JPH04305526A - Medicinal composition - Google Patents
Medicinal compositionInfo
- Publication number
- JPH04305526A JPH04305526A JP9134091A JP9134091A JPH04305526A JP H04305526 A JPH04305526 A JP H04305526A JP 9134091 A JP9134091 A JP 9134091A JP 9134091 A JP9134091 A JP 9134091A JP H04305526 A JPH04305526 A JP H04305526A
- Authority
- JP
- Japan
- Prior art keywords
- anilino
- oxo
- dihydro
- pyrimidinecarboxylic acid
- methylpropoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title abstract description 7
- ZKPYFMVPKVVIRW-UHFFFAOYSA-N 2-[2-(2-methylpropoxy)anilino]-6-oxo-1h-pyrimidine-5-carboxylic acid Chemical group CC(C)COC1=CC=CC=C1NC1=NC=C(C(O)=O)C(=O)N1 ZKPYFMVPKVVIRW-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229920001477 hydrophilic polymer Polymers 0.000 claims abstract description 7
- 239000011230 binding agent Substances 0.000 claims abstract description 6
- 229920002785 Croscarmellose sodium Polymers 0.000 claims abstract description 5
- 239000002245 particle Substances 0.000 claims abstract description 5
- 239000004480 active ingredient Substances 0.000 claims abstract 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- 239000007884 disintegrant Substances 0.000 claims description 6
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 2
- -1 methylpropoxy Chemical group 0.000 claims description 2
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 7
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 abstract description 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 230000002708 enhancing effect Effects 0.000 abstract 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 9
- 229960001375 lactose Drugs 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 7
- 239000008101 lactose Substances 0.000 description 7
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000005469 granulation Methods 0.000 description 6
- 230000003179 granulation Effects 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 4
- 239000008187 granular material Substances 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 238000005280 amorphization Methods 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 238000010298 pulverizing process Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- CRCVTNHORFBTSX-UHFFFAOYSA-N 2-oxo-1h-pyrimidine-5-carboxylic acid Chemical compound OC(=O)C=1C=NC(=O)NC=1 CRCVTNHORFBTSX-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000002467 anti-pepsin effect Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000000748 compression moulding Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 210000000245 forearm Anatomy 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000010030 laminating Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【0001】0001
【産業上の利用分野】本発明は薬剤組成物に関し、さら
に詳しくは、有効成分として1,6−ジヒドロ−2−{
2−(2−メチルプロポキシ)アニリノ}−6−オキソ
−5−ピリミジンカルボン酸を含有する経口投与用製剤
に関する。TECHNICAL FIELD The present invention relates to pharmaceutical compositions, and more particularly, to pharmaceutical compositions containing 1,6-dihydro-2-{
The present invention relates to a preparation for oral administration containing 2-(2-methylpropoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid.
【0002】0002
【従来の技術】1,6−ジヒドロ−2−{2−(2−メ
チルプロポキシ)アニリノ}−6−オキソ−5−ピリミ
ジンカルボン酸は、特開昭60−100559に抗アレ
ルギー作用を有する新規化合物として、また特開昭62
−267229に抗消化性潰瘍薬としてその一般的な錠
剤、顆粒剤、軟カプセル剤が開示されている。[Prior Art] 1,6-dihydro-2-{2-(2-methylpropoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid was disclosed as a novel compound having antiallergic effect in JP-A-60-100559. Also as JP-A-62
-267229 discloses its general tablets, granules, and soft capsules as an anti-peptic ulcer drug.
【0003】1,6−ジヒドロ−2−{2−(2−メチ
ルプロポキシ)アニリノ}−6−オキソ−5−ピリミジ
ンカルボン酸は極めて水に溶けにくく、従来の前記経口
投与製剤、特に錠剤においては、その大部分が糞中に排
泄されてしまい、生物学的利用率が著しく低い。このた
め、所定の薬理効果を得るためには、多量投与が必要で
あり、コスト高であるのみならず、服用しやすい小型の
錠剤を製造することができなかった。[0003] 1,6-dihydro-2-{2-(2-methylpropoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid is extremely difficult to dissolve in water, and has not been used in conventional oral preparations, especially tablets. Most of it is excreted in feces, and its bioavailability is extremely low. Therefore, in order to obtain a desired pharmacological effect, it is necessary to administer a large amount, which not only increases the cost, but also makes it impossible to manufacture small tablets that are easy to take.
