KR20190117469A - Granule formulation - Google Patents
Granule formulation Download PDFInfo
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- KR20190117469A KR20190117469A KR1020197007437A KR20197007437A KR20190117469A KR 20190117469 A KR20190117469 A KR 20190117469A KR 1020197007437 A KR1020197007437 A KR 1020197007437A KR 20197007437 A KR20197007437 A KR 20197007437A KR 20190117469 A KR20190117469 A KR 20190117469A
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- South Korea
- Prior art keywords
- valine
- leucine
- granule formulation
- isoleucine
- gelling agent
- Prior art date
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- 239000008187 granular material Substances 0.000 title claims abstract description 119
- 239000000203 mixture Substances 0.000 title claims abstract description 65
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- 239000003349 gelling agent Substances 0.000 claims abstract description 48
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims abstract description 47
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims abstract description 47
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims abstract description 45
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Abstract
본 발명은, 복용감이 개선된 이소류신, 류신 및 발린을 포함하는 과립 제제를 제공한다. 본 발명은, 이소류신, 류신 및 발린 유효 성분으로서 포함하는 과립 제제로서, 겔화제를 포함하는 과립 제제에 관한 것이다.The present invention provides granule formulations comprising isoleucine, leucine and valine with improved dosage. The present invention relates to a granule formulation comprising isoleucine, leucine and valine as active ingredients, and to a granule formulation comprising a gelling agent.
Description
본 발명은 과립 제제에 관한 것이다. 구체적으로는 본 발명은 이소류신, 류신 및 발린을 포함하는 과립 제제에 관한 것이다. The present invention relates to granule formulations. Specifically, the present invention relates to granule formulations comprising isoleucine, leucine and valine.
이소류신, 류신 및 발린을 포함하는 의약품으로서는, 간 질환 등에 유효한 치료약인 리박트(등록 상표, 이하 동일하다.) 배합 과립이 시판되고 있다.As medicines containing isoleucine, leucine, and valine, Libact (registered trademark, the same applies hereinafter), which is a therapeutic drug effective for liver disease, is commercially available.
리박트 배합 과립은 1포(4.15g) 중에 4g의 유효 성분을 포함하고, 식사 섭취량이 충분함에도 불구하고 저알부민 혈증을 나타내는 비대상성 간경변 환자의 저알부민 혈증의 개선에 사용되고 있다(비특허문헌 1). Liebt-containing granules contain 4 g of active ingredient in one packet (4.15 g), and are used to improve hypoalbuminemia in non-target cirrhosis patients who exhibit hypoalbuminemia despite a sufficient amount of meal intake (Non-Patent Document 1) ).
리박트 배합 과립은, 대량의 아미노산 성분을 포함하는 과립 제제인 점에서, 아미노산에서 유래되는 쓴맛이나 과립의 입 안 잔여물과 같은 복용감의 더 한층의 개선이 요구되고 있다.Since Reacted granules are granule preparations containing a large amount of amino acid components, further improvement of the feeling of taking such as bitterness derived from amino acids and the mouth residue of granules is required.
본 발명이 해결하고자 하는 과제는, 복용감이 개선된 이소류신, 류신 및 발린을 포함하는 과립 제제를 제공하는 것이다. The problem to be solved by the present invention is to provide a granule preparation comprising isoleucine, leucine and valine with improved feeling of taking.
본 발명자들은 예의 검토한 결과, 이소류신, 류신 및 발린을 포함하는 과립 제제에 있어서, 겔화제를 배합함으로써, 상기 과제를 해결할 수 있음을 알아내고, 본 발명을 완성하였다.MEANS TO SOLVE THE PROBLEM As a result of earnestly examining, the present inventors discovered that the said subject could be solved by mix | blending a gelling agent in the granule formulation containing isoleucine, leucine, and valine, and completed this invention.
즉 본 발명은 이하와 같다.That is, this invention is as follows.
(1)(One)
이소류신, 류신 및 발린 유효 성분으로서 포함하는 과립 제제로서, 겔화제를 포함하는 과립 제제.A granule formulation comprising isoleucine, leucine and valine as active ingredients, the granule formulation comprising a gelling agent.
(2)(2)
겔화제가 카르복시비닐 중합체 또는 폴리에틸렌옥시드인, (1)에 기재된 과립 제제The granule formulation according to (1), wherein the gelling agent is a carboxyvinyl polymer or polyethylene oxide.
(3)(3)
겔화제가 50만 이상의 평균 분자량을 갖는 폴리에틸렌옥시드인, (1) 또는 (2)에 기재된 과립 제제.The granule formulation according to (1) or (2), wherein the gelling agent is a polyethylene oxide having an average molecular weight of 500,000 or more.
(4)(4)
겔화제가 분말 첨가되어 있는, (1) 내지 (3) 중 어느 한 항에 기재된 과립 제제.The granule formulation according to any one of (1) to (3), wherein the gelling agent is powdered.
(5)(5)
과립 제제 전체량에 대하여, 겔화제를 0.05 내지 2% 포함하는, (1) 내지 (4) 중 어느 한 항에 기재된 과립 제제.The granule formulation according to any one of (1) to (4), which contains 0.05 to 2% of a gelling agent based on the total amount of the granule formulation.
(6)(6)
이소류신/류신/발린=1/1.9 내지 2.2/1.1 내지 1.3의 중량비로 포함하는, (1) 내지 (5) 중 어느 한 항에 기재된 과립 제제.The granule preparation according to any one of (1) to (5), which is included in a weight ratio of isoleucine / leucine / valine = 1 / 1.9 to 2.2 / 1.1 to 1.3.
