KR102636176B1 - Solid preparations containing vitamin B1 or its derivatives - Google Patents
Solid preparations containing vitamin B1 or its derivatives Download PDFInfo
- Publication number
- KR102636176B1 KR102636176B1 KR1020207003358A KR20207003358A KR102636176B1 KR 102636176 B1 KR102636176 B1 KR 102636176B1 KR 1020207003358 A KR1020207003358 A KR 1020207003358A KR 20207003358 A KR20207003358 A KR 20207003358A KR 102636176 B1 KR102636176 B1 KR 102636176B1
- Authority
- KR
- South Korea
- Prior art keywords
- vitamin
- tablet
- starch
- mass
- powdered
- Prior art date
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- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 title claims description 5
- 239000007787 solid Substances 0.000 title abstract description 41
- 238000002360 preparation method Methods 0.000 title abstract description 37
- 229960003495 thiamine Drugs 0.000 title description 2
- 229930003451 Vitamin B1 Natural products 0.000 title 1
- 239000011691 vitamin B1 Substances 0.000 title 1
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- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims abstract description 55
- JZRWCGZRTZMZEH-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 claims abstract description 30
- 229960003512 nicotinic acid Drugs 0.000 claims abstract description 18
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- 150000004347 all-trans-retinol derivatives Chemical class 0.000 claims abstract description 7
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- JTLXCMOFVBXEKD-FOWTUZBSSA-N fursultiamine Chemical compound C1CCOC1CSSC(\CCO)=C(/C)N(C=O)CC1=CN=C(C)N=C1N JTLXCMOFVBXEKD-FOWTUZBSSA-N 0.000 claims description 36
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 32
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- UIERGBJEBXXIGO-UHFFFAOYSA-N thiamine mononitrate Chemical compound [O-][N+]([O-])=O.CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N UIERGBJEBXXIGO-UHFFFAOYSA-N 0.000 claims description 9
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- IWXAZSAGYJHXPX-BCEWYCLDSA-N Bisbentiamine Chemical compound C=1C=CC=CC=1C(=O)OCC/C(SS\C(CCOC(=O)C=1C=CC=CC=1)=C(/C)N(CC=1C(=NC(C)=NC=1)N)C=O)=C(/C)N(C=O)CC1=CN=C(C)N=C1N IWXAZSAGYJHXPX-BCEWYCLDSA-N 0.000 claims description 4
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- BTNNPSLJPBRMLZ-LGMDPLHJSA-N benfotiamine Chemical compound C=1C=CC=CC=1C(=O)SC(/CCOP(O)(O)=O)=C(/C)N(C=O)CC1=CN=C(C)N=C1N BTNNPSLJPBRMLZ-LGMDPLHJSA-N 0.000 claims description 4
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- NRLOCOXPOJIONU-ZABRKXACSA-N ethyl [(z)-2-[(4-amino-2-methylpyrimidin-5-yl)methyl-formylamino]-5-ethoxycarbonyloxypent-2-en-3-yl]sulfanylformate;hydrate;hydrochloride Chemical compound O.Cl.CCOC(=O)OCC\C(SC(=O)OCC)=C(/C)N(C=O)CC1=CN=C(C)N=C1N NRLOCOXPOJIONU-ZABRKXACSA-N 0.000 claims 2
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Classifications
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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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
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
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- A—HUMAN NECESSITIES
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
- A61K31/51—Thiamines, e.g. vitamin B1
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A—HUMAN NECESSITIES
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- 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
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Abstract
니코틴산 또는 이의 유도체 및 비타민 B1 또는 이의 유도체를 함유하는 안정한 고형 제제가 제공된다. 본 발명에 따른 고형 제제는 니코틴산 또는 이의 유도체, 비타민 B1 또는 이의 유도체 및 알파 전분을 함유하는 것을 특징으로 한다.A stable solid preparation containing nicotinic acid or a derivative thereof and vitamin B 1 or a derivative thereof is provided. The solid preparation according to the present invention is characterized by containing nicotinic acid or a derivative thereof, vitamin B 1 or a derivative thereof and alpha starch.
Description
본 발명은 니코틴산 부류 및 비타민 B1 부류를 포함하는 고형 제제에 관한 것이다.The present invention relates to solid preparations comprising nicotinic acid class and vitamin B 1 class.
비타민 보충을 위해 시판되고 있는 의약품 및 서플리먼트는 종종, 복수의 비타민을 동시에 포함한다. 비타민 종류인 비타민 B1 부류는 당질로부터의 에너지 생성 및 신경 기능 유지에 유용하고, 티아민 니트레이트, 티아민 클로라이드 히드로클로라이드, 푸르술티아민 히드로클로라이드, 벤포티아민, 비스벤티아민, 디세티아민 히드로클로라이드 등을 포함하는 것으로 알려져 있다. 비타민 B1 부류는 수많은 의약품 및 서플리먼트에 첨가되는데, 종종 비타민 B6, 비타민 B12 와 동시에 첨가된다. Medicines and supplements marketed for vitamin supplementation often contain multiple vitamins simultaneously. Vitamin B 1 class, a type of vitamin, is useful for generating energy from carbohydrates and maintaining nerve function, and includes thiamine nitrate, thiamine chloride hydrochloride, fursultiamine hydrochloride, benfotiamine, bisbentiamine, and disetiamine hydrochloride. It is known to do so. Vitamin B 1 is added to many medicines and supplements, often at the same time as vitamin B 6 and vitamin B 12 .
또한 비타민 종류인 니코틴산 부류는 피부의 기능 유지 및 혈류 개선 효과를 기대하여 의약품 및 서플리먼트에 첨가된다. 니코틴산 부류는 종종 비타민 C 및 비타민 E 와 동시에 첨가된다. Additionally, nicotinic acid, a type of vitamin, is added to medicines and supplements in hopes of maintaining skin function and improving blood flow. Nicotinic acid is often added simultaneously with vitamin C and vitamin E.
그러나, 비타민 부류는 서로의 안정성에 영향을 주는 것으로 알려져 있으며 따라서 복수의 비타민을 동시에 첨가하는 경우에는 세심한 주의를 가지고 안정성을 연구해야 한다.However, vitamin classes are known to affect each other's stability, so when multiple vitamins are added simultaneously, the stability must be studied with great care.
특허 문헌 1 은, 푸르술티아민 히드로클로라이드, 비타민 B2 부류, 비타민 B6 부류, 비타민 B12 부류 및 칼슘 판토테네이트를 포함하는 고형 제제를 개시하고 있다. 상기 고형 제제에 있어서는, 칼슘 판토테네이트 및 비타민 B12 부류 둘 모두는 칼슘 판토테네이트를 함유하는 조성물을 건조 상태에서 제형화하고, 수 중 비타민 B12 부류의 용액 또는 분산액을 칼슘 판토테네이트 외의 약물 및/또는 부형제에 분무한 후 혼합물을 건조시켜 수득한 과립을 제형화함으로써 안정화된다. Patent Document 1 discloses a solid preparation containing fursultiamine hydrochloride, vitamin B 2 class, vitamin B 6 class, vitamin B 12 class and calcium pantothenate. In the above solid formulations, both calcium pantothenate and vitamin B 12 family are formulated in a dry state with a composition containing calcium pantothenate, and a solution or dispersion of vitamin B 12 family in water is formulated in a dry form other than calcium pantothenate. It is stabilized by spraying the drug and/or excipients and then drying the mixture to formulate the resulting granules.
특허 문헌 2 는, 아스코르브산, 티아민 또는 피리독신에 추가로, 칼슘 판토테네이트를 포함하며 칼슘 판토테네이트가 안정한, 조성물을 개시하고 있다. 상기 조성물에 있어서, 칼슘 판토테네이트는, 칼슘 판토테네이트와, 그 자체가 중성 내지 염기성인 마그네슘 또는 칼슘의 락테이트 또는 카르보네이트를, 물 및/또는 저급 알코올의 존재 하에 혼합하고, 상기 조성물을 건조시킴으로써 안정화된다. Patent Document 2 discloses a composition containing calcium pantothenate in addition to ascorbic acid, thiamine, or pyridoxine, and in which calcium pantothenate is stable. In the composition, calcium pantothenate is mixed with calcium pantothenate and lactate or carbonate of magnesium or calcium, which itself is neutral to basic, in the presence of water and/or lower alcohol, and the composition It is stabilized by drying.
특허 문헌 3 은, 비타민 E 및 비타민 B12 부류를 포함하며 비타민 둘 모두가 안정한, 과립성 조성물을 개시하고 있다. 상기 과립성 조성물에 있어서, 상기 과립성 조성물의 용액 또는 현탁액의 pH 를 4 이상으로 조정함으로써, 비타민 B12 부류의 분해가 억제된다.Patent Document 3 discloses a granular composition containing 12 classes of vitamin E and vitamin B, both of which are stable. In the granular composition, decomposition of vitamin B 12 class is suppressed by adjusting the pH of the solution or suspension of the granular composition to 4 or higher.
특허 문헌 4 는, 콘드로이틴과 비타민 B12 부류를 동시에 포함하며 불안정한 비타민 B12 부류가 안정화되는, 제형을 개시하고 있다. 상기 제형에 있어서, 비타민 B12 는, 비타민 B12 및 무코다당류에 규산 및/또는 마그네슘 옥시드를 동시에 첨가함으로써 안정화된다.Patent Document 4 discloses a formulation that simultaneously contains chondroitin and the vitamin B 12 class and stabilizes the unstable vitamin B 12 class. In this formulation, vitamin B 12 is stabilized by simultaneously adding silicic acid and/or magnesium oxide to vitamin B 12 and mucopolysaccharide.
특허 문헌 5 는, 2종 이상의 비타민 B 부류와 조합으로 아데노신 5'-트리포스페이트를 포함하는, 피로 회복을 위한 의약을 개시하고 있다. 상기 의약은, 2종 이상의 비타민 B 부류와 조합으로 아데노신 5'-트리포스페이트를 사용함으로써, 혈관 작용 장 폴리펩티드 유전자의 발현을 촉진하고 정신 피로의 회복 효과를 갖는 것으로 간주된다.Patent Document 5 discloses a medicine for relieving fatigue containing adenosine 5'-triphosphate in combination with two or more types of vitamin B. This medicine is considered to promote the expression of vasoactive intestinal polypeptide genes and have a recovery effect from mental fatigue by using adenosine 5'-triphosphate in combination with two or more types of vitamin B.
상기 모든 문헌은 여러 종류의 비타민 B 부류를 포함하는 제제에 관한 것이나, 비타민 B1 부류 및 니코틴산 부류의 안정성에 주목한 것이 아니며, 이들의 병용이 정제 팽윤과 같은 외관 안정성에 영향을 주는 문제에 대해서는 전혀 기재도, 제시도 하지 않는다. All of the above documents relate to preparations containing several types of vitamin B classes, but do not focus on the stability of vitamin B class 1 and nicotinic acid class, and do not address problems in which their combined use affects the appearance stability such as tablet swelling. It is not described or presented at all.
본 발명자는, 비타민 B1 부류 및 니코틴산 부류를 포함하는 고형 제제가, 저장 동안, 예를 들어, 60℃ 에서 밀봉된 유리 병 또는 40℃/75%RH 에서 개방된 유리 병에서 저장 동안, 두께 팽윤 및 균열과 같은 현저한 외관 변화를 나타낸다는 것을 발견하였다. 이러한 현상은, 푸르술티아민 히드로클로라이드가 비타민 B1 부류로서 사용되고 니코틴아미드가 니코틴산 부류로서 사용된 경우 현저하게 발생하였다.The present inventors have discovered that solid preparations comprising vitamin B 1 class and nicotinic acid class swell in thickness during storage, for example in sealed glass bottles at 60°C or in open glass bottles at 40°C/75%RH. and significant changes in appearance, such as cracks. This phenomenon occurred significantly when fursultiamine hydrochloride was used as the vitamin B 1 class and nicotinamide was used as the nicotinic acid class.
본 발명자는 예의 검토한 결과, 비타민 B1 부류 및 니코틴산 부류를 포함하는 고형 제제의 상기 외관 변화가, 고형 제제에 알파 전분 (pregelatinized starch) 과 같은 가공 전분을 첨가함으로써 해결될 수 있다는 것을 발견하였다. As a result of intensive study, the present inventor has found that the above-mentioned appearance changes of solid preparations containing vitamin B 1 class and nicotinic acid class can be solved by adding processed starch such as alpha starch (pregelatinized starch) to the solid preparation.
즉, 본 발명은 하기 구현예를 포함한다.That is, the present invention includes the following embodiments.
[1] 니코틴산 부류, 비타민 B1 부류 및 가공 전분을 포함하는 고형 제제.[1] Solid preparation containing nicotinic acid class, vitamin B class 1 and processed starch.
[2] 가공 전분이 알파 전분인, [1] 에 따른 고형 제제.[2] A solid preparation according to [1], wherein the processed starch is alpha starch.
[3] 1 질량부의 니코틴산 부류에 대해 0.5 질량부 이상의 알파 전분을 포함하는, [2] 에 따른 고형 제제.[3] The solid preparation according to [2], comprising at least 0.5 parts by mass of alpha starch for 1 part by mass of nicotinic acid.
[4] 니코틴산 부류가 니코틴아미드인, [1] 내지 [3] 중 어느 하나에 따른 고형 제제.[4] The solid preparation according to any one of [1] to [3], wherein the nicotinic acid class is nicotinamide.
[5] 비타민 B1 부류가 푸르술티아민, 푸르술티아민 히드로클로라이드 또는 티아민 니트레이트인, [1] 내지 [4] 중 어느 하나에 따른 고형 제제.[5] The solid preparation according to any one of [1] to [4], wherein the vitamin B 1 class is fursultiamine, fursultiamine hydrochloride, or thiamine nitrate.
[6] 알파 전분이 부분 알파 전분인, [2] 내지 [5] 중 어느 하나에 따른 고형 제제.[6] The solid preparation according to any one of [2] to [5], wherein the alpha starch is partial alpha starch.
[7] 니코틴산 부류, 비타민 B1 부류 및 알파 전분을 물리적으로 분리되어 있지 않은 상태로 포함하는, [2] 내지 [6] 중 어느 하나에 따른 고형 제제.[7] The solid preparation according to any one of [2] to [6], comprising nicotinic acid class, vitamin B 1 class and alpha starch in a state where they are not physically separated.
[8] 가공 전분을 고형 제제에 첨가하는 것을 포함하는, 니코틴산 부류 및 비타민 B1 부류를 포함하는 고형 제제의 외관 변화를 억제하는 방법.[8] A method for suppressing changes in the appearance of a solid preparation containing nicotinic acid class and vitamin B 1 class, comprising adding processed starch to the solid preparation.
본 발명에 따르면, 니코틴산 부류 및 비타민 B1 부류를 포함하고, 우수한 외관 품질을 가지며, 저장 동안, 예를 들어, 60℃ 에서 밀봉된 유리 병 또는 40℃/75%RH 에서 개방된 유리 병에서 저장 동안 두께 팽윤 및 균열과 같은 현저한 외관 변화를 나타내지 않는 고형 제제가 제공될 수 있다. 안정한 형상, 특히 두께를 갖는 이러한 고형 제제는 필름 코팅 또는 당의 (sugar coating) 로 코팅되어도 외관에 균열과 같은 문제가 생길 가능성이 적고, 따라서 매우 높은 상품 가치를 갖는다.According to the invention, it contains nicotinic acid class and vitamin B 1 class, has good external quality and during storage, for example in a sealed glass bottle at 60°C or in an open glass bottle at 40°C/75%RH. Solid formulations can be provided that do not exhibit significant changes in appearance, such as thickness swelling and cracking. Such solid preparations with a stable shape, especially thickness, are less likely to cause problems such as cracks in appearance even when coated with a film coating or sugar coating, and therefore have a very high commercial value.
구현예의 설명Description of Implementation Example
본 발명에서의 "니코틴산 부류" 는, 예를 들어 니코틴산 또는 이의 염 (예를 들어, 니코틴아미드), 특히 바람직하게는 니코틴아미드이다.The “nicotinic acid class” in the present invention is, for example, nicotinic acid or a salt thereof (e.g. nicotinamide), particularly preferably nicotinamide.
본 발명의 고형 제제 중 니코틴산 부류의 함량은 1 유닛 (1 정제, 1 캡슐, 1 패키지) 당 일반적으로 1 mg 내지 100 mg 이다. 바람직하게는 이는 5 mg 내지 80 mg 이다. The content of the nicotinic acid class in the solid preparation of the present invention is generally 1 mg to 100 mg per unit (1 tablet, 1 capsule, 1 package). Preferably it is 5 mg to 80 mg.
본 발명의 고형 제제 중 니코틴산 부류의 함량은 1 유닛 (1 정제, 1 캡슐, 1 패키지) 당 일반적으로 0.1 질량% 내지 30 질량%, 바람직하게는 0.5 질량% 내지 20 질량% 이다.The content of the nicotinic acid family in the solid preparation of the present invention is generally 0.1% by mass to 30% by mass, preferably 0.5% by mass to 20% by mass per unit (1 tablet, 1 capsule, 1 package).