【0004】従来このような問題を改善するための製剤
学的手段として、非晶質化、複合体化等の方法が提案さ
れている。しかし、非晶質化においては、有機溶媒の利
用を必須としている点に問題がある。すなわち、有機溶
媒は工程中において火災または、爆発の危険性を伴うだ
けでなく、製剤中に残留した有機溶媒が人体に悪影響を
与える懸念もある。有機溶媒を使用しない方法として薬
剤と担体を混合粉砕する方法もあるが、充分な生物学的
利用率を確保するためには長時間粉砕する必要があり、
また、薬剤の数倍量の担体を必要とするなど問題がある
。複合体化においては、その形成に際して、多量の高分
子化合物を用いるため、その乾燥、粉砕に長時間を要し
、生産性に優れた手段とはいえない。[0004] Conventionally, methods such as amorphization and complexation have been proposed as pharmaceutical means to improve such problems. However, a problem with amorphization is that it requires the use of an organic solvent. That is, organic solvents not only pose a risk of fire or explosion during the process, but also there is a concern that the organic solvents remaining in the formulation may have an adverse effect on the human body. There is also a method of mixing and pulverizing the drug and carrier as a method that does not use organic solvents, but it is necessary to pulverize for a long time to ensure sufficient bioavailability.
In addition, there are other problems, such as requiring several times the amount of carrier than the drug. In complex formation, since a large amount of a polymer compound is used to form the complex, a long time is required for drying and pulverizing the complex, and therefore it cannot be said to be a method with excellent productivity.
【0005】[0005]
【発明が解決しようとする課題】本発明は、従来の技術
の有するこのような問題点に鑑みてなされたものであり
、1,6−ジヒドロ−2−{2−(2−メチルプロポキ
シ)アニリノ}−6−オキソ−5−ピリミジンカルボン
酸を含有する経口投与製剤に関して、生物学的利用率が
改善でき、したがって、製造工程が比較的簡単で、製造
コストの低減を図れるとともに服用し易い経口投与製剤
を提供することを課題とする。SUMMARY OF THE INVENTION The present invention has been made in view of the above-mentioned problems of the prior art, and is directed to the production of 1,6-dihydro-2-{2-(2-methylpropoxy)anilino } Regarding oral preparations containing -6-oxo-5-pyrimidinecarboxylic acid, the bioavailability can be improved, the manufacturing process is relatively simple, the manufacturing cost can be reduced, and oral administration is easy to take. The objective is to provide a formulation.
【0006】[0006]
【課題を解決するための手段】本発明者らは、1,6−
ジヒドロ−2−{2−(2−メチルプロポキシ)アニリ
ノ}−6−オキソ−5−ピリミジンカルボン酸は、その
粉末の生物学的利用率は低いものの、懸濁液では高い生
物学的利用率を示すこと、および前記化合物は、接触角
が大きく、著しいはっ水性を示すことから、消化管内で
懸濁状態となるまでに長時間を要することが、生物学的
利用率を低下させる原因のひとつであると推定した。よ
り詳しくは、1,6−ジヒドロ−2−{2−(2−メチ
ルプロポキシ)アニリノ}−6−オキソ−5−ピリミジ
ンカルボン酸は、消化管内で凝集しやすく、分散、懸濁
化が充分でないまま、吸収部位を通過するため低い生物
学的利用率しか得られないものと考えられる。[Means for Solving the Problems] The present inventors have discovered that 1,6-
Dihydro-2-{2-(2-methylpropoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid has low bioavailability in its powder form but high bioavailability in suspension. Because the above compounds have large contact angles and exhibit significant water repellency, it takes a long time for them to become suspended in the gastrointestinal tract, which is one of the causes of reduced bioavailability. It was estimated that More specifically, 1,6-dihydro-2-{2-(2-methylpropoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid tends to aggregate in the gastrointestinal tract and cannot be sufficiently dispersed or suspended. It is thought that only a low bioavailability can be obtained because it passes directly through the absorption site.
【0007】本発明は、上記考察に基づいてさらに研究
を重ねた結果完成されたもので、1,6−ジヒドロ−2
−{2−(2−メチルプロポキシ)アニリノ}−6−オ
キソ−5−ピリミジンカルボン酸の経口投与製剤におい
て、結合剤として親水性高分子および崩壊剤として架橋
カルボキシメチルセルロースナトリウムを用いることを
特徴とする薬剤組成物である。[0007] The present invention was completed as a result of further research based on the above considerations.
- An oral preparation of {2-(2-methylpropoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid, characterized by using a hydrophilic polymer as a binder and cross-linked sodium carboxymethyl cellulose as a disintegrant. A pharmaceutical composition.
