JP6697402B2 - Highly functional tablet-containing tablet and method for producing the same - Google Patents
Highly functional tablet-containing tablet and method for producing the same Download PDFInfo
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- JP6697402B2 JP6697402B2 JP2016572180A JP2016572180A JP6697402B2 JP 6697402 B2 JP6697402 B2 JP 6697402B2 JP 2016572180 A JP2016572180 A JP 2016572180A JP 2016572180 A JP2016572180 A JP 2016572180A JP 6697402 B2 JP6697402 B2 JP 6697402B2
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- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- 235000003441 saturated fatty acids Nutrition 0.000 description 1
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 1
- DVQHRBFGRZHMSR-UHFFFAOYSA-N sodium methyl 2,2-dimethyl-4,6-dioxo-5-(N-prop-2-enoxy-C-propylcarbonimidoyl)cyclohexane-1-carboxylate Chemical compound [Na+].C=CCON=C(CCC)[C-]1C(=O)CC(C)(C)C(C(=O)OC)C1=O DVQHRBFGRZHMSR-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 239000000892 thaumatin Substances 0.000 description 1
- 235000010436 thaumatin Nutrition 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- ZCIHMQAPACOQHT-ZGMPDRQDSA-N trans-isorenieratene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/c1c(C)ccc(C)c1C)C=CC=C(/C)C=Cc2c(C)ccc(C)c2C ZCIHMQAPACOQHT-ZGMPDRQDSA-N 0.000 description 1
- KBPHJBAIARWVSC-XQIHNALSSA-N trans-lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C KBPHJBAIARWVSC-XQIHNALSSA-N 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
- 239000011712 vitamin K Substances 0.000 description 1
- 150000003721 vitamin K derivatives Chemical class 0.000 description 1
- 235000019143 vitamin K2 Nutrition 0.000 description 1
- 239000011728 vitamin K2 Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 229940046010 vitamin k Drugs 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- FJHBOVDFOQMZRV-XQIHNALSSA-N xanthophyll Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C=C(C)C(O)CC2(C)C FJHBOVDFOQMZRV-XQIHNALSSA-N 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Description
本発明は、機能性物質を高含有する錠剤及びその製造方法に関する。 The present invention relates to a tablet containing a high amount of a functional substance and a method for producing the tablet.
機能性物質を経口摂取する際の剤形としては、散剤、顆粒剤、カプセル剤、錠剤等がある。このうち錠剤は、取り扱いや摂取が容易であり、最もよく使用されているが、効果の期待できる量の機能性物質を摂取するには、以下の通り問題を有している。例えば、オルニチン塩酸塩を含有する錠剤は、オルニチン塩酸塩の比率が高くなるほど、適当な硬度の錠剤に成形することが困難であり、そのため、結合剤を増量して圧縮成形を補う必要がある。しかし、錠剤中に含まれる結合剤を増量すると、オルニチン塩酸塩の含有率が減少してしまう。
オルニチン塩酸塩、及びマルトース又は直鎖状もしくは環状のデキストリンを含有する混合物を圧縮成形もしくは、造粒及びそれに続く圧縮成形によって、均質で適度に高い硬度を有するオルニチン塩酸塩錠剤を得る技術が報告されている（特許文献１）。しかし、当該技術においても、錠剤を成形する際に２８質量％もの微結晶セルロース、並びにマルトース又は直鎖状もしくは環状のデキストリンを用いなければならず、Ｌ−オルニチン塩酸塩を錠剤質量の６８．１％含有する錠剤が市販されているのみである（協和発酵バイオ株式会社製「協和発酵バイオ オルニチン」）。
また、造粒用結合剤としてセルロース誘導体であるヒドロキシプロピルセルロースを機能性物質に均一に付着させ、打錠に適した粉末を製造する技術が報告されている（特許文献２及び３）。しかし、滑沢剤としてグリセリン脂肪酸エステルを用いることにより、錠剤中の機能性物質の含有率が高められたことについては示されていない。The dosage form for oral ingestion of the functional substance includes powders, granules, capsules, tablets and the like. Of these, tablets are easy to handle and ingest and are most often used, but ingesting an amount of the functional substance that can be expected to have an effect has the following problems. For example, tablets containing ornithine hydrochloride are more difficult to form into tablets of appropriate hardness as the proportion of ornithine hydrochloride is higher, so it is necessary to increase the amount of binder to supplement compression molding. However, if the amount of binder contained in the tablet is increased, the content of ornithine hydrochloride will decrease.
A technique for obtaining an ornithine hydrochloride tablet which is homogeneous and has moderately high hardness by compression molding or granulation and subsequent compression molding of a mixture containing ornithine hydrochloride and maltose or a linear or cyclic dextrin has been reported. (Patent Document 1). However, even in the art, 28% by mass of microcrystalline cellulose and maltose or linear or cyclic dextrin have to be used in molding a tablet, and L-ornithine hydrochloride is used in an amount of 68.1% of the tablet mass. % Contained tablets are only commercially available ("Kyowa Hakko Bio Ornithine" manufactured by Kyowa Hakko Bio Co., Ltd.).
In addition, a technique has been reported in which hydroxypropyl cellulose, which is a cellulose derivative, is uniformly attached to a functional substance as a granulation binder to produce a powder suitable for tableting (Patent Documents 2 and 3). However, it has not been shown that the content of the functional substance in the tablet was increased by using glycerin fatty acid ester as the lubricant.
本発明の目的は、機能性物質を高含有する錠剤及びその製造方法を提供することにある。 An object of the present invention is to provide a tablet containing a high amount of a functional substance and a method for producing the tablet.
本発明者らは、機能性物質を高含有する錠剤とするために、機能性物質を結合剤を用いて造粒した後に、滑沢剤を混合して圧縮成形することに着目した。しかし、上記方法において、滑沢剤として一般に知られているステアリン酸カルシウム又はショ糖脂肪酸エステルを用いた場合には、製造時に打錠障害（スティッキング、キャッピング）が起こる問題を見出した。
本発明者らは、鋭意検討した結果、造粒後に混合する滑沢剤として、グリセリン脂肪酸エステルを用いることで、高含有量の機能性物質を含有することが可能であり、かつ製造時の打錠障害が生じない錠剤が得られることを見出して、本発明を完成させた。The present inventors have focused on granulating the functional substance with a binder, and then mixing the mixture with a lubricant to perform compression molding in order to obtain a tablet containing a high amount of the functional substance. However, in the above method, when calcium stearate or sucrose fatty acid ester, which is generally known as a lubricant, is used, it has been found that a tableting problem (sticking, capping) occurs during production.
As a result of diligent studies, the present inventors have found that it is possible to contain a high content of a functional substance by using glycerin fatty acid ester as a lubricant to be mixed after granulation, and it is possible to improve the performance during production. The present invention has been completed by finding that a tablet that does not cause tablet damage can be obtained.