본 발명에서 "비타민 B1 부류" 는, 비타민 B1 또는 이의 유도체, 또는 이의 염을 나타내며, 예를 들어, 푸르술티아민, 푸르술티아민 히드로클로라이드, 티아민 클로라이드 히드로클로라이드, 티아민 니트레이트, 디세티아민 히드로클로라이드 히드레이트, 옥토티아민, 시코티아민, 비시부티아민, 비스벤티아민, 벤포티아민 등, 바람직하게는 푸르술티아민, 푸르술티아민 히드로클로라이드, 티아민 니트레이트, 특히 바람직하게는 푸르술티아민 히드로클로라이드를 포함한다.In the present invention, “vitamin B 1 class” refers to vitamin B 1 or a derivative thereof, or a salt thereof, for example, fursultiamine, fursultiamine hydrochloride, thiamine chloride hydrochloride, thiamine nitrate, and dicethiamine hydrochloride. Chloride hydrate, octothiamine, cycotiamine, bisibentiamine, bisbentiamine, benfotiamine, etc., preferably fursultiamine, fursultiamine hydrochloride, thiamine nitrate, particularly preferably fursultiamine hydrochloride. do.
본 발명의 고형 제제 중 비타민 B1 부류의 함량은 1 유닛 (1 정제, 1 캡슐, 1 패키지) 당 일반적으로 1 mg 내지 200 mg 이다. 바람직하게는, 이는 5 mg 내지 150 mg 이다.The content of vitamin B class 1 in the solid preparation of the present invention is generally 1 mg to 200 mg per unit (1 tablet, 1 capsule, 1 package). Preferably, it is 5 mg to 150 mg.
본 발명의 고형 제제 중 비타민 B1 부류의 함량은 1 유닛 (1 정제, 1 캡슐, 1 패키지) 당 일반적으로 0.1 질량% 내지 60 질량%, 바람직하게는 0.5 질량% 내지 40 질량% 이다.The content of vitamin B 1 class in the solid preparation of the present invention is generally 0.1% by mass to 60% by mass, preferably 0.5% by mass to 40% by mass per unit (1 tablet, 1 capsule, 1 package).
본 발명에서 "가공 전분" 은, 각종 화학적 개질 또는 가공을 실시하여 각종 기능이 부여된 전분을 나타내며, 글루코오스 화합물 (예를 들어, 시클로덱스트린), 전분의 염 (예를 들어, 나트륨 전분 글리콜레이트), 알파 전분 (예를 들어, 부분 알파 전분) 등을 포함한다. 그 중에서, 알파 전분이 바람직하다. In the present invention, “processed starch” refers to starch to which various functions have been imparted through various chemical modifications or processing, and includes glucose compounds (e.g., cyclodextrin), salts of starch (e.g., sodium starch glycolate) , alpha starch (e.g., partial alpha starch), etc. Among them, alpha starch is preferable.
본 발명에서 "알파 전분" 은, 물과 함께 가열하여 알파화된 전분을 나타내며, 전분 전체가 알파화된 것 (알파 전분), 부분적으로 알파화된 것 (부분 알파 전분) 의 둘 모두를 포함한다. 전분에 대한 원료는, 옥수수 전분, 감자 전분, 쌀 전분 등, 바람직하게는 옥수수 전분 및 감자 전분을 포함한다. 본 발명에서의 "알파 전분" 의 팽윤도는 바람직하게는 5 내지 30 cm3/g, 보다 바람직하게는 7 내지 25 cm3/g 이다. 알파 전분의 예는 "Encyclopedia of Pharmaceutical Additives 2000 (International Pharmaceutical Excipients Council Japan 편) 에 기재된 것들을 포함하며, 시판 제품의 예는 부분 알파 전분 PCS(R), 알파 전분 PD-1, 알파 전분 WB-1 (모두 Asahi Kasei Corporation사제) 등을 포함한다. In the present invention, “alpha starch” refers to starch that has been pregelatinized by heating with water, and includes both fully pregelatinized starch (alpha starch) and partially pregelatinized starch (partial alpha starch). . Raw materials for starch include corn starch, potato starch, rice starch, etc., preferably corn starch and potato starch. The swelling degree of “alpha starch” in the present invention is preferably 5 to 30 cm 3 /g, more preferably 7 to 25 cm 3 /g. Examples of alpha starch include those listed in the "Encyclopedia of Pharmaceutical Additives 2000 (edited by the International Pharmaceutical Excipients Council Japan), and examples of commercially available products include partial alpha starch PCS (R) , alpha starch PD-1, and alpha starch WB-1 ( (all manufactured by Asahi Kasei Corporation), etc.
본 발명의 고형 제제 중 알파 전분의 함량은 1 유닛 (1 정제, 1 캡슐, 1 패키지) 당 일반적으로 1 질량% 내지 90 질량% 이다. 이는 바람직하게는 3 질량% 내지 60 질량%, 보다 바람직하게는 5 질량% 내지 60 질량% 이다.The content of alpha starch in the solid preparation of the present invention is generally 1% by mass to 90% by mass per unit (1 tablet, 1 capsule, 1 package). It is preferably 3% by mass to 60% by mass, more preferably 5% by mass to 60% by mass.
본 발명에서, 알파 전분은 1 질량부의 니코틴산 부류에 대해 바람직하게는 0.5 질량부 이상, 바람직하게는 1 질량부 이상 20 질량부 이하, 보다 바람직하게는 3 질량부 이상 10 질량부 이하, 보다 더 바람직하게는 3.5 질량부 이상 10 질량부 이하의 양으로 첨가된다. In the present invention, the amount of alpha starch is preferably 0.5 parts by mass or more, preferably 1 part by mass or more and 20 parts by mass or less, more preferably 3 parts by mass or more and 10 parts by mass or less, even more preferably, for 1 part by mass of nicotinic acid. Typically, it is added in an amount of 3.5 parts by mass or more and 10 parts by mass or less.
본 발명이 해결하고자 하는 과제인 니코틴산 부류 및 비타민 B1 부류를 포함하는 고형 제제의, 저장 동안의 팽윤 및 균열과 같은 현저한 외관 변화는, 니코틴산 부류와 비타민 B1 부류가 접촉함으로써 초래되는 것으로 여겨진다. It is believed that significant changes in appearance, such as swelling and cracking during storage, of solid preparations containing the nicotinic acid class and the vitamin B 1 class, which are the problems to be solved by the present invention, are caused by the contact of the nicotinic acid class with the vitamin B 1 class.
따라서, 본 발명의 고형 제제는, 특히, 니코틴산 부류, 비타민 B1 부류 및 알파 전분을 물리적으로 분리되어 있지 않은 상태로 포함하는 것들을 포함한다.Accordingly, the solid preparations of the present invention include, inter alia, those comprising nicotinic acid class, vitamin B 1 class and alpha starch in a physically unseparated state.
"물리적으로 분리되어 있지 않은 상태" 는, 니코틴산 부류, 비타민 B1 부류 및 알파 전분이 물리적으로 분리되지 않고 서로 접촉할 수 있는 한, 특별히 한정되지 않는다. 이러한 고형 제제는, 예를 들어, 비타민 B1 부류, 니코틴산 부류 및 알파 전분을 혼합하고 혼합물을 타정하여 제조된 정제; 비타민 B1 부류 및 니코틴산 부류를 별개 군으로 과립화한 후 혼합하고 이를 타정하여 제조된 정제; 등을 포함한다. The “state of not being physically separated” is not particularly limited, as long as the nicotinic acid class, vitamin B 1 class and alpha starch can contact each other without being physically separated. Such solid preparations include, for example, tablets prepared by mixing vitamin B class 1 , nicotinic acid class and alpha starch and compressing the mixture into tablets; Tablets prepared by granulating vitamin B class 1 and nicotinic acid class into separate groups, mixing them, and compressing them into tablets; Includes etc.
본 발명에서, 비타민 B1 부류 및 니코틴산 부류 외에, 첨가될 수 있는 다른 약물은, 비타민, 해열진통제, 진해거담제, 소염제, 코 염증약, 위장약, 지사제, 생약, 아미노산 등을 포함한다. 비타민은 비타민 A 부류 (레티놀 아세테이트, 레티놀 팔미테이트, 비타민 A 오일, 대구간유, 강력 대구간유), 비타민 D 부류 (에르고칼시페롤, 콜레칼시페롤), 비타민 B2 부류 (리보플라빈, 리보플라빈 나트륨 포스페이트, 리보플라빈 부티레이트), 비타민 B6 부류 (피리독신 히드로클로라이드, 피리독살 포스페이트), 비타민 B12 부류 (시아노코발라민, 히드록소코발라민 아세테이트, 메코발라민), 칼슘 판토테네이트, 칼슘 판토테네이트 S 형, 감마 오리자놀, 오르트산, 글루쿠로노락톤, 글루쿠론아미드, 이인, 헤스페리딘, 비오틴, 콘드로이틴 술페이트 나트륨, 비타민 C 부류 (아스코르브산, 칼슘 아스코르베이트, 나트륨 아스코르베이트), 비타민 E 부류 (dl-α-토코페롤 칼슘 숙시네이트, d-α-토코페롤 숙시네이트, d-α-토코페롤 아세테이트) 를 포함한다. In the present invention, in addition to the vitamin B 1 class and the nicotinic acid class, other drugs that can be added include vitamins, antipyretic analgesics, antitussive expectorants, anti-inflammatory drugs, nasal inflammation drugs, gastrointestinal drugs, antidiarrheal drugs, herbal medicines, amino acids, etc. Vitamins include vitamin A class (retinol acetate, retinol palmitate, vitamin A oil, cod liver oil, strong cod liver oil), vitamin D class (ergocalciferol, cholecalciferol), vitamin B class 2 (riboflavin, riboflavin sodium phosphate) , riboflavin butyrate), vitamin B class 6 (pyridoxine hydrochloride, pyridoxal phosphate), vitamin B class 12 (cyanocobalamin, hydroxocobalamin acetate, mecobalamin), calcium pantothenate, calcium pantothenate type S, gamma Oryzanol, ortic acid, glucuronolactone, glucuronamide, diphosphorus, hesperidin, biotin, sodium chondroitin sulfate, vitamin C class (ascorbic acid, calcium ascorbate, sodium ascorbate), vitamin E class (dl- α-tocopherol calcium succinate, d-α-tocopherol succinate, d-α-tocopherol acetate).
해열진통제는 록소프로펜 나트륨 히드레이트, 아세트아미노펜, 이부프로펜, 아스피린, 에텐아미드, 살리실아미드, 나트륨 살리실레이트, 무수 카페인, 카페인 등을 포함한다.Antipyretic analgesics include loxoprofen sodium hydrate, acetaminophen, ibuprofen, aspirin, ethenamide, salicylamide, sodium salicylate, anhydrous caffeine, and caffeine.
진해거담제는 코데인 포스페이트, 디히드로코데인 포스페이트, 덱스트로메토르판 히드로브로마이드, 메틸에페드린 히드로클로라이드, 노스카핀, 메틸시스테인 히드로클로라이드, 에틸시스테인 히드로클로라이드, 카르보시스테인 등을 포함한다. Antitussive expectorants include codeine phosphate, dihydrocodeine phosphate, dextromethorphan hydrobromide, methylephedrine hydrochloride, noscapine, methylcysteine hydrochloride, ethylcysteine hydrochloride, carbocysteine, etc.
소염제는 리소자임 클로라이드, 트라넥삼산, 나트륨 아줄렌 술포네이트 등을 포함한다. Anti-inflammatory agents include lysozyme chloride, tranexamic acid, sodium azulene sulfonate, etc.
코 염증약은 슈도에페드린 히드로클로라이드, dl-클로르페니라민 말레에이트, d-클로르페니라민 말레에이트, 벨라돈나 총 알칼로이드, 이소프로파미드 요오디드, 이칼륨 글리시리지네이트 등을 포함한다.Nasal inflammatory drugs include pseudoephedrine hydrochloride, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, belladonna total alkaloids, isopropamide iodide, and dipotassium glycyrrhizinate.
위장약은 건조 알루미늄 히드록시드 겔, 마그네슘 알루미노실리케이트, 마그네슘 실리케이트, 합성 히드로탈시트, 마그네슘 옥시드, 마그네슘 알루미늄 히드록시드, 알루미늄 히드록시드 겔, 알루미늄 히드록시드-나트륨 바이카르보네이트 공침물, 알루미늄 히드록시드-마그네슘 카르보네이트 혼합 건조 겔, 알루미늄 히드록시드-마그네슘 카르보네이트-칼륨 카르보네이트 공침물, 마그네슘 히드록시드, 나트륨 바이카르보네이트, 마그네슘 카르보네이트, 침강 칼슘 카르보네이트, 마그네슘 알루미노메타실리케이트, 무수 이염기성 칼슘 포스페이트, 이염기성 칼슘 포스페이트, 아미노아세트산, 디히드록시알루미늄 아미노아세테이트, 스코폴리아 추출물, 알로에, 회향, 강황, 황백, 황연, 가공 마늘, 홍삼, 후박, 생강, 당약, 계피, 루바브, 죽절삼 근경, 진피, 등피, 고목, 인삼, 박하, 홉, 회향 오일, 시나몬 오일, 생강 오일, 등피 오일, 박하 오일, 레몬 오일, l-멘톨, 베타인 히드로클로라이드, 카르니틴 클로라이드, 건조 효모, 전분 소화 효소, 단백질 소화 효소, 지방 소화 효소, 피브린 소화 효소, 우르소데속시콜산, 담즙 분말 등을 포함한다.Gastrointestinal medications include dry aluminum hydroxide gel, magnesium aluminosilicate, magnesium silicate, synthetic hydrotalcite, magnesium oxide, magnesium aluminum hydroxide, aluminum hydroxide gel, and aluminum hydroxide-sodium bicarbonate coprecipitate. , aluminum hydroxide-magnesium carbonate mixed dry gel, aluminum hydroxide-magnesium carbonate-potassium carbonate coprecipitate, magnesium hydroxide, sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate. Bonate, Magnesium Aluminomethasilicate, Anhydrous Dibasic Calcium Phosphate, Dibasic Calcium Phosphate, Aminoacetic Acid, Dihydroxyaluminum Aminoacetate, Scofolia Extract, Aloe, Fennel, Turmeric, Yellow White, Yellow Scallop, Processed Garlic, Red Ginseng, Cucurbita , ginger, cinnamon, rhubarb, ginseng rhizome, dermis, bark, old tree, ginseng, peppermint, hops, fennel oil, cinnamon oil, ginger oil, bark oil, peppermint oil, lemon oil, l-menthol, betaine Contains hydrochloride, carnitine chloride, dry yeast, starch-digesting enzyme, protein-digesting enzyme, fat-digesting enzyme, fibrin-digesting enzyme, ursodesoxycholic acid, bile powder, etc.
지사제는 아크리놀, 베르베린 클로라이드, 구아야콜, 크레오소트, 비스무트 서브살리실레이트, 비스무트 서브니트레이트, 비스무트 서브카르보네이트, 비스무트 서브갈레이트, 탄닌산, 카올린, 펙틴, 약용탄, 칼슘 락테이트, 침강 칼슘 카르보네이트, 이염기성 칼슘 포스페이트, 파파베린 히드로클로라이드, 에틸 아미노벤조에이트, 나트륨 아줄렌 술포네이트, 알디옥사, L-글루타민, 칼륨 구리 클로로필린, 나트륨 구리 클로로필린, 메틸메티오닌 술포늄 클로라이드, 디메틸폴리실록산 등을 포함한다.Antidiarrheal drugs include acrinol, berberine chloride, guaiacol, creosote, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth subgallate, tannic acid, kaolin, pectin, medicinal charcoal, calcium lactate, Precipitated Calcium Carbonate, Dibasic Calcium Phosphate, Papaverine Hydrochloride, Ethyl Aminobenzoate, Sodium Azulene Sulfonate, Aldioxa, L-Glutamine, Potassium Copper Chlorophyllin, Sodium Copper Chlorophylline, Methylmethionine Sulfonium Chloride, Includes dimethylpolysiloxane, etc.