【0008】1,6−ジヒドロ−2−{2−(2−メチ
ルプロポキシ)アニリノ}−6−オキソ−5−ピリミジ
ンカルボン酸の粉末において、平均粒子径が10μm以
下で、比表面積が2m2/g〜10m2/gに微細化し
たもの用いることが、生物学的利用率を改善するうえで
効果的である。[0008] In the powder of 1,6-dihydro-2-{2-(2-methylpropoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid, the average particle diameter is 10 μm or less and the specific surface area is 2 m2/g. It is effective to use fine particles of ~10 m2/g in improving the bioavailability.
【0009】本発明の薬剤組成物の結合剤に用いられる
親水性高分子としては、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、メチルセルロ
ース、ポリビニルピロリドン、プルランおよびポリビニ
ルアルコール等が挙げられる。また親水性高分子の使用
比率については、1,6−ジヒドロ−2−{2−(2−
メチルプロポキシ)アニリノ}−6−オキソ−5−ピリ
ミジンカルボン酸の重量に基づき0.3〜2重量%を用
いるのが好ましい。Hydrophilic polymers used as binders in the pharmaceutical composition of the present invention include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, pullulan, and polyvinyl alcohol. Regarding the usage ratio of hydrophilic polymer, 1,6-dihydro-2-{2-(2-
Preferably, from 0.3 to 2% by weight, based on the weight of the methylpropoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid, is used.
【0010】本発明の薬剤組成物には、必要に応じて前
記結合剤に乳糖、澱粉などの賦形剤を加え造粒すること
ができる。造粒はどのような方法によって行ってもよい
が、好ましくは、湿潤液を霧化して添加できる流動層造
粒法、噴霧造粒法、攪拌造粒法等が挙げられる。The pharmaceutical composition of the present invention can be granulated by adding excipients such as lactose and starch to the binder, if necessary. Granulation may be carried out by any method, but preferred are fluidized bed granulation, spray granulation, agitation granulation, etc. in which a wetting liquid can be atomized and added.
【0011】また、前記造粒物を圧縮成形する場合には
、さらに崩壊剤や滑沢剤を使用することができるが、崩
壊剤として架橋カルボキシメチルセルロースナトリウム
を使用すると、カルボキシメチルセルロースナトリウム
、カルボキシメチルセルロースカルシウムおよび微結晶
セルロース等の他の崩壊剤を使用した場合に比べ、硬度
、崩壊時間、表面摩損度等の錠剤品質が優れており、好
適に使用できる。[0011] In addition, when compression molding the granules, a disintegrant or a lubricant can be further used, but when cross-linked sodium carboxymethyl cellulose is used as the disintegrant, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose Compared to cases where other disintegrants such as microcrystalline cellulose are used, tablet quality such as hardness, disintegration time, and surface friability is superior, and it can be used preferably.
【0012】賦形剤として添加する乳糖は、粉末乳糖、
結晶乳糖に比べ流動性に優れ、塑性変形の起こりやすい
粒子形をしている造粒乳糖(商品名ダイラクトース,フ
ロイント産業社製)を使用することにより、スティッキ
ング、ラミネーティング等の高速連続打錠時に発生しや
すい打錠障害もなく、優れた錠剤品質を得られ、好適に
使用できる。[0012] The lactose added as an excipient is powdered lactose,
By using granulated lactose (trade name: Dilactose, manufactured by Freund Sangyo Co., Ltd.), which has a particle shape that has superior fluidity and is more susceptible to plastic deformation than crystalline lactose, it is possible to perform high-speed continuous tableting such as sticking and laminating. Excellent tablet quality can be obtained without any tableting problems that sometimes occur, and it can be used conveniently.
【0013】[0013]
【実施例】本発明を以下の実施例によって具体的に説明
する。1,6−ジヒドロ−2−{2−(2−メチルプロ
ポキシ)アニリノ}−6−オキソ−5−ピリミジンカル
ボン酸(以下化合物という)を粉砕して得た比表面積4
m2/gの粉末1400gに、ヒドロキシプロピルセル
ロースSL(日本曹達社製)560g、粉末乳糖196
0g(HMS社製)、およびトウモロコシデンプン(日
本食品加工社製)1120gを流動造粒コーティング装
置フローコーターFLO−5A型(フロイント産業社製
)に仕込み、入口温度65℃の空気中で流動させながら
、溶媒(30%エタノール溶液)を噴霧空気圧3kg/
cm2、噴霧空気量200NL/分で噴霧して造粒した
。EXAMPLES The present invention will be specifically explained by the following examples. Specific surface area 4 obtained by crushing 1,6-dihydro-2-{2-(2-methylpropoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid (hereinafter referred to as compound)
m2/g powder, 560 g of hydroxypropyl cellulose SL (manufactured by Nippon Soda Co., Ltd.), and 196 g of powdered lactose.
