cyanocobalamin and glyceryl palmitostearate is as follows.

단, 표시량에 대하여 엽산은 130%, 시아노코발라민은 150% 배합하였다.However, 130% of folic acid and 150% of cyanocobalamin were blended with respect to the indicated amounts.

폴리삭카리드철착염 326.1Polysaccharide Ferric Salt 326.1

엽산 1Folic acid 1

0.1% 시아노코발라민 250.1% cyanocobalamin 25

글리세릴 팔미토스테아레이트 17.605Glyceryl Palmitostearate 17.605

1) 상기 혼합비에 따라 폴리삭카리드철착염 326.1g, 엽산 1.3g, 0.1%시아노코발라민 37.5g 및 글리세릴 팔미토스테아레이트 17.605g를 각각 측량하고 5분간 혼합한 후, 용융코팅기에 넣고 온도를 65℃에서 10분간 교반한 후 실온에서 냉각시킨다.1) According to the above mixing ratio, 326.1 g of polysaccharide iron salt, 1.3 g of folic acid, 37.5 g of 0.1% cyanocobalamin and 17.605 g of glyceryl palmitostearate were respectively measured and mixed for 5 minutes, and then placed in a melt coater. Stir at 65 ° C. for 10 minutes and then cool at room temperature.

3) 제조한 리피드 코팅물을 18호체를 통과시켜, 1 캡슐 중 382.505mg의 코팅물을 충진한다.3) The prepared lipid coating was passed through No. 18 to fill 382.505 mg of the coating in 1 capsule.

[[ 실시예Example 2]  2] 폴리삭카리드철착염Polysaccharide Ferric Salt , 엽산 및 , Folic acid and 시아노코발라민의Cyanocobalamin 글리세릴Glyceryl 팔미토스테아레이트Palmitostearate 코팅 - 2 Coating-2

실시예 1의 제조 방법에 따라 아래 조성의 복합철분제 코팅물을 얻고 1캡슐 중 400.11mg을 충진한다.According to the preparation method of Example 1, a composite iron coating of the following composition was obtained and 400.11 mg of one capsule was filled.

폴리삭카리드철착염 326.1Polysaccharide Ferric Salt 326.1

엽산 1Folic acid 1

0.1% 시아노코발라민 250.1% cyanocobalamin 25

글리세릴 팔미토스테아레이트 35.21Glyceryl Palmitostearate 35.21

[[ 실시예Example 3]  3] 폴리삭카리드철착염Polysaccharide Ferric Salt , 엽산 및 , Folic acid and 시아노코발라민의Cyanocobalamin 글리세릴Glyceryl 팔미토스테아레이트Palmitostearate 코팅 - 3 Coating-3

실시예 1의 제조 방법에 따라 아래 조성의 복합철분제 코팅물을 얻고 1캡슐 중 435.3mg을 충진한다.According to the preparation method of Example 1, a composite iron coating of the following composition was obtained, and 435.3 mg of one capsule was filled.

폴리삭카리드철착염 326.1Polysaccharide Ferric Salt 326.1

엽산 1Folic acid 1

0.1% 시아노코발라민 250.1% cyanocobalamin 25

글리세릴 팔미토스테아레이트 70.4Glyceryl Palmitostearate 70.4

[[ 실시예Example 4]  4] 폴리삭카리드철착염Polysaccharide Ferric Salt , , 시아노코발라민Cyanocobalamin 및 엽산의  And folic acid 글리세릴Glyceryl 베헤네이트Behenate 코팅 coating

실시예 1의 제조 방법에 따라 아래 조성의 복합철분제 코팅물을 얻고 1캡슐 중 400.11mgAccording to the preparation method of Example 1 to obtain a composite iron coating of the composition below 400.11mg in 1 capsule

을 충진한다. 단, 용융코팅기의 온도는 78℃이다.To fill. However, the temperature of a melt coater is 78 degreeC.