本発明は以下の（１）〜（９）に関する。
（１）機能性物質及び結合剤を含有する造粒物、並びにグリセリン脂肪酸エステルを含有する錠剤であって、機能性物質を高含有量で含有する、錠剤。
（２）機能性物質が、アミノ酸又はその塩である、上記（１）に記載の錠剤。
（３）アミノ酸又はその塩が、オルニチン又はその塩である、上記（２）に記載の錠剤。
（４）結合剤が、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース及びプルランからなる群より選ばれる１種又は２種以上である、上記（１）〜（３）のいずれかに記載の錠剤。
（５）結合剤が、機能性物質に均一に付着している、上記（１）〜（４）のいずれかに記載の錠剤。
（６）さらに、流動化剤を含有する、上記（１）〜（５）のいずれかに記載の錠剤。
（７）錠剤硬度が３０〜１５０Ｎである、上記（１）〜（６）のいずれかに記載の錠剤。
（８）マルトース、直鎖状のデキストリン及び環状のデキストリンの含有量が１質量％未満である、上記（１）〜（７）のいずれかに記載の錠剤。
（９）機能性物質を、結合剤を用いて造粒する工程、並びに、得られた造粒物及びグリセリン脂肪酸エステルを混合し、圧縮成形する工程を含む、錠剤の製造方法。The present invention relates to the following (1) to (9).
(1) A tablet containing a granulated product containing a functional substance and a binder, and a glycerin fatty acid ester, wherein the functional substance is contained in a high content.
(2) The tablet according to (1) above, wherein the functional substance is an amino acid or a salt thereof.
(3) The tablet according to (2) above, wherein the amino acid or a salt thereof is ornithine or a salt thereof.
(4) The tablet according to any one of (1) to (3) above, wherein the binder is one kind or two or more kinds selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose and pullulan.
(5) The tablet according to any of (1) to (4) above, wherein the binder is uniformly attached to the functional substance.
(6) The tablet according to any of (1) to (5) above, which further comprises a fluidizing agent.
(7) The tablet according to any one of (1) to (6) above, which has a tablet hardness of 30 to 150N.
(8) The tablet according to any one of (1) to (7) above, wherein the content of maltose, linear dextrin and cyclic dextrin is less than 1% by mass.
(9) A method for producing a tablet, which comprises a step of granulating a functional substance using a binder, and a step of mixing the obtained granulated product and glycerin fatty acid ester and compression-molding the mixture.
本発明によれば、機能性物質を高含有し、かつ製造時の打錠障害が生じない錠剤を提供することができる。
また、本発明によれば、十分な錠剤硬度を有する、機能性物質を高含有する錠剤を提供することができる。According to the present invention, it is possible to provide a tablet that contains a high amount of a functional substance and does not cause a tableting problem during production.
Further, according to the present invention, it is possible to provide a tablet having a sufficient tablet hardness and a high content of a functional substance.
本発明において、「機能性物質」とは、医薬組成物又はサプリメントの有効成分をいう。
機能性物質としては、医薬組成物又はサプリメントの有効成分であれば限定されないが、例えば、アミノ酸、核酸関連物質、糖関連物質、ペプチド、ビタミン、カロチノイド、コエンザイムＱ１０、及びコラーゲンからなる群より選ばれる機能性物質を、好ましくは、アミノ酸を挙げることができる。
アミノ酸としては、アラニン、アスパラギン、アスパラギン酸、グルタミン、グルタミン酸、グリシン、ヒスチジン、イソロイシン、ロイシン、リジン、アルギニン、メチオニン、フェニルアラニン、プロリン、セリン、スレオニン、トリプトファン、チロシン、バリン、システイン、カルボシステイン、オルニチン、シトルリン、ヒドロキシプロリン、γ−アミノ酪酸、及びＧＡＢＡからなる群より選ばれるアミノ酸を、好ましくは、オルニチン、シトルリン、アルギニン、ヒスチジン、リジン、及びトリプトファンからなる群より選ばれるアミノ酸を、さらに好ましくは、オルニチン、シトルリン、及びアルギニンからなる群より選ばれるアミノ酸を、最も好ましくはオルニチンを挙げることができる。
アミノ酸は、Ｄ体又はＬ体のいずれであってもよいが、Ｌ体が好ましい。
核酸関連物質としては、アデノシン三リン酸二ナトリウム、シチコリン、及びフラビンアデニンジヌクレオチドナトリウムからなる群より選ばれる核酸を挙げることができる。
糖関連物質としては、グルコサミン、シアル酸、及びオリゴ糖からなる群より選ばれる糖関連物質を挙げることができる。
ペプチドとしては、アラニルグルタミン及びアラニルチロシン等のジペプチド、並びにグルタチオン等のトリペプチドからなる群より選ばれるペプチドを挙げることができる。
ビタミンとしては、ビタミンＡ、ビタミンＤ、ビタミンＥ、ビタミンＫ、ビタミンＫ２、ビタミンＢ群、ナイアシン、パントテン酸、葉酸、ビオチン、及びビタミンＣからなる群より選ばれるビタミンを挙げることができる。
カロチノイドとしては、リコピン及びルテインからなる群より選ばれるカロチノイドを挙げることができる。
機能性物質は、機能性物質の塩として用いることもできる。機能性物質の塩としては、例えば、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩、アンモニウム塩、塩酸塩、クエン酸塩、アスパラギン酸塩、リンゴ酸塩、及び酒石酸塩からなる群より選ばれる機能性物質の塩を挙げることができる。特に、機能性物質がアミノ酸である場合には、塩酸塩が好ましい。
また、機能性物質は、２種類以上を混合して用いることもできる。In the present invention, the “functional substance” refers to an active ingredient of a pharmaceutical composition or supplement.
The functional substance is not limited as long as it is an active ingredient of a pharmaceutical composition or supplement, and is selected from the group consisting of amino acids, nucleic acid-related substances, sugar-related substances, peptides, vitamins, carotenoids, coenzyme Q10, and collagen. The functional substance is preferably an amino acid.
As the amino acid, alanine, asparagine, aspartic acid, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, arginine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, cysteine, carbocysteine, ornithine, An amino acid selected from the group consisting of citrulline, hydroxyproline, γ-aminobutyric acid, and GABA, preferably ornithine, citrulline, arginine, histidine, lysine, and an amino acid selected from the group consisting of tryptophan, more preferably ornithine. An amino acid selected from the group consisting of, citrulline, and arginine, most preferably, ornithine can be mentioned.
The amino acid may be either D-form or L-form, but the L-form is preferred.
Examples of the nucleic acid-related substance include a nucleic acid selected from the group consisting of adenosine triphosphate disodium, citicoline, and flavin adenine dinucleotide sodium.
Examples of the sugar-related substance include a sugar-related substance selected from the group consisting of glucosamine, sialic acid, and oligosaccharides.
Examples of the peptides include peptides selected from the group consisting of dipeptides such as alanylglutamine and alanyltyrosine, and tripeptides such as glutathione.
Examples of vitamins include vitamins selected from the group consisting of vitamin A, vitamin D, vitamin E, vitamin K, vitamin K2, vitamin B group, niacin, pantothenic acid, folic acid, biotin, and vitamin C.
Examples of carotenoids include carotenoids selected from the group consisting of lycopene and lutein.
The functional substance can also be used as a salt of the functional substance. As the salt of the functional substance, for example, a function selected from the group consisting of sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, hydrochloride, citrate, aspartate, malate, and tartrate. Mention may be made of salts of organic substances. Particularly, when the functional substance is an amino acid, hydrochloride is preferable.
Further, the functional substance may be used as a mixture of two or more kinds.