(7)(7)
과립 제제 전체량에 대하여, 이소류신, 류신 및 발린을 80% 이상 포함하는, (1) 내지 (6) 중 어느 한 항에 기재된 과립 제제.The granule formulation according to any one of (1) to (6), which contains 80% or more of isoleucine, leucine and valine relative to the total amount of granule formulation.
(8)(8)
결합제 및/또는 교미제를 더 포함하는, (1) 내지 (7) 중 어느 한 항에 기재된 과립 제제.The granule formulation according to any one of (1) to (7), further comprising a binder and / or a mating agent.
(9)(9)
이소류신, 류신 및 발린을 유효 성분으로서 포함하는 과립 제제의 제조 방법으로서,As a method for producing a granule formulation containing isoleucine, leucine and valine as active ingredients,
이소류신, 류신 및 발린을 포함하는 과립에, 겔화제를 첨가하는 제조 방법.A manufacturing method of adding a gelling agent to granules containing isoleucine, leucine and valine.
(10) 겔화제를 분말 첨가하는, (9)에 기재된 제조 방법. (10) The manufacturing method as described in (9) which powder-adds a gelling agent.
본 발명에 따르면, 복용감이 개선된 이소류신, 류신 및 발린을 포함하는 과립 제제를 제공할 수 있다. According to the present invention, it is possible to provide granule preparations comprising isoleucine, leucine and valine with improved dosage.
도 1은 실시예 1의 과립 제제의 용출 시험에 있어서의 결과를 나타낸다.
도 2는 비교예 1의 과립 제제의 용출 시험에 있어서의 결과를 나타낸다. 1 shows the results in the dissolution test of the granule formulation of Example 1. FIG.
The result in the dissolution test of the granule formulation of the comparative example 1 is shown.
본 발명을, 발명을 실시하기 위한 형태에 의해 구체적으로 설명하지만, 본 발명은 이하의 발명을 실시하기 위한 형태에 한정되는 것은 아니며, 각종 변형되어 실시할 수 있다.Although this invention is demonstrated concretely by the form for implementing this invention, this invention is not limited to the form for implementing the following invention, It can variously deform and implement.
본 발명의 과립 제제는 이소류신, 류신 및 발린을 유효 성분으로서 포함하고, 겔화제를 포함한다.The granule formulation of the present invention contains isoleucine, leucine and valine as active ingredients, and includes a gelling agent.
본 발명의 과립 제제에 있어서, 유효 성분으로서 사용되는 이소류신, 류신 및 발린은, 분지쇄 아미노산으로서 알려지는 아미노산이다.In the granule preparation of the present invention, isoleucine, leucine and valine used as active ingredients are amino acids known as branched chain amino acids.
본 발명에 있어서는 각각 D체, L체를 사용해도 되고, D체와 L체의 임의의 혼합비의 혼합물을 사용해도 되고, DL체를 사용해도 된다.In the present invention, each of D and L forms may be used, a mixture of any of D and L forms may be used, and DL may be used.
이소류신, 류신 및 발린은 각각 화학 합성품이어도 발효품이어도 된다.Isoleucine, leucine and valine may each be a chemical synthetic product or a fermented product.
일본 약전 제17 개정에 있어서(각각 483, 1711 내지 1712, 1248 페이지), L-이소류신, L-류신 및 L-발린으로서 기재되어 있는 규격을 만족시키는 것을 사용하는 것이 바람직하다.It is preferable to use the thing which satisfy | fills the specification described as L-isoleucine, L-leucine, and L-valine in Revision 17 of the Japanese Pharmacopoeia (pages 483, 1711-1712, 1248 respectively).
본 발명에 있어서, 이소류신, 류신 및 발린을 유효 성분으로서 포함한다는 것은, 본 발명의 과립 제제를 의약품으로서 사용한 경우에, 효능 효과를 발휘하는 성분으로서, 이소류신, 류신 및 발린을 포함하고 있다는 것을 의미한다.In the present invention, the inclusion of isoleucine, leucine and valine as active ingredients means that isoleucine, leucine, and valine are included as components that exert an efficacy effect when the granule preparation of the present invention is used as a medicine. .
이소류신, 류신 및 발린을 유효 성분으로서 포함하는 의약품의 효능 효과로서는, 일본에 있어서는, 시판 제품인 리박트 배합 과립에서의 효능 효과인 「식사 섭취량이 충분함에도 불구하고 저알부민 혈증을 나타내는 비대상성 간경변 환자의 저알부민 혈증의 개선」이 알려져 있지만, 본 발명의 이소류신, 류신 및 발린을 유효 성분으로서 포함하는 과립 제제의 효능 효과로서는, 이러한 효능 효과에만 한정되지 않는다.As a potent effect of a drug containing isoleucine, leucine and valine as active ingredients, in Japan, a potent effect of a commercially available Ribect compounded granule is `` of a non-target cirrhosis patient who exhibits hypoalbuminemia despite a sufficient food intake. Improvement of hypoalbuminemia ”is known, but the efficacy effect of the granule preparation which contains the isoleucine, leucine, and valine of this invention as an active ingredient is not limited only to such an efficacy effect.
본 발명에 있어서는 유효 성분으로서, 다른 성분을 포함하는 것도 무방하지만, 이소류신, 류신 및 발린만을 포함하는 것이 바람직하다.In the present invention, other active ingredients may be included as active ingredients, but only isoleucine, leucine and valine are preferable.
본 발명의 과립 제제는 이소류신, 류신 및 발린을 유효 성분으로서 포함함으로써, 의약용 과립 제제로서 사용할 수 있다.The granule formulation of the present invention can be used as a pharmaceutical granule formulation by containing isoleucine, leucine and valine as active ingredients.
