JP7383626B2 - カルシウム欠乏に起因する状態の治療に使用するための組成物 - Google Patents
カルシウム欠乏に起因する状態の治療に使用するための組成物 Download PDFInfo
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- JP7383626B2 JP7383626B2 JP2020549788A JP2020549788A JP7383626B2 JP 7383626 B2 JP7383626 B2 JP 7383626B2 JP 2020549788 A JP2020549788 A JP 2020549788A JP 2020549788 A JP2020549788 A JP 2020549788A JP 7383626 B2 JP7383626 B2 JP 7383626B2
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Description
本発明は、少なくとも1種の胆汁酸又はその塩、少なくとも1種の脂肪酸又はその塩を含む組成物に関する。本組成物はまた、カルシウム及びビタミンDも含んでもよく、医薬品としての使用、特に腸のカルシウム取り込み欠乏に関係する障害の治療及び/又は予防のためのものである。
世界的な肥満症の蔓延は、2003年に15億人を超す人々を襲っていると推計されたが、その発生は世界中で増加し続けている。肥満症の罹患率の増加は、肥満症の併存疾患(例えば、2型糖尿病、高脂血症、高血圧症、虚血性心疾患、卒中、喘息、背中及び下肢の関節変性の問題、数種のがん、うつ病など)の罹患率の増加に結びついている。西欧では年間約32万人が肥満症により死亡していると推定される。このため、肥満症を原因とする平均余命の喪失は深刻である。正常体重の人と比較して、病的肥満の25歳男性の寿命の喪失は、平均でおよそ12年である。
本発明の目的は、上記の問題を解決すること、並びに少なくとも1種の胆汁酸又はその塩、及び少なくとも1種の脂肪酸又はその塩を含む組成物を提供することである。本組成物はまた、カルシウム及びビタミンDも含有することもできる。本組成物は、医薬品としての使用が意図される。
本発明は、添付の図面と併せて考慮される以下の詳細な説明から、より深く理解されることになる。
本発明の原理及び機能を全般的に理解できるように、例示的なある特定の実施形態を以下に記載する。記載される例示的な実施形態は非制限的であり、本発明の範囲は特許請求の範囲によって規定されることを当業者は理解されよう。
a)少なくとも1種の胆汁酸又はその塩、
b)少なくとも1種の脂肪酸又はその塩、
c)カルシウム、及び
d)ビタミンD
を含む組成物に関する。
a.少なくとも1種の胆汁酸又はその塩を、約1×10-7~1×10-3Mの腸内濃度をもたらす量、
b.少なくとも1種の脂肪酸又はその塩を、0.5g~約20gの量、
c.カルシウムを、100~2500mgの量、及び
d.ビタミンDを、800~2500mgの量
含む組成物。
a)一次胆汁酸であるコール酸(CA)及びケノデオキシコール酸(CDCA)、並びにそれぞれ、対応するそれらの抱合形態である、グリココール酸(GCA)及びグリコケノコール酸(GCDCA)、又は対応するそれらの二次胆汁酸である、デオキシコール酸(DCA)、リトコール酸(LCA)、ウルソデオキシコール酸(UDCA)及びヒオデオキシコール酸(HDCA)、並びにそれぞれ、対応するそれらの抱合形態である、グリチョデオキシコール酸(glychodeoxycholic acid:GDCA)、グリチョリトコール酸(glycholithocholic acid:GLCA)、グリコウルソデオキシコール酸(GUDCA)及びグリコヒオデオキシコール酸(GHDCA)から選択される、少なくとも1種の胆汁酸又はその塩を、約1×10-7~1×10-3Mの腸内濃度をもたらす量、
b)短鎖脂肪酸(SCFA、脂肪族末端に6個未満の炭素)、例えばブチレート、中鎖脂肪酸(MCFA、脂肪族末端に6~12個の炭素原子、直鎖又は分岐鎖)、例えば飽和のカプリル酸(8個の炭素原子)及びラウリン酸(12個の炭素)、長鎖脂肪酸(LCFA;13~21個の炭素)、例えば不飽和のパルミトレイン酸、オレイン酸、リノール酸、並びに飽和のパルミチン酸及びステアリン酸、若しくは極長鎖脂肪酸(VLCFA、21個を超える炭素原子)又はそれらの塩から選択される少なくとも1種の脂肪酸を、0.5g~約20gの量、