機能性物質としてオルニチン又はその塩を用いる場合、オルニチン塩酸塩、特に、Ｌ−オルニチン塩酸塩を用いることができる。本発明におけるＬ−オルニチン塩酸塩は、結晶又は結晶性の粉末であることが好ましく、純度は９８％以上であることが好ましく、乾燥減量は０．２％以下であることが好ましい。Ｌ−オルニチン塩酸塩の製造方法は特に限定されず、発酵法、合成法、精製法等を含む製造法によって製造することができる。Ｌ−オルニチン塩酸塩の粒度分布は特に限定されない。オルニチン塩酸塩は、協和発酵バイオ株式会社から購入することができる（製品名：Ｌ−オルニチン塩酸塩）。 When ornithine or a salt thereof is used as the functional substance, ornithine hydrochloride, particularly L-ornithine hydrochloride can be used. The L-ornithine hydrochloride in the present invention is preferably crystalline or crystalline powder, preferably has a purity of 98% or more, and a loss on drying of 0.2% or less. The method for producing L-ornithine hydrochloride is not particularly limited, and it can be produced by a production method including a fermentation method, a synthesis method, a purification method and the like. The particle size distribution of L-ornithine hydrochloride is not particularly limited. Ornithine hydrochloride can be purchased from Kyowa Hakko Bio Co., Ltd. (product name: L-ornithine hydrochloride).
本発明の錠剤は、機能性物質を高含有量で含有することを特徴とする。
本発明の錠剤における機能性物質の含有量は、例えば、７０質量％以上、好ましくは８０質量％以上、より好ましくは８５質量％以上、さらに好ましくは９０質量％以上、最も好ましくは９４質量％以上である。本発明の錠剤における機能性物質の含有量は、例えば、９８質量％以下である。The tablet of the present invention is characterized by containing a functional substance in a high content.
The content of the functional substance in the tablet of the present invention is, for example, 70% by mass or more, preferably 80% by mass or more, more preferably 85% by mass or more, further preferably 90% by mass or more, most preferably 94% by mass or more. Is. The content of the functional substance in the tablet of the present invention is, for example, 98% by mass or less.
本発明の錠剤は、機能性物質及び結合剤を含有する造粒物を含有することを特徴とする。
結合剤としては、食品等に使用できるものであれば特に制限されないが、例えば、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、プルラン等が挙げられ、ヒドロキシプロピルセルロースが好ましく、例えば、セルニーＳＳＬ（日本曹達社製）等が挙げられる。結合剤は、１種又は２種以上を組合せて使用することができる。
本発明において用いられるヒドロキシプロピルセルロースの平均分子量は１４０，０００程度以下である事が好ましく、粘度(ｍＰａ・ｓ ２０℃/２％水溶液)は１０程度以下が好ましい。The tablet of the present invention is characterized by containing a granulated product containing a functional substance and a binder.
The binder is not particularly limited as long as it can be used in foods and the like, and examples thereof include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, pullulan and the like, and hydroxypropyl cellulose is preferable, and for example, Celney SSL (manufactured by Nippon Soda Co., Ltd. ) And the like. The binder may be used alone or in combination of two or more.
The average molecular weight of the hydroxypropyl cellulose used in the present invention is preferably about 140,000 or less, and the viscosity (mPa · s 20 ° C./2% aqueous solution) is preferably about 10 or less.
「機能性物質及び結合剤を含有する造粒物」の「結合剤」の含有量は、錠剤質量に対して、例えば１０質量％以下、好ましくは６質量％以下、さらに好ましくは４質量％以下である。「機能性物質及び結合剤を含有する造粒物」の「結合剤」の含有量は、錠剤質量に対して、例えば、１質量％以上である。 The content of the "binder" in the "granulated product containing a functional substance and a binder" is, for example, 10 mass% or less, preferably 6 mass% or less, and more preferably 4 mass% or less with respect to the tablet mass. Is. The content of the "binder" in the "granulated product containing the functional substance and the binder" is, for example, 1% by mass or more based on the tablet mass.
ここで、本発明の錠剤は、「機能性物質及び結合剤を含有する造粒物」以外の部分に（すなわち、造粒物と混合して圧縮成形に付す成分として）、結合剤を含有していてもよい。
本発明において、「機能性物質及び結合剤を含有する造粒物」以外の部分に含有される結合剤としては、上記例示したものが挙げられるが、メディアン径が２０μｍ程度であるヒドロキシプロピルセルロースが好ましく、例えば、セルニーＳＳＬ ＳＦＰ（日本曹達社製）等が挙げられる。
「機能性物質及び結合剤を含有する造粒物」以外の部分に含有される「結合剤」の含有量は、錠剤質量に対して、例えば６質量％以下、好ましくは４質量％以下、さらに好ましくは２質量％以下、最も好ましくは１質量％以下である。Here, the tablet of the present invention contains a binder in a portion other than the “granulate containing a functional substance and a binder” (that is, as a component to be mixed with the granule and subjected to compression molding). May be.
In the present invention, examples of the binder contained in the portion other than the “granulated product containing the functional substance and the binder” include those exemplified above, and hydroxypropyl cellulose having a median diameter of about 20 μm is used. Preferable examples include Cernie SSL SFP (manufactured by Nippon Soda Co., Ltd.).
The content of the "binder" contained in the portion other than the "granulated product containing the functional substance and the binder" is, for example, 6% by mass or less, preferably 4% by mass or less, with respect to the tablet mass. It is preferably 2% by mass or less, and most preferably 1% by mass or less.
本発明の錠剤における結合剤の含有量は、オルニチン塩酸塩の含有量を高めるため、６質量％以下が好ましく、４質量％以下がより好ましい。 The content of the binder in the tablet of the present invention is preferably 6% by mass or less and more preferably 4% by mass or less in order to increase the content of ornithine hydrochloride.
本発明において、機能性物質及び結合剤を含有する造粒物は、製剤分野で公知の方法を用いて製造することができるが、例えば、後述の製造方法により製造することができる。
機能性物質及び結合剤を含有する造粒物の平均粒子径は、例えば、１〜１０００μｍ、好ましくは１０〜５００μｍ、最も好ましくは２０〜２００μｍである。平均粒子径は、例えばレーザー回折型粒度分布測定装置（ＨＥＲＯＳ＆ＲＯＤＯＳ、日本電子社製）を用いて測定することができる。In the present invention, the granulated product containing the functional substance and the binder can be produced by a method known in the field of formulation, for example, the production method described below.
The average particle size of the granulated product containing the functional substance and the binder is, for example, 1 to 1000 μm, preferably 10 to 500 μm, and most preferably 20 to 200 μm. The average particle size can be measured using, for example, a laser diffraction type particle size distribution measuring device (HEROS & RODOS, manufactured by JEOL Ltd.).
本発明において、機能性物質及び結合剤を含有する造粒物は、結合剤が機能性物質に均一に付着していることが、打錠時の結合力を向上し、打錠障害を防止するとの理由から、好ましい。
本発明において、「結合剤が機能性物質に均一に付着している」とは、造粒時、結合剤を機能性物質に均一に付着させる事をいう。
結合剤が機能性物質に均一に付着している造粒物は、例えば、後述の製造方法により製造することができる。In the present invention, the granulated product containing the functional substance and the binder, when the binder is evenly attached to the functional substance, improves the binding force during tableting and prevents tableting failure. For this reason, it is preferable.