본 발명의 과립 제제에 있어서, 이소류신, 류신 및 발린의 함유비는 특별히 한정되지 않지만, 중량비로서 이소류신/류신/발린=1/1.9 내지 2.2/1.1 내지 1.3인 것이 바람직하다.In the granule preparation of the present invention, the content ratio of isoleucine, leucine and valine is not particularly limited, but is preferably isoleucine / leucine / valine = 1 / 1.9 to 2.2 / 1.1 to 1.3 as weight ratio.
이소류신, 류신 및 발린의 함유량은 적절히 설정되지만, 과립 제제 전체량에 대한 질량%로서, 그 함유량의 하한값으로서 80% 이상인 것이 바람직하고, 90% 이상인 것이 보다 바람직하고, 95% 이상인 것이 더욱 바람직하다.Although content of isoleucine, leucine, and valine is set suitably, it is preferable that it is 80% or more as a lower limit of the content as mass% with respect to the granule preparation whole quantity, It is more preferable that it is 90% or more, It is further more preferable that it is 95% or more.
이소류신, 류신 및 발린의 함유량의 상한값으로서는 특별히 한정되지 않지만, 이소류신, 류신 및 발린의 함유량은 100% 미만인 것이 바람직하고, 99% 이하인 것이 보다 바람직하고, 98% 이하인 것이 더욱 바람직하고, 97% 이하인 것이 보다 더욱 바람직하다.Although it does not specifically limit as an upper limit of content of isoleucine, leucine and valine, It is preferable that content of isoleucine, leucine and valine is less than 100%, It is more preferable that it is 99% or less, It is still more preferable that it is 98% or less, It is 97% or less Even more preferred.
이소류신, 류신 및 발린의 함유량은, 상한값 및 하한값으로서 바람직한 값으로서 기재하는 각각의 값을 조합한 범위이면 된다.Content of isoleucine, leucine, and valine should just be the range which combined each value described as a preferable value as an upper limit and a lower limit.
본 발명의 과립 제제는 겔화제를 포함한다.Granule formulations of the present invention include a gelling agent.
본 발명에 있어서 겔화제란, 물을 포함함으로써 겔화되는 기재인 제제 첨가물인 것을 의미한다.In the present invention, the gelling agent means a preparation additive which is a base material which is gelled by containing water.
겔화제로서는 특별히 한정되지 않지만, 예를 들어 히프로멜로오스, 메틸셀룰로오스, 히드록시프로필셀룰로오스, 카르복시비닐 중합체, 알긴산나트륨, 카라기난, 크산탄검, 타마린드검, 펙틴, 로커스트빈검, 젤란검, 한천 및 폴리에틸렌옥시드 등을 들 수 있다.Although it does not specifically limit as a gelling agent, For example, hypromellose, methylcellulose, hydroxypropyl cellulose, carboxyvinyl polymer, sodium alginate, carrageenan, xanthan gum, tamarind gum, pectin, locust bean gum, gellan gum, agar And polyethylene oxides.
겔화능과 겔화 속도의 관점에서, 카르복시비닐 중합체 및 폴리에틸렌옥시드가 바람직하고, 폴리에틸렌옥시드가 보다 바람직하다. 겔화제는 1종으로 사용해도 되고, 2종 이상의 혼합물로서 사용해도 된다.From the viewpoint of gelling ability and gelling rate, carboxyvinyl polymer and polyethylene oxide are preferable, and polyethylene oxide is more preferable. A gelling agent may be used by 1 type, and may be used as 2 or more types of mixtures.
겔화제의 평균 분자량은, 겔화능과 겔화 속도와 같은 지표의 관점에서, 겔화제의 종류에 의해 적절히 설정된다.The average molecular weight of the gelling agent is appropriately set according to the type of gelling agent from the viewpoint of the index such as gelling ability and gelling rate.
겔화능은, 예를 들어 겔화제를 고농도, 저농도로 물에 용해시켰을 때의 외관을 관찰함으로써 확인할 수 있다.The gelling ability can be confirmed, for example, by observing the appearance when the gelling agent is dissolved in water at high or low concentration.
또한, 겔화 속도는, 겔화제를 물에 첨가 용해 후에 교반하고, 경시적으로 겔화의 상황을 관찰해감으로써 확인할 수 있다.In addition, a gelation rate can be confirmed by adding a gelling agent to water, stirring after dissolution, and observing the gelation condition over time.
겔화능의 측정 농도로서는, 예를 들어 고농도(10w/v%) 및 저농도(1w/v%)가, 겔화 속도의 측정 농도로서는, 예를 들어 10w/v% 등을 들 수 있다.As a measurement density | concentration of a gelation ability, high density | concentration (10w / v%) and low density | concentration (1w / v%) are 10w / v% etc. as a measurement density | concentration of a gelation rate, for example.
폴리에틸렌옥시드에 있어서는, 그 평균 분자량의 하한값으로서, 15만 이상의 평균 분자량을 갖는 것이 바람직하고, 50만 이상의 평균 분자량을 갖는 것이 보다 바람직하고, 100만 이상의 평균 분자량을 갖는 것이 더욱 바람직하고, 200만 이상의 평균 분자량을 갖는 것이 보다 더욱 바람직하다.In polyethylene oxide, as a lower limit of the average molecular weight, it is preferable to have an average molecular weight of 150,000 or more, It is more preferable to have an average molecular weight of 500,000 or more, It is further more preferable to have an average molecular weight of 1 million or more, 2 million It is still more preferable to have the above average molecular weight.
