JP2016069339A - Inflammatory bowel disease therapeutic agent - Google Patents
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本発明は、治療効果が強く、全身性副作用が少ない炎症性腸疾患治療薬に関する。さらに詳しくは、本発明は、シクレソニドの活性代謝物であるデスイソブチリルシクレソニドの21位をアシル化単糖で置換した糖ステロイド化合物を用いることにより、治療効果が強く、全身性副作用が少ない炎症性腸疾患治療薬に関するものである。 The present invention relates to a therapeutic agent for inflammatory bowel disease having a strong therapeutic effect and few systemic side effects. More specifically, the present invention uses a sugar steroid compound in which the 21-position of desisobutyryl ciclesonide, which is an active metabolite of ciclesonide, is substituted with an acylated monosaccharide, thereby causing inflammation with a strong therapeutic effect and fewer systemic side effects. The present invention relates to a therapeutic agent for sexual bowel disease.
潰瘍性大腸炎やクローン病などの炎症性腸疾患(Inflammatory Bowel Diesease;IBD)に罹患する患者数は、年々増加している。炎症性腸疾患は、大腸および小腸に慢性的な炎症が生じる疾患で、未だ発症原因が解明されていない。炎症は一般的に緩解と再燃を繰り返すことから、生涯にわたって治療を行う必要があり、その治療方法として、軽症から重症患者まで幅広く薬物療法が行われている。 The number of patients suffering from inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease is increasing year by year. Inflammatory bowel disease is a disease in which chronic inflammation occurs in the large and small intestines, and the cause of its onset has not been elucidated. Inflammation generally repeats remission and relapse, and it is necessary to treat it for a lifetime. As a treatment method, pharmacotherapy is widely used from mild to severe patients.
薬物療法では、主に5−アミノサリチル酸剤やステロイド剤が用いられている。特にステロイド剤は、中等症以上の活動期の炎症に非常に有効であり、プレドニゾロンやヒドロコルチゾンなどの薬物が経口剤、静脈注射剤および注腸投与剤などとして用いられている。プレドニゾロンやヒドロコルチゾンは強力で即効性のある薬効を有するが、その一方で、ムーンフェイス、にきび、体重増加、不眠、感染症や長期使用による骨粗しょう症、糖尿病、胃潰瘍などの深刻な全身性副作用のため、使用量、使用期間に制限があるという課題があった。一方、肝初回通過効果が大きく代謝を受けやすいため全身性副作用が少ないステロイド剤であるブデソニド(非特許文献1)が薬物療法に用いられることもあるが、炎症性腸疾患に対する治療効果が弱い(非特許文献2)という課題があった。 In drug therapy, 5-aminosalicylic acid agents and steroid agents are mainly used. In particular, steroids are very effective for inflammation in the active phase of moderate or higher, and drugs such as prednisolone and hydrocortisone are used as oral preparations, intravenous injections, enema preparations and the like. Prednisolone and hydrocortisone have powerful and fast-acting effects, while serious systemic side effects such as moonface, acne, weight gain, insomnia, osteoporosis due to infection and long-term use, diabetes, gastric ulcers, etc. Therefore, there has been a problem that there is a limit to the amount used and the period of use. On the other hand, budesonide (Non-patent Document 1), which is a steroidal agent with a large effect on the first pass of the liver and is easily metabolized, has few systemic side effects, is sometimes used for drug therapy, but the therapeutic effect on inflammatory bowel disease is weak ( There was a problem of non-patent document 2).