In the present invention, “the binder is uniformly attached to the functional substance” means that the binder is uniformly attached to the functional substance during granulation.
The granulated product in which the binder is evenly attached to the functional substance can be produced, for example, by the production method described below.
本発明の錠剤は、グリセリン脂肪酸エステルを含有することを特徴とする。
本発明において用いられるグリセリン脂肪酸エステルとしては、食品等に使用できるものであれば特に制限されず、モノグリセリド、ジグリセリド、トリグリセリドが含まれる。グリセリン脂肪酸エステルを構成する脂肪酸としては、例えば、炭素数１０〜２４の飽和又は不飽和脂肪酸を挙げることができる。すなわち、本発明において用いられるグリセリン脂肪酸エステルには、グリセリンと、炭素数１０〜２４の飽和又は不飽和脂肪酸とのエステルが含まれる。
また、本発明において用いられるグリセリン脂肪酸エステルには、グリセリンの２〜１０量体を主成分とするポリグリセリンと、炭素数１０〜２４の飽和又は不飽和脂肪酸とのエステルが含まれる。そのような例としては、グリセリン３分子が結合したトリグリセリンと、炭素数１８〜２２の飽和又は不飽和脂肪酸とのエステルである、トリグリセリン脂肪酸エステルを挙げることができる。
グリセリン脂肪酸エステルは、市販品を用いることもでき、例えば、ポエムＴＲ−ＦＢ（理研ビタミン社製）が挙げられる。
本発明において、グリセリン脂肪酸エステルは、滑沢剤として用いることで本発明の上記効果を発揮する。すなわち、本発明においては、グリセリン脂肪酸エステルを、上記の機能性物質及び結合剤を含有する造粒物と混合し、圧縮成形することで、高含有量の機能性物質を含有し、かつ製造時の打錠障害が生じない錠剤が提供できる。The tablet of the present invention is characterized by containing glycerin fatty acid ester.
The glycerin fatty acid ester used in the present invention is not particularly limited as long as it can be used in foods and the like, and includes monoglyceride, diglyceride and triglyceride. Examples of the fatty acid that constitutes the glycerin fatty acid ester include saturated or unsaturated fatty acids having 10 to 24 carbon atoms. That is, the glycerin fatty acid ester used in the present invention includes an ester of glycerin and a saturated or unsaturated fatty acid having 10 to 24 carbon atoms.
Further, the glycerin fatty acid ester used in the present invention includes an ester of polyglycerin having a dimer to decylmer of glycerin as a main component and a saturated or unsaturated fatty acid having 10 to 24 carbon atoms. As such an example, a triglycerin fatty acid ester, which is an ester of triglycerin to which three glycerin molecules are bound, and a saturated or unsaturated fatty acid having 18 to 22 carbon atoms can be mentioned.
As the glycerin fatty acid ester, a commercially available product may be used, and examples thereof include Poem TR-FB (manufactured by Riken Vitamin Co.).
In the present invention, the glycerin fatty acid ester exhibits the above effects of the present invention when used as a lubricant. That is, in the present invention, a glycerin fatty acid ester is mixed with a granulated product containing the above functional substance and a binder, and compression-molded to contain a high content of the functional substance, and at the time of production. It is possible to provide a tablet that does not cause tableting problems.
本発明の錠剤におけるグリセリン脂肪酸エステルの含有量は、例えば０．１〜５質量％、好ましくは０．５〜４質量％、より好ましくは１〜３質量％である。 The content of the glycerin fatty acid ester in the tablet of the present invention is, for example, 0.1 to 5% by mass, preferably 0.5 to 4% by mass, more preferably 1 to 3% by mass.
本発明の錠剤は、さらに流動化剤を含有してもよい。
流動化剤としては、食品等に使用できるものであれば特に制限されないが、例えば、リン酸三カルシウム、リン酸水素カルシウム、微粒二酸化ケイ素等が挙げられ、リン酸三カルシウムが好ましい。流動化剤は、１種又は２種以上を組合せて使用することができる。The tablet of the present invention may further contain a fluidizing agent.
The fluidizing agent is not particularly limited as long as it can be used in foods and the like, and examples thereof include tricalcium phosphate, calcium hydrogen phosphate, and finely divided silicon dioxide, with tricalcium phosphate being preferred. The fluidizing agents may be used alone or in combination of two or more.
本発明の錠剤における流動化剤の含有量は、例えば０．１〜２質量％である。本発明の錠剤における流動化剤の含有量は、機能性物質の含有率を高めるため、２質量％以下が好ましく、１質量％以下がより好ましい。 The content of the fluidizing agent in the tablet of the present invention is, for example, 0.1 to 2% by mass. The content of the fluidizing agent in the tablet of the present invention is preferably 2% by mass or less and more preferably 1% by mass or less in order to increase the content of the functional substance.
本発明の錠剤においては、マルトース、直鎖状のデキストリン及び環状のデキストリンを実質的に含まないことが好ましい。実質的に含まないとは、例えば、マルトース、直鎖状のデキストリン及び環状のデキストリンの含有量が１質量％未満であることをいう。本発明においては、マルトース、直鎖状のデキストリン及び環状のデキストリンを含有しなくても、上記本発明の効果を有する錠剤を提供することができる。 The tablet of the present invention preferably contains substantially no maltose, linear dextrin, or cyclic dextrin. The phrase "substantially free from" means, for example, that the content of maltose, linear dextrin and cyclic dextrin is less than 1% by mass. In the present invention, it is possible to provide a tablet having the above-mentioned effects of the present invention without containing maltose, linear dextrin and cyclic dextrin.
本発明の錠剤は、所望により糖類、甘味剤、酸味料、抗酸化剤、着色剤、香料、崩壊剤等の添加剤を含有していてもよい。また、本発明の錠剤は、グリセリン脂肪酸エステル以外の滑沢剤を含有していてもよい。 The tablet of the present invention may optionally contain additives such as sugars, sweeteners, acidulants, antioxidants, colorants, flavors and disintegrants. Further, the tablet of the present invention may contain a lubricant other than glycerin fatty acid ester.
糖類としては、食品等に使用できるものであれば特に制限されないが、例えば単糖類、二糖類、糖アルコール、オリゴ糖等があげられ、好ましくは糖アルコールが挙げられる。 The saccharide is not particularly limited as long as it can be used in foods and the like, and examples thereof include monosaccharides, disaccharides, sugar alcohols, oligosaccharides, and the like, and sugar alcohols are preferable.
単糖類としては、例えばグルコース、キシロース、ガラクトース、フラクトース等が挙げられる。二糖類としては、例えばトレハロース、蔗糖、乳糖、パラチノース等が挙げられる。糖アルコールとしては、例えばマルチトール、エリスリトール、ソルビトール、キシリトール等が挙げられる。オリゴ糖としては、例えばラフィノース、イヌロオリゴ糖（チコリオリゴ糖）、パラチノースオリゴ糖等が挙げられる。 Examples of monosaccharides include glucose, xylose, galactose, fructose and the like. Examples of the disaccharide include trehalose, sucrose, lactose, palatinose and the like. Examples of sugar alcohols include maltitol, erythritol, sorbitol, xylitol and the like. Examples of oligosaccharides include raffinose, inulooligosaccharides (chicoryoligosaccharides), palatinose oligosaccharides, and the like.