폴리에틸렌옥시드의 평균 분자량의 상한값으로서는 특별히 한정되지 않지만, 폴리에틸렌옥시드의 평균 분자량은 1000만 이하인 것이 바람직하고, 500만 이하인 것이 보다 바람직하다.Although it does not specifically limit as an upper limit of the average molecular weight of polyethylene oxide, It is preferable that it is 10 million or less, and, as for the average molecular weight of polyethylene oxide, it is more preferable that it is 5 million or less.
폴리에틸렌옥시드의 평균 분자량은, 상한값 및 하한값으로서 바람직한 값으로서 기재하는 각각의 값을 조합한 범위이면 된다.The average molecular weight of polyethylene oxide should just be a range which combined each value described as a preferable value as an upper limit and a lower limit.
본 발명에 있어서 겔화제의 평균 분자량은, 제품에 표시되는 값이어도 되지만, 겔화제의 용액의 점도를 측정함으로써, 점도 평균 분자량으로서 측정할 수 있다.Although the value displayed on a product may be sufficient as the average molecular weight of a gelling agent in this invention, it can measure as a viscosity average molecular weight by measuring the viscosity of the solution of a gelling agent.
본 발명의 과립 제제에 포함되는 겔화제는, 분말 첨가되어 존재하고 있는 것이 바람직하다.It is preferable that the gelling agent contained in the granule preparation of this invention exists in powder addition.
겔화제의 분말 첨가는 이소류신, 류신 및 발린을 포함하는 소과립(素顆粒)에 대하여 행해진다. 소과립에 대하여, 겔화제가 분말 첨가됨으로써 과립 제제로 하여, 과립의 표면에 겔화제가 분말 첨가된 상태로 존재하게 된다.Powder addition of the gelling agent is performed on the small granules containing isoleucine, leucine and valine. With respect to the small granules, the gelling agent is added to the granules by the powder addition, and the gelling agent is present on the surface of the granules in the state where the gelling agent is added.
본 발명의 과립 제제에 있어서 겔화제가 분말 첨가되어 있는 경우, 과립 표면에 겔화제가 분말 첨가된 상태로 존재하고 있으므로, 본 발명의 과립 제제는 소위 코팅 과립(피복 과립)로서, 과립 표면에 겔화제가 코팅되어 있는 과립 제제와는 상이하다.In the granule formulation of the present invention, when the gelling agent is powdered, since the gelling agent is present in the powdered state, the granulation formulation of the present invention is so-called coated granules (coated granules), and the gelling agent is coated on the granule surface. It is different from the granule formulation.
코팅 과립에 있어서는, 이소류신, 류신 및 발린을 포함하는 소과립에 대하여 코팅액에 의해 코팅된다. 이 경우, 겔화제는 코팅액 중에 포함된다.In the coated granules, the microgranules including isoleucine, leucine and valine are coated by the coating liquid. In this case, the gelling agent is included in the coating liquid.
과립 제제에 있어서, 겔화제가 분말 첨가되어 존재하고 있는 것은, 특별히 한정되지 않지만, 예를 들어 체 분류 등에 의해 분리함으로써 얻어진 분말의 겔화능 등을 평가함으로써 확인할 수 있다. 또한, 분광 화상 관찰 등에 의해, 겔화제가 분말 첨가되어 존재하고 있는 것을 확인할 수도 있다.In the granule formulation, it is not particularly limited that the gelling agent is added by powder, but it can be confirmed by evaluating the gelling ability of the powder obtained by, for example, separating by sieve classification or the like. It is also possible to confirm that the gelling agent is added by powder by spectral image observation or the like.
겔화제의 함유량은 겔화제의 종류에 의해 적절히 설정되지만, 겔화능과 겔화 속도의 관점에서, 과립 제제 전체량에 대한 질량%로서, 0.01 내지 5%인 것이 바람직하고, 0.05 내지 2%인 것이 보다 바람직하고, 0.05 내지 1%인 것이 더욱 바람직하다. 겔화제의 함유량은 상기 범위 내에서 0.1% 이상이어도 된다.Although content of a gelling agent is set suitably according to the kind of gelling agent, it is preferable that it is 0.01 to 5% as mass% with respect to the granule formulation whole quantity from a viewpoint of a gelling ability and a gelation rate, and it is more preferable that it is 0.05 to 2%. It is preferable and it is more preferable that it is 0.05 to 1%. The content of the gelling agent may be 0.1% or more within the above range.
본 발명의 과립 제제는 종래 공지된 방법에 의해 제조한, 이소류신, 류신 및 발린을 포함하는 과립에, 겔화제를 첨가함으로써 제조할 수 있다.The granule formulation of the present invention can be prepared by adding a gelling agent to granules containing isoleucine, leucine and valine, prepared by a conventionally known method.
본 발명에 있어서 이소류신, 류신 및 발린은, 일본 특허 제3228288호에 기재되는 방법에 의해, 이소류신, 류신 및 발린인 고형 원료 아미노산을 혼합 분쇄하여 입도를 조정해도 된다.In the present invention, isoleucine, leucine and valine may be mixed and pulverized with solid raw material amino acids that are isoleucine, leucine and valine by the method described in Japanese Patent No. 3328288.
혼합 분쇄는 이소류신, 류신 및 발린을 미리 혼합한 후에 분쇄하는 방법, 또는 이소류신, 류신 및 발린을 혼합하면서 분쇄하는 방법을 모두 이용할 수 있다.Mixed pulverization may use both the method of preliminarily mixing isoleucine, leucine, and valine, or the method of grinding while mixing isoleucine, leucine and valine.