c)カルシウムを、100~2500mgの量、及び
d)ビタミンD3などのビタミンDを、800~2500mgの量
含む。
a)少なくとも1種の胆汁酸又はその塩、
b)少なくとも1種の脂肪酸又はその塩、
c)カルシウム、
d)ビタミンD、及び任意選択により、
e)微量栄養素の群から選択されるさらに1種の成分、例えば、鉄、マグネシウム、ジンク(zink)、銅、及びビタミン類(例えばビタミンA、ビタミンD又はビタミンE)からなる群から選択される成分、及び任意選択により、
f)充填剤、結合剤、湿潤剤、崩壊剤、緩衝剤、賦形剤、補助剤、抗酸化剤、保存剤から選択される1種又は複数種の成分
を含む。
a)グリココール酸(GCA)を、少なくとも1種の胆汁酸又はその塩として、
b)オレイン酸又は酪酸を、少なくとも1種の脂肪酸又はその塩として、
c)カルシウム、
d)ビタミンD、及び任意選択により、
e)微量栄養素の群から選択されるさらに1種の成分、例えば、鉄、マグネシウム、ジンク(zink)、銅、及びビタミン類(例えばビタミンA、ビタミンD又はビタミンE)からなる群から選択される成分、及び任意選択により、
f)充填剤、結合剤、湿潤剤、崩壊剤、緩衝剤、賦形剤、補助剤、抗酸化剤、保存剤から選択される1種又は複数種の成分
を含む。
実験の目的は、例えばRYGB又はSGの手術を受けた患者において、近位小腸内でのビタミンDの誘導によるカルシウム取り込みを改善する方法を調査することである。前記事項は、特定の胆汁酸(又はヒト胆汁)及び脂肪酸を添加して、ビタミンD-受容体活性化補助因子であるHsp90βの発現を誘導することによって試験される。Hsp90βを誘導することにより、ビタミンDの誘導によるカルシウム輸送の発現を実質的に増加させることができる。即ちカルシウム取り込みの増加を必要とするいかなる患者においても、例えばRYGBの患者、及びおそらくSGの患者においても、それを正常化させることができる。
Caco-2細胞株は、Sloan-Kettering institute for Cancer Researchが開発した非均質なヒト上皮大腸腺癌細胞の連続株である。この細胞は癌腫をもつ結腸又は大腸に由来するが、この細胞が特定の条件下で培養されると、分化し、極性化してその表現型を作り、小腸を覆う腸管上皮細胞に形態的及び機能的に類似する。
継代数1又は約45(分離した回数)のCaco-2細胞(Sigma-Aldrich、Stockholm、スウェーデン)を、10%ウシ胎仔血清(FBS)(Life Technologies)、1%非必須アミノ酸(NEAA)(Life Technologies)、100IU/mLペニシリンストレプトマイシン(Pen-Strep)(Life Technologies)を添加したダルベッコ変法イーグル培地(Life Technologies Invitrogen AB、Lidingo、スウェーデン)中で培養した。細胞を37℃、5%CO2でインキュベートし、細胞培養フラスコ(BD Falcon(登録商標)、VWR Internationals、Stockholm、スウェーデン)の中で培養し、培地を毎週月曜、水曜、金曜に交換した。
タンパク質を回収するために、細胞を掻き取り、プロテインキナーゼ阻害剤緩衝液(10mMのリン酸カリウム緩衝液pH6.8、10mMの3-[(3-コラミドプロピル)ジメチルアンモニオ]-1-プロパンスルホネート(CHAPS:Boehringer Mannheim、Mannheim、独国)及びプロテアーゼ阻害剤カクテル錠Complete(Roche Diagnostics AB、Stockholm、スウェーデン)を含有するプロテインキナーゼ阻害溶液(1%Triton x-100、EDTA;エチレンジアミン四酢酸)に入れて溶解緩衝液にした。氷上で数回振盪させた後に、細胞片を遠心分離(10000×g、4℃で10分間)によって除去し、上清のタンパク質含量を、ブラッドフォード法を使用して分析した。
Caco-2細胞を、透過性支持体上で、Giuliano A. R., & Wood R.Jに従い多少の変更を加えて、11~14日間培養した。実験日に経上皮電気抵抗を測定し、400~900オーム×cm2の値の標本のみをカウントした。試験物質は上部のコンパートメントに入っており、24~48時間後に結果を読み取った。液体シンチレーションを使用してCa2+流束を測定し、下部コンパートメントと上部コンパートメントとを比較した。