糖類の形状は特に制限されないが、微結晶又は微粒子の形態が好ましく、その平均粒子径は、例えば１〜１００μｍ、好ましくは５〜８０μｍ、より好ましくは１０〜６０μｍ、特に好ましくは３０〜５０μｍである。本発明の錠剤中で糖類が占める割合は、製剤における一般的な使用の量の範囲内であれば特に限定されない。 The shape of the saccharide is not particularly limited, but the form of fine crystals or fine particles is preferable, and the average particle size thereof is, for example, 1 to 100 μm, preferably 5 to 80 μm, more preferably 10 to 60 μm, and particularly preferably 30 to 50 μm. .. The ratio of sugars in the tablet of the present invention is not particularly limited as long as it is within the range of the amount generally used in the preparation.
グリセリン脂肪酸エステル以外の滑沢剤としては、食品等に使用できるものであれば特に制限されないが、例えば、ステアリン酸、ステアリン酸マグネシウム、ステアリン酸カルシウム等のステアリン酸又はその金属塩、ショ糖脂肪酸エステル、硬化油脂、二酸化ケイ素、リン酸カルシウム等が挙げられる。滑沢剤は、錠剤の表面のみにあっても、錠剤内部に分散していてもよい。本発明の錠剤中でグリセリン脂肪酸エステル以外の滑沢剤が占める割合は、０．１〜１０質量％であることが好ましく、０．５〜８質量％であることがより好ましい。 Lubricants other than glycerin fatty acid ester is not particularly limited as long as it can be used in foods, for example, stearic acid, magnesium stearate, stearic acid or a metal salt thereof such as calcium stearate, sucrose fatty acid ester, Hardened oil and fat, silicon dioxide, calcium phosphate and the like can be mentioned. The lubricant may be only on the surface of the tablet or may be dispersed inside the tablet. The proportion of the lubricant other than the glycerin fatty acid ester in the tablet of the present invention is preferably 0.1 to 10% by mass, more preferably 0.5 to 8% by mass.
甘味剤としては、食品等に使用できるものであれば特に制限されないが、例えば、サッカリンナトリウム、グリチルリチン二カリウム、アスパルテーム、ステビア、ソーマチン等が挙げられる。本発明の錠剤中で甘味剤が占める割合は、製剤における一般的な使用の量の範囲内であれば特に限定されない。 The sweetener is not particularly limited as long as it can be used in foods and the like, and examples thereof include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin and the like. The proportion of the sweetener in the tablet of the present invention is not particularly limited as long as it is within the range of the amount generally used in the preparation.
酸味料としては、食品等に使用できるものであれば特に制限されないが、例えば、クエン酸、酒石酸、リンゴ酸等が挙げられる。本発明の錠剤中で酸味料が占める割合は、製剤における一般的な使用の量の範囲内であれば特に限定されない。 The acidulant is not particularly limited as long as it can be used in foods and the like, and examples thereof include citric acid, tartaric acid, malic acid and the like. The proportion of the acidulant in the tablet of the present invention is not particularly limited as long as it is within the range of the amount generally used in the preparation.
抗酸化剤としては、食品等に使用できるものであれば特に制限されないが、例えば、トコフェロール、アスコルビン酸、塩酸システイン、Ｌ−アスコルビン酸ステアリン酸エステル等が挙げられる。本発明の錠剤中で抗酸化剤が占める割合は、製剤における一般的な使用の量の範囲内であれば特に限定されない。 The antioxidant is not particularly limited as long as it can be used in foods and the like, and examples thereof include tocopherol, ascorbic acid, cysteine hydrochloride, L-ascorbic acid stearate and the like. The proportion of the antioxidant in the tablet of the present invention is not particularly limited as long as it is within the range of the amount generally used in the preparation.
着色剤としては、食品等に使用できるものであれば特に制限はされないが、例えば、食用黄色５号、食用赤色２号、食用青色２号、カロチノイド色素、トマト色素等が挙げられる。本発明の錠剤中で着色剤が占める割合は、製剤における一般的な使用の量の範囲内であれば特に限定されない。 The colorant is not particularly limited as long as it can be used in foods and the like, and examples thereof include Food Yellow No. 5, Food Red No. 2, Food Blue No. 2, carotenoid pigments, tomato pigments and the like. The proportion of the colorant in the tablet of the present invention is not particularly limited as long as it is within the range of the amount generally used in the preparation.
香料としては、食品等に使用できるものであれば特に制限されないが、例えば、レモンフレーバー、レモンライムフレーバー、グレープフルーツフレーバー、アップルフレーバー等が挙げられる。本発明の錠剤中で香料が占める割合は、製剤における一般的な使用の量の範囲内であれば特に限定されない。 The fragrance is not particularly limited as long as it can be used in foods and the like, and examples thereof include lemon flavor, lemon lime flavor, grapefruit flavor, apple flavor and the like. The proportion of the flavor in the tablet of the present invention is not particularly limited as long as it is within the range of the amount generally used in the preparation.
崩壊剤としては、食品等に使用できるものであれば特に制限されないが、例えば、コーンスターチ、バレイショデンプン等が挙げられる。本発明の錠剤中で崩壊剤が占める割合は、製剤における一般的な使用の量の範囲内であれば特に限定されない。 The disintegrator is not particularly limited as long as it can be used in foods and the like, and examples thereof include corn starch and potato starch. The proportion of the disintegrant in the tablet of the present invention is not particularly limited as long as it is within the range of the amount generally used in the preparation.
本発明の錠剤は、例えばかけ、くずれ等が生じない硬度を有しているのが好ましい。錠剤の硬度は、一般的に錠剤硬度計で錠剤の直径方向の破壊強度として測定されるが、その値は２０〜２００Ｎであるのが好ましく、３０〜１５０Ｎであるのがより好ましく、４０〜１００Ｎであるのが特に好ましい。錠剤の硬度は、市販の錠剤破壊強度測定機、例えば、ＨＡＲＤＮＥＳＳ ＴＥＳＴＥＲ ＫＨＴ−２０Ｎ（藤原製作所製）等により測定できる。 The tablet of the present invention preferably has a hardness that does not cause, for example, breaking or breaking. The hardness of the tablet is generally measured as a breaking strength in the diameter direction of the tablet with a tablet hardness meter, and the value is preferably 20 to 200 N, more preferably 30 to 150 N, and more preferably 40 to 100 N. Is particularly preferable. The hardness of the tablet can be measured by a commercially available tablet breaking strength measuring machine, for example, HARDNESS TESTER KHT-20N (manufactured by Fujiwara Seisakusho).
本発明の錠剤の形状は、特に制限されないが、例えば丸錠、三角錠、砲丸錠等が好ましい。本発明の錠剤の大きさは、特に制限されないが、例えば質量で０．１〜２ｇ、直径で０．３〜２．０ｃｍであるのが好ましい。 The shape of the tablet of the present invention is not particularly limited, but for example, a round tablet, a triangular tablet, a gunball tablet and the like are preferable. The size of the tablet of the present invention is not particularly limited, but it is preferably, for example, 0.1 to 2 g in mass and 0.3 to 2.0 cm in diameter.