생약은 예덕나무 껍질, 갬비어, 분말화 갬비어, 수국차잎, 분말화 수국차잎, 알로에, 분말화 알로에, 벤조인, 클레마티스 뿌리, 사철쑥 꽃, 음양곽, 회향, 분말화 회향, 강황, 생강나무 뿌리, 베어베리 잎, 장미 열매, 분말화 장미 열매, 현호색, 황기, 황금, 분말화 황금, 황정, 황백, 분말화 황백, 황연, 분말화 황연, 원지, 분말화 원지, 하고초, 호장근 뿌리, 아출, 갈근, 자포니즈 발레리안, 분말화 자포니즈 발레리안, 괄루근, 가공 생강, 감초, 분말화 감초, 한천, 분말화 한천, 도라지, 분말화 도라지, 국화꽃, 자실, 미숙 오렌지, 강활, 살구씨, 구기자, 고삼, 분말화 고삼, 형개, 계피, 분말화 계피, 결명자, 견우자, 용담, 분말화 용담, 현초, 분말화 현초, 잇꽃, 홍삼, 향부자, 분말화 향부자, 후박, 분말화 후박, 우황, 우슬, 유오디아 열매, 우엉 열매, 오미자 열매, 쌀 전분, 칼룸바, 분말화 칼룸바, 콘두란고, 시호 열매, 족두리풀 뿌리, 사프란, 스마일락스 근경, 분말화 스마일락스 근경, 치자 열매, 분말화 치자 열매, 층층나무 열매, 자포니즈 잔톡실룸 필, 분말화 자포니즈 잔톡실룸 필, 대추씨, 산약, 분말화 산약, 지황, 가시오갈피 근경, 지골피, 자근, 질려자, 작약, 분말화 작약, 사상자, 차전자, 차전초, 약모밀, 사인, 분말화 사인, 생강, 분말화 생강, 카더몬, 승마 근경, 망춘화, 석고, 세네가, 분말화 세네가, 천궁, 분말화 천궁, 누파르 근경, 섬소, 센나 잎, 분말화 센나 잎, 당약, 분말화 당약, 창출 근경, 분말화 창출 근경, 뽕나무 껍질, 소방, 자소엽, 루바브, 분말화 루바브, 대추, 알리스마 괴경, 분말화 알리스마 괴경, 죽절삼 근경, 분말화 죽절삼 근경, 지모, 정향, 분말화 정향, 조구등, 저령, 분말화 저령, 진피, 천마 괴경, 아스파라거스 뿌리, 동아씨, 고추, 분말화 고추, 일당귀, 분말화 일당귀, 복숭아씨, 분말화 복숭아씨, 등피, 토근, 분말화 토근, 두충, 트래거캔스, 분말화 트래거캔스, 고목, 분말화 고목, 인삼, 분말화 인삼, 인동덩굴 잎 및 줄기, 프라틸라리아 구근, 맥문동, 벌꿀, 박하, 빈방풍 뿌리 및 근경, 반하, 백지, 창출, 분말화 창출, 비파잎, 빈랑, 복령, 분말화 복령, 가공 부자, 분말화 가공 부자, 베라도나 뿌리, 백편두, 한방기 줄기 및 근경, 모근, 방풍 뿌리 및 근경, 목단피, 분말화 목단피, 호미카, 패분, 분말화 패분, 마황, 이생목, 햄프 열매, 목통, 목향, 익지, 웅담, 이인, 분말화 이인, 용골, 일본 용담, 분말화 일본 용담, 고량강, 당개나리 열매, 연자, 로진, 스코폴리아 근경 등을 포함한다. Herbal medicines include Yadeok tree bark, Gambier, powdered Gambier, hydrangea tea leaves, powdered hydrangea tea leaves, aloe, powdered aloe, benzoin, clematis root, mugwort flowers, yin-yang extract, fennel, powdered fennel, turmeric, and ginger tree. Root, bearberry leaf, rose fruit, powdered rose fruit, corydalis, astragalus, golden, powdered golden, yellow crystal, yellow white, powdered yellow white, yellow yellow, powdered yellow yellow, raw paper, powdered raw paper, hagocho, knotweed root , Achul, Kulgeun, Japonis valerian, powdered Japonis valerian, brachyurysis, processed ginger, licorice, powdered licorice, agar, powdered agar, bellflower root, powdered bellflower root, chrysanthemum flower, fruiting, immature orange, strong root , apricot seed, goji berry, sophora ginseng, powdered sophora ginseng, hyunggae, cinnamon, powdered cinnamon, apricot root, gyeongwija, gentian root, powdered gentian root, hyangcho, powdered hyangcho, safflower, red ginseng, fennel root, powdered fennel root, red ginseng, powdered ginseng root Cucurbita, burdock, sycamore, euodia fruit, burdock fruit, Schisandra fruit, rice starch, calumba, powdered calumba, condurango, cypress fruit, eucalyptus root, saffron, Smilax rhizome, powdered Smilax rhizome, gardenia Fruit, powdered gardenia fruit, dogwood fruit, Japonis xanthoxylum peel, powdered Japonis xanthoxylum peel, jujube seed, acid herb, powdered acid herb, Rehmannia glutinosa, Acanthophyllum rhizome, Phalaenopsis rhododendron, rhizome root, chinensis chinensis, peony, powder Flower peony, casualty, psyllium, psyllium, medicinal ginseng, sine, powdered sine, ginger, powdered ginger, cardamom, horseback riding rhizome, mangchunhwa, gypsum, senega, powdered senega, cheongung, powdered cheongung, silkworm Parr rhizome, sorghum, senna leaf, powdered senna leaf, sugar, powdered sugar, rhizome, powdered rhizome, mulberry bark, fire, perilla leaf, rhubarb, powdered rhubarb, jujube, Alisma tuber, powder Flowered Alisma tuber, Powdered ginseng rhizome, Powdered Bamboo ginseng rhizome, Cloves, cloves, Powdered cloves, Alyssum root, Powdered Cloves, Dermis, Cheonma tubers, Asparagus root, Donga seed, Red pepper, Powdered red pepper, Angelica root, Powdered angelica root, peach seed, powdered peach seed, lanceolate, peach root, powdered peach seed, cephalic root, tragacanth, powdered tragacanth, old tree, powdered old tree, ginseng, powdered ginseng, honeysuckle leaves and stems, Fratillaria bulbs, MacMoondong, honey, peppermint, betel root and rhizome, Banha, white paper, creation, powdered creation, loquat leaves, betel nut, Bokryeong, powdered Bokryeong, processed rich, powdered processed rich, veradona root, Baekpyeondu, oriental medicine stems and rhizomes, hair roots, windbreak roots and rhizomes, wood bark, powdered wood bark, homica, shell powder, powdered shell powder, ephedra, bisaeng tree, hemp fruit, wood barrel, wood incense, ripe root, gall, gin, powder Contains Hwayin, Yonggol, Japanese Gentian, powdered Japanese Gentian, Gaoliangang, Forsythia fruit, Lotus root, Rosin, Scofolia rhizome, etc.
아미노산은 L-시스테인, 칼륨 및 마그네슘 아스파르테이트의 등량 혼합물, L-발린, L-류신, L-이소로신, 타우린 등을 포함한다.Amino acids include L-cysteine, an equal mixture of potassium and magnesium aspartate, L-valine, L-leucine, L-isorosine, taurine, etc.
본 발명의 고형 제제는 알파 전분에 추가로, 고형 제제를 제조하는데 일반적으로 사용되는 부형제, 결합제, 붕괴제, 윤활제, 활택제, 착색제, pH 조절제, 감미제 및 향료와 같은 첨가제를 함유할 수 있다.In addition to alpha starch, the solid formulation of the present invention may contain additives commonly used in preparing solid formulations, such as excipients, binders, disintegrants, lubricants, lubricants, colorants, pH adjusters, sweeteners, and flavoring agents.
부형제는 예를 들어, 에리트리톨, 말티톨, 분말 수소화 말토오스 전분 시럽, 만니톨, 수크로오스, 백당, 트레할로오스, 소르비톨, 자일리톨, 락토오스, 수소화 말토오스 전분 시럽, 글루코오스, 말토오스, 락티톨, 옥수수 전분, 결정질 셀룰로오스, 분말화 셀룰로오스, 칼슘 모노히드로겐 포스페이트, 이염기성 칼슘 포스페이트, 무수 이염기성 칼슘 포스페이트, 칼슘 락테이트, 침강 칼슘 카르보네이트 등을 포함한다.Excipients include, for example, erythritol, maltitol, powdered hydrogenated maltose starch syrup, mannitol, sucrose, white sugar, trehalose, sorbitol, xylitol, lactose, hydrogenated maltose starch syrup, glucose, maltose, lactitol, corn starch, crystalline Includes cellulose, powdered cellulose, calcium monohydrogen phosphate, dibasic calcium phosphate, dibasic anhydrous calcium phosphate, calcium lactate, precipitated calcium carbonate, etc.
결합제는 예를 들어, 분말화 아카시아, 히드록시프로필셀룰로오스 (HPC), 히프로멜로오스, 메틸셀룰로오스, 히드록시에틸 셀룰로오스, 카르복시메틸에틸 셀룰로오스, 포비돈 (PVP), 폴리비닐 알코올 (PVA), 풀루란, 덱스트린, 히드록시프로필 전분, 분말화 트래거캔스, 결정질 셀룰로오스, 저치환도 히드록시프로필셀룰로오스 (L-HPC) 등을 포함한다.Binders include, for example, powdered acacia, hydroxypropylcellulose (HPC), hypromellose, methylcellulose, hydroxyethyl cellulose, carboxymethylethyl cellulose, povidone (PVP), polyvinyl alcohol (PVA), pullulan. , dextrin, hydroxypropyl starch, powdered tragacanth, crystalline cellulose, low-substituted hydroxypropylcellulose (L-HPC), etc.
붕괴제는 예를 들어, 크로스카르멜로오스 나트륨, 저치환도 히드록시프로필셀룰로오스, 카르멜로오스 칼슘, 옥수수 전분, 나트륨 카르복시메틸 전분, 히드록시프로필 전분, 크로스포비돈 등을 포함한다.Disintegrants include, for example, croscarmellose sodium, low-substituted hydroxypropylcellulose, carmellose calcium, corn starch, sodium carboxymethyl starch, hydroxypropyl starch, crospovidone, and the like.
윤활제는 예를 들어, 마그네슘 스테아레이트, 칼슘 스테아레이트, 수크로오스 지방산 에스테르, 탈크, 마크로골 6000 등을 포함한다.Lubricants include, for example, magnesium stearate, calcium stearate, sucrose fatty acid ester, talc, Macrogol 6000, etc.
활택제는 예를 들어, 경질 무수 규산, 수화 이산화규소, 카올린 등을 포함한다.Lubricants include, for example, light anhydrous silicic acid, hydrated silicon dioxide, kaolin, etc.
착색제는 예를 들어, 리보플라빈, 비타민 B12, 산화티탄, 황색 산화제2철, 적색 산화제2철, 식용 적색 제 2 호, 식용 적색 제 3 호, 식용 적색 제 102 호, 식용 적색 제 104 호, 식용 적색 제 105 호, 식용 적색 제 106 호, 식용 황색 제 4 호, 식용 황색 제 5 호, 식용 녹색 제 3 호, 식용 청색 제 1 호, 식용 청색 제 2 호, 나트륨 구리 클로로필, 구리 클로로필 등을 포함한다.Colorants are, for example, riboflavin, vitamin B 12 , titanium oxide, yellow ferric oxide, red ferric oxide, food grade Red No. 2, food grade Red No. 3, food grade Red No. 102, food grade Red No. 104, food grade. Includes Red No. 105, Edible Red No. 106, Edible Yellow No. 4, Edible Yellow No. 5, Edible Green No. 3, Edible Blue No. 1, Edible Blue No. 2, Sodium Copper Chlorophyll, Copper Chlorophyll, etc. do.
pH 조절제는 예를 들어, 나트륨 히드록시드, 나트륨 시트레이트, 염산, 나트륨 바이카르보네이트, 나트륨 카르보네이트, 칼슘 락테이트, 인산, 이칼륨 포스페이트, 이염기성 나트륨 포스페이트, 칼륨 디히드로겐 포스페이트, 나트륨 디히드로겐 포스페이트 등을 포함한다.pH adjusting agents include, for example, sodium hydroxide, sodium citrate, hydrochloric acid, sodium bicarbonate, sodium carbonate, calcium lactate, phosphoric acid, dipotassium phosphate, dibasic sodium phosphate, potassium dihydrogen phosphate, Contains sodium dihydrogen phosphate, etc.
감미제는 예를 들어, 아스파탐, 스테비아, 이칼륨 글리시리지네이트, 아세술팜 K, 수크랄로오스 등을 포함한다.Sweeteners include, for example, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame K, sucralose, etc.
향료는 예를 들어, L-멘톨, 페퍼민트 오일, 유칼립투스 오일, 오렌지 오일, 정향 오일, 터펜타인 오일, 회향 오일, 바닐린 등을 포함한다.Flavoring agents include, for example, L-menthol, peppermint oil, eucalyptus oil, orange oil, clove oil, turpentine oil, fennel oil, vanillin, etc.
본 발명의 고형 제제는 수용성 중합체 (히프로멜로오스, 히드록시프로필셀룰로오스, 메틸셀룰로오스, 폴리비닐 알코올 (PVA) 등), 불용성 중합체 (에틸셀룰로오스, 메타크릴산 공중합체 등), 당류 (수크로오스, 에리트리톨 등), 폴리비닐 알코올 (PVA) 및 폴리에틸렌 글리콜 (PEG) 의 그래프트 공중합체 (Kollicoat IR, BASF) 등으로 코팅될 수 있다.The solid preparation of the present invention contains water-soluble polymers (hypromellose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol (PVA), etc.), insoluble polymers (ethylcellulose, methacrylic acid copolymer, etc.), sugars (sucrose, erythate, etc.) litol, etc.), graft copolymers of polyvinyl alcohol (PVA) and polyethylene glycol (PEG) (Kollicoat IR, BASF), etc.
코팅을 위해서는, 부형제 (탈크, 침강 칼슘 카르보네이트, 산화티탄 등), 윤활제 (마크로골 6000, 마그네슘 스테아레이트 등), 결합제 (분말화 아카시아, 결정질 셀룰로오스, 메틸셀룰로오스, 히드록시프로필셀룰로오스, 히프로멜로오스, 덱스트린, 폴리비닐 알코올 (PVA) 등), 염료 (리보플라빈, 황색 산화제2철 등) 가 첨가될 수 있다. 대안적으로, 프리믹스 코팅 용액 (Opadry, Nippon Colorcon) 을 사용할 수 있다.For coating, excipients (talc, precipitated calcium carbonate, titanium oxide, etc.), lubricants (Macrogol 6000, magnesium stearate, etc.), binders (powdered acacia, crystalline cellulose, methylcellulose, hydroxypropylcellulose, hypro) Melose, dextrin, polyvinyl alcohol (PVA), etc.), dyes (riboflavin, yellow ferric oxide, etc.) may be added. Alternatively, premix coating solutions (Opadry, Nippon Colorcon) can be used.
본 발명의 고형 제제에서, 부형제로서 첨가될 수 있는 결정질 셀룰로오스의 함량은 가능한 한 적은 것이 바람직하다. 결정질 셀룰로오스의 함량을 감소시킴으로써, 외관의 변화를 보다 현저하게 억제할 수 있다. 구체적으로는, 본 발명의 고형 제제 중 결정질 셀룰로오스의 함량은 바람직하게는 8 질량% 이하, 보다 바람직하게는 5 질량% 이하이다.In the solid preparation of the present invention, the content of crystalline cellulose that can be added as an excipient is preferably as small as possible. By reducing the content of crystalline cellulose, changes in appearance can be more significantly suppressed. Specifically, the content of crystalline cellulose in the solid preparation of the present invention is preferably 8% by mass or less, more preferably 5% by mass or less.
본 발명의 고형 제제는 바람직하게는, 외관 변화를 억제하는 목적을 위해 코팅된다. 코팅제는 바람직하게는 수용성 중합체, 특히 바람직하게는 히프로멜로오스이다.The solid preparation of the present invention is preferably coated for the purpose of suppressing changes in appearance. The coating agent is preferably a water-soluble polymer, particularly preferably hypromellose.
코팅량은 중심정 (core tablet) 의 질량비를 기준으로, 바람직하게는 약 1 내지 6%, 특히 바람직하게는 약 2 내지 4% 이다.The coating amount is preferably about 1 to 6%, particularly preferably about 2 to 4%, based on the mass ratio of the core tablet.
본 발명의 고형 제제는 각종 정제, 예컨대 중심정, 필름 코팅정, 당의정, 박층 당의정, 무가당 박층 당의정, 경구 붕해정, 츄어블정 및 초콜릿정, 과립, 세립, 캡슐 등을 포함한다. 추가로, 2층 정제, 3층 정제 및 유핵정이 또한 포함된다.The solid preparation of the present invention includes various tablets, such as core tablets, film-coated tablets, dragees, thin-layer dragees, sugar-free thin-layer dragees, orally disintegrating tablets, chewable tablets and chocolate tablets, granules, fine granules, capsules, etc. Additionally, two-layer tablets, three-layer tablets and nucleated tablets are also included.