これらの課題を解決するために、特許文献1には、炎症性腸疾患の治療薬として、単糖、二糖またはオリゴ糖をブデソニドの21位にグリコシド結合させた糖ステロイド化合物が公開されている。この糖ステロイド化合物は、経口投与した際にグルコシダーゼを有する腸内細菌によって、ブデソニド・糖間のグリコシド結合が加水分解され、ブデソニドが放出されることで薬効を示すように設計されたプロドラッグである。この糖ステロイド化合物は、ブデソニドに糖を結合させることで確かに治療効果を強めることができたが、その一方で、全身性副作用がブデソニドよりも増強しており、強い治療効果と全身性副作用の低減を両立させることができず、IDBの治療薬として十分でなかった。 In order to solve these problems, Patent Document 1 discloses a sugar steroid compound in which a monosaccharide, disaccharide or oligosaccharide is glycoside-bonded to position 21 of budesonide as a therapeutic agent for inflammatory bowel disease. . This sugar steroid compound is a prodrug designed to have a medicinal effect by intestinal bacteria having glucosidase hydrolyzing the glycoside bond between budesonide and sugar and releasing budesonide when orally administered. . This sugar steroid compound was able to enhance the therapeutic effect by binding sugar to budesonide, but on the other hand, the systemic side effects were stronger than budesonide, and the strong therapeutic effect and systemic side effects Reduction could not be achieved at the same time, and it was not sufficient as a therapeutic agent for IDB.
以上より、治療効果が強く、全身性副作用が少ない炎症性腸疾患治療薬の開発が望まれていた。 From the above, it has been desired to develop a therapeutic agent for inflammatory bowel disease having a strong therapeutic effect and few systemic side effects.
本発明の目的は、上述の状況を鑑みてなされたもので、治療効果が強く、全身性副作用が少ない炎症性腸疾患治療薬を提供することである。 An object of the present invention is to provide a therapeutic agent for inflammatory bowel disease, which has been made in view of the above-described circumstances, and has a strong therapeutic effect and few systemic side effects.
本発明者らは、上述の課題を解決すべく鋭意検討した結果、シクレソニドの活性代謝物であるデスイソブチリルシクレソニドの21位をアシル化単糖で置換した糖ステロイド化合物を用いることにより、治療効果が強く、全身性副作用が少ない炎症性腸疾患治療薬を得ることができることを見出し、この知見に基づき、本発明を完成するに至った。
すなわち、本発明は、以下の(1)〜(3)に示したものである。
(1)「デスイソブチリルシクレソニドの21位の炭素−O−糖−O−アシル基」なる構造を有する糖ステロイド化合物を有効成分とすることを特徴とする炎症性腸疾患治療薬。
(2)前記糖がグルコースである請求項1に記載の炎症性腸疾患治療薬。
(3)前記アシル基がアセチル基である請求項1または2に記載の炎症性腸疾患治療薬。
As a result of intensive studies to solve the above-mentioned problems, the present inventors have used a sugar steroid compound in which the 21-position of desisobutyryl ciclesonide, which is an active metabolite of ciclesonide, is substituted with an acylated monosaccharide. The inventors have found that a therapeutic agent for inflammatory bowel disease having a strong effect and few systemic side effects can be obtained, and based on this finding, the present invention has been completed.
That is, this invention is shown to the following (1)-(3).
(1) A therapeutic agent for inflammatory bowel disease, comprising a saccharide steroid compound having a structure of “carbon-O-sugar-O-acyl group at position 21 of desisobutyryl ciclesonide” as an active ingredient.
(2) The therapeutic agent for inflammatory bowel disease according to claim 1, wherein the sugar is glucose.
(3) The therapeutic agent for inflammatory bowel disease according to claim 1 or 2, wherein the acyl group is an acetyl group.
以上述べたように、本発明は、治療効果が強く、全身性副作用が少ない炎症性腸疾患治療薬を提供することができる。 As described above, the present invention can provide a therapeutic agent for inflammatory bowel disease having a strong therapeutic effect and few systemic side effects.
以下、本発明の炎症性腸疾患治療薬を詳細に説明する。なお、本明細書に記載の例示は、本発明を特に限定するものではない。 Hereinafter, the therapeutic agent for inflammatory bowel disease of the present invention will be described in detail. Note that the examples described in the present specification do not particularly limit the present invention.
本発明の「炎症抑制率」とは、絶食したラットの肛門からチューブを挿入し、4%酢酸水溶液2mLを注入することで作製した炎症性腸疾患モデルに、各被験治療薬を1.0mL/100g体重となるように経口ゾンデを用いて1日1回6日間連続で経口投与した際の対照群に対する炎症の抑制率を意味し、値が大きいほど効果が強いことを示す。 The “inflammation inhibition rate” of the present invention refers to an inflammatory bowel disease model prepared by inserting a tube from the anus of a fasted rat and injecting 2 mL of 4% acetic acid aqueous solution, and adding 1.0 mL / It means the suppression rate of inflammation with respect to the control group when it is orally administered once a day for 6 consecutive days using an oral sonde so that the body weight becomes 100 g, and the larger the value, the stronger the effect.