本発明の錠剤は、機能性物質（例えば、オルニチン塩酸塩）を、結合剤（例えば、ヒドロキシプロピルセルロース（セルニーＳＳＬ（日本曹達社製））等）を用いて造粒する工程、及び、得られた造粒物、グリセリン脂肪酸エステル及び任意に含有してもよい添加剤（例えば、ヒドロキシプロピルセルロース（セルニーＳＳＬ ＳＦＰ（日本曹達社製））等の結合剤）を混合し、圧縮成形する工程を含んで製造することができる。
上記した造粒する工程においては、機能性物質及び添加剤、好ましくは、例えば、リン酸三カルシウムなどの流動化剤を、結合剤を用いて造粒してもよい。
機能性物質を、結合剤を用いて造粒する工程における造粒方法としては、例えば精製水、エタノール等の溶媒又は分散媒を用いた湿式造粒法が好ましい。具体的には、例えば、機能性物質を流動混合させながら、溶媒又は分散媒に溶解又は分散した結合剤を噴霧して造粒し、乾燥して、造粒物を得ることができる。
造粒に用いる機器は、特に限定されず、例えば流動層造粒機、転動撹拌造粒機、押し出し造粒機等を用いることができる。
圧縮成形に用いる機器は、特に限定されず、例えばロータリー圧縮成形機、油圧プレス機等の圧縮機を用いることができる。The tablet of the present invention is obtained by granulating a functional substance (for example, ornithine hydrochloride) with a binder (for example, hydroxypropyl cellulose (Celney SSL (manufactured by Nippon Soda Co., Ltd.)) and the like, and Including a step of mixing the granulated product, glycerin fatty acid ester, and optionally added additive (for example, binder such as hydroxypropyl cellulose (Celny SSL SFP (manufactured by Nippon Soda Co., Ltd.)) and compression molding. Can be manufactured in.
In the above-mentioned granulation step, a functional substance and an additive, preferably a fluidizing agent such as tricalcium phosphate, may be granulated using a binder.
As a granulation method in the step of granulating the functional substance with a binder, for example, a wet granulation method using a solvent such as purified water or ethanol or a dispersion medium is preferable. Specifically, for example, while fluid-mixing the functional substance, a binder dissolved or dispersed in a solvent or a dispersion medium is sprayed, granulated, and dried to obtain a granulated product.
The equipment used for granulation is not particularly limited, and for example, a fluidized bed granulator, a tumbling stirring granulator, an extrusion granulator, or the like can be used.
The equipment used for compression molding is not particularly limited, and a compressor such as a rotary compression molding machine or a hydraulic press machine can be used.
本発明の錠剤は、さらに、防湿性、保存安定性等の向上のため、例えば糖、糖アルコール等によりコーティングされた糖衣錠又はコーティング錠であってもよい。 The tablet of the present invention may be a sugar-coated tablet or coated tablet coated with, for example, sugar, sugar alcohol or the like in order to further improve moisture resistance and storage stability.
本発明の錠剤は、食品、医薬品等として、摂取することができる。摂取量は機能性物質の種類に応じて、公知の有効量に基づき設定することができるが、例えばオルニチン塩酸塩を日々の栄養摂取を目的に錠剤食品の形態で摂取する場合、オルニチン塩酸塩としての摂取量は１日あたり、１００ｍｇ〜２ｇであることが好ましい。本発明の錠剤では、オルニチン塩酸塩を、錠剤中に７０質量％以上、好ましくは８０質量％以上、より好ましくは８５質量％以上、さらに好ましくは９０質量％以上、最も好ましくは９４質量％以上含有させることで、服用する錠剤数を減らすことが可能である。１日に服用する錠剤の個数は、１〜１５個となるようにすることが好ましい。 The tablet of the present invention can be ingested as a food, a drug, etc. The intake amount can be set based on a known effective amount according to the type of the functional substance.For example, when ingesting ornithine hydrochloride in the form of a tablet food for the purpose of daily nutrition intake, as the ornithine hydrochloride, The daily intake is preferably 100 mg to 2 g. In the tablet of the present invention, ornithine hydrochloride is contained in the tablet in an amount of 70% by mass or more, preferably 80% by mass or more, more preferably 85% by mass or more, further preferably 90% by mass or more, and most preferably 94% by mass or more. By doing so, it is possible to reduce the number of tablets to be taken. The number of tablets to be taken daily is preferably 1 to 15.
以下、本発明を実施例によりさらに具体的に説明するが、本発明は以下の実施例により限定されるものではない。
実施例、比較例、及び参考例において、以下を使用した。
Ｌ−オルニチン塩酸塩：製品名 Ｌ−オルニチン塩酸塩（協和発酵バイオ社製）
リン酸三カルシウム：製品名 リン酸三カルシウム（太平化学産業社製）
ヒドロキシプロピルセルロース（１）：製品名 セルニーＳＳＬ（日本曹達社製）
ヒドロキシプロピルセルロース（２）：製品名 セルニーＳＳＬ ＳＦＰ（日本曹達社製）
グリセリン脂肪酸エステル：製品名 ポエムＴＲ−ＦＢ（理研ビタミン社製）
ウコン抽出物：製品名 クルクミンＣ３コンプレックス（サビンサジャパンコーポレーション社製）
プルラン：製品名 プルラン（林原社製）Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited to the following Examples.
The following were used in the examples, comparative examples, and reference examples.
L-ornithine hydrochloride: product name L-ornithine hydrochloride (manufactured by Kyowa Hakko Bio Co., Ltd.)
Tricalcium phosphate: Product name Tricalcium phosphate (manufactured by Taihei Chemical Industry Co., Ltd.)
Hydroxypropyl cellulose (1): Product name CELNY SSL (manufactured by Nippon Soda Co., Ltd.)
Hydroxypropyl cellulose (2): Product name CELNY SSL SFP (Nippon Soda)
Glycerin fatty acid ester: Product name Poem TR-FB (manufactured by Riken Vitamin Co.)
Turmeric extract: Product name Curcumin C3 Complex (manufactured by Sabinsa Japan Corporation)
Pullulan: Product name Pullulan (made by Hayashibara)
Ｌ−オルニチン塩酸塩４７３０ｇ、リン酸三カルシウム２０ｇを流動層造粒機（フロイント産業製：ＦＬＯ−５Ａ型）に投入し、流動混合させながらヒドロキシプロピルセルロース（表１中、ヒドロキシプロピルセルロース（１）と記載する）１５０ｇを水に溶解して１５００ｇとした液を噴霧した。その後、乾燥して得られた造粒物３９２０ｇにグリセリン脂肪酸エステル８０ｇを混合し、ロータリー式打錠機（畑鐵工所製：ＨＴ−ＡＰ１５ＳＳ−Ｕ、以下同じ。）を用いて、圧縮成形圧１０ｋＮで圧縮成形して直径８ｍｍ、２７０ｍｇの錠剤を得た。本錠剤は、打錠障害を起こす事無く製造出来た。また、任意に１０個の錠剤を選んで錠剤硬度を測定したところ、錠剤硬度の平均は１００Ｎであった。 4730 g of L-ornithine hydrochloride and 20 g of tricalcium phosphate were put into a fluidized bed granulator (FLO-5A type manufactured by Freund Sangyo), and hydroxypropyl cellulose (hydroxypropyl cellulose (1) in Table 1) while being fluidized and mixed. 150 g) was dissolved in water to make 1500 g, and the solution was sprayed. Then, 80 g of glycerin fatty acid ester was mixed with 3920 g of the granulated product obtained by drying, and a compression molding pressure was applied using a rotary tableting machine (HT-AP15SS-U manufactured by Hata Works). By compression molding at 10 kN, tablets with a diameter of 8 mm and 270 mg were obtained. This tablet could be produced without causing a tableting failure. Further, when 10 tablets were arbitrarily selected and the tablet hardness was measured, the average tablet hardness was 100N.