폴리삭카리드철착염 326.1Polysaccharide Ferric Salt 326.1

엽산 1Folic acid 1

0.1% 시아노코발라민 250.1% cyanocobalamin 25

글리세릴 베헤네이트 35.21Glyceryl Behenate 35.21

[[ 비교예Comparative example 1]  One] 폴리삭카리드철착염Polysaccharide Ferric Salt , 엽산 및 , Folic acid and 시아노코발라민의Cyanocobalamin 습식 제조 Wet manufacturing

일반적인 습식 제조방법으로 폴리삭카리드철착염, 엽산 및 시아노코발라민을 함유하는 복합철분제를 하기와 같이 제조하였다.As a general wet manufacturing method, a complex iron powder containing polysaccharide iron salt, folic acid and cyanocobalamin was prepared as follows.

단, 표시량에 대하여 엽산은 130%, 시아노코발라민은 150% 배합하였다.However, 130% of folic acid and 150% of cyanocobalamin were blended with respect to the indicated amounts.

폴리삭카리드철착염 326.1Polysaccharide Ferric Salt 326.1

엽산 1Folic acid 1

0.1% 시아노코발라민 250.1% cyanocobalamin 25

유당 54Lactose 54

포비돈 20Povidone 20

스테아린산마그네슘 3.9Magnesium Stearate 3.9

1) 상기 혼합비에 따라 폴리삭카리드철착염 326.1g, 엽산 1.3g, 0.1%시아노코발라민 37.5g, 유당 54g을 각각 측량하고 5분간 혼합 후, 하이스피드 믹서에 투입한다.1) According to the above mixing ratio, 326.1 g of polysaccharide iron salt, 1.3 g of folic acid, 37.5 g of 0.1% cyanocobalamin, and 54 g of lactose were respectively measured and mixed for 5 minutes, and then put into a high speed mixer.

2) 미리 정제수 70g에 포비돈 20g을 녹인 결합액을 전량 가하고 블레이드 600rpm, 초퍼 2000rpm의 조건으로 5분간 작동 시켜 습식 과립을 얻는다.2) Add the total amount of the binder solution of 20 g of povidone to 70 g of purified water in advance and operate for 5 minutes under the condition of blade 600rpm and chopper 2000rpm to obtain wet granules.

3) 55℃ 오븐에서 12시간 건조 후 18 호체를 통과시켜 정립물을 얻고, 스테아린산마그네슘을 첨가한 후 1 캡슐 중 442.8mg을 충진한다.3) After drying for 12 hours in an oven at 55 ° C., a No. 18 sieve is passed to obtain a crystalline substance. After adding magnesium stearate, 442.8 mg of one capsule is filled.

[[ 비교예Comparative example 2]  2] 폴리삭카리드철착염Polysaccharide Ferric Salt , 엽산 및 , Folic acid and 시아노코발라민의Cyanocobalamin 건식 제조 Dry manufacturing

일반적인 건식 제조 방법으로 폴리삭카리드철착염, 엽산 및 시아노코발라민을 함유하는 복합철분제를 하기와 같이 제조하였다.In a general dry manufacturing method, a complex iron powder containing polysaccharide iron salt, folic acid and cyanocobalamin was prepared as follows.

단, 표시량에 대하여 엽산은 130%, 시아노코발라민은 150% 배합하였다.However, 130% of folic acid and 150% of cyanocobalamin were blended with respect to the indicated amounts.

폴리삭카리드철착염 326.1Polysaccharide Ferric Salt 326.1

엽산 1Folic acid 1

0.1% 시아노코발라민 250.1% cyanocobalamin 25

스테아린산마그네슘 3.5Magnesium Stearate 3.5

1) 상기 혼합비에 따라 폴리삭카리드철착염 326.1g, 엽산 1.3g, 0.1%시아노코발라민 37.5g을 각각 측량하고 5분간 혼합 후, 스테아린산마그네슘 3.5g을 넣고 3분간 혼합한다.1) According to the above mixing ratio, 326.1 g of polysaccharide iron salt, 1.3 g of folic acid, and 37.5 g of 0.1% cyanocobalamin were respectively measured and mixed for 5 minutes, and 3.5 g of magnesium stearate was added and mixed for 3 minutes.

2) 1 캡슐 중 380.1mg을 충진한다.2) Fill 380.1 mg in 1 capsule.