本発明の「脾臓萎縮率」とは、絶食したラットの肛門からチューブを挿入し、4%酢酸水溶液2mLを注入することで作製した炎症性腸疾患モデルに、各被験治療薬を1.0mL/100g体重となるように、経口ゾンデを用いて1日1回6日間連続で経口投与した際の対照群に対する脾臓重量の変化量を意味し、全身性副作用の指標となる。脾臓重量の変化量の値が大きいほど脾臓が萎縮しており、全身性副作用があることを示す。 The “spleen atrophy rate” of the present invention refers to an inflammatory bowel disease model prepared by inserting a tube through the anus of a fasted rat and injecting 2 mL of a 4% aqueous acetic acid solution. It means the amount of change in spleen weight relative to the control group when it is orally administered once a day for 6 consecutive days using an oral sonde so as to be 100 g body weight, and serves as an index of systemic side effects. The larger the value of change in spleen weight, the more the spleen is atrophied, indicating that there are systemic side effects.
本発明の炎症性腸疾患治療薬に用いる糖ステロイド化合物は、シクレソニド(16α,17−[(1R)−Cyclohexylemethylidenedioxy]−11β,21−dihydroxypregna−1,4−diene−3,20−dione 21−(2−methylpropionate))の活性代謝物であるデスイソブチリルシクレソニド(16α,17−[(1R)−Cyclohexylemethylidenedioxy]−11β,21−dihydroxypregna−1,4−diene−3,20−dione;desCIC)の21位に、糖の1位の水酸基がα−またはβ−グリコシド結合してできた化合物であり、該糖の残りの水酸基の全部または一部がアシル基で修飾した構造をもつ。本発明の「糖−O−アシル基」とは、糖の水酸基のうち、ステロイドとの結合に関与していない複数の水酸基への置換基を意味する。 The sugar steroid compound used for the therapeutic agent for inflammatory bowel disease of the present invention is ciclesonide (16α, 17-[(1R) -Cyclohexylethylenenedioxy] -11β, 21-dihydroxypregna-1,4-diene-3,20-dione 21- ( 2-methylpropionate)), an active metabolite of desisobutyryl ciclesonide (16α, 17-[(1R) -Cyclohexylmethylenedioxy] -11β, 21-dihydroxypregna-1,4-diene-3,20-dione; desCIC) It is a compound formed by bonding the hydroxyl group at the 1-position of the sugar at the 21-position with an α- or β-glycoside, and has a structure in which all or part of the remaining hydroxyl groups of the sugar are modified with an acyl groupThe “sugar-O-acyl group” of the present invention means a substituent to a plurality of hydroxyl groups that are not involved in the binding to steroid among the hydroxyl groups of the sugar.
糖としては、例えば、グルコース(Glc)、アロース(All)、アルトロース(Alt)、グロース(Gul)、イドース(Ido)、ガラクトース(Gal)、タロース(Tal)およびマンノース(Man)などのヘキソース、フコース(Fuc)などのデオキシ糖ならびにグルコサミン(GlcN)、ガラクトサミン(GalN)、マンノサミン(ManN)、N−アセチルグルコサミン(GlcNAc)、N−アセチルガラクトサミン(GalNAc)およびN−アセチルマンノサミン(ManNAc)などのアミノ糖
などを挙げることができ、好ましくは、グルコースである。
Examples of sugars include hexoses such as glucose (Glc), allose (All), altrose (Alt), growth (Gul), idose (Ido), galactose (Gal), talose (Tal), and mannose (Man). Deoxy sugars such as fucose (Fuc) and glucosamine (GlcN), galactosamine (GalN), mannosamine (ManN), N-acetylglucosamine (GlcNAc), N-acetylgalactosamine (GalNAc) and N-acetylmannosamine (ManNAc) And the like, preferably glucose.