Ｌ−オルニチン塩酸塩１４１９ｇ、リン酸三カルシウム１３．５ｇを流動層造粒機（フロイント産業製：ＦＬＯ−２Ａ型）に投入し、流動混合させながらヒドロキシプロピルセルロース（表１中、ヒドロキシプロピルセルロース（１）と記載する）３０ｇを水に溶解して３７５ｇとした液を噴霧した。その後、乾燥して得られた造粒物９７５ｇにヒドロキシプロピルセルロース（表１中、ヒドロキシプロピルセルロース（２）と記載する）５ｇ、グリセリン脂肪酸エステル２０ｇを混合し、ロータリー式打錠機を用いて、圧縮成形圧１０ｋＮで圧縮成形して直径８ｍｍ、２７０ｍｇの錠剤を得た。本錠剤は、打錠障害を起こす事無く製造出来た。また、任意に１０個の錠剤を選んで錠剤硬度を測定したところ、錠剤硬度の平均は９０Ｎであった。 1419 g of L-ornithine hydrochloride and 13.5 g of tricalcium phosphate were put into a fluid bed granulator (FLO-2A type manufactured by Freund Sangyo), and hydroxypropyl cellulose (in Table 1, hydroxypropyl cellulose ( A solution in which 30 g (described as 1)) was dissolved in water to make 375 g was sprayed. Thereafter, 5 g of hydroxypropyl cellulose (described as hydroxypropyl cellulose (2) in Table 1) and 20 g of glycerin fatty acid ester were mixed with 975 g of the granulated product obtained by drying, and the mixture was mixed with a rotary tableting machine. Compression molding was carried out at a compression molding pressure of 10 kN to obtain tablets having a diameter of 8 mm and 270 mg. This tablet could be produced without causing a tableting failure. Further, when 10 tablets were arbitrarily selected and the tablet hardness was measured, the average tablet hardness was 90N.
Ｌ−オルニチン塩酸塩１４１９ｇ、リン酸三カルシウム４．５ｇを流動層造粒機（フロイント産業製：ＦＬＯ−２Ａ型）に投入し、流動混合させながらヒドロキシプロピルセルロース（表１中、ヒドロキシプロピルセルロース（１）と記載する）４９．５ｇを水に溶解して４９５ｇとした液を噴霧した。その後、乾燥して得られた造粒物９８２ｇにグリセリン脂肪酸エステル１８ｇを混合し、ロータリー式打錠機を用いて、圧縮成形圧１０ｋＮで圧縮成形して直径８ｍｍ、２７０ｍｇの錠剤を得た。本錠剤は、打錠障害を起こす事無く製造出来た。また、任意に１０個の錠剤を選んで錠剤硬度を測定したところ、錠剤硬度の平均は１００Ｎであった。 1419 g of L-ornithine hydrochloride and 4.5 g of tricalcium phosphate were put into a fluidized bed granulator (FLO-2A type manufactured by Freund Sangyo), and hydroxypropyl cellulose (in Table 1, hydroxypropyl cellulose ( A solution in which 49.5 g (described as 1)) was dissolved in water to make 495 g was sprayed. Then, 182 g of glycerin fatty acid ester was mixed with 982 g of the granulated product obtained by drying, and compression molding was carried out using a rotary tableting machine at a compression molding pressure of 10 kN to obtain tablets having a diameter of 8 mm and 270 mg. This tablet could be produced without causing a tableting failure. Further, when 10 tablets were arbitrarily selected and the tablet hardness was measured, the average tablet hardness was 100N.
［比較例１］
Ｌ−オルニチン塩酸塩１４１９ｇ、リン酸三カルシウム４．５ｇを流動層造粒機（フロイント産業製：ＦＬＯ−２Ａ型）に投入し、流動混合させながらヒドロキシプロピルセルロース（表１中、ヒドロキシプロピルセルロース（１）と記載する）４９．５ｇを水に溶解して４９５ｇとした液を噴霧した。その後、乾燥して得られた造粒物９８２ｇにヒドロキシプロピルセルロース（表１中、ヒドロキシプロピルセルロース（２）と記載する）８ｇ、ステアリン酸カルシウム１０ｇ（製品名：ステアリン酸カルシウム（太平化学産業社製））を混合し、ロータリー式打錠機を用いて、圧縮成形圧１０ｋＮで圧縮成形して直径８ｍｍ、２７０ｍｇの錠剤を得た。しかし、得られた錠剤は打錠機下杵からの杵離れが悪くスティッキング が見られた。また、得られた錠剤は適当な容器でシェーキングするとキャッピングが見られた。[Comparative Example 1]
1419 g of L-ornithine hydrochloride and 4.5 g of tricalcium phosphate were put into a fluidized bed granulator (FLO-2A type manufactured by Freund Sangyo), and hydroxypropyl cellulose (in Table 1, hydroxypropyl cellulose ( A solution in which 49.5 g (described as 1)) was dissolved in water to make 495 g was sprayed. Then, to 982 g of the granulated product obtained by drying, 8 g of hydroxypropyl cellulose (described as hydroxypropyl cellulose (2) in Table 1) and 10 g of calcium stearate (product name: calcium stearate (manufactured by Taihei Chemical Industry Co., Ltd.)) Were mixed and compressed using a rotary tableting machine at a compression molding pressure of 10 kN to obtain tablets having a diameter of 8 mm and 270 mg. However, the obtained tablets had poor sticking from the punch under the tableting machine and sticking was observed. Moreover, capping was observed when the obtained tablets were shaken in an appropriate container.
［比較例２］
Ｌ−オルニチン塩酸塩１４１９ｇ、リン酸三カルシウム６ｇを流動層造粒機（フロイント産業製：ＦＬＯ−２Ａ型）に投入し、流動混合させながらヒドロキシプロピルセルロース（表１中、ヒドロキシプロピルセルロース（１）と記載する）４５ｇを水に溶解して４５０ｇとした液を噴霧した。その後、乾燥して得られた造粒物９８０ｇにショ糖脂肪酸エステル２０ｇ（製品名：リョートーシュガーエステルＳ−３７０ＦＵ（三菱化学フーズ社製））を混合し、ロータリー式打錠機を用いて、圧縮成形圧１０ｋＮで圧縮成形して直径８ｍｍ、２７０ｍｇの錠剤を得た。しかし、得られた錠剤は打錠機下杵からの杵離れが悪くスティッキングが見られた。[Comparative example 2]
1419 g of L-ornithine hydrochloride and 6 g of tricalcium phosphate were put into a fluid bed granulator (FLO-2A type manufactured by Freund Sangyo), and hydroxypropyl cellulose (hydroxypropyl cellulose (1) in Table 1) while being fluidized and mixed. 45 g was dissolved in water to make 450 g. Thereafter, 20 g of sucrose fatty acid ester (product name: Ryoto Sugar Ester S-370FU (manufactured by Mitsubishi Kagaku Foods Co., Ltd.)) was mixed with 980 g of the granulated product obtained by drying, and using a rotary tableting machine, Compression molding was carried out at a compression molding pressure of 10 kN to obtain tablets having a diameter of 8 mm and 270 mg. However, the obtained tablets had poor sticking from the punch under the tableting machine and sticking was observed.