[[ 실험예Experimental Example 1] 본 발명에 의해 제조된  1] manufactured by the present invention 복합철분제Compound Iron 중 철, 엽산 및  Heavy iron, folic acid and 시아노코발라민의Cyanocobalamin 안정성 확인 Check stability

본 발명의 제조방법에 의해 제조된 복합철분제 중의 철, 엽산 및 시아노코발라민의 안정성을 다음과 같이 확인하였다.The stability of iron, folic acid and cyanocobalamin in the composite iron powder prepared by the production method of the present invention was confirmed as follows.

상기 실시예 1~4 및 비교예 1의 복합철분제를 35℃/75%RH 항온항습기에서 비포장 상태로 보관하고 1, 2, 3개월에 꺼내어 제제 중의 철, 엽산 및 시아노코발라민의 함량을 고속액체크로마토그래피법으로 측정하였다. 상기 실험을 3회 반복하고 그 결과를 표 1에 비교하여 나타내었다.The composite iron powders of Examples 1 to 4 and Comparative Example 1 were stored in an unpacked state in a 35 ° C./75% RH constant temperature and humidity cabinet and taken out at 1, 2, and 3 months to extract iron, folic acid, and cyanocobalamin in the formulation. It was measured by chromatography. The experiment was repeated three times and the results are shown in comparison with Table 1.

표 1 함량(%)Table 1 Content (%)

구분division 경과 시간Elapsed time 개시시At the start 1개월1 month 2개월2 months 3개월3 months 실시예 1Example 1 철iron 100.6100.6 98.698.6 98.298.2 97.997.9 엽산Folic acid 123.5123.5 116.9116.9 110.3110.3 92.392.3 시아노코발라민Cyanocobalamin 144.4144.4 133.1133.1 118.5118.5 105.6105.6 실시예 2Example 2 철iron 101.2101.2 99.599.5 98.998.9 97.697.6 엽산Folic acid 124.1124.1 120.1120.1 111.3111.3 98.698.6 시아노코발라민Cyanocobalamin 146.5146.5 126.4126.4 123.6123.6 115.3115.3 실시예 3Example 3 철iron 102.1102.1 100.3100.3 99.099.0 98.498.4 엽산Folic acid 122.4122.4 121.3121.3 118.5118.5 110.9110.9 시아노코발라민Cyanocobalamin 153.6153.6 131.7131.7 126.5126.5 125.9125.9 실시예 4Example 4 철iron 101.6101.6 100.1100.1 98.398.3 97.597.5 엽산Folic acid 126.3126.3 120.4120.4 116.8116.8 106.8106.8 시아노코발라민Cyanocobalamin 148.6148.6 130.2130.2 124.3124.3 122.4122.4 비교예 1Comparative Example 1 철iron 100.9100.9 99.699.6 98.798.7 97.297.2 엽산Folic acid 126.9126.9 123.9123.9 92.692.6 58.158.1 시아노코발라민Cyanocobalamin 140.8140.8 98.898.8 65.665.6 58.058.0

[[ 실험예Experimental Example 2] 본 발명에 의해 제조된  2] produced by the present invention 복합철분제Compound Iron 중 엽산 및  Folic acid and 시아노코발라민의Cyanocobalamin 용출성Elution 확인 Confirm

본 발명의 제조방법에 의해 제조된 복합철분제 중의 엽산 및 시아노코발라민의 용 출성을 다음과 같이 확인하였다.The elution of folic acid and cyanocobalamin in the composite iron powder prepared by the production method of the present invention was confirmed as follows.

상기 실시예 1~4 및 비교예 1의 복합철분제에 대해 대한약전 일반시험법의 용출시험법 중 제 2법에 따라 용출 실험을 실행하고 엽산 및 시아노코발라민의 용출율을 측정하였다. 시험액으로 정제수 500mL를 사용하고 패들의 회전속도는 50rpm으로 하였으며, 시험 개시 60분 후 시험액을 채취하고 엽산 및 시아노코발라민의 농도를 측정하였다. 각각의 약물 용출율을 표 2에 비교하여 나타내었다.The dissolution test of the composite iron powder of Examples 1 to 4 and Comparative Example 1 was carried out according to the second method of the dissolution test method of the Korean Pharmacopoeia General Test Method and the dissolution rate of folic acid and cyanocobalamin was measured. 500 mL of purified water was used as the test solution, and the rotation speed of the paddle was 50 rpm. The test solution was taken 60 minutes after the start of the test, and the concentrations of folic acid and cyanocobalamin were measured. Each drug dissolution rate is shown in Table 2.