본 발명의 고형 제제의 제조 방법은 [Handbook of Granulation (The Association of Powder Process Industry and Engineering, JAPAN, Ohmusha Ltd.), Formulation Design of Oral Dosage Forms (Prof. Mitsuru Hashida, Kyoto University, Graduate Schools, Faculty of Pharmaceutical Sciences, Yakugyo Jiho Co., Ltd. 편)], [Compression Technology of Powder (The Society of Powder Technology, Japan / Division of Particulate Design and Preparations, Nikkan Kogyo Shimbun, Ltd. 편)], 및 [Handbook of Pharmaceutical Machinery and Engineering (2nd edition, Publishing and Editorial Committee of the 20th Anniversary of Japan Society of Pharmaceutical Machinery and Engineering, Japan Society of Pharmaceutical Machinery and Engineering 편)] 과 같은 발행물에 기재된 바와 같은 통상의 방법을 포함할 수 있으나 이에 제한되지 않는다. The manufacturing method of the solid preparation of the present invention is described in [Handbook of Granulation (The Association of Powder Process Industry and Engineering, JAPAN, Ohmusha Ltd.), Formulation Design of Oral Dosage Forms (Prof. Mitsuru Hashida, Kyoto University, Graduate Schools, Faculty of Pharmaceutical Sciences, edited by Yakugyo Jiho Co., Ltd.], [Compression Technology of Powder (The Society of Powder Technology, Japan / Division of Particulate Design and Preparations, edited by Nikkan Kogyo Shimbun, Ltd.)], and [Handbook of Pharmaceutical It may include conventional methods as described in publications such as Machinery and Engineering ( 2nd edition, Publishing and Editorial Committee of the 20th Anniversary of Japan Society of Pharmaceutical Machinery and Engineering, Japan Society of Pharmaceutical Machinery and Engineering)] It is not limited to this.
본 발명은 또한, 알파 전분과 같은 가공 전분을 고형 제제에 첨가하는 것을 포함하는, 니코틴산 부류 및 비타민 B1 부류를 포함하는 고형 제제의 외관 변화 (두께 팽윤, 균열 등) 를 억제하는 방법을 제공한다. 이러한 방법에서의 요소 (구성성분, 그의 사용량, 그의 사용 비율 등) 는 본 발명의 고형 제제에 대해 기재된 바와 같다. 예를 들어, 가공 전분은 1 질량부의 니코틴산 부류에 대해 바람직하게는 0.5 질량부 이상, 보다 바람직하게는 3 질량부 이상, 더 바람직하게는 3.5 질량부 이상 10 질량부 이하의 양으로 첨가된다. The present invention also provides a method for suppressing changes in appearance (thickness swelling, cracking, etc.) of solid formulations containing the nicotinic acid class and vitamin B 1 class, comprising adding a processed starch, such as alpha starch, to the solid formulation. . The elements in this method (constituents, their usage amount, their usage ratio, etc.) are as described for the solid preparation of the present invention. For example, the processed starch is preferably added in an amount of 0.5 parts by mass or more, more preferably 3 parts by mass or more, and even more preferably 3.5 parts by mass or more and 10 parts by mass or less, based on 1 part by mass of nicotinic acid.
가공 전분이 알파 전분인 경우, 알파 전분은 1 질량부의 니코틴산 부류에 대해 바람직하게는 0.5 질량부 이상, 바람직하게는 1 질량부 이상 20 질량부 이하, 보다 바람직하게는 3 질량부 이상 10 질량부 이하, 더 바람직하게는 3.5 질량부 이상 10 질량부 이하의 양으로 첨가된다.When the processed starch is alpha starch, the amount of alpha starch is preferably 0.5 parts by mass or more, preferably 1 part by mass or more and 20 parts by mass or less, more preferably 3 parts by mass or more and 10 parts by mass or less, relative to 1 part by mass of nicotinic acid. , more preferably added in an amount of 3.5 parts by mass or more and 10 parts by mass or less.
실시예Example
본 발명을 이하 실시예를 참조로 하여 보다 상세히 설명하지만, 본 발명이 이에 제한되는 것은 아니다. The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.
(실시예 1)(Example 1)
니코틴아미드 (Lonza Japan), 리보플라빈 (BASF JAPAN), 피리독신 히드로클로라이드 (BASF JAPAN), 결정질 셀룰로오스 (CEOLUS PH-101, Asahi Kasei) 및 부분 알파 전분 (PCS, Asahi Kasei) 을 유동층 건조기에 충전하였다. 히드록시프로필셀룰로오스 (HPC, Nippon Soda) 용액 및 히프로멜로오스 (TC-5, Shin-Etsu Chemical) 용액을 이에 분무하고, 혼합물을 과립화하고 건조시켰다. 그런 다음, 과립을 밀링 머신 (Power Mill) 에 의해 밀링하여, 밀링된 분말 1 을 수득하였다. 밀링된 분말 1 의 조성비는 니코틴아미드 11.1%, 리보플라빈 3.3%, 피리독신 히드로클로라이드 13.9%, 결정질 셀룰로오스 (CEOLUS PH-101, Asahi Kasei) 8.4%, 부분 알파 전분 50.0%, HPC 3.3%, 및 TC-5 10% 였다.Nicotinamide (Lonza Japan), riboflavin (BASF JAPAN), pyridoxine hydrochloride (BASF JAPAN), crystalline cellulose (CEOLUS PH-101, Asahi Kasei) and partial alpha starch (PCS, Asahi Kasei) were charged into a fluidized bed dryer. Hydroxypropylcellulose (HPC, Nippon Soda) solution and hypromellose (TC-5, Shin-Etsu Chemical) solution were sprayed thereon, and the mixture was granulated and dried. Then, the granules were milled by a milling machine (Power Mill) to obtain milled powder 1. The composition of milled powder 1 is 11.1% nicotinamide, 3.3% riboflavin, 13.9% pyridoxine hydrochloride, 8.4% crystalline cellulose (CEOLUS PH-101, Asahi Kasei), 50.0% partial alpha starch, 3.3% HPC, and TC-5. It was 10%.
또한, 푸르술티아민 히드로클로라이드 (Mikuni Pharmaceutical) 및 결정질 셀룰로오스 (CEOLUS PH-101, Asahi Kasei) 를 유동층 건조기에 충전하였다. 히드록시프로필셀룰로오스 (HPC, Nippon Soda) 용액을 이에 분무하고, 혼합물을 과립화하고 건조시켰다. 그런 다음, 과립을 밀링 머신 (Power Mill) 에 의해 밀링하여, 밀링된 분말 2 를 수득하였다. 밀링된 분말 2 의 조성비는 푸르술티아민 히드로클로라이드 60.6%, 결정질 셀룰로오스 35.4%, 및 HPC 4% 였다.Additionally, fursultiamine hydrochloride (Mikuni Pharmaceutical) and crystalline cellulose (CEOLUS PH-101, Asahi Kasei) were charged into the fluidized bed dryer. Hydroxypropylcellulose (HPC, Nippon Soda) solution was sprayed thereon, and the mixture was granulated and dried. Then, the granules were milled by a milling machine (Power Mill) to obtain milled powder 2. The composition ratio of milled powder 2 was 60.6% fursultiamine hydrochloride, 35.4% crystalline cellulose, and 4% HPC.
밀링된 분말 1: 720 g, 밀링된 분말 2: 360 g, 칼슘 판토테네이트 S 형 (BASF JAPAN) 92.4 g, VB12 세립 (Mitsubishi Chemical Foods) 13.2 g, 결정질 셀룰로오스 (CEOLUS PH-101, Asahi Kasei) 127.3 g 및 마그네슘 스테아레이트 (Taihei Chemical Industrial) 6.6 g 을 혼합하여, 타정용 혼합 분말을 수득하였다. 생성된 타정용 혼합 분말을, 220 mg 의 질량을 갖는 중심정이 수득되도록, 8.5 mmφ 펀치를 갖는 회전식 타정기 (AQU3, Kikusui Seisakusho) 를 사용하여 타정하여, 두께 4.8 mm 의 중심정을 수득하였다.Milled Powder 1: 720 g, Milled Powder 2: 360 g, Calcium Pantothenate Type S (BASF JAPAN) 92.4 g, VB12 fine grain (Mitsubishi Chemical Foods) 13.2 g, Crystalline Cellulose (CEOLUS PH-101, Asahi Kasei) 127.3 g and 6.6 g of magnesium stearate (Taihei Chemical Industrial) were mixed to obtain a mixed powder for tableting. The resulting mixed powder for tableting was compressed using a rotary tablet press (AQU3, Kikusui Seisakusho) with an 8.5 mmϕ punch to obtain a core tablet with a mass of 220 mg, thereby obtaining a core tablet with a thickness of 4.8 mm.
그런 다음, 중심정을 히프로멜로오스 (Shin-Etsu Chemical) 및 멸균 탈크 (Matsumura Sangyo) 를 정제수에 용해 또는 분산하여 수득한 언더코트 용액, 및 에리트리톨 (Cargill Japan), 멸균 탈크, 침강 칼슘 카르보네이트 (Nitto Powder Chemical), 산화티탄 (Ishihara Sangyo), 결정질 셀룰로오스 (CEOLUS PH-F20, Asahi Kasei) 및 분말화 아카시아 (San-Ei Yakuhin Boeki) 를 정제수에 용해 또는 분산하여 수득한 빌드업 코팅 용액으로, 코팅기 (Doria Coater, Powrex) 를 사용하여 코팅하여, 5 mg/정제 및 96 mg/정제의 코팅 층을 갖는 코팅정을 수득하였다. 그런 다음, 코팅정을 수크로오스 (Mitsui Sugar), 에리트리톨 및 리보플라빈을 정제수에 용해하여 수득한 시럽 용액으로, 당의 팬 (sugar coating pan) (Kikusui Seisakusho) 을 사용하여 추가 코팅하여, 24 mg/정제의 당의를 갖는 당의정을 수득하였다. Then, the core tablets were coated with an undercoat solution obtained by dissolving or dispersing hypromellose (Shin-Etsu Chemical) and sterilized talc (Matsumura Sangyo) in purified water, and erythritol (Cargill Japan), sterilized talc, and precipitated calcium carbonate. Build-up coating solution obtained by dissolving or dispersing bonate (Nitto Powder Chemical), titanium oxide (Ishihara Sangyo), crystalline cellulose (CEOLUS PH-F20, Asahi Kasei), and powdered acacia (San-Ei Yakuhin Boeki) in purified water. By coating using a coating machine (Doria Coater, Powrex), coated tablets with a coating layer of 5 mg/tablet and 96 mg/tablet were obtained. Then, the coated tablets were further coated with a syrup solution obtained by dissolving sucrose (Mitsui Sugar), erythritol, and riboflavin in purified water using a sugar coating pan (Kikusui Seisakusho), giving a concentration of 24 mg/tablet. A dragee having a sugar content was obtained.
(실시예 2)(Example 2)
니코틴아미드 (Lonza Japan), 리보플라빈 (BASF JAPAN), 피리독신 히드로클로라이드 (BASF JAPAN), 결정질 셀룰로오스 (CEOLUS PH-101, Asahi Kasei) 및 알파 전분 (PD-1, Asahi Kasei) 을 유동층 건조기에 충전하였다. 히드록시프로필셀룰로오스 (HPC, Nippon Soda) 용액 및 히프로멜로오스 (TC-5, Shin-Etsu Chemical) 용액을 이에 분무하고, 혼합물을 과립화하고 건조시켰다. 그런 다음, 과립을 밀링 머신 (Power Mill) 에 의해 밀링하여, 밀링된 분말 1 을 수득하였다. 밀링된 분말 1 의 조성비는 니코틴아미드 12.4%, 리보플라빈 3.7%, 피리독신 히드로클로라이드 15.5%, 결정질 셀룰로오스 7.7%, 알파 전분 49.6%, HPC 2.0%, 및 TC-5 9.1% 였다.Nicotinamide (Lonza Japan), riboflavin (BASF JAPAN), pyridoxine hydrochloride (BASF JAPAN), crystalline cellulose (CEOLUS PH-101, Asahi Kasei) and alpha starch (PD-1, Asahi Kasei) were charged into a fluidized bed dryer. Hydroxypropylcellulose (HPC, Nippon Soda) solution and hypromellose (TC-5, Shin-Etsu Chemical) solution were sprayed thereon, and the mixture was granulated and dried. Then, the granules were milled by a milling machine (Power Mill) to obtain milled powder 1. The composition of milled powder 1 was 12.4% nicotinamide, 3.7% riboflavin, 15.5% pyridoxine hydrochloride, 7.7% crystalline cellulose, 49.6% alpha starch, 2.0% HPC, and 9.1% TC-5.
또한, 푸르술티아민 히드로클로라이드 (Mikuni Pharmaceutical) 및 결정질 셀룰로오스를 유동층 건조기에 충전하였다. 히드록시프로필셀룰로오스 (HPC, Nippon Soda) 용액을 이에 분무하고, 혼합물을 과립화하고 건조시켰다. 그런 다음, 과립을 밀링 머신 (Power Mill) 에 의해 밀링하여, 밀링된 분말 2 를 수득하였다. 밀링된 분말 2 의 조성비는 푸르술티아민 히드로클로라이드 72.8%, 결정질 셀룰로오스 24.2%, 및 HPC 3% 였다.Additionally, fursultiamine hydrochloride (Mikuni Pharmaceutical) and crystalline cellulose were charged into the fluidized bed dryer. Hydroxypropylcellulose (HPC, Nippon Soda) solution was sprayed thereon, and the mixture was granulated and dried. Then, the granules were milled by a milling machine (Power Mill) to obtain milled powder 2. The composition ratio of milled powder 2 was 72.8% fursultiamine hydrochloride, 24.2% crystalline cellulose, and 3% HPC.
생성된 밀링된 분말 1: 644.8 g, 밀링된 분말 2: 300 g, 칼슘 판토테네이트 S 형 (BASF JAPAN) 92.4 g, VB12 세립 (Mitsubishi Chemical Foods) 12 g, 결정질 셀룰로오스 (CEOLUS PH-101, Asahi Kasei) 79.4 g, Sylysia (Fuji Silysia) 5.7 g 및 마그네슘 스테아레이트 (Taihei Chemical Industrial) 5.7 g 을 혼합하여, 타정용 혼합 분말을 수득하였다. 생성된 타정용 혼합 분말을, 190 mg 의 질량을 갖는 중심정이 수득되도록, 8.0 mmφ 펀치를 갖는 회전식 타정기 (AQU3, Kikusui Seisakusho) 를 사용하여 타정하여, 두께 4.2 mm 의 중심정을 수득하였다.Resulting milled powder 1: 644.8 g, milled powder 2: 300 g, calcium pantothenate S type (BASF JAPAN) 92.4 g, VB12 fine grain (Mitsubishi Chemical Foods) 12 g, crystalline cellulose (CEOLUS PH-101, Asahi) Kasei) 79.4 g, Sylysia (Fuji Silysia) 5.7 g, and magnesium stearate (Taihei Chemical Industrial) 5.7 g were mixed to obtain a mixed powder for tableting. The resulting mixed powder for tableting was tableted using a rotary tablet press (AQU3, Kikusui Seisakusho) with an 8.0 mm phi punch so as to obtain a core tablet with a mass of 190 mg, and a core tablet with a thickness of 4.2 mm was obtained.
그런 다음, 중심정을 히프로멜로오스 (Shin-Etsu Chemical) 및 멸균 탈크 (Matsumura Sangyo) 를 정제수에 용해 또는 분산하여 수득한 언더코트 용액, 및 에리트리톨 (Cargill Japan), 멸균 탈크, 산화티탄 (Ishihara Sangyo), 결정질 셀룰로오스 (CEOLUS PH-F20, Asahi Kasei) 및 분말화 아카시아 (San-Ei Yakuhin Boeki) 를 정제수에 용해 또는 분산하여 수득한 빌드업 코팅 용액으로, 코팅기 (Doria Coater, Powrex) 를 사용하여 코팅하여, 5 mg/정제 및 115 mg/정제의 코팅 층을 갖는 코팅정을 수득하였다. 그런 다음, 코팅정을 수크로오스 (Mitsui Sugar), 에리트리톨 및 리보플라빈을 정제수에 용해하여 수득한 시럽 용액으로, 당의 팬 (Kikusui Seisakusho) 을 사용하여 추가 코팅하여, 22 mg/정제의 당의를 갖는 당의점을 수득하였다. Then, the core tablet was coated with an undercoat solution obtained by dissolving or dispersing hypromellose (Shin-Etsu Chemical) and sterilized talc (Matsumura Sangyo) in purified water, and erythritol (Cargill Japan), sterilized talc, and titanium oxide ( Ishihara Sangyo), a build-up coating solution obtained by dissolving or dispersing crystalline cellulose (CEOLUS PH-F20, Asahi Kasei) and powdered acacia (San-Ei Yakuhin Boeki) in purified water, using a coater (Doria Coater, Powrex) By coating, coated tablets having a coating layer of 5 mg/tablet and 115 mg/tablet were obtained. Then, the coated tablets were further coated with a syrup solution obtained by dissolving sucrose (Mitsui Sugar), erythritol, and riboflavin in purified water using a sugar pan (Kikusui Seisakusho) to obtain a sugar coating with a sugar coating of 22 mg/tablet. was obtained.