［参考例１］
特許文献１に記載の方法で、オルニチン塩酸塩の含有率を高めることができるか否かについて、以下のとおり試みた。
Ｌ−オルニチン塩酸塩８３．４ｇ、βシクロデキストリン（製品名：セルデックスＢ−１００（日本食品化工社製））１３ｇ、ウコン抽出物０．３ｇを流動層造粒機（フロイント産業製：ＦＬ-ＭＩＮＩ）に投入し、流動混合させながらプルラン０．８ｇを水に溶解して１６ｇとした液を噴霧した。その後、乾燥して得られた造粒物７８ｇにショ糖脂肪酸エステル（製品名：ＤＫエステルＦ-２０Ｗ（第一工業製薬社製））２ｇを混合し、単発式打錠機（菊水製作所製：６Ｂ-２Ｍ、以下同じ。）を用いて、圧縮成形圧１５ｋＮで圧縮成形して直径８ｍｍ、２５５ｍｇの錠剤を得た。しかし、得られた錠剤はキャッピングおよびラミネーションが見られた。[Reference Example 1]
Whether or not the content of ornithine hydrochloride can be increased by the method described in Patent Document 1 was tried as follows.
83.4 g of L-ornithine hydrochloride, 13 g of β cyclodextrin (product name: Celldex B-100 (manufactured by Nippon Shokuhin Kako Co., Ltd.)), 0.3 g of turmeric extract were used in a fluid bed granulator (Freund Industrial: FL-). MINI), and 0.8 g of pullulan was dissolved in water to 16 g while spray-mixing. Then, 2 g of sucrose fatty acid ester (product name: DK ester F-20W (manufactured by Daiichi Kogyo Seiyaku Co., Ltd.)) was mixed with 78 g of the granulated product obtained by drying, and a single-shot tableting machine (manufactured by Kikusui Seisakusho: 6B-2M, the same shall apply hereinafter), and compression molding was carried out at a compression molding pressure of 15 kN to obtain tablets having a diameter of 8 mm and 255 mg. However, the resulting tablets showed capping and lamination.
［参考例２］
Ｌ−オルニチン塩酸塩８３．４ｇ、結晶セルロース１３ｇ（製品名：セオラスＦＤ１０１（旭化成ケミカルズ社製））、ウコン抽出物０．３ｇを流動層造粒機（フロイント産業製：ＦＬ-ＭＩＮＩ）に投入し、流動混合させながらプルラン０．８ｇを水に溶解して１６ｇとした液を噴霧した。その後、乾燥して得られた造粒物７８ｇにショ糖脂肪酸エステル（製品名：ＤＫエステルＦ-２０Ｗ（第一工業製薬社製））２ｇを混合し、単発式打錠機を用いて、圧縮成形圧１５ｋＮで圧縮成形して直径８ｍｍ、２５５ｍｇの錠剤を得た。しかし、得られた錠剤はキャッピングが見られた。[Reference Example 2]
83.4 g of L-ornithine hydrochloride, 13 g of crystalline cellulose (product name: Ceorus FD101 (manufactured by Asahi Kasei Chemicals Corporation)), and 0.3 g of turmeric extract were put into a fluidized bed granulator (Freund Industrial: FL-MINI). While fluidizing and mixing, 0.8 g of pullulan was dissolved in water to obtain 16 g of liquid. Then, 2 g of sucrose fatty acid ester (product name: DK ester F-20W (manufactured by Daiichi Kogyo Seiyaku Co., Ltd.)) was mixed with 78 g of the granulated product obtained by drying, and the mixture was compressed using a single-shot tableting machine. Compression molding was carried out at a molding pressure of 15 kN to obtain tablets having a diameter of 8 mm and 255 mg. However, the obtained tablets showed capping.
参考例１及び２より、特許文献１に記載の方法では、オルニチン塩酸塩の含有率を高めることはできなかった。 From Reference Examples 1 and 2, the method described in Patent Document 1 could not increase the content of ornithine hydrochloride.
実施例、比較例、及び参考例の各成分の含有率、打錠障害の有無、打錠圧力、錠剤硬度を表１に記載する。 Table 1 shows the content of each component in Examples, Comparative Examples, and Reference Examples, the presence or absence of tableting failure, the tableting pressure, and the tablet hardness.
本発明により、機能性物質を高含有する錠剤及びその製造方法を提供することができる。 According to the present invention, a tablet containing a high amount of a functional substance and a method for producing the same can be provided.
本出願は、日本で出願された特願２０１５−０１７６２８を基礎としており、その内容は本明細書にすべて包含されるものである。 The present application is based on Japanese Patent Application No. 2005-017628 filed in Japan, the contents of which are incorporated in full herein.
Claims (6)
前記機能性物質がオルニチン又はその塩であり、
前記機能性物質の含有量が７０質量％以上９８質量％以下であり、
マルトース、直鎖状のデキストリン及び環状のデキストリンの含有量が１質量％未満である、錠剤。 Granules containing a functional substance and a binder, and a tablet containing glycerol fatty acid ester, a functional substance having free,
The functional substance is ornithine or a salt thereof,
The content of the functional substance is 70% by mass or more and 98% by mass or less,
A tablet having a maltose content, a linear dextrin content, and a cyclic dextrin content of less than 1% by mass.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2015017628 | 2015-01-30 | ||
| JP2015017628 | 2015-01-30 | ||
| PCT/JP2016/052651 WO2016121925A1 (en) | 2015-01-30 | 2016-01-29 | Tablet containing high proportion of functional substance, and manufacturing method for said tablet |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPWO2016121925A1 JPWO2016121925A1 (en) | 2017-11-16 |
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| JP7235193B2 (en) * | 2017-04-26 | 2023-03-08 | 大正製薬株式会社 | solid composition |
| US20200205456A1 (en) * | 2017-07-26 | 2020-07-02 | Abbott Laboratories | Nutritional tablets and methods of making the same |
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| US5126145A (en) * | 1989-04-13 | 1992-06-30 | Upsher Smith Laboratories Inc | Controlled release tablet containing water soluble medicament |
| US20090028937A1 (en) * | 2005-01-31 | 2009-01-29 | Kyowa Hakko Kogyo Co., Ltd. | Tablet comprising ornithine hydrochloride |
| WO2008044331A1 (en) * | 2006-10-05 | 2008-04-17 | Kowa Company, Ltd. | Solid preparation comprising ibuprofen and tranexamic acid |
| MX2011007771A (en) * | 2009-01-21 | 2011-08-12 | Hoffmann La Roche | Pharmaceutical compositions with superior product performance and patient compliance. |
| JP5415837B2 (en) * | 2009-06-12 | 2014-02-12 | アサヒグループホールディングス株式会社 | Method for producing granules and tablets from a powdery functional substance having inferior compression moldability |
| WO2011051742A1 (en) * | 2009-10-28 | 2011-05-05 | Modutech S.A. | Preparation comprising amino acids and plants and its activity in the alcohol detoxification |
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