표 2TABLE 2

구분division 60분 후의 용출율Dissolution rate after 60 minutes 엽산Folic acid 시아노코발라민Cyanocobalamin 실시예 1Example 1 123.5%123.5% 146.5%146.5% 실시예 2Example 2 120.9%120.9% 144.2%144.2% 실시예 3Example 3 122.0%122.0% 140.1%140.1% 실시예 4Example 4 121.5%121.5% 141.6%141.6% 비교예 1Comparative Example 1 122.4%122.4% 145.7%145.7%

[[ 실험예Experimental Example 3] 본 발명에 의해 제조된  3] produced by the present invention 복합철분제Compound Iron 중 철, 엽산 및  Heavy iron, folic acid and 시아노코발라민의Cyanocobalamin 함량균일성 확인 Content uniformity check

본 발명의 제조방법에 의해 제조된 복합철분제 중의 철, 엽산 및 시아노코발라민의 함량균일성을 다음과 같이 확인하였다.The content uniformity of iron, folic acid and cyanocobalamin in the composite iron powder prepared by the production method of the present invention was confirmed as follows.

상기 실시예 1~4 및 비교예 2의 복합철분제에 대해 철, 엽산 및 시아노코발라민을 지표로 하여 함량균일성을 확인하였다. 6개 캡슐의 함량을 각각 정량하여 표 3에 비교하여 나타내었다.For the composite iron powders of Examples 1 to 4 and Comparative Example 2, the content uniformity was confirmed using iron, folic acid, and cyanocobalamin as indicators. The contents of the six capsules were quantified, respectively, and shown in Table 3.

표 3 함량(%)Table 3 Content (%)

1One 22 33 44 55 66 평균 ± 표준편차Mean ± standard deviation 실시예 1Example 1 철iron 102.1102.1 98.798.7 99.699.6 95.495.4 103.2103.2 97.597.5 99.4±2.8999.4 ± 2.89 엽산Folic acid 120.4120.4 118.6118.6 119.3119.3 125.3125.3 126.4126.4 122.8122.8 122.1±3.23122.1 ± 3.23 시아노코발라민Cyanocobalamin 144.1144.1 130.5130.5 125.6125.6 139.1139.1 142.0142.0 150.2150.2 140.7±7.2140.7 ± 7.2 실시예 2Example 2 철iron 99.499.4 95.395.3 96.896.8 103.2103.2 104.8104.8 103.8103.8 100.6±3.96100.6 ± 3.96 엽산Folic acid 124.3124.3 114.9114.9 118.3118.3 122.5122.5 126.5126.5 124.9124.9 121.9±4.43121.9 ± 4.43 시아노코발라민Cyanocobalamin 148.0148.0 132.1132.1 145.7145.7 123.6123.6 144.3144.3 143.6143.6 138.3±9.0138.3 ± 9.0 실시예 3Example 3 철iron 104.3104.3 104.2104.2 95.695.6 98.498.4 96.296.2 106.2106.2 100.8±4.62100.8 ± 4.62 엽산Folic acid 114.2114.2 116.8116.8 117.6117.6 121.0121.0 122.3122.3 123.8123.8 119.3±3.67119.3 ± 3.67 시아노코발라민Cyanocobalamin 148.0148.0 148.2148.2 131.6131.6 141.4141.4 142.0142.0 138.2138.2 140.8±5.6140.8 ± 5.6 실시예 4Example 4 철iron 105.2105.2 100.4100.4 94.594.5 95.695.6 99.199.1 100.4100.4 99.2±3.8599.2 ± 3.85 엽산Folic acid 119.4119.4 125.6125.6 124.1124.1 120.4120.4 115.3115.3 119.8119.8 120.8±3.67120.8 ± 3.67 시아노코발라민Cyanocobalamin 142.0142.0 133.4133.4 143.4143.4 144.3144.3 143.9143.9 136.6136.6 138.4±7.1138.4 ± 7.1 비교예 2Comparative Example 2 철iron 100.2100.2 99.999.9 99.199.1 101.3101.3 100.7100.7 99.899.8 100.1±0.76100.1 ± 0.76 엽산Folic acid 91.391.3 120.1120.1 81.281.2 102.3102.3 125.1125.1 95.395.3 102.6±17.0102.6 ± 17.0 시아노코발라민Cyanocobalamin 136.5136.5 126.5126.5 118.9118.9 142.3142.3 121.1121.1 136.9136.9 130.4±9.5130.4 ± 9.5

본 발명의 제조방법에 의해 제조된 복합철분제는 기존의 복합철분제에 비해 안정성 이 매우 우수하면서도 주성분의 함량 균일성도 뛰어나다.The composite iron powder prepared by the production method of the present invention has excellent stability and excellent content uniformity of the main components compared to the conventional composite iron powder.