고형 원료 아미노산의 혼합에 있어서는, 특별히 한정되지 않지만, 예를 들어 컨테이너식 혼합기 등의 용기 회전형 혼합기, 유동층형 혼합기 등의 에어 교반형 혼합기, 교반 블레이드 및 교반 리본의 회전에 의한 교반 혼합기, 분체 수송 라인 중에서 혼합하는 라인 혼합기 또는 분쇄기 등의 원료 공급구에 설치되는 피더형 혼합기를 이용할 수 있다.Although it does not specifically limit in mixing of a solid raw material amino acid, For example, stirring stirring by rotation of the container rotation type mixers, such as a container type mixer, and fluidized-bed mixer, stirring blade, and stirring ribbon, and powder transportation A feeder type mixer which is provided in a raw material supply port such as a line mixer or a pulverizer that is mixed in a line can be used.
고형 원료 아미노산의 분쇄에 있어서는, 특별히 한정되지 않지만, 예를 들어 해머 밀이나 핀 밀 등의 충격식(고속 회전식) 분쇄기, 볼 밀 등의 텀블러식(매체식) 분쇄기 또는 제트 밀 등의 유체식(기류식) 분쇄기를 이용할 수 있다.The pulverization of the solid raw material amino acid is not particularly limited, but, for example, impact type (high-speed rotary) pulverizers such as hammer mills and pin mills, tumbler type (medium) pulverizers such as ball mills or fluids such as jet mills ( Air type grinder can be used.
본 발명의 이소류신, 류신 및 발린을 포함하는 과립의 제조에 있어서는, 특별히 한정되지 않지만, 예를 들어 고속 교반 조립(造粒)기, 유동층 조립기, 플라네터리 믹서, 건식 압편(壓扁) 조립기, 파쇄 조립기, 압출 조립기, 전동 조립기, 분무 건조 조립기 또는 코팅 조립기를 이용할 수 있다.In the production of granules containing the isoleucine, leucine and valine of the present invention, it is not particularly limited, but for example, a high speed stirring granulator, a fluidized bed granulator, a planetary mixer, a dry pelletizer granulator, Crushing granulators, extrusion granulators, electric granulators, spray dried granulators or coated granulators can be used.
고속 교반 조립기 또는 압출 조립기를 사용하여, 과립을 제조하는 것이 바람직하다.It is preferable to produce granules using a high speed stirring granulator or an extrusion granulator.
압출 조립기로서는 특별히 한정되지 않지만, 예를 들어 전(前) 압출식 조립기, 디스크 펠릿터식 조립기, 링 다이식 조립기, 바스켓식 조립기, 오실레이팅식 조립기 및 실린더식 조립기 등을 들 수 있다.Although it does not specifically limit as an extrusion granulator, For example, a pre extrusion granulator, a disk pellet granulator, a ring die granulator, a basket granulator, an oscillating granulator, a cylindrical granulator, etc. are mentioned.
과립을 제조하는 경우에는, 일본 약전 또는 의약품 첨가물 규격 등의 규격을 만족시키고 있는 의약용으로서 사용할 수 있는 공지된 첨가제를 배합할 수 있다. 첨가제로서는 특별히 한정되지 않지만, 예를 들어 결합제, 활택제, 착색제, 가소제, 계면 활성제, 감미료, 교미제, 교취제 및 향료 등으로서 알려진 첨가제를 들 수 있고, 그 중에서도 결합제 및/또는 교미제가 바람직하다.In the case of producing granules, known additives that can be used as medicaments satisfying standards such as the Japanese Pharmacopoeia or the pharmaceutical additive standard can be blended. Although it does not specifically limit as an additive, For example, additives known as a binder, a lubricating agent, a coloring agent, a plasticizer, surfactant, a sweetener, a copper, a flavourant, a fragrance | flavor, etc. are mentioned, Especially, a binder and / or a mating agent are preferable.
첨가제는 1종으로 사용해도 되고, 2종 이상의 혼합물로서 사용해도 된다.An additive may be used by 1 type and may be used as 2 or more types of mixtures.
결합제로서는 특별히 한정되지 않지만, 예를 들어 메틸셀룰로오스, 히드록시프로필셀룰로오스, 히드록시프로필메틸셀룰로오스, 히드록시프로필메틸셀룰로오스 프탈레이트 등의 셀룰로오스 유도체, 옥수수 전분, 소맥 전분 등의 전분류, 폴리비닐피롤리돈(포비돈), 폴리비닐알코올, 아크릴산폴리머 등의 합성 고분자류 및 아라비아 고무, 젤라틴 등의 천연 고분자류 등을 들 수 있다.Although it does not specifically limit as a binder, For example, cellulose derivatives, such as methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, starches, such as corn starch and wheat starch, polyvinylpyrrolidone Synthetic polymers such as (povidone), polyvinyl alcohol and acrylic acid polymers, and natural polymers such as gum arabic and gelatin.
교미제로서는 특별히 한정되지 않지만, 예를 들어 시트르산, 타르타르산, 아스파탐, 사카린, 사카린 나트륨, 에리트리톨, 크실리톨, 만니톨 및 스테비아 등을 들 수 있다. 교미제에는, 감미료로서 알려지는 첨가제도 포함된다.Although it does not specifically limit as a mating agent, For example, citric acid, tartaric acid, aspartame, saccharin, saccharin sodium, erythritol, xylitol, mannitol, stevia, etc. are mentioned. The mating agent also includes an additive known as a sweetener.