アシル基としては、例えば、アセチル基、プロピオニル基、イソブチリル基、ベンゾイル基およびトルイル基などを挙げることができ、好ましくはアセチル基である。 Examples of the acyl group include an acetyl group, a propionyl group, an isobutyryl group, a benzoyl group, and a toluyl group, and an acetyl group is preferable.
本発明の炎症性腸疾患治療薬の製造に際しては、従来公知の常法または今後新しく提供される方法で製造することができる。例えば、次のような方法で製造することができる。
糖の水酸基にアセチル基やトルオイル基などのアシル基を付加した後、このアノメリック位を臭素やフッ素などのハロゲンで置換し、炭酸銀、銀トリフレートおよび過塩素酸銀などのルイス酸の存在下で、デスイソブチリルシクレソニドと反応させることで製造することができる。
In producing the therapeutic agent for inflammatory bowel disease of the present invention, it can be produced by a conventionally known conventional method or a method newly provided in the future. For example, it can be manufactured by the following method.
After adding an acyl group such as acetyl group or toluoyl group to the hydroxyl group of sugar, this anomeric position is substituted with halogen such as bromine or fluorine, and in the presence of Lewis acid such as silver carbonate, silver triflate and silver perchlorate. Thus, it can be produced by reacting with desisobutyryl ciclesonide.
本発明の炎症性腸疾患治療薬を含有する医薬品の剤形としては、本発明の効果を損なわなければ特に限定されないが、例えば、口腔内崩壊錠、チュアブル錠、発泡錠、分散錠および溶解錠などの錠剤、エリキシル剤、懸濁剤、乳剤およびリモナーデ剤などの経口液剤、カプセル剤、顆粒剤、散剤、シロップ剤、経口ゼリー剤、注射剤、坐剤、直腸用半固形剤および注腸剤などを挙げることができ、好ましくは、錠剤、カプセル剤、坐剤、直腸用半固形剤および注腸剤である。これらの剤形は、例えば、以下のような方法で製造することができる。 The pharmaceutical dosage form containing the therapeutic agent for inflammatory bowel disease of the present invention is not particularly limited as long as the effects of the present invention are not impaired. For example, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets and dissolving tablets Oral solutions such as tablets, elixirs, suspensions, emulsions and limonades, capsules, granules, powders, syrups, oral jelly, injections, suppositories, rectal semisolids and enemas Preferred are tablets, capsules, suppositories, rectal semisolids and enemas. These dosage forms can be produced, for example, by the following method.
錠剤は、例えば、糖ステロイド化合物と乳糖水和物、結晶セルロースおよびトウモロコシでんぷんなどの賦形剤に、必要に応じてヒドロキシプロピルセルロースなどの結合剤と均一・均質になるまで混合し、この混合物を造粒し、必要に応じてステアリン酸マグネシウム、タルク、カルナウバロウなどの滑沢剤と均質になるまで混合し、打錠機にて錠剤化することで製造することができる。さらに、必要に応じて、錠剤に糖衣、フィルムコーティングを施すことができる。 Tablets are mixed with excipients such as sugar steroid compounds and lactose hydrate, crystalline cellulose and corn starch, for example, with a binder such as hydroxypropylcellulose as necessary until uniform and homogeneous. It can be produced by granulating, mixing with a lubricant such as magnesium stearate, talc, carnauba wax or the like until necessary, and tableting with a tableting machine. Furthermore, sugar coating and film coating can be applied to the tablets as necessary.
カプセル剤は、例えば、糖ステロイド化合物と結晶セルロース、コンスターチなどの賦形剤などと均質になるまで混合し、この混合物を造粒後、必要に応じて球形することができ、これをマクロゴール、ヒドロキシプロピルメチルセルロースおよびゼラチンなどからなるカプセルに充てんすることで製造することができる。 Capsules can be mixed with sugar steroid compounds and excipients such as crystalline cellulose and constarch until homogenous, and the mixture can be granulated and then spheroidized as necessary. It can be produced by filling capsules made of hydroxypropylmethylcellulose and gelatin.