(실시예 3)(Example 3)
니코틴아미드 (Lonza Japan), 리보플라빈 (BASF JAPAN), 피리독신 히드로클로라이드 (BASF JAPAN), 락토오스 히드레이트 (GranuLac 200, Meggle) 및 부분 알파 전분 (PCS, Asahi Kasei) 을 유동층 건조기에 충전하였다. 히드록시프로필셀룰로오스 (HPC, Nippon Soda) 용액 및 히프로멜로오스 (TC-5, Shin-Etsu Chemical) 용액을 이에 분무하고, 혼합물을 과립화하고 건조시켰다. 그런 다음, 과립을 밀링 머신 (Power Mill) 에 의해 밀링하여, 밀링된 분말 1 을 수득하였다. 밀링된 분말 1 의 조성비는 니코틴아미드 12.1%, 리보플라빈 3.6%, 피리독신 히드로클로라이드 15.2%, 락토오스 히드레이트 19.4%, 부분 알파 전분 36.4%, HPC 3.3%, 및 TC-5 10% 였다.Nicotinamide (Lonza Japan), riboflavin (BASF JAPAN), pyridoxine hydrochloride (BASF JAPAN), lactose hydrate (GranuLac 200, Meggle) and partial alpha starch (PCS, Asahi Kasei) were charged to a fluidized bed dryer. Hydroxypropylcellulose (HPC, Nippon Soda) solution and hypromellose (TC-5, Shin-Etsu Chemical) solution were sprayed thereon, and the mixture was granulated and dried. Then, the granules were milled by a milling machine (Power Mill) to obtain milled powder 1. The composition of milled powder 1 was 12.1% nicotinamide, 3.6% riboflavin, 15.2% pyridoxine hydrochloride, 19.4% lactose hydrate, 36.4% partial alpha starch, 3.3% HPC, and 10% TC-5.
또한, 푸르술티아민 히드로클로라이드 (Mikuni Pharmaceutical) 및 결정질 셀룰로오스 (CEOLUS PH-101, Asahi Kasei) 를 유동층 건조기에 충전하였다. 히드록시프로필셀룰로오스 (HPC, Nippon Soda) 용액을 이에 분무하고, 혼합물을 과립화하고 건조시켰다. 그런 다음, 과립을 밀링 머신 (Power Mill) 에 의해 밀링하여, 밀링된 분말 2 를 수득하였다. 밀링된 분말 2 의 조성비는 푸르술티아민 히드로클로라이드 60.6%, 결정질 셀룰로오스 (CEOLUS PH-101, Asahi Kasei) 35.4%, 및 HPC 4% 였다.Additionally, fursultiamine hydrochloride (Mikuni Pharmaceutical) and crystalline cellulose (CEOLUS PH-101, Asahi Kasei) were charged into the fluidized bed dryer. Hydroxypropylcellulose (HPC, Nippon Soda) solution was sprayed thereon, and the mixture was granulated and dried. Then, the granules were milled by a milling machine (Power Mill) to obtain milled powder 2. The composition of milled powder 2 was 60.6% fursultiamine hydrochloride, 35.4% crystalline cellulose (CEOLUS PH-101, Asahi Kasei), and 4% HPC.
생성된 밀링된 분말 1: 660 g, 밀링된 분말 2: 360 g, 칼슘 판토테네이트 S 형 (BASF JAPAN) 92.4 g, VB12 세립 (Mitsubishi Chemical Foods) 13.2 g, 옥수수 전분 69 g, 결정질 셀룰로오스 (CEOLUS PH-101, Asahi Kasei) 78 g, Sylysia (Fuji Silysia) 5.7 g 및 마그네슘 스테아레이트 (Taihei Chemical Industrial) 5.7 g 을 혼합하여, 타정용 혼합 분말을 수득하였다. 생성된 타정용 혼합 분말을, 210 mg 의 질량을 갖는 중심정이 수득되도록, 8.3 mmφ 펀치를 갖는 회전식 타정기 (AQU3, Kikusui Seisakusho) 를 사용하여 타정하여, 두께 4.3 mm 의 중심정을 수득하였다.Resulting milled powder 1: 660 g, milled powder 2: 360 g, calcium pantothenate S type (BASF JAPAN) 92.4 g, VB12 fine grain (Mitsubishi Chemical Foods) 13.2 g, corn starch 69 g, crystalline cellulose (CEOLUS) 78 g of PH-101 (Asahi Kasei), 5.7 g of Sylysia (Fuji Silysia), and 5.7 g of magnesium stearate (Taihei Chemical Industrial) were mixed to obtain a mixed powder for tableting. The resulting mixed powder for tableting was compressed using a rotary tablet press (AQU3, Kikusui Seisakusho) with an 8.3 mm ϕ punch to obtain a core tablet with a mass of 210 mg, thereby obtaining a core tablet with a thickness of 4.3 mm.
그런 다음, 중심정을 히프로멜로오스 (Shin-Etsu Chemical) 및 멸균 탈크 (Matsumura Sangyo) 를 정제수에 용해 또는 분산하여 수득한 언더코트 용액, 및 에리트리톨 (Cargill Japan), 멸균 탈크, 침강 칼슘 카르보네이트 (Nitto Powder Chemical), 산화티탄 (Ishihara Sangyo), 결정질 셀룰로오스 (CEOLUS PH-F20, Asahi Kasei) 및 분말화 아카시아 (San-Ei Yakuhin Boeki) 를 정제수에 용해 또는 분산하여 수득한 빌드업 코팅 용액으로, 코팅기 (Doria Coater, Powrex) 를 사용하여 코팅하여, 5 mg/정제 및 96 mg/정제의 코팅 층을 갖는 코팅정을 수득하였다. 그런 다음, 코팅정을 수크로오스 (Mitsui Sugar), 에리트리톨 및 리보플라빈을 정제수에 용해하여 수득한 시럽 용액으로, 당의 팬 (Kikusui Seisakusho) 을 사용하여 추가 코팅하여, 24 mg/정제의 당의를 갖는 당의점을 수득하였다.Then, the core tablets were coated with an undercoat solution obtained by dissolving or dispersing hypromellose (Shin-Etsu Chemical) and sterilized talc (Matsumura Sangyo) in purified water, and erythritol (Cargill Japan), sterilized talc, and precipitated calcium carbonate. Build-up coating solution obtained by dissolving or dispersing bonate (Nitto Powder Chemical), titanium oxide (Ishihara Sangyo), crystalline cellulose (CEOLUS PH-F20, Asahi Kasei), and powdered acacia (San-Ei Yakuhin Boeki) in purified water. By coating using a coating machine (Doria Coater, Powrex), coated tablets with a coating layer of 5 mg/tablet and 96 mg/tablet were obtained. Then, the coated tablets were further coated with a syrup solution obtained by dissolving sucrose (Mitsui Sugar), erythritol, and riboflavin in purified water using a sugar pan (Kikusui Seisakusho) to obtain a sugar coating with a sugar coating of 24 mg/tablet. was obtained.
(실시예 4)(Example 4)
리보플라빈 (BASF JAPAN), 피리독신 히드로클로라이드 (BASF JAPAN), 락토오스 히드레이트 (GranuLac 200, Meggle) 및 옥수수 전분 (Japan Corn Starch) 을 유동층 건조기에 충전하였다. 히드록시프로필셀룰로오스 (HPC, Nippon Soda) 용액을 이에 분무하고, 혼합물을 과립화하고 건조시켰다. 그런 다음, 과립을을 밀링 머신 (Power Mill) 에 의해 밀링하여, 밀링된 분말 1 을 수득하였다. 밀링된 분말 1 의 조성비는 리보플라빈 8.8%, 피리독신 히드로클로라이드 37.0%, 락토오스 히드레이트 30.2%, 옥수수 전분 20%, 및 HPC 4% 였다.Riboflavin (BASF JAPAN), pyridoxine hydrochloride (BASF JAPAN), lactose hydrate (GranuLac 200, Meggle) and corn starch (Japan Corn Starch) were charged into a fluidized bed dryer. Hydroxypropylcellulose (HPC, Nippon Soda) solution was sprayed thereon, and the mixture was granulated and dried. Then, the granules were milled by a milling machine (Power Mill) to obtain milled powder 1. The composition ratio of milled powder 1 was 8.8% riboflavin, 37.0% pyridoxine hydrochloride, 30.2% lactose hydrate, 20% corn starch, and 4% HPC.
또한, 푸르술티아민 히드로클로라이드 (Mikuni Pharmaceutical), 니코틴아미드 (Lonza Japan), 옥수수 전분, 부분 알파 전분 (PCS, Asahi Kasei) 및 결정질 셀룰로오스를 유동층 건조기에 충전하였다. 히드록시프로필셀룰로오스 (HPC, Nippon Soda) 용액을 이에 분무하고, 혼합물을 과립화하고 건조시켰다. 그런 다음, 과립을 밀링 머신 (Power Mill) 에 의해 밀링하여, 밀링된 분말 2 를 수득하였다. 밀링된 분말 2 의 조성비는 푸르술티아민 히드로클로라이드 36.4%, 니코틴아미드 13.3%, 옥수수 전분 4.8%, 부분 알파 전분 40.0%, 결정질 셀룰로오스 2.0%, 및 HPC 3.5% 였다.Additionally, fursultiamine hydrochloride (Mikuni Pharmaceutical), nicotinamide (Lonza Japan), corn starch, partial alpha starch (PCS, Asahi Kasei), and crystalline cellulose were charged into the fluidized bed dryer. Hydroxypropylcellulose (HPC, Nippon Soda) solution was sprayed thereon, and the mixture was granulated and dried. Then, the granules were milled by a milling machine (Power Mill) to obtain milled powder 2. The composition of milled powder 2 was 36.4% fursultiamine hydrochloride, 13.3% nicotinamide, 4.8% corn starch, 40.0% partial alpha starch, 2.0% crystalline cellulose, and 3.5% HPC.
시아노코발라민 용액을 부분 알파 전분 및 옥수수 전분에 분무한 후, 히프로멜로오스 용액을 이에 분무하고, 혼합물을 과립화하고 건조시켰다. 그런 다음, 과립을 밀링 머신 (Power Mill) 에 의해 밀링하여, 밀링된 분말 3 을 수득하였다. 밀링된 분말 3 의 조성비는 시아노코발라민 0.09%, 부분 알파 전분 90.76%, 옥수수 전분 0.06%, 및 히프로멜로오스 9.09% 였다.The cyanocobalamin solution was sprayed onto the partial alpha starch and corn starch, followed by the hypromellose solution, and the mixture was granulated and dried. Then, the granules were milled by a milling machine (Power Mill) to obtain milled powder 3. The composition ratio of milled powder 3 was 0.09% cyanocobalamin, 90.76% partial alpha starch, 0.06% corn starch, and 9.09% hypromellose.
생성된 밀링된 분말 1: 270 g, 밀링된 분말 2: 600 g, 밀링된 분말 3: 132 g, 칼슘 판토테네이트 S 형 (BASF JAPAN) 92.4 g, 옥수수 전분 21.6 g, 결정질 셀룰로오스 (CEOLUS PH-101, Asahi Kasei) 72 g, Sylysia (Fuji Silysia) 6.0 g 및 마그네슘 스테아레이트 (Taihei Chemical Industrial) 6.0 g 을 혼합하여, 타정용 혼합 분말을 수득하였다. 생성된 타정용 혼합 분말을, 190 mg 의 질량을 갖는 중심정이 수득되도록, 8.3 mmφ 펀치를 갖는 회전식 타정기 (AQU3, Kikusui Seisakusho) 를 사용하여 타정하여, 두께 4.2 mm 의 중심정을 수득하였다.Resulting Milled Powder 1: 270 g, Milled Powder 2: 600 g, Milled Powder 3: 132 g, Calcium Pantothenate Type S (BASF JAPAN) 92.4 g, Corn Starch 21.6 g, Crystalline Cellulose (CEOLUS PH- 72 g of 101, Asahi Kasei), 6.0 g of Sylysia (Fuji Silysia), and 6.0 g of magnesium stearate (Taihei Chemical Industrial) were mixed to obtain a mixed powder for tableting. The resulting mixed powder for tableting was compressed using a rotary tablet press (AQU3, Kikusui Seisakusho) with an 8.3 mm phi punch to obtain a core tablet with a mass of 190 mg, thereby obtaining a core tablet with a thickness of 4.2 mm.
그런 다음, 중심정을 히프로멜로오스 (Shin-Etsu Chemical) 및 멸균 탈크 (Matsumura Sangyo) 를 정제수에 용해 또는 분산하여 수득한 언더코트 용액, 및 에리트리톨 (Cargill Japan), 멸균 탈크, 산화티탄 (Ishihara Sangyo), 결정질 셀룰로오스 (CEOLUS PH-F20, Asahi Kasei) 및 분말화 아카시아 (San-Ei Yakuhin Boeki) 를 정제수에 용해 또는 분산하여 수득한 빌드업 코팅 용액으로, 코팅기 (Doria Coater, Powrex) 를 사용하여 코팅하여, 6 mg/정제 및 94 mg/정제의 코팅 층을 갖는 코팅정을 수득하였다. 그런 다음, 코팅정을 수크로오스 (Mitsui Sugar), 에리트리톨 및 리보플라빈을 정제수에 용해하여 수득한 시럽 용액으로, 당의 팬 (Kikusui Seisakusho) 을 사용하여 추가 코팅하여, 24 mg/정제의 당의를 갖는 당의정을 수득하였다.Then, the core tablet was coated with an undercoat solution obtained by dissolving or dispersing hypromellose (Shin-Etsu Chemical) and sterilized talc (Matsumura Sangyo) in purified water, and erythritol (Cargill Japan), sterilized talc, and titanium oxide ( Ishihara Sangyo), a build-up coating solution obtained by dissolving or dispersing crystalline cellulose (CEOLUS PH-F20, Asahi Kasei) and powdered acacia (San-Ei Yakuhin Boeki) in purified water, using a coater (Doria Coater, Powrex) By coating, coated tablets having a coating layer of 6 mg/tablet and 94 mg/tablet were obtained. Then, the coated tablets were further coated with a syrup solution obtained by dissolving sucrose (Mitsui Sugar), erythritol and riboflavin in purified water using a sugar pan (Kikusui Seisakusho) to obtain dragees with a sugar coating of 24 mg/tablet. Obtained.
(실시예 5)(Example 5)
니코틴아미드 (Lonza Japan), 리보플라빈 (BASF JAPAN), 피리독신 히드로클로라이드 (BASF JAPAN), 락토오스 히드레이트 (GranuLac200, Meggle), 옥수수 전분 (Japan Corn Starch) 및 부분 알파 전분 (PCS, Asahi Kasei) 을 유동층 건조기에 충전하였다. HPC 용액을 이에 분무하고, 혼합물을 과립화하고 건조시켰다. 그런 다음, 과립을 밀링 머신 (Power Mill) 에 의해 밀링하여, 밀링된 분말 1 을 수득하였다. 밀링된 분말 1 의 조성비는 니코틴아미드 13.3%, 리보플라빈 3.9%, 피리독신 히드로클로라이드 16.7%, 락토오스 히드레이트 7.0%, 옥수수 전분 2.1%, 부분 알파 전분 50%, 및 HPC 7% 였다.Nicotinamide (Lonza Japan), riboflavin (BASF JAPAN), pyridoxine hydrochloride (BASF JAPAN), lactose hydrate (GranuLac200, Meggle), corn starch (Japan Corn Starch) and partial alpha starch (PCS, Asahi Kasei) were dried in a fluidized bed dryer. was charged. The HPC solution was sprayed onto it and the mixture was granulated and dried. Then, the granules were milled by a milling machine (Power Mill) to obtain milled powder 1. The composition of milled powder 1 was 13.3% nicotinamide, 3.9% riboflavin, 16.7% pyridoxine hydrochloride, 7.0% lactose hydrate, 2.1% corn starch, 50% partial alpha starch, and 7% HPC.
또한, 푸르술티아민 히드로클로라이드 (Mikuni Pharmaceutical), 옥수수 전분 및 결정질 셀룰로오스 (CEOLUS PH-101, Asahi Kasei) 를 유동층 건조기에 충전하였다. HPC 용액을 이에 분무하고, 혼합물을 과립화하고 건조시켰다. 그런 다음, 과립을 밀링 머신 (Power Mill) 에 의해 밀링하여, 밀링된 분말 2 를 수득하였다. 밀링된 분말 2 의 조성비는 푸르술티아민 히드로클로라이드 77.4%, 옥수수 전분 9.0%, 결정질 셀룰로오스 6.4%, 및 HPC 7.2% 였다.Additionally, fursultiamine hydrochloride (Mikuni Pharmaceutical), corn starch and crystalline cellulose (CEOLUS PH-101, Asahi Kasei) were charged into the fluidized bed dryer. The HPC solution was sprayed onto it and the mixture was granulated and dried. Then, the granules were milled by a milling machine (Power Mill) to obtain milled powder 2. The composition ratio of milled powder 2 was 77.4% fursultiamine hydrochloride, 9.0% corn starch, 6.4% crystalline cellulose, and 7.2% HPC.