교취제 및 향료로서는, 특별히 한정되지 않지만, 예를 들어 멘톨, 레몬 플레이버, 슈가리스, 스위트 플레이버 및 스트로베리 오일 등을 들 수 있다.Although it does not specifically limit as a malodorant and a fragrance | flavor, For example, menthol, lemon flavor, sugarless, sweet flavor, strawberry oil, etc. are mentioned.
본 발명에 있어서는, 적합하게는 이소류신, 류신 및 발린을 포함하는 과립에 대하여, 일본 특허 제3405342호에 기재되는 방법에 의해, 교미제 및/또는 교취제가 과립의 표면에 부착된다.In the present invention, for the granules preferably containing isoleucine, leucine and valine, the mating agent and / or the caustic agent are adhered to the surface of the granules by the method described in Japanese Patent No. 3405342.
교미제 및/또는 교취제가 부착되는 과립의 입도는, 통상의 유동화층값에 있어서 용이하게 유동 상태를 유지할 수 있는 한, 특별히 한정되지 않지만, 일반적으로는 100 내지 2000㎛이며, 바람직하게는 200 내지 1700㎛ 정도이다.The particle size of the granule to which the mating agent and / or the corpuscle is adhered is not particularly limited as long as it can easily maintain a fluid state in a normal fluidized bed value, but is generally 100 to 2000 µm, preferably 200 to 1700. About μm.
교미제 및/또는 교취제를 과립에 부착시키기 위한 유동화 장치로서는, 특별히 한정되지 않지만, 예를 들어 프로인트 산교(주)제의 유동 건조 장치 「플로우 드라이어」, 프로인트 산교(주)제의 유동층 조립 코팅 장치 「플로우 코터」, (주) 파우렉스제의 「글라트 GPCG」, (주)달톤제 「마루메라이저」 및 (주)기꾸스이 세이사꾸쇼제 「멀티프로세서」 등을 들 수 있다.Although it does not specifically limit as a fluidizing apparatus for attaching a mating agent and / or an aviding agent to granules, For example, the fluidized-bed granulation of the fluid drying apparatus "flow drier" made by Freundt Sankyo Co., Ltd., and the Freundt Sankyo Co., Ltd. make Coating apparatus "flow coater", "Gratt GPCG" by Faurex, "Marumeiser" by Dalton, "Multiprocessor" by Kikusui Seisakusho, etc. are mentioned.
본 발명에 있어서는, 이소류신, 류신 및 발린을 포함하는 과립, 바람직하게는 교미제 및/또는 교취제가 부착되어 있는 과립에, 겔화제를 혼합한다.In the present invention, a gelling agent is mixed with granules containing isoleucine, leucine and valine, preferably granules with a mating agent and / or a coring agent attached thereto.
본 발명에 있어서는, 이소류신, 류신 및 발린을 포함하는 과립, 바람직하게는 교미제 및/또는 교취제가 부착되어 있는 과립에, 겔화제를 분말 첨가하여 혼합하는 것이 적합하다.In the present invention, it is preferable to add a gelling agent to the granules containing isoleucine, leucine and valine, preferably to the granules to which the mating agent and / or the corpuscle is attached, and to mix them.
이러한 혼합 방법으로서는, 대략 균일하게 혼합하게 할 수 있는 방법이면 특별히 한정되지 않지만, 예를 들어 일반적인 용기 회전형 혼합기(예, V형, 이중 원추형, 회전 요동형 등), 용기 고정형 혼합기(예, 리본형, 원추 스크루형 등) 또는 기류 교반형 혼합기 등의 혼합기를 사용한 방법을 들 수 있다.The mixing method is not particularly limited as long as it is a method capable of mixing substantially uniformly. For example, a general container rotary mixer (eg, V-type, double cone, rotary swing type, etc.), container fixed mixer (eg, ribbon) Die, conical screw type, or the like, or a method using a mixer such as an air-flow stirring mixer.
분포기 등에 의해 각각의 제제의 규정량을 정해진 용기에 투입하여 혼합하는 방법을 이용해도 된다.You may use the method of adding the prescribed amount of each preparation to the predetermined container by a distributor, etc., and mixing.
이소류신, 류신 및 발린을 포함하는 과립에, 겔화제를 분말 첨가하여 혼합함으로써, 겔화제가 분말 첨가된 상태로 존재하는 과립 제제가 얻어진다.By adding the gelling agent to the granules containing isoleucine, leucine and valine, the granulation formulation in which the gelling agent is present in the powder added state is mixed.
본 발명의 과립 제제는, 겔화제를 첨가한 과립을 포함하지만, 이러한 과립은 일본 약전에 규정되어 있는 과립제이다(일본 약전 제17 개정라면 11페이지를 참조.).Although the granule preparation of this invention contains granules which added the gelling agent, these granules are granules prescribed | regulated by the Japanese Pharmacopoeia (refer page 11 if Japanese Pharmacopoeia 17 revision).
본 발명에 있어서, 과립 제제의 입도는 일반적으로는 100 내지 2000㎛이며, 바람직하게는 200 내지 1700㎛ 정도이다.In the present invention, the particle size of the granule formulation is generally 100 to 2000 µm, and preferably about 200 to 1700 µm.
본 발명에 있어서 입도란, 입자의 평균 입자 직경을 의미하지만, 일본 약전 제17 개정 기재된 일반 시험법 3.04 「입도 측정법」 제2법 「체 분류법」에 의해 측정할 수 있다(95 내지 97페이지). 또한, 일본 약전 제17 개정 기재된 일반 시험법 6.03 「제제의 입도 시험법」에 의해 측정해도 된다(135 페이지).In this invention, particle size means the average particle diameter of particle | grains, but can measure it by the general test method 3.04 "particle size measurement method" 2nd method "sieve classification method" of the JP 17th revision (pages 95-97). In addition, you may measure by the general test method 6.03 "particle size test method of preparation" of the Japanese Pharmacopoeia 17 revision (page 135).