坐剤は、例えば、糖ステロイド化合物とマクロゴールなどの水溶性基剤またはハードファットなどの油脂性基剤に、必要に応じて分散剤、乳化剤および吸収促進剤などを添加し、均一・均質になるまで混合し、これを容器に充てんし固化・成形することで製造することができる。坐剤の形状としては、円錐形および紡錘形などにすることができる。 For suppositories, for example, a sugar, a steroid compound and a water-soluble base such as macrogol or an oleaginous base such as hard fat are added with a dispersing agent, an emulsifier and an absorption accelerator as necessary, to make it uniform and homogeneous. It mixes until it becomes, It can manufacture by filling this into a container, and solidifying and shape | molding. The shape of the suppository can be a conical shape or a spindle shape.
直腸用半固形剤は、例えば、糖ステロイド化合物と精製水、滅菌精製水および注射用水などの水性溶媒またはグリセリン、エチレングリコールおよびプロピレングリコールなどの油性溶媒と、必要に応じてカルボキシメチルセルロースおよびカルボキシビニルポリマーなどの増粘剤などを添加し、均一・均質になるまで混合することで製造することができる。 Rectal semi-solid preparations include, for example, sugar steroid compounds and aqueous solvents such as purified water, sterile purified water and water for injection or oily solvents such as glycerin, ethylene glycol and propylene glycol, and optionally carboxymethylcellulose and carboxyvinyl polymers. It can be manufactured by adding a thickener such as and mixing until uniform and homogeneous.
注腸剤は、例えば、糖ステロイド化合物と精製水、滅菌精製水および注射用水などの水性溶媒またはグリセリン、プロピレングリコールおよびポリプロピレングリコールなどの油性溶媒に、必要に応じてカルボキシメチルセルロースおよびカルボキシビニルポリマーなどの増粘剤などを添加し、均一・均質になるまで混合することで製造することができる。 Enemas can be formulated in, for example, sugar steroid compounds and purified water, sterilized purified water, and aqueous solvents such as water for injection, or oily solvents such as glycerin, propylene glycol and polypropylene glycol, and carboxymethylcellulose and carboxyvinyl polymers as necessary. It can be manufactured by adding a thickener and mixing until uniform and homogeneous.
以下に、実施例によりさらに詳細に本発明を説明するが、本発明は、これに限定されるものではない。
(実施例1)
「デスイソブチリルシクレソニドの21位の炭素―O―グルコース―O―アセチル基」なる構造を有する糖ステロイド化合物(以下、desCIC−Glc(Ac)) 0.1mgを1%カルボキシメチルセルロース水溶液10mLに少量ずつ撹拌しながら加え、その後、超音波処理を行い懸濁し、本発明の炎症性腸疾患治療薬1を得た。得られた炎症性腸疾患治療薬1を試験例1に従って薬効評価試験を行った際の炎症抑制率は、30.4%であった。また、試験例2に従って全身性副作用試験を行った際の脾臓委縮率は、1.8%であった。結果を表1に示す。
Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.
Example 1
A small amount of 0.1 mg of a sugar steroid compound having a structure of “carbon-O-glucose-O-acetyl group at position 21 of desisobutyryl ciclesonide” (hereinafter desCIC-Glc (Ac)) in 10 mL of 1% carboxymethylcellulose aqueous solution The mixture was added while stirring, and then sonicated and suspended to obtain the therapeutic agent 1 for inflammatory bowel disease of the present invention. When the obtained inflammatory bowel disease therapeutic drug 1 was subjected to a drug efficacy evaluation test according to Test Example 1, the inflammation suppression rate was 30.4%. Further, the spleen atrophy rate when the systemic side effect test was conducted according to Test Example 2 was 1.8%. The results are shown in Table 1.