시아노코발라민 용액을 부분 알파 전분 및 옥수수 전분에 분무한 후, 히프로멜로오스 용액을 이에 분무하고, 혼합물을 과립화하고 건조시켰다. 그런 다음, 과립을 밀링 머신 (Power Mill) 에 의해 밀링하여, 밀링된 분말 3 을 수득하였다. 밀링된 분말 3 의 조성비는 시아노코발라민 0.09%, 부분 알파 전분 90.76%, 옥수수 전분 0.06%, 및 히프로멜로오스 9.09% 였다.The cyanocobalamin solution was sprayed onto the partial alpha starch and corn starch, followed by the hypromellose solution, and the mixture was granulated and dried. Then, the granules were milled by a milling machine (Power Mill) to obtain milled powder 3. The composition ratio of milled powder 3 was 0.09% cyanocobalamin, 90.76% partial alpha starch, 0.06% corn starch, and 9.09% hypromellose.
생성된 밀링된 분말 1: 600 g, 밀링된 분말 2: 282 g, 밀링된 분말 3: 132 g, 칼슘 판토테네이트 S 형 (BASF JAPAN) 92.4 g, 옥수수 전분 8.4 g, 결정질 셀룰로오스 (CEOLUS PH-F20, Asahi Kasei) 72 g, Sylysia (Fuji Silysia) 8.4 g 및 마그네슘 스테아레이트 (Taihei Chemical Industrial) 4.8 g 을 혼합하여, 타정용 혼합 분말을 수득하였다. 생성된 타정용 혼합 분말을, 200 mg 의 질량을 갖는 중심정이 수득되도록, 8.3 mmφ 펀치를 갖는 회전식 타정기 (AQU3, Kikusui Seisakusho) 를 사용하여 타정하여, 두께 4.3 mm 의 중심정을 수득하였다.Resulting milled powder 1: 600 g, milled powder 2: 282 g, milled powder 3: 132 g, calcium pantothenate S type (BASF JAPAN) 92.4 g, corn starch 8.4 g, crystalline cellulose (CEOLUS PH- 72 g of F20 (Asahi Kasei), 8.4 g of Sylysia (Fuji Silysia), and 4.8 g of magnesium stearate (Taihei Chemical Industrial) were mixed to obtain a mixed powder for tableting. The resulting mixed powder for tableting was compressed using a rotary tablet press (AQU3, Kikusui Seisakusho) with an 8.3 mm ϕ punch to obtain a core tablet with a mass of 200 mg, thereby obtaining a core tablet with a thickness of 4.3 mm.
그런 다음, 중심정을 히프로멜로오스 (Shin-Etsu Chemical) 및 멸균 탈크 (Matsumura Sangyo) 를 정제수에 용해 또는 분산하여 수득한 언더코트 용액, 및 에리트리톨 (Cargill Japan), 멸균 탈크, 침강 칼슘 카르보네이트 (Nitto Powder Chemical), 산화티탄 (Ishihara Sangyo), 결정질 셀룰로오스 (CEOLUS PH-F20, Asahi Kasei) 및 분말화 아카시아 (San-Ei Yakuhin Boeki) 를 정제수에 용해 또는 분산하여 수득한 빌드업 코팅 용액으로, 코팅기 (Doria Coater, Powrex) 를 사용하여 코팅하여, 8 mg/정제 및 80 mg/정제의 코팅 층을 갖는 코팅정을 수득하였다. 그런 다음, 코팅정을 수크로오스 (Mitsui Sugar), 에리트리톨 및 리보플라빈을 정제수에 용해하여 수득한 시럽 용액으로, 당의 팬 (Kikusui Seisakusho) 을 사용하여 추가 코팅하여, 20 mg/정제의 당의를 갖는 당의정을 수득하였다.Then, the core tablets were coated with an undercoat solution obtained by dissolving or dispersing hypromellose (Shin-Etsu Chemical) and sterilized talc (Matsumura Sangyo) in purified water, and erythritol (Cargill Japan), sterilized talc, and precipitated calcium carbonate. Build-up coating solution obtained by dissolving or dispersing bonate (Nitto Powder Chemical), titanium oxide (Ishihara Sangyo), crystalline cellulose (CEOLUS PH-F20, Asahi Kasei), and powdered acacia (San-Ei Yakuhin Boeki) in purified water. By coating using a coating machine (Doria Coater, Powrex), coated tablets with a coating layer of 8 mg/tablet and 80 mg/tablet were obtained. Then, the coated tablets were further coated with a syrup solution obtained by dissolving sucrose (Mitsui Sugar), erythritol, and riboflavin in purified water using a sugar pan (Kikusui Seisakusho) to obtain dragees with a sugar coating of 20 mg/tablet. Obtained.
(실시예 6)(Example 6)
니코틴아미드 (Lonza Japan), 리보플라빈 (BASF JAPAN), 피리독신 히드로클로라이드 (BASF JAPAN), 락토오스 히드레이트 (GranuLac 200, Meggle), 옥수수 전분 (Japan Corn Starch) 및 부분 알파 전분 (PCS, Asahi Kasei) 을 유동층 건조기에 충전하였다. HPC 용액을 이에 분무하고, 혼합물을 과립화하고 건조시켰다. 그런 다음, 과립을 밀링 머신 (Power Mill) 에 의해 밀링하여, 밀링된 분말 1 을 수득하였다. 밀링된 분말 1 의 조성비는 니코틴아미드 13.7%, 리보플라빈 4.1%, 피리독신 히드로클로라이드 17.2%, 락토오스 히드레이트 7.2%, 옥수수 전분 2.5%, 부분 알파 전분 51.5%, 및 HPC 3.8% 였다.Nicotinamide (Lonza Japan), riboflavin (BASF JAPAN), pyridoxine hydrochloride (BASF JAPAN), lactose hydrate (GranuLac 200, Meggle), corn starch (Japan Corn Starch) and partial alpha starch (PCS, Asahi Kasei) were mixed in a fluidized bed. The dryer was charged. The HPC solution was sprayed onto it and the mixture was granulated and dried. Then, the granules were milled by a milling machine (Power Mill) to obtain milled powder 1. The composition of milled powder 1 was 13.7% nicotinamide, 4.1% riboflavin, 17.2% pyridoxine hydrochloride, 7.2% lactose hydrate, 2.5% corn starch, 51.5% partial alpha starch, and 3.8% HPC.
또한, 푸르술티아민 히드로클로라이드 (Mikuni Pharmaceutical), 옥수수 전분 및 결정질 셀룰로오스 (CEOLUS PH-101, Asahi Kasei) 를 유동층 건조기에 충전하였다. HPC 용액을 이에 분무하고, 혼합물을 과립화하고 건조시켰다. 그런 다음, 과립을 밀링 머신 (Power Mill) 에 의해 밀링하여, 밀링된 분말 2 를 수득하였다. 밀링된 분말 2 의 조성비는 푸르술티아민 히드로클로라이드 74.3%, 옥수수 전분 7.5%, 결정질 셀룰로오스 14.3%, 및 HPC 3.9% 였다.Additionally, fursultiamine hydrochloride (Mikuni Pharmaceutical), corn starch and crystalline cellulose (CEOLUS PH-101, Asahi Kasei) were charged into the fluidized bed dryer. The HPC solution was sprayed onto it and the mixture was granulated and dried. Then, the granules were milled by a milling machine (Power Mill) to obtain milled powder 2. The composition ratio of milled powder 2 was 74.3% fursultiamine hydrochloride, 7.5% corn starch, 14.3% crystalline cellulose, and 3.9% HPC.
생성된 밀링된 분말 1: 582 g, 밀링된 분말 2: 294 g, 칼슘 판토테네이트 S 형 (BASF JAPAN) 92.4 g, VB12 세립 (Mitsubishi Chemical Foods) 13.2 g, 옥수수 전분 69 g, 결정질 셀룰로오스 (CEOLUS PH-F20, Asahi Kasei) 78 g, Sylysia (Fuji Silysia) 5.7 g 및 마그네슘 스테아레이트 (Taihei Chemical Industrial) 5.7 g 를 혼합하여, 타정용 혼합 분말을 수득하였다. 생성된 타정용 혼합 분말을, 190 mg 의 질량을 갖는 중심정이 수득되도록, 8.3 mmφ 펀치를 갖는 회전식 타정기 (AQU3, Kikusui Seisakusho) 를 사용하여 타정하여, 두께 4.2 mm 의 중심정을 수득하였다.Resulting milled powder 1: 582 g, milled powder 2: 294 g, calcium pantothenate S type (BASF JAPAN) 92.4 g, VB12 fine grain (Mitsubishi Chemical Foods) 13.2 g, corn starch 69 g, crystalline cellulose (CEOLUS) 78 g of PH-F20 (Asahi Kasei), 5.7 g of Sylysia (Fuji Silysia), and 5.7 g of magnesium stearate (Taihei Chemical Industrial) were mixed to obtain a mixed powder for tableting. The resulting mixed powder for tableting was compressed using a rotary tablet press (AQU3, Kikusui Seisakusho) with an 8.3 mm phi punch to obtain a core tablet with a mass of 190 mg, thereby obtaining a core tablet with a thickness of 4.2 mm.
그런 다음, 중심정을 히프로멜로오스 (Shin-Etsu Chemical) 및 멸균 탈크 (Matsumura Sangyo) 를 정제수에 용해 또는 분산하여 수득한 언더코트 용액, 및 에리트리톨 (Cargill Japan), 멸균 탈크, 침강 칼슘 카르보네이트 (Nitto Powder Chemical), 산화티탄 (Ishihara Sangyo), 결정질 셀룰로오스 (CEOLUS PH-F20, Asahi Kasei) 및 분말화 아카시아 (San-Ei Yakuhin Boeki) 를 정제수에 용해 또는 분산하여 수득한 빌드업 코팅 용액으로, 코팅기 (Doria Coater, Powrex) 를 사용하여 코팅하여, 6 mg/정제 및 80 mg/정제의 코팅 층을 갖는 코팅정을 수득하였다. 그런 다음, 코팅정을 수크로오스 (Mitsui Sugar), 에리트리톨 및 리보플라빈을 정제수에 용해하여 수득한 시럽 용액으로, 당의 팬 (Kikusui Seisakusho) 을 사용하여 추가 코팅하여, 20 mg/정제의 당의를 갖는 당의정을 수득하였다.Then, the core tablets were coated with an undercoat solution obtained by dissolving or dispersing hypromellose (Shin-Etsu Chemical) and sterilized talc (Matsumura Sangyo) in purified water, and erythritol (Cargill Japan), sterilized talc, and precipitated calcium carbonate. Build-up coating solution obtained by dissolving or dispersing bonate (Nitto Powder Chemical), titanium oxide (Ishihara Sangyo), crystalline cellulose (CEOLUS PH-F20, Asahi Kasei), and powdered acacia (San-Ei Yakuhin Boeki) in purified water. By coating using a coating machine (Doria Coater, Powrex), coated tablets with a coating layer of 6 mg/tablet and 80 mg/tablet were obtained. Then, the coated tablets were further coated with a syrup solution obtained by dissolving sucrose (Mitsui Sugar), erythritol, and riboflavin in purified water using a sugar pan (Kikusui Seisakusho) to obtain dragees with a sugar coating of 20 mg/tablet. Obtained.
(실시예 7)(Example 7)
부분 알파 전분 대신 알파 전분 (PD-1, Asahi Kasei) 을 사용한 것을 제외하고는, 실시예 6 에서와 동일한 방식으로 당의정을 수득하였다. Dragees were obtained in the same manner as in Example 6, except that alpha starch (PD-1, Asahi Kasei) was used instead of partial alpha starch.
(실시예 8)(Example 8)
부분 알파 전분 대신 알파 전분 (WB-1, Asahi Kasei) 을 사용한 것을 제외하고는, 실시예 6 에서와 동일한 방식으로 당의정을 수득하였다.Dragees were obtained in the same manner as in Example 6, except that alpha starch (WB-1, Asahi Kasei) was used instead of partial alpha starch.
(실시예 9)(Example 9)
니코틴아미드 (Lonza Japan), 리보플라빈 (BASF JAPAN), 피리독신 히드로클로라이드 (BASF JAPAN), 락토오스 히드레이트 (GranuLac 200, Meggle), 옥수수 전분 (Japan Corn Starch) 및 알파 전분 (PD-1, Asahi Kasei) 을 유동층 건조기에 충전하였다. HPC 용액을 이에 분무하고, 혼합물을 과립화하고 건조시켰다. 그런 다음, 과립을 밀링 머신 (Power Mill) 에 의해 밀링하여, 밀링된 분말 1 을 수득하였다. 밀링된 분말 1 의 조성비는 니코틴아미드 13.7%, 리보플라빈 4.1%, 피리독신 히드로클로라이드 17.2%, 락토오스 히드레이트 7.2%, 옥수수 전분 23.1%, 알파 전분 27.5%, 및 HPC 7.2% 였다.Nicotinamide (Lonza Japan), riboflavin (BASF JAPAN), pyridoxine hydrochloride (BASF JAPAN), lactose hydrate (GranuLac 200, Meggle), corn starch (Japan Corn Starch) and alpha starch (PD-1, Asahi Kasei). It was charged into a fluidized bed dryer. The HPC solution was sprayed onto it and the mixture was granulated and dried. Then, the granules were milled by a milling machine (Power Mill) to obtain milled powder 1. The composition ratio of milled powder 1 was 13.7% nicotinamide, 4.1% riboflavin, 17.2% pyridoxine hydrochloride, 7.2% lactose hydrate, 23.1% corn starch, 27.5% alpha starch, and 7.2% HPC.
또한, 푸르술티아민 히드로클로라이드 (Mikuni Pharmaceutical), 옥수수 전분, 결정질 셀룰로오스 (CEOLUS PH-101, Asahi Kasei) 및 Sylysia (Fuji Silysia) 를 유동층 건조기에 충전하였다. HPC 용액을 이에 분무하고, 혼합물을 과립화하고 건조시켰다. 그런 다음, 과립을 밀링 머신 (Power Mill) 에 의해 밀링하여, 밀링된 분말 2 를 수득하였다. 밀링된 분말 2 의 조성비는 푸르술티아민 히드로클로라이드 77.4%, 옥수수 전분 8.6%, Sylysia 0.4%, 결정질 셀룰로오스 6.4%, 및 HPC 7.2% 였다.Additionally, fursultiamine hydrochloride (Mikuni Pharmaceutical), corn starch, crystalline cellulose (CEOLUS PH-101, Asahi Kasei) and Sylysia (Fuji Silysia) were charged into the fluidized bed dryer. The HPC solution was sprayed onto it and the mixture was granulated and dried. Then, the granules were milled by a milling machine (Power Mill) to obtain milled powder 2. The composition ratio of milled powder 2 was 77.4% fursultiamine hydrochloride, 8.6% corn starch, 0.4% Sylysia, 6.4% crystalline cellulose, and 7.2% HPC.
생성된 밀링된 분말 1: 582 g, 밀링된 분말 2: 282 g, 칼슘 판토테네이트 S 형 (BASF JAPAN) 92.4 g, VB12 세립 (Mitsubishi Chemical Foods) 13.2 g, 옥수수 전분 129 g, 결정질 셀룰로오스 30 g, Sylysia 5.7 g 및 마그네슘 스테아레이트 (Taihei Chemical Industrial) 5.7 g 를 혼합하여, 타정용 혼합 분말을 수득하였다. 생성된 타정용 혼합 분말을, 190 mg 의 질량을 갖는 중심정이 수득되도록, 8.3 mmφ 펀치를 갖는 회전식 타정기 (AQU3, Kikusui Seisakusho) 를 사용하여 타정하여, 두께 4.0 mm 의 중심정을 수득하였다.Resulting Milled Powder 1: 582 g, Milled Powder 2: 282 g, Calcium Pantothenate Type S (BASF JAPAN) 92.4 g, VB12 fine grain (Mitsubishi Chemical Foods) 13.2 g, Corn Starch 129 g, Crystalline Cellulose 30 g. , 5.7 g of Sylysia, and 5.7 g of magnesium stearate (Taihei Chemical Industrial) were mixed to obtain a mixed powder for tableting. The resulting mixed powder for tableting was compressed using a rotary tablet press (AQU3, Kikusui Seisakusho) with an 8.3 mm ϕ punch to obtain a core tablet with a mass of 190 mg, thereby obtaining a core tablet with a thickness of 4.0 mm.