본 발명의 과립 제제는, 본 발명의 과립 제제의 제조 방법에 의해 얻어지는 과립 제제일 수 있다.The granule formulation of the present invention may be a granule formulation obtained by the method for producing a granule formulation of the present invention.
본 발명의 과립 제제는, 아미노산에서 유래되는 쓴맛이나 과립의 입 안 잔여물과 같은 복용감이 개선되어 있다.In the granule preparation of the present invention, the feeling of taking such as bitterness derived from the amino acid and the residue in the mouth of the granule is improved.
본 발명에 있어서는, 겔화제를 분말 첨가해두는 것에 의한, 이소류신, 류신 및 발린을 유효 성분으로서 포함하는 과립 제제의 복용감의 개선 방법을 제공한다. 복용감의 개선으로서는, 아미노산에서 유래되는 쓴맛의 개선이나, 과립 제제의 입 안 잔여물 개선 등을 들 수 있다. In the present invention, a method for improving the feeling of taking a granule preparation containing isoleucine, leucine and valine as active ingredients by adding a gelling agent in powder is provided. Examples of the improvement in the feeling of taking include improvement in bitterness derived from amino acids, improvement in mouth residue of granule preparations, and the like.
실시예Example
이하, 본 발명을 실시예에 기초하여 구체적으로 설명하지만, 본 발명은 이것에 전혀 한정되지 않는다. 당업자는 본 발명의 의의를 일탈하지 않고 각종 양태로 본 발명을 변경할 수 있으며, 이러한 변경도 본 발명의 범위에 포함된다.EMBODIMENT OF THE INVENTION Hereinafter, although this invention is demonstrated concretely based on an Example, this invention is not limited to this at all. Those skilled in the art can change the present invention in various aspects without departing from the meaning of the present invention, and such changes are included in the scope of the present invention.
실시예 1Example 1
표 1에 기재하는 처방에 기초하여, 과립 제제를 조제하였다.Based on the prescription shown in Table 1, granule formulations were prepared.
L-이소류신, L-류신 및 L-발린의 혼합물에 대하여, 포비돈(콜리돈, 90F), 폴리비닐알코올(부분 비누화물), 타르타르산 및 사카린나트륨 수화물의 수용액을 첨가하여, 교반 조립기에 의해 조립하고, 정립(整粒), 건조시킴으로써 소과립을 얻었다.To a mixture of L-isoleucine, L-leucine and L-valine, an aqueous solution of povidone (collidone, 90F), polyvinylalcohol (partially saponified), tartaric acid and sodium saccharin hydrate was added and granulated by stirring granulator Small granules were obtained by sizing, drying and drying.
소과립에 대하여, 향료를 전연하여 정립한 후, 폴리에틸렌옥시드(평균 분자량: 500만)를 분말 첨가하여, 과립 제제를 조제하였다.The granules were prepared by powder-adding polyethylene oxide (average molecular weight: 5 million) after the fragrance was granulated for the small granules.
비교예 1Comparative Example 1
표 1에 기재하는 처방에 기초하여, 과립 제제를 조제하였다.Based on the prescription shown in Table 1, granule formulations were prepared.
실시예 1과 동일하게 하여 소과립을 얻었다.In the same manner as in Example 1, small granules were obtained.
소과립에 대하여, 포비돈(콜리돈, 90F)의 수용액을 사용하여 코팅한 후, 향료를 전연하여 정립함으로써, 과립 제제를 조제하였다.The granules were prepared by coating the small granules with an aqueous solution of povidone (collidone, 90F) and then scenting the fragrances.
실시예 1 및 비교예 1에서 조제한 과립 제제를 사용하여, 삼키기 쉬움, 과립이 남기 어려움, 쓴맛의 약함을 지표로 하여, 관능 평가를 행하였다. (n=9)Using the granule preparation prepared in Example 1 and Comparative Example 1, sensory evaluation was performed by making it easy to swallow, difficulty of leaving granules, and weakness of bitter taste. (n = 9)
삼키기 쉬움에 대해서는, 복용하였을 때의 양쪽 과립 제제를 비교하여, 삼키기 쉬운 쪽을 선택하였다.For ease of swallowing, both granule formulations at the time of taking were compared and the one which is easy to swallow was selected.
과립이 남기 어려움에 대해서는, 복용하였을 때의 양쪽 과립 제제를 비교하여, 입 안에 남기 어려운 쪽을 선택하였다.For the difficulty of leaving the granules, the granules at the time of taking were compared, and the one which was hard to remain in the mouth was selected.
쓴맛의 약함에 대해서는, 양쪽 과립 제제를 비교하여, 쓴맛이 약한 쪽을 선택하였다. 결과를 표 2에 나타낸다.About the weakness of bitterness, the granule preparation of both was compared and the one with the weaker bitterness was selected. The results are shown in Table 2.
실시예 1의 과립 제제는, 리박트 배합 과립의 처방인 비교예 1의 과립 제제에 대하여, 삼키기 쉬움, 과립이 남기 어려움, 쓴맛에 대하여 우수한 점에서, 복용감이 우수한 과립 제제인 것을 알았다.It was found that the granule formulation of Example 1 was a granule formulation having an excellent feeling of taking from the granule formulation of Comparative Example 1, which is a prescription of the compounded granules, in terms of ease of swallowing, difficulty in leaving granules, and bitter taste.