0g (manufactured by HMS) and 1120g of corn starch (manufactured by Nihon Shokuhin Kogyo Co., Ltd.) were charged into a fluidized granulation coating device Flow Coater FLO-5A type (manufactured by Freund Sangyo Co., Ltd.), and while fluidized in air at an inlet temperature of 65°C. , the solvent (30% ethanol solution) was sprayed at an air pressure of 3 kg/
cm2, and granulated by spraying at an atomizing air amount of 200 NL/min.
【0014】乾燥後、篩にかけた造粒物600g(自社
製)に、滑沢剤としてタルク(富士タルク社製)12.
5gとステアリン酸マグネシウム(太平化学)12.5
g、崩壊剤として架橋カルボキシメチルセルロースナト
リウム(商品名アクジゾル、旭化成社製)33.3gお
よび造粒乳糖(商品名ダイラクトース、フロイント産業
社製)341.7gをV型混合機(品川製作所製)に入
れ、12分間混合した。After drying, add talc (manufactured by Fuji Talc Co., Ltd.) as a lubricant to 600 g of the sieved granules (manufactured in-house).12.
5g and magnesium stearate (Taihei Chemical) 12.5
g, 33.3 g of cross-linked sodium carboxymethyl cellulose (trade name: Acdisol, manufactured by Asahi Kasei Corporation) as a disintegrant and 341.7 g of granulated lactose (trade name: Dilactose, manufactured by Freund Sangyo Co., Ltd.) were placed in a V-type mixer (manufactured by Shinagawa Seisakusho). and mixed for 12 minutes.
【0015】次に、V型混合機で混合した前記組成物を
、打錠機コレクト12HUK(菊水製作所製)にて、直
径8mmの杵で、240mgずつ打錠し裸錠を得た。こ
の、裸錠にヒドロキシプロピルメチルセルロース(信越
化学社製)を主成分としたフイルムコーティング層を、
1錠当り12mgコーティングし化合物を40mg含有
したフイルム錠を得た。Next, the composition mixed in the V-type mixer was compressed into 240 mg tablets using a tablet machine Collect 12HUK (manufactured by Kikusui Seisakusho) with a punch having a diameter of 8 mm to obtain plain tablets. A film coating layer containing hydroxypropyl methyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.) as the main component is applied to this bare tablet.
Film tablets containing 12 mg of the compound and 40 mg of the compound per tablet were obtained.
【0016】[0016]
【試験例】1.前記実施例で調製したフイルム錠と化合
物を微細化した粉末および懸濁液を被検薬として、pH
5.6の緩衝液900ml(37℃)、パドル法(パド
ル回転数100rpm)で溶出試験を行い、その結果を
図1に示した.図1から明らかなように、本発明のフイ
ルム錠は、化合物を微細化した粉末に比べ著しく高い溶
出性を示し、はっ水性を示すことなく、短時間に懸濁化
する結果を得た。[Test example] 1. The film tablets prepared in the above examples, finely divided powders and suspensions of the compounds were used as test drugs, and the pH
An elution test was conducted using 900 ml of the buffer solution (37°C) of No. 5.6 using the paddle method (paddle rotation speed: 100 rpm), and the results are shown in Figure 1. As is clear from FIG. 1, the film tablet of the present invention exhibited a significantly higher dissolution property than a finely divided powder of the compound, and was able to be suspended in a short time without exhibiting water repellency.
【0017】2.前記試験例と同様の被検薬をビーグル
犬に経口投与し、血中濃度を測定後、各被検薬の血中濃
度より求められる血中濃度パラメーターを表1に示した
。表1から明らかなように、本発明のフイルム錠は、微
細化した化合物の粉末と比較して最高血中濃度が高く、
また血中濃度下面積も大きい値を示し、生物学的利用率
が改善されていた。2. The same test drugs as in the above test example were orally administered to beagle dogs, and the blood concentrations were measured. Table 1 shows the blood concentration parameters determined from the blood concentrations of each test drug. As is clear from Table 1, the film tablet of the present invention has a higher maximum blood concentration than the finely divided powder of the compound;
The area under blood concentration also showed a large value, indicating that the bioavailability was improved.
【0018】試験条件
被検動物:雄性ビーグル犬(10〜12kg) 8頭
投与 :24時間絶食後、それぞれの製剤を水2
0mlと共に強制的に経口投与した。なお、投与後は摂
水自由とした。
採血 :投与前、投与後0.25、0.5、0.