그런 다음, 중심정을 히프로멜로오스 (Shin-Etsu Chemical) 및 멸균 탈크 (Matsumura Sangyo) 를 정제수에 용해 또는 분산하여 수득한 언더코트 용액, 및 에리트리톨 (Cargill Japan), 멸균 탈크, 침강 칼슘 카르보네이트 (Nitto Powder Chemical), 산화티탄 (Ishihara Sangyo), 결정질 셀룰로오스 (CEOLUS PH-F20, Asahi Kasei) 및 분말화 아카시아 (San-Ei Yakuhin Boeki) 를 정제수에 용해 또는 분산하여 수득한 빌드업 코팅 용액으로, 코팅기 (Doria Coater, Powrex) 를 사용하여 코팅하여, 10 mg/정제 및 80 mg/정제의 코팅 층을 갖는 코팅정을 수득하였다. 그런 다음, 코팅정을 수크로오스 (Mitsui Sugar), 에리트리톨 및 리보플라빈을 정제수에 용해하여 수득한 시럽 용액으로, 당의 팬 (Kikusui Seisakusho) 을 사용하여 추가 코팅하여, 20 mg/정제의 당의를 갖는 당의정을 수득하였다.Then, the core tablets were coated with an undercoat solution obtained by dissolving or dispersing hypromellose (Shin-Etsu Chemical) and sterilized talc (Matsumura Sangyo) in purified water, and erythritol (Cargill Japan), sterilized talc, and precipitated calcium carbonate. Build-up coating solution obtained by dissolving or dispersing bonate (Nitto Powder Chemical), titanium oxide (Ishihara Sangyo), crystalline cellulose (CEOLUS PH-F20, Asahi Kasei), and powdered acacia (San-Ei Yakuhin Boeki) in purified water. By coating using a coating machine (Doria Coater, Powrex), coated tablets with a coating layer of 10 mg/tablet and 80 mg/tablet were obtained. Then, the coated tablets were further coated with a syrup solution obtained by dissolving sucrose (Mitsui Sugar), erythritol, and riboflavin in purified water using a sugar pan (Kikusui Seisakusho) to obtain dragees with a sugar coating of 20 mg/tablet. Obtained.
(실시예 10)(Example 10)
니코틴아미드 (Lonza Japan), 리보플라빈 (BASF JAPAN), 피리독신 히드로클로라이드 (BASF JAPAN), 락토오스 히드레이트 (GranuLac 200, Meggle), 옥수수 전분 (Japan Corn Starch) 및 알파 전분 (PD-1, Asahi Kasei) 을 유동층 건조기에 충전하였다. HPC 용액을 이에 분무하고, 혼합물을 과립화하고 건조시켰다. 그런 다음, 과립을 밀링 머신 (Power Mill) 에 의해 밀링하여, 밀링된 분말 1 을 수득하였다. 밀링된 분말 1 의 조성비는 니코틴아미드 13.7%, 리보플라빈 4.1%, 피리독신 히드로클로라이드 17.2%, 락토오스 히드레이트 7.2%, 옥수수 전분 36.8%, 알파 전분 13.7%, 및 HPC 7.2% 였다.Nicotinamide (Lonza Japan), riboflavin (BASF JAPAN), pyridoxine hydrochloride (BASF JAPAN), lactose hydrate (GranuLac 200, Meggle), corn starch (Japan Corn Starch) and alpha starch (PD-1, Asahi Kasei). It was charged into a fluidized bed dryer. The HPC solution was sprayed onto it and the mixture was granulated and dried. Then, the granules were milled by a milling machine (Power Mill) to obtain milled powder 1. The composition ratio of milled powder 1 was 13.7% nicotinamide, 4.1% riboflavin, 17.2% pyridoxine hydrochloride, 7.2% lactose hydrate, 36.8% corn starch, 13.7% alpha starch, and 7.2% HPC.
또한, 푸르술티아민 히드로클로라이드 (Mikuni Pharmaceutical), 옥수수 전분, 결정질 셀룰로오스 (CEOLUS PH-101, Asahi Kasei), Sylysia (Fuji Silysia) 를 유동층 건조기에 충전하였다. HPC 용액을 이에 분무하고, 혼합물을 과립화하고 건조시켰다. 그런 다음, 과립을 밀링 머신 (Power Mill) 에 의해 밀링하여, 밀링된 분말 2 를 수득하였다. 밀링된 분말 2 의 조성비는 푸르술티아민 히드로클로라이드 77.4%, 옥수수 전분 8.6%, Sylysia 0.4%, 결정질 셀룰로오스 6.4%, 및 HPC 7.2% 였다.Additionally, fursultiamine hydrochloride (Mikuni Pharmaceutical), corn starch, crystalline cellulose (CEOLUS PH-101, Asahi Kasei), and Sylysia (Fuji Silysia) were charged into a fluidized bed dryer. The HPC solution was sprayed onto it and the mixture was granulated and dried. Then, the granules were milled by a milling machine (Power Mill) to obtain milled powder 2. The composition ratio of milled powder 2 was 77.4% fursultiamine hydrochloride, 8.6% corn starch, 0.4% Sylysia, 6.4% crystalline cellulose, and 7.2% HPC.
생성된 밀링된 분말 1: 582 g, 밀링된 분말 2: 282 g, 칼슘 판토테네이트 S 형 (BASF JAPAN) 92.4 g, VB12 세립 (Mitsubishi Chemical Foods) 13.2 g, 옥수수 전분 129 g, 결정질 셀룰로오스 30 g, Sylysia 5.7 g 및 마그네슘 스테아레이트 (Taihei Chemical Industrial) 5.7 g 을 혼합하여, 타정용 혼합 분말을 수득하였다. 생성된 타정용 혼합 분말을, 190 mg 의 질량을 갖는 중심정이 수득되도록, 8.3 mmφ 펀치를 갖는 회전식 타정기 (AQU3, Kikusui Seisakusho) 를 사용하여 타정하여, 두께 4.0 mm 의 중심정을 수득하였다.Resulting Milled Powder 1: 582 g, Milled Powder 2: 282 g, Calcium Pantothenate Type S (BASF JAPAN) 92.4 g, VB12 fine grain (Mitsubishi Chemical Foods) 13.2 g, Corn Starch 129 g, Crystalline Cellulose 30 g. , 5.7 g of Sylysia, and 5.7 g of magnesium stearate (Taihei Chemical Industrial) were mixed to obtain a mixed powder for tableting. The resulting mixed powder for tableting was compressed using a rotary tablet press (AQU3, Kikusui Seisakusho) with an 8.3 mm ϕ punch to obtain a core tablet with a mass of 190 mg, thereby obtaining a core tablet with a thickness of 4.0 mm.
그런 다음, 중심정을 히프로멜로오스 (Shin-Etsu Chemical) 및 멸균 탈크 (Matsumura Sangyo) 를 정제수에 용해 또는 분산하여 수득한 언더코트 용액, 및 에리트리톨 (Cargill Japan), 멸균 탈크, 침강 칼슘 카르보네이트 (Nitto Powder Chemical), 산화티탄 (Ishihara Sangyo), 결정질 셀룰로오스 (CEOLUS PH-F20, Asahi Kasei) 및 분말화 아카시아 (San-Ei Yakuhin Boeki) 를 정제수에 용해 또는 분산하여 수득한 빌드업 코팅 용액으로, 코팅기 (Doria Coater, Powrex) 를 사용하여 코팅하여, 10 mg/정제 및 80 mg/정제의 코팅 층을 갖는 코팅정을 수득하였다. 그런 다음, 코팅정을 수크로오스 (Mitsui Sugar), 에리트리톨 및 리보플라빈을 정제수에 용해하여 수득한 시럽 용액으로, 당의 팬 (Kikusui Seisakusho) 을 사용하여 추가 코팅하여, 20 mg/정제의 당의를 갖는 당의점을 수득하였다.Then, the core tablets were coated with an undercoat solution obtained by dissolving or dispersing hypromellose (Shin-Etsu Chemical) and sterilized talc (Matsumura Sangyo) in purified water, and erythritol (Cargill Japan), sterilized talc, and precipitated calcium carbonate. Build-up coating solution obtained by dissolving or dispersing bonate (Nitto Powder Chemical), titanium oxide (Ishihara Sangyo), crystalline cellulose (CEOLUS PH-F20, Asahi Kasei), and powdered acacia (San-Ei Yakuhin Boeki) in purified water. By coating using a coating machine (Doria Coater, Powrex), coated tablets with a coating layer of 10 mg/tablet and 80 mg/tablet were obtained. Then, the coated tablets were further coated with a syrup solution obtained by dissolving sucrose (Mitsui Sugar), erythritol, and riboflavin in purified water using a sugar pan (Kikusui Seisakusho) to obtain a sugar coating with a sugar coating of 20 mg/tablet. was obtained.
(실시예 11)(Example 11)
니코틴아미드 (Lonza Japan), 리보플라빈 (BASF JAPAN), 피리독신 히드로클로라이드 (BASF JAPAN), 락토오스 히드레이트 (GranuLac 200, Meggle), 옥수수 전분 (Japan Corn Starch) 및 알파 전분 (PD-1, Asahi Kasei) 을 유동층 건조기에 충전하였다. HPC 용액을 이에 분무하고, 혼합물을 과립화하고 건조시켰다. 그런 다음, 과립을 밀링 머신 (Power Mill) 에 의해 밀링하여, 밀링된 분말 1 을 수득하였다. 밀링된 분말 1 의 조성비는 니코틴아미드 13.7%, 리보플라빈 4.1%, 피리독신 히드로클로라이드 17.2%, 락토오스 히드레이트 7.2%, 옥수수 전분 43.7%, 알파 전분 6.9%, 및 HPC 7.2% 였다.Nicotinamide (Lonza Japan), riboflavin (BASF JAPAN), pyridoxine hydrochloride (BASF JAPAN), lactose hydrate (GranuLac 200, Meggle), corn starch (Japan Corn Starch) and alpha starch (PD-1, Asahi Kasei). It was charged into a fluidized bed dryer. The HPC solution was sprayed onto it and the mixture was granulated and dried. Then, the granules were milled by a milling machine (Power Mill) to obtain milled powder 1. The composition ratio of milled powder 1 was 13.7% nicotinamide, 4.1% riboflavin, 17.2% pyridoxine hydrochloride, 7.2% lactose hydrate, 43.7% corn starch, 6.9% alpha starch, and 7.2% HPC.
또한, 푸르술티아민 히드로클로라이드 (Mikuni Pharmaceutical), 옥수수 전분, 결정질 셀룰로오스 (CEOLUS PH-101, Asahi Kasei) 및 Sylysia (Fuji Silysia) 를 유동층 건조기에 충전하였다. HPC 용액을 이에 분무하고, 혼합물을 과립화하고 건조시켰다. 그런 다음, 과립을 밀링 머신 (Power Mill) 에 의해 밀링하여, 밀링된 분말 2 를 수득하였다. 밀링된 분말 2 의 조성비는 푸르술티아민 히드로클로라이드 77.4%, 옥수수 전분 8.6%, Sylysia 0.4%, 결정질 셀룰로오스 6.4%, 및 HPC 7.2% 였다.Additionally, fursultiamine hydrochloride (Mikuni Pharmaceutical), corn starch, crystalline cellulose (CEOLUS PH-101, Asahi Kasei) and Sylysia (Fuji Silysia) were charged into the fluidized bed dryer. The HPC solution was sprayed onto it and the mixture was granulated and dried. Then, the granules were milled by a milling machine (Power Mill) to obtain milled powder 2. The composition ratio of milled powder 2 was 77.4% fursultiamine hydrochloride, 8.6% corn starch, 0.4% Sylysia, 6.4% crystalline cellulose, and 7.2% HPC.
생성된 밀링된 분말 1: 582 g, 밀링된 분말 2: 282 g, 칼슘 판토테네이트 S 형 (BASF JAPAN) 92.4 g, VB12 세립 (Mitsubishi Chemical Foods) 13.2 g, 옥수수 전분 129 g, 결정질 셀룰로오스 30 g, Sylysia 5.7 g 및 마그네슘 스테아레이트 (Taihei Chemical Industrial) 5.7 g 을 혼합하여, 타정용 혼합 분말을 수득하였다. 생성된 타정용 혼합 분말을, 190 mg 의 질량을 갖는 중심정이 수득되도록, 8.3 mmφ 펀치를 갖는 회전식 타정기 (AQU3, Kikusui Seisakusho) 를 사용하여 타정하여, 두께 4.0 mm 의 중심정을 수득하였다.Resulting Milled Powder 1: 582 g, Milled Powder 2: 282 g, Calcium Pantothenate Type S (BASF JAPAN) 92.4 g, VB12 fine grain (Mitsubishi Chemical Foods) 13.2 g, Corn Starch 129 g, Crystalline Cellulose 30 g. , 5.7 g of Sylysia, and 5.7 g of magnesium stearate (Taihei Chemical Industrial) were mixed to obtain a mixed powder for tableting. The resulting mixed powder for tableting was compressed using a rotary tablet press (AQU3, Kikusui Seisakusho) with an 8.3 mm ϕ punch to obtain a core tablet with a mass of 190 mg, thereby obtaining a core tablet with a thickness of 4.0 mm.
그런 다음, 중심정을 히프로멜로오스 (Shin-Etsu Chemical) 및 멸균 탈크 (Matsumura Sangyo) 를 정제수에 용해 또는 분산하여 수득한 언더코트 용액, 및 에리트리톨 (Cargill Japan), 멸균 탈크, 침강 칼슘 카르보네이트 (Nitto Powder Chemical), 산화티탄 (Ishihara Sangyo), 결정질 셀룰로오스 (CEOLUS PH-F20, Asahi Kasei) 및 분말화 아카시아 (San-Ei Yakuhin Boeki) 를 정제수에 용해 또는 분산하여 수득한 빌드업 코팅 용액으로, 코팅기 (Doria Coater, Powrex) 를 사용하여 코팅하여, 10 mg/정제 및 80 mg/정제의 코팅 층을 갖는 코팅정을 수득하였다. 그런 다음, 코팅정을 수크로오스 (Mitsui Sugar), 에리트리톨 및 리보플라빈을 정제수에 용해하여 수득한 시럽 용액으로, 당의 팬 (Kikusui Seisakusho) 을 사용하여 추가 코팅하여, 20 mg/정제의 당의를 갖는 당의정을 수득하였다.Then, the core tablets were coated with an undercoat solution obtained by dissolving or dispersing hypromellose (Shin-Etsu Chemical) and sterilized talc (Matsumura Sangyo) in purified water, and erythritol (Cargill Japan), sterilized talc, and precipitated calcium carbonate. Build-up coating solution obtained by dissolving or dispersing bonate (Nitto Powder Chemical), titanium oxide (Ishihara Sangyo), crystalline cellulose (CEOLUS PH-F20, Asahi Kasei), and powdered acacia (San-Ei Yakuhin Boeki) in purified water. By coating using a coating machine (Doria Coater, Powrex), coated tablets with a coating layer of 10 mg/tablet and 80 mg/tablet were obtained. Then, the coated tablets were further coated with a syrup solution obtained by dissolving sucrose (Mitsui Sugar), erythritol, and riboflavin in purified water using a sugar pan (Kikusui Seisakusho) to obtain dragees with a sugar coating of 20 mg/tablet. Obtained.
(비교예 1)(Comparative Example 1)
니코틴아미드 (Lonza Japan), 리보플라빈 (BASF JAPAN), 피리독신 히드로클로라이드 (BASF JAPAN) 및 결정질 셀룰로오스 (CEOLUS PH-101, Asahi Kasei) 를 유동층 건조기에 충전하였다. 히드록시프로필셀룰로오스 (HPC, Nippon Soda) 용액을 이에 분무하고, 혼합물을 과립화하고 건조시켰다. 그런 다음, 과립을 밀링 머신 (Power Mill) 에 의해 밀링하여, 밀링된 분말 1 을 수득하였다. 밀링된 분말 1 의 조성비는 니코틴아미드 11.1%, 리보플라빈 3.3%, 피리독신 히드로클로라이드 13.9%, 결정질 셀룰로오스 68.4%, 및 HPC 3.3% 였다.Nicotinamide (Lonza Japan), riboflavin (BASF JAPAN), pyridoxine hydrochloride (BASF JAPAN) and crystalline cellulose (CEOLUS PH-101, Asahi Kasei) were charged into a fluidized bed dryer. Hydroxypropylcellulose (HPC, Nippon Soda) solution was sprayed thereon, and the mixture was granulated and dried. Then, the granules were milled by a milling machine (Power Mill) to obtain milled powder 1. The composition ratio of milled powder 1 was 11.1% nicotinamide, 3.3% riboflavin, 13.9% pyridoxine hydrochloride, 68.4% crystalline cellulose, and 3.3% HPC.
또한, 푸르술티아민 히드로클로라이드 (Mikuni Pharmaceutical) 및 결정질 셀룰로오스 (CEOLUS PH-101, Asahi Kasei) 를 유동층 건조기에 충전하였다. 히드록시프로필셀룰로오스 용액을 이에 분무하고, 혼합물을 과립화하고 건조시켰다. 그런 다음, 과립을 밀링 머신 (Power Mill) 에 의해 밀링하여, 밀링된 분말 2 를 수득하였다. 밀링된 분말 2 의 조성비는 푸르술티아민 히드로클로라이드 60.6%, 결정질 셀룰로오스 35.4%, 및 HPC 4% 였다.Additionally, fursultiamine hydrochloride (Mikuni Pharmaceutical) and crystalline cellulose (CEOLUS PH-101, Asahi Kasei) were charged into the fluidized bed dryer. The hydroxypropylcellulose solution was sprayed onto it and the mixture was granulated and dried. Then, the granules were milled by a milling machine (Power Mill) to obtain milled powder 2. The composition ratio of milled powder 2 was 60.6% fursultiamine hydrochloride, 35.4% crystalline cellulose, and 4% HPC.