(試験例1)
薬効評価試験
前述の実施例1の炎症性腸疾患治療薬ならびに後述する比較例1および2の治療薬を使用し、次に示す方法で薬効評価試験を行った。
絶食したラット(1群5匹)の肛門からチューブを挿入し、4%酢酸水溶液2mLを注入することで炎症性腸疾患モデルを作製した。4%酢酸水溶液注入翌日から、各被験治療薬を1.0mL/100g体重となるように、経口ゾンデを用いて1日1回6日間連続で経口投与した。最終投与の翌日、ラットから大腸を摘出し、大腸の長さおよび重量を測定し、単位長さ当たりの大腸重量を求めた後、炎症抑制率(%)を次の式1から算出した。なお、4%酢酸水溶液の代わりに生理食塩水を注入し、被験治療薬の代わりに1%カルボキシメチルセルロース水溶液を投与した以外は同じ操作を繰り返して得られた群を正常群とした。また、被験治療薬の代わりに1%カルボキシメチルセルロース水溶液を投与した以外は同じ方法を繰り返して得られた群を対照群とした。
(Test Example 1)
Medicinal Efficacy Evaluation Test Using the therapeutic agent for inflammatory bowel disease of Example 1 described above and the therapeutic agents of Comparative Examples 1 and 2 described later, a medicinal efficacy evaluation test was performed by the following method.
A tube was inserted from the anus of fasted rats (5 mice per group), and 2 mL of 4% acetic acid aqueous solution was injected to prepare an inflammatory bowel disease model. From the day after the injection of 4% aqueous acetic acid, each test drug was orally administered once a day for 6 consecutive days using an oral sonde so that the body weight was 1.0 mL / 100 g body weight. The day after the final administration, the large intestine was removed from the rat, the length and weight of the large intestine were measured, the weight of the large intestine per unit length was determined, and the inflammation inhibition rate (%) was calculated from the following formula 1. In addition, the group obtained by injecting physiological saline instead of 4% acetic acid aqueous solution and administering 1% carboxymethyl cellulose aqueous solution instead of the test therapeutic agent was defined as a normal group. Moreover, the group obtained by repeating the same method except having administered 1% carboxymethylcellulose aqueous solution instead of the test therapeutic agent was made into the control group.
(数1)
炎症抑制率(%)=(1―(各被験薬剤群の単位長さ当たりの大腸重量(mg/cm)―正常群の単位長さ当たりの大腸重量(mg/cm))/(対照群の単位長さ当たりの大腸重量(mg/cm)―正常群の単位長さ当たりの大腸重量(mg/cm)))×100・・・・(式1)
(Equation 1)
Inflammation suppression rate (%) = (1− (colon weight per unit length of each test drug group (mg / cm) −colon weight per unit length of normal group (mg / cm)) / (control group Large intestine weight per unit length (mg / cm) —large intestine weight per unit length of normal group (mg / cm))) × 100 (Equation 1)
(試験例2)
全身性副作用評価試験
前述の実施例1の炎症性腸疾患治療薬ならびに後述する比較例1および2の治療薬を使用し、次に示す方法で全身性副作用評価試験を行った。
絶食したラット(1群5匹)の肛門からチューブを挿入し、4%酢酸水溶液2mLを注入することで炎症性腸疾患モデルを作製した。4%酢酸水溶液注入翌日から、各被験治療薬を1.0mL/100g体重となるように、経口ゾンデを用いて1日1回6日間連続で経口投与した。被験治療薬を投与していない以外は同じ方法を繰り返して得られた群を対照群とした。最終投与の翌日、ラットから脾臓を摘出後、重量を測定し、脾臓萎縮率(%)を次の式2から算出した。なお、被験治療薬の代わりに1%カルボキシメチルセルロース水溶液を投与した以外は同じ方法を繰り返して得られた群を対照群とした。
(Test Example 2)
Systemic side effect evaluation test Using the therapeutic agent for inflammatory bowel disease of Example 1 described above and the therapeutic agents of Comparative Examples 1 and 2 described later, a systemic side effect evaluation test was performed by the following method.
A tube was inserted from the anus of fasted rats (5 mice per group), and 2 mL of 4% acetic acid aqueous solution was injected to prepare an inflammatory bowel disease model. From the day after the injection of 4% aqueous acetic acid, each test drug was orally administered once a day for 6 consecutive days using an oral sonde so that the body weight was 1.0 mL / 100 g body weight. A group obtained by repeating the same method except that the test drug was not administered was used as a control group. The day after the final administration, the spleen was removed from the rat, the weight was measured, and the spleen atrophy rate (%) was calculated from the following formula 2. In addition, the group obtained by repeating the same method except having administered 1% carboxymethylcellulose aqueous solution instead of the test therapeutic agent was made into the control group.