실시예 1 및 비교예 1에서 조제한 과립 제제를 사용하여, 일본 약전 제17 개정에 있어서의 용출 시험 제2액을 사용한 패들법에 의한 용출 시험에 의해, 용출성을 평가하였다(141 내지 145페이지 일반 시험법 6.10 「용출 시험법」).Using the granule preparation prepared in Example 1 and Comparative Example 1, the dissolution property was evaluated by the dissolution test by the paddle method using the dissolution test second liquid in the JP 17th Amendment (p. 141 to 145 General) Test Method 6.10 Dissolution Test Method).
결과를 도 1 및 도 2에 도시한다.The results are shown in FIGS. 1 and 2.
실시예 1의 과립 제제는, 비교예 1의 과립 제제에 대하여, 초기(5분값)에서의 용출성이 낮은 것이 확인되었지만, 15분 이후에 있어서는 양쪽 제제 모두 거의 100%의 용출성을 나타내는 것이 확인되었다. 실시예 1의 과립 제제도, 리박트 배합 과립과 동일한 약효를 나타낸다고 생각되었다.The granule formulation of Example 1 was confirmed to have a low dissolution property in the initial stage (5 minutes value) with respect to the granule formulation of Comparative Example 1, but after 15 minutes, both formulations showed an almost 100% dissolution ability. It became. It was thought that the granule formulation of Example 1 also exhibited the same effect as the compound compound granules.
실시예 2 내지 4Examples 2-4
폴리에틸렌옥시드(평균 분자량: 500만)의 함량이, 과립 제제 전체량에 대하여 0.1%, 1% 또는 2%가 되도록 한 것 이외에는, 실시예 1과 동일하게 하여 과립 제제를 조제하였다.A granule formulation was prepared in the same manner as in Example 1 except that the content of polyethylene oxide (average molecular weight: 5 million) was 0.1%, 1%, or 2% based on the total amount of the granule formulation.
실시예 5 내지 7Examples 5-7
평균 분자량이 50만, 100만 또는 200만인 폴리에틸렌옥시드를 사용하는 것 이외에는, 실시예 1과 동일하게 하여 과립 제제를 조제하였다.A granule formulation was prepared in the same manner as in Example 1 except that polyethylene oxide having an average molecular weight of 500,000, 1 million, or 2 million was used.
실시예 1 내지 7에서 조제한 과립 제제를 사용하여, 이물감, 쓴맛, 연하(嚥下) 용이성을 지표로 하여, 관능 평가를 행하였다. (n=10)Using the granule preparation prepared in Examples 1-7, the sensory evaluation was performed using foreign matter, bitterness, and swallowability as an index. (n = 10)
각 지표에 대하여, 느끼지 못함: 1점, 그다지 느끼지 못함: 2점, 그럭저럭 느낌: 3점, 느낌: 4점으로 하여 점수를 부여하고, 평균값을 구하였다. 결과를 표 3에 나타낸다.For each index, scores were given as not feeling: 1 point, not feeling very much: 2 points, and managing feeling: 3 points, feeling: 4 points, and the average value was obtained. The results are shown in Table 3.
본 발명의 과립 제제는, 현행 제제의 리박트 배합 과립에 대하여 개량된 복용성을 갖는다고 생각되기 때문에, 의약용 과립 제제로서 산업상 이용 가능성을 갖는다.Since the granule preparation of this invention is considered to have the improved dose property with respect to the compound of the present compound, it has industrial applicability as a pharmaceutical granule preparation.
Claims (10)
이소류신, 류신 및 발린을 포함하는 과립에, 겔화제를 첨가하는 제조 방법. As a method for producing a granule formulation containing isoleucine, leucine and valine as active ingredients,
A manufacturing method of adding a gelling agent to granules containing isoleucine, leucine and valine.
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KR20010072151A (en) * | 1998-07-31 | 2001-07-31 | 히구치 다츠오 | Pharmaceutical composition having improved taste |
KR20100129761A (en) * | 2008-03-11 | 2010-12-09 | 다케다 야쿠힌 고교 가부시키가이샤 | Orally-disintegrating solid preparation |
JP2011093879A (en) * | 2009-10-02 | 2011-05-12 | Ajinomoto Co Inc | Granule containing branched-chain amino acid, and method for producing the same |
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JP3211824B1 (en) * | 2000-10-26 | 2001-09-25 | 味の素株式会社 | Pharmaceutical granule preparation containing branched-chain amino acid and method for producing the same |
CN100528233C (en) * | 2003-10-29 | 2009-08-19 | 盐野义制药株式会社 | Process for producing coated preparation having relieved unpleasantness |
TWI503128B (en) * | 2007-07-31 | 2015-10-11 | Ajinomoto Kk | A granule preparation containing an amino acid with excellent taste |
JP5360368B2 (en) * | 2008-09-05 | 2013-12-04 | 味の素株式会社 | Amino acid preparation for oral use with improved dosage |
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KR20010072151A (en) * | 1998-07-31 | 2001-07-31 | 히구치 다츠오 | Pharmaceutical composition having improved taste |
KR20100129761A (en) * | 2008-03-11 | 2010-12-09 | 다케다 야쿠힌 고교 가부시키가이샤 | Orally-disintegrating solid preparation |
JP2011093879A (en) * | 2009-10-02 | 2011-05-12 | Ajinomoto Co Inc | Granule containing branched-chain amino acid, and method for producing the same |
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Title |
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첨부 문서 분지쇄 아미노산 제제 일본 약전 이소류신·류신·발린 과립 리박트(등록 상표) 배합 과립 2016년 4월 개정(제17판) |
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