생성된 밀링된 분말 1: 720 g, 밀링된 분말 2: 360 g, 칼슘 판토테네이트 S 형 (BASF JAPAN) 92.4 g, VB12 세립 (Mitsubishi Chemical Foods) 13.2 g, 결정질 셀룰로오스 (CEOLUS PH-101, Asahi Kasei) 127.3 g 및 마그네슘 스테아레이트 (Taihei Chemical Industrial) 6.6 g 을 혼합하여, 타정용 혼합 분말을 수득하였다. 생성된 타정용 혼합 분말을, 220 mg 의 질량을 갖는 중심정이 수득되도록, 8.5 mmφ 펀치를 갖는 회전식 타정기 (AQU3, Kikusui Seisakusho) 를 사용하여 타정하여, 두께 4.7 mm 의 중심정을 수득하였다.Resulting milled powder 1: 720 g, milled powder 2: 360 g, calcium pantothenate S type (BASF JAPAN) 92.4 g, VB12 fine grain (Mitsubishi Chemical Foods) 13.2 g, crystalline cellulose (CEOLUS PH-101, Asahi 127.3 g of Kasei) and 6.6 g of magnesium stearate (Taihei Chemical Industrial) were mixed to obtain a mixed powder for tableting. The resulting mixed powder for tableting was compressed using a rotary tablet press (AQU3, Kikusui Seisakusho) with an 8.5 mmϕ punch to obtain a core tablet with a mass of 220 mg, thereby obtaining a core tablet with a thickness of 4.7 mm.
그런 다음, 중심정을 히프로멜로오스 (Shin-Etsu Chemical) 및 멸균 탈크 (Matsumura Sangyo) 를 정제수에 용해 또는 분산하여 수득한 언더코트 용액, 및 에리트리톨 (Cargill Japan), 멸균 탈크, 침강 칼슘 카르보네이트 (Nitto Powder Chemical), 산화티탄 (Ishihara Sangyo), 결정질 셀룰로오스 (CEOLUS PH-F20, Asahi Kasei) 및 분말화 아카시아 (San-Ei Yakuhin Boeki) 를 정제수에 용해 또는 분산하여 수득한 빌드업 코팅 용액으로, 코팅기 (Doria Coater, Powrex) 를 사용하여 코팅하여, 5 mg/정제 및 96 mg/정제의 코팅 층을 갖는 코팅정을 수득하였다. 그런 다음, 코팅정을 수크로오스 (Mitsui Sugar), 에리트리톨 및 리보플라빈을 정제수에 용해하여 수득한 시럽 용액으로, 당의 팬 (Kikusui Seisakusho) 을 사용하여 추가 코팅하여, 24 mg/정제의 당의를 갖는 당의정을 수득하였다.Then, the core tablets were coated with an undercoat solution obtained by dissolving or dispersing hypromellose (Shin-Etsu Chemical) and sterilized talc (Matsumura Sangyo) in purified water, and erythritol (Cargill Japan), sterilized talc, and precipitated calcium carbonate. Build-up coating solution obtained by dissolving or dispersing bonate (Nitto Powder Chemical), titanium oxide (Ishihara Sangyo), crystalline cellulose (CEOLUS PH-F20, Asahi Kasei), and powdered acacia (San-Ei Yakuhin Boeki) in purified water. By coating using a coating machine (Doria Coater, Powrex), coated tablets with a coating layer of 5 mg/tablet and 96 mg/tablet were obtained. Then, the coated tablets were further coated with a syrup solution obtained by dissolving sucrose (Mitsui Sugar), erythritol and riboflavin in purified water using a sugar pan (Kikusui Seisakusho) to obtain dragees with a sugar coating of 24 mg/tablet. Obtained.
(비교예 2)(Comparative Example 2)
니코틴아미드 (Lonza Japan), 리보플라빈 (BASF JAPAN), 피리독신 히드로클로라이드 (BASF JAPAN), 결정질 셀룰로오스 (CEOLUS PH-101, Asahi Kasei), 락토오스 히드레이트 (GranuLac 200, Meggle) 및 옥수수 전분 (Japan Corn Starch) 을 유동층 건조기에 충전하였다. 히드록시프로필셀룰로오스 (HPC, Nippon Soda) 용액을 이에 분무하고, 혼합물을 과립화하고 건조시켰다. 그런 다음, 과립을 밀링 머신 (Power Mill) 에 의해 밀링하여, 밀링된 분말 1 을 수득하였다. 밀링된 분말 1 의 조성비는 니코틴아미드 13.7%, 리보플라빈 4.1%, 피리독신 히드로클로라이드 17.2%, 결정질 셀룰로오스 51.5%, 락토오스 히드레이트 7.2%, 옥수수 전분 2.5%, 및 HPC 3.8% 였다.Nicotinamide (Lonza Japan), riboflavin (BASF JAPAN), pyridoxine hydrochloride (BASF JAPAN), crystalline cellulose (CEOLUS PH-101, Asahi Kasei), lactose hydrate (GranuLac 200, Meggle) and corn starch (Japan Corn Starch). was charged into a fluidized bed dryer. Hydroxypropylcellulose (HPC, Nippon Soda) solution was sprayed thereon, and the mixture was granulated and dried. Then, the granules were milled by a milling machine (Power Mill) to obtain milled powder 1. The composition ratio of milled powder 1 was 13.7% nicotinamide, 4.1% riboflavin, 17.2% pyridoxine hydrochloride, 51.5% crystalline cellulose, 7.2% lactose hydrate, 2.5% corn starch, and 3.8% HPC.
또한, 티아민 니트레이트 (Watanabe Chemical), 옥수수 전분 및 결정질 셀룰로오스 (CEOLUS PH-101, Asahi Kasei) 를 유동층 건조기에 충전하였다. 히드록시프로필셀룰로오스 용액을 이에 분무하고, 혼합물을 과립화하고 건조시켰다. 그런 다음, 과립을 밀링 머신 (Power Mill) 에 의해 밀링하여, 밀링된 분말 2 를 수득하였다. 밀링된 분말 2 의 조성비는 티아민 니트레이트 74.3%, 옥수수 전분 7.6%, 결정질 셀룰로오스 14.3%, 및 HPC 3.9% 였다.Additionally, thiamine nitrate (Watanabe Chemical), corn starch, and crystalline cellulose (CEOLUS PH-101, Asahi Kasei) were charged into the fluidized bed dryer. The hydroxypropylcellulose solution was sprayed onto it and the mixture was granulated and dried. Then, the granules were milled by a milling machine (Power Mill) to obtain milled powder 2. The composition ratio of milled powder 2 was 74.3% thiamine nitrate, 7.6% corn starch, 14.3% crystalline cellulose, and 3.9% HPC.
생성된 밀링된 분말 1: 582 g, 밀링된 분말 2: 294 g, 칼슘 판토테네이트 S 형 (BASF JAPAN) 92.4 g, VB12 세립 (Mitsubishi Chemical Foods) 13.2 g, 옥수수 전분 69 g, 결정질 셀룰로오스 (CEOLUS PH-F20, Asahi Kasei) 78 g, Sylysia (Fuji Silysia) 5.7 g 및 마그네슘 스테아레이트 (Taihei Chemical Industrial) 5.7 g 을 혼합하여, 타정용 혼합 분말을 수득하였다. 생성된 타정용 혼합 분말을, 190 mg 의 질량을 갖는 중심정이 수득되도록, 8.5 mmφ 펀치를 갖는 회전식 타정기 (AQU3, Kikusui Seisakusho) 를 사용하여 타정하여, 두께 4.2 mm 의 중심정을 수득하였다.Resulting milled powder 1: 582 g, milled powder 2: 294 g, calcium pantothenate S type (BASF JAPAN) 92.4 g, VB12 fine grain (Mitsubishi Chemical Foods) 13.2 g, corn starch 69 g, crystalline cellulose (CEOLUS) 78 g of PH-F20, Asahi Kasei), 5.7 g of Sylysia (Fuji Silysia), and 5.7 g of magnesium stearate (Taihei Chemical Industrial) were mixed to obtain a mixed powder for tableting. The resulting mixed powder for tableting was compressed using a rotary tablet press (AQU3, Kikusui Seisakusho) with an 8.5 mmϕ punch to obtain a core tablet with a mass of 190 mg, thereby obtaining a core tablet with a thickness of 4.2 mm.
그런 다음, 중심정을 히프로멜로오스 (Shin-Etsu Chemical) 및 멸균 탈크 (Matsumura Sangyo) 를 정제수에 용해 또는 분산하여 수득한 언더코트 용액, 및 에리트리톨 (Cargill Japan), 멸균 탈크, 침강 칼슘 카르보네이트 (Nitto Powder Chemical), 산화티탄 (Ishihara Sangyo), 결정질 셀룰로오스 (CEOLUS PH-F20, Asahi Kasei) 및 분말화 아카시아 (San-Ei Yakuhin Boeki) 를 정제수에 용해 또는 분산하여 수득한 빌드업 코팅 용액으로, 코팅기 (Doria Coater, Powrex) 를 사용하여 코팅하여, 6 mg/정제 및 80 mg/정제의 코팅 층을 갖는 코팅정을 수득하였다. 그런 다음, 코팅정을 수크로오스 (Mitsui Sugar), 에리트리톨 및 리보플라빈을 정제수에 용해하여 수득한 시럽 용액으로, 당의 팬 (Kikusui Seisakusho) 을 사용하여 추가 코팅하여, 20 mg/정제의 당의를 갖는 당의정을 수득하였다.Then, the core tablets were coated with an undercoat solution obtained by dissolving or dispersing hypromellose (Shin-Etsu Chemical) and sterilized talc (Matsumura Sangyo) in purified water, and erythritol (Cargill Japan), sterilized talc, and precipitated calcium carbonate. Build-up coating solution obtained by dissolving or dispersing bonate (Nitto Powder Chemical), titanium oxide (Ishihara Sangyo), crystalline cellulose (CEOLUS PH-F20, Asahi Kasei), and powdered acacia (San-Ei Yakuhin Boeki) in purified water. By coating using a coating machine (Doria Coater, Powrex), coated tablets with a coating layer of 6 mg/tablet and 80 mg/tablet were obtained. Then, the coated tablets were further coated with a syrup solution obtained by dissolving sucrose (Mitsui Sugar), erythritol and riboflavin in purified water using a sugar pan (Kikusui Seisakusho) to obtain dragees with a sugar coating of 20 mg/tablet. Obtained.
(시험예 1) (Test Example 1)
당의정의 안정성 (정제 외관의 평가)Stability of dragees (evaluation of tablet appearance)
실시예 및 비교예의 당의정을 60℃ 에서 밀봉된 유리 병에, 그리고 40℃/75%RH 에서 개방된 유리 병에 저장하였다. 저장 후, 불량한 외관을 갖는 당의정을 추출하고, 양호한 생성물의 잔여 비율을 계산하였다. 불량한 외관을 갖는 정제는, 정제의 측면 상의 당의층에 균열이 있는 것을 나타낸다.Dragees of Examples and Comparative Examples were stored in sealed glass bottles at 60°C and in open glass bottles at 40°C/75%RH. After storage, dragees with poor appearance were extracted and the remaining percentage of good product was calculated. Tablets with poor appearance indicate cracks in the sugar layer on the sides of the tablet.
양호한 생성물의 잔여 비율 (%) = (저장 후 양호한 정제의 수 / 저장 전 정제의 수) Х 100Residual proportion of good product (%) = (number of good tablets after storage / number of tablets before storage) Х 100
60℃ 에서 밀봉된 유리 병에서의 저장 후 비교예 1 및 비교예 2 에서의 양호한 생성물의 잔여 비율은 각각 47.5% 및 0% 였으며, 정제의 외관 품질이 현저하게 손상된 것이 확인되었다. 한편, 실시예 1 ~ 11 에서는, 불량한 외관이 관찰되지 않았으며, 안정하다는 것이 확인되었다.After storage in a sealed glass bottle at 60°C, the remaining proportions of good products in Comparative Examples 1 and 2 were 47.5% and 0%, respectively, and it was confirmed that the external quality of the tablets was significantly damaged. On the other hand, in Examples 1 to 11, poor appearance was not observed, and it was confirmed that it was stable.
40℃/75%RH 에서 개방된 유리 병에서의 저장 후 비교예 1 및 비교예 2 에서의 양호한 생성물의 잔여 비율은 각각 0% 및 31.0% 였으며, 정제의 외관 품질이 현저하게 손상된 것이 확인되었다. 한편, 실시예 1 ~ 11 에서는, 양호한 생성물의 잔여 비율이 80% 이상으로 높았으며, 안정하다는 것이 확인되었다.After storage in an open glass bottle at 40°C/75%RH, the remaining proportions of good products in Comparative Examples 1 and 2 were 0% and 31.0%, respectively, and it was confirmed that the external quality of the tablets was significantly damaged. On the other hand, in Examples 1 to 11, the residual ratio of good products was high at over 80%, and it was confirmed that they were stable.
알파 전분과 같은 가공 전분을 첨가함으로써, 니코틴산 부류 및 비타민 B1 부류를 포함하는, 외관에 있어서 안정한 고형 제제가 제공될 수 있다. 이러한 고형 제제, 예를 들어 정제는, 균열 및 결손과 같은 불량한 외관을 나타내지 않으며, 양호한 안정성을 나타낸다.By adding processed starch, such as alpha starch, a solid preparation that is stable in appearance can be provided, containing the nicotinic acid family and the vitamin B 1 family. These solid preparations, such as tablets, do not exhibit poor appearance such as cracks and defects and exhibit good stability.
Claims (8)
니코틴산 또는 이의 염 1 질량부에 대해 3.5 질량부 이상 20 질량부 이하의 알파 전분을 포함하고,
비타민 B1 또는 이의 유도체, 또는 이의 염이 푸르술티아민, 푸르술티아민 히드로클로라이드, 티아민 클로라이드 히드로클로라이드, 티아민 니트레이트, 디세티아민 히드로클로라이드 히드레이트, 옥토티아민, 시코티아민, 비시부티아민, 비스벤티아민 및 벤포티아민으로부터 선택되는 정제.Nicotinic acid or its salt; Vitamin B 1 or a derivative thereof, or a salt thereof; A tablet comprising alpha starch,
Containing 3.5 parts by mass or more and 20 parts by mass or less of alpha starch per 1 part by mass of nicotinic acid or its salt,
Vitamin B 1 or its derivatives, or salts thereof, include fursultiamine, fursultiamine hydrochloride, thiamine chloride hydrochloride, thiamine nitrate, dicethiamine hydrochloride hydrate, octothiamine, cycotiamine, bisibentiamine, and bisbentiamine. and benfotiamine.
비타민 B1 또는 이의 유도체, 또는 이의 염이 푸르술티아민, 푸르술티아민 히드로클로라이드, 티아민 클로라이드 히드로클로라이드, 티아민 니트레이트, 디세티아민 히드로클로라이드 히드레이트, 옥토티아민, 시코티아민, 비시부티아민, 비스벤티아민 및 벤포티아민으로부터 선택되는 정제의 두께 팽윤 또는 균열을 억제하는 방법.
Nicotinic acid or a salt thereof, comprising adding 3.5 parts by mass to 20 parts by mass of alpha starch to tablets based on 1 part by mass of nicotinic acid or salt thereof; And a method of suppressing thickness swelling or cracking of a tablet containing vitamin B 1 or a derivative thereof, or a salt thereof,
Vitamin B 1 or its derivatives, or salts thereof include fursultiamine, fursultiamine hydrochloride, thiamine chloride hydrochloride, thiamine nitrate, dicethiamine hydrochloride hydrate, octothiamine, cycotiamine, bisibentiamine, and bisbentiamine. and a method for suppressing thickness swelling or cracking of a tablet selected from benfotiamine.
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JPH0952832A (en) * | 1995-08-10 | 1997-02-25 | Takeda Chem Ind Ltd | Medicinal composition |
JP2000016940A (en) * | 1998-04-28 | 2000-01-18 | Takeda Chem Ind Ltd | Composition containing vitamins b12 |
JP2001097849A (en) * | 1999-09-29 | 2001-04-10 | Eisai Co Ltd | Stable film tablet |
JP4841130B2 (en) | 2004-10-12 | 2011-12-21 | 武田薬品工業株式会社 | Stabilized vitamin preparation |
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JP5524130B2 (en) * | 2011-05-19 | 2014-06-18 | 武田薬品工業株式会社 | Stabilized vitamin preparation |
JP5897916B2 (en) * | 2012-01-31 | 2016-04-06 | アサヒフードアンドヘルスケア株式会社 | Vitamin-containing tablet and method for producing the same |
JP6196847B2 (en) * | 2012-08-30 | 2017-09-13 | 興和株式会社 | Anti-containing composition |
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2018
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JP2004357506A (en) * | 2003-05-30 | 2004-12-24 | Fancl Corp | Supplement for pet |
JP2008520576A (en) * | 2004-11-16 | 2008-06-19 | ニュー‐ティーン カンパニー,インク. | Compositions useful for the treatment of ocular neovascularization and macular degeneration |
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