(数2)
脾臓委縮率(%)=(1−各被験治療薬投与群の脾臓重量(mg)/対照群の脾臓重量(mg))×100・・・・(式2)
(比較例1)
実施例1においてdesCIC−Glc(Ac) 0.1mgを除き、代わりにプレドニゾロン 1mgを加えた以外は実施例1と全く同じ調製法を繰り返して治療薬1を得た。得られた治療薬1を試験例1に従って薬効評価試験を行った際の炎症抑制率は、7.6%であった。次に、試験例2に従って全身性副作用評価試験を行った際の脾臓萎縮率は、21.5%であった。結果を表1に示した。
(Equation 2)
Spleen contraction rate (%) = (1-spleen weight (mg) of each test drug administration group / spleen weight (mg) of control group) × 100 (Equation 2)
(Comparative Example 1)
Except for desCIC-Glc (Ac) 0.1 mg in Example 1, except that 1 mg of prednisolone was added instead, therapeutic agent 1 was obtained by repeating exactly the same preparation method as Example 1. The inflammation suppression rate when the obtained therapeutic drug 1 was subjected to a drug efficacy evaluation test according to Test Example 1 was 7.6%. Next, the spleen atrophy rate when the systemic side effect evaluation test was conducted according to Test Example 2 was 21.5%. The results are shown in Table 1.
(比較例2)
実施例1においてdesCIC−Glc(Ac) 0.1mgを除き、代わりにブデソニド 0.1mgを加えた以外は実施例1と全く同じ調製法を繰り返して治療薬2を得た。得られた治療薬2を試験例1に従って薬効評価試験を行った際の炎症抑制率は、−4.8%であった。次に、試験例2に従って全身性副作用評価試験を行った際の脾臓萎縮率は、18.4%であった。結果を表1に示した。
(Comparative Example 2)
Except for desCIC-Glc (Ac) 0.1 mg in Example 1 and adding budesonide 0.1 mg instead, therapeutic agent 2 was obtained by repeating exactly the same preparation method as Example 1. The inflammation suppression rate when the obtained therapeutic drug 2 was subjected to a drug efficacy evaluation test according to Test Example 1 was -4.8%. Next, the spleen atrophy rate when the systemic side effect evaluation test was conducted according to Test Example 2 was 18.4%. The results are shown in Table 1.
本発明は、治療効果が強く、全身性の副作用が少ない炎症性腸疾患治療薬に関するものであって、産業上十分に利用できるものである。 The present invention relates to a therapeutic agent for inflammatory bowel disease having a strong therapeutic effect and few systemic side effects, and can be used sufficiently industrially.
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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US3206359A (en) * | 1963-02-18 | 1965-09-14 | Merck & Co Inc | Galacturonides of the anti-inflammatory pregnane series |
WO1999047542A1 (en) * | 1998-03-19 | 1999-09-23 | Nissin Food Products Co., Ltd. | Drugs containing as the main ingredient 21-substituted glycosyl steroid compounds |
WO1999047541A1 (en) * | 1998-03-19 | 1999-09-23 | Nissin Food Products Co., Ltd. | 21-substituted glycosyl steroid compounds |
JP2010104187A (en) * | 2008-10-27 | 2010-05-06 | Yaskawa Electric Corp | Motor controller equipped with safety shutdown circuit |
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Publication number | Priority date | Publication date | Assignee | Title |
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US3206359A (en) * | 1963-02-18 | 1965-09-14 | Merck & Co Inc | Galacturonides of the anti-inflammatory pregnane series |
WO1999047542A1 (en) * | 1998-03-19 | 1999-09-23 | Nissin Food Products Co., Ltd. | Drugs containing as the main ingredient 21-substituted glycosyl steroid compounds |
WO1999047541A1 (en) * | 1998-03-19 | 1999-09-23 | Nissin Food Products Co., Ltd. | 21-substituted glycosyl steroid compounds |
JP2010104187A (en) * | 2008-10-27 | 2010-05-06 | Yaskawa Electric Corp | Motor controller equipped with safety shutdown circuit |
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