또한 본 발명의 제조방법에 의해 제조된 복합철분제는 리피드를 코팅 물질로 사용하였음에도 불구하고 기존의 복합철분제와 비슷한 정도의 우수한 용출율을 나타낸다.In addition, the composite iron powder prepared by the production method of the present invention shows an excellent dissolution rate similar to that of the conventional composite iron powder, although lipid is used as a coating material.

본 발명의 복합철분제 제조방법에 따르면 제조 시간을 줄이고 공정을 단순화 하여 제조의 편의성 및 효율성을 높일 수 있다. According to the method for producing a composite iron powder of the present invention can reduce the manufacturing time and simplify the process to increase the convenience and efficiency of manufacturing.

따라서 본 발명의 복합철분제 및 그 제조 방법은 빈혈의 예방 및 치료에 유용하게 사용될 수 있다.Therefore, the complex iron agent of the present invention and a method for producing the same can be usefully used for the prevention and treatment of anemia.

Claims (6)

리피드(liquid)층으로 코팅된 철, 엽산 및 비타민 B12를 함유하는 복합철분제.A complex iron powder containing iron, folic acid and vitamin B 12 coated with a liquid layer. 제 1항에 있어서, 상기 철, 엽산 및 비타민 B12의 혼합 분말 1 중량부에 리피드 0.1~5 중량부가 코팅되어 있는 것을 특징으로 하는 복합철분제The method of claim 1, wherein the iron, folic acid and vitamin B 12 Mixed powder Composite iron powder, characterized in that the coating 0.1 to 5 parts by weight of lipid part in 1 part 제1항 또는 제 2항에 있어서, 상기 리피드는 왁스류 및 지방산에스테르류로 이루어진 군 중에서 선택된 하나 이상임을 특징으로 하는 복합철분제The complex iron powder according to claim 1 or 2, wherein the lipid is at least one selected from the group consisting of waxes and fatty acid esters. 제 3항에 있어서, 상기 왁스류는 카르나우바 납, 밀납, 백납, 파라핀, 경화유 중에서 선택되는 것을 특징으로 하는 복합철분제4. The complex iron powder according to claim 3, wherein the waxes are selected from carnauba lead, beeswax, white lead, paraffin and hardened oil. 제 3항에 있어서, 지방상에스테르류는 글리세릴 팔미토스테아레이트, 글리세릴 베헤네이트, 글리세릴 스테아레이트, 글리세릴 올레이트, 글리세릴 미리스테이트, 세틸 팔미테이트, 세틸 카프레이트, 스테아릴 팔미테이트, 스테아릴 스테아레이트 중에서 선택되는 것을 특징으로 하는 복합철분제The fatty acid esters according to claim 3, wherein the fatty esters are glyceryl palmitostearate, glyceryl behenate, glyceryl stearate, glyceryl oleate, glyceryl myristate, cetyl palmitate, cetyl caprate, stearyl palmitate , Composite iron powder selected from stearyl stearate 복합철분제를 제조함에 있어서, 1) 철, 엽산 및 비타민 B12와 리피드를 용융혼합 후 실온에서 냉각하여 철, 엽산 및 비타민 B12를 리피드로 코팅하는 단계, 2) 제조한 철, 엽산 및 비타민 B12의 코팅물을 캡슐에 충진하는 단계로 이루어짐을 특징으로 하는 방법In producing the composite cheolbunje, 1) iron, folic acid and vitamin B comprising: after melt mixing 12 with lipid to cool at room temperature for coating the iron, folic acid and vitamin B 12 in lipid, 2) are manufactured of iron, folic acid and vitamin B Filling the capsule with a coating of 12
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