75、1、1.5、2、3、4、5および8時間に前腕
上肢静脈より2.5mlを採取し、遠心分離により、血
漿を得た。
定量 :検出器に紫外部検出器を用いたHPLC
法により定量した。Test conditions Test animals: 8 male beagle dogs (10-12 kg) Administration: After fasting for 24 hours, each preparation was mixed with 2 ml of water.
Administered orally by gavage with 0 ml. After administration, the subjects were allowed to drink water freely. Blood collection: before administration, after administration 0.25, 0.5, 0.
75, 1, 1.5, 2, 3, 4, 5 and 8 hours, 2.5 ml was collected from the forearm brachial vein and centrifuged to obtain plasma. Quantification: HPLC using an ultraviolet detector as a detector
Quantitated by method.
【0019】[0019]
【表1】[Table 1]
【0020】[0020]
【発明の効果】以上説明したように本発明によれば、特
殊な処理を加えることなく、簡便に1,6−ジヒドロ−
2−{2−(2−メチルプロポキシ)アニリノ}−6−
オキソ−5−ピリミジンカルボン酸の溶解性を高め、生
物学的利用率を改善することができる。また、造粒、打
錠工程等において、優れた生産性を示し、製造コストの
低減が図られ、服用し易い製剤が得られる。Effects of the Invention As explained above, according to the present invention, 1,6-dihydro-
2-{2-(2-methylpropoxy)anilino}-6-
The solubility of oxo-5-pyrimidinecarboxylic acid can be increased and the bioavailability can be improved. In addition, it shows excellent productivity in the granulation, tabletting, etc. processes, reduces manufacturing costs, and provides a preparation that is easy to take.
【図1】溶出試験の結果を示した図である。FIG. 1 is a diagram showing the results of a dissolution test.
Claims (3)
−{2−(2−メチルプロポキシ)アニリノ}−6−オ
キソ−5−ピリミジンカルボン酸、結合剤として親水性
高分子および崩壊剤として架橋カルボキシメチルセルロ
ースナトリウムを含有することを特徴とする薬剤組成物
。[Claim 1] 1,6-dihydro-2 as an active ingredient
A pharmaceutical composition comprising -{2-(2-methylpropoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid, a hydrophilic polymer as a binder, and crosslinked carboxymethyl cellulose sodium as a disintegrant.
メチルプロポキシ)アニリノ}−6−オキソ−5−ピリ
ミジンカルボン酸の平均粒子径が10μm以下であり、
比表面積が2m2/g〜10m2/gであることを特徴
とする請求項1記載の薬剤組成物。[Claim 2] 1,6-dihydro-2-{2-(2-
methylpropoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid has an average particle diameter of 10 μm or less,
The pharmaceutical composition according to claim 1, having a specific surface area of 2 m2/g to 10 m2/g.
メチルプロポキシ)アニリノ}−6−オキソ−5−ピリ
ミジンカルボン酸の重量に基づき0.2〜2重量%の親
水性高分子を含むことを特徴とする請求項1記載の薬剤
組成物。[Claim 3] 1,6-dihydro-2-{2-(2-
Pharmaceutical composition according to claim 1, characterized in that it contains 0.2 to 2% by weight of hydrophilic polymer based on the weight of the methylpropoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP9134091A JPH04305526A (en) | 1991-03-28 | 1991-03-28 | Medicinal composition |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP9134091A JPH04305526A (en) | 1991-03-28 | 1991-03-28 | Medicinal composition |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH04305526A true JPH04305526A (en) | 1992-10-28 |
Family
ID=14023693
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP9134091A Pending JPH04305526A (en) | 1991-03-28 | 1991-03-28 | Medicinal composition |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH04305526A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996005177A1 (en) * | 1994-08-13 | 1996-02-22 | Yuhan Corporation | Novel pyrimidine derivatives and processes for the preparation thereof |
JP4868695B2 (en) * | 2000-09-22 | 2012-02-01 | 大日本住友製薬株式会社 | Oral preparation with good disintegration |
-
1991
- 1991-03-28 JP JP9134091A patent/JPH04305526A/en active Pending
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996005177A1 (en) * | 1994-08-13 | 1996-02-22 | Yuhan Corporation | Novel pyrimidine derivatives and processes for the preparation thereof |
JP4868695B2 (en) * | 2000-09-22 | 2012-02-01 | 大日本住友製薬株式会社 | Oral preparation with good disintegration |
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