この実験では、Caco-2細胞に、脂肪酸である酪酸(又はブチレートと呼ばれる)、胆汁酸であるグリココール酸(GCA)、又は酪酸とGCAとの組合せを加えて試験した。
クローディン-2は、遠位小腸におけるカルシウム吸収を、傍細胞経路によって増加させる(通常、「受動」カルシウム吸収と呼ばれる)、許容性のタイトジャンクション構成タンパク質である。図2は、ビタミン-Dには、Caco-2細胞においてクローディン-2タンパク質の発現を用量依存的に増加させ、それにより、「受動」カルシウム吸収を促進する効果があることを示す。ビタミン-D活性化補助因子であるHsp90βを特異的阻害剤ゲルダナマイシンで抑制すると、明らかにビタミン-D活性の阻害によってクローディン-2の発現も抑制され、これは、Hsp90βが「受動」カルシウム吸収についても重要であることを立証している。したがって、小腸内でのHsp90βの発現を促進すると、ヒト小腸における受動カルシウム吸収にも有益な効果があるはずである。Caco-2細胞を、実験1と同じ実験条件で培養した。ビタミンDを10μM(低用量)又は100μM(高用量)の濃度で添加した。ゲルダナマイシンを0.5μMの濃度で添加した。
本実験では、Caco-2細胞を、上皮状のコンフルエントになるまで14日かけて培養し、増殖させた。その後の各実験は、Giuliano A. R.、& Wood R.Jに従って実施した。カルシウム輸送に対する10nMの1.25(OH)2-ビタミンD3の効果を、最後の48時間で試験した。カルシウム(Ca2+)勾配をつけずに流束を試験し、カルシウムの濃度は細胞の層の各側で1.8mMとした。このようにして、ビタミンDの能動輸送を確認した。結果は図3に示されている。
本実験では、Caco-2細胞を、上皮状のコンフルエントになるまで12日かけて培養し、増殖させた。次いで、0.1mMのGCAの存在下で、若しくは0.5mMのブチレートの存在下で、又はGCAとブチレートとを組み合わせて存在させて、細胞をさらに4日増殖させた。
本実験では、Caco-2細胞を、上皮状のコンフルエントになるまで12日かけて培養し、増殖させた。次いで、ビタミンD3を単独で、又は0.5mMのブチレートと組み合わせて、若しくは0.1mMのGCAと組み合わせて、若しくはGCA及びブチレートの両方と組み合わせて、若しくは0.1mMのTCA、若しくはTCA及びブチレートの両方と組み合わせて存在させて、細胞をさらに4日増殖させた。
本実験では、Caco-2細胞を、上皮状のコンフルエントになるまで12日かけて培養し、増殖させた。次いで、ビタミンD3を単独で、又は0.5mMのブチレートと組み合わせて、若しくは0.1mMのGCAと組み合わせて、若しくはGCA及びブチレートの両方と組み合わせて、若しくはGCA及びオレイン酸と組み合わせて存在させて、細胞をさらに4日増殖させた。
Elias et al., Bone Mineral Density and expression of vitamin D receptor-dependent calcium uptake mechanisms in the proximal small intestine after bariatric surgery, Br J Surg. 2014 Nov; 101(12):1566-75).
Crawford et al. ‘Increased bone turnover in type 2 diabetes patients randomized to bariatric surgery vs. medical therapy at 5 years’, Endocrine practice, 2018, DOI:10.4158/EP-2017-0072).
Hewit S et al., Secondary hyperparathyroidism, vitamin D sufficiency and serum calcium 5 years after gastric bypass and duodenal switch, Obes Surg. 2013, Mar;23(3):384-90).
Schafer A L, et al., Intestinal Calcium Absorption Decreases Dramatically After Gastric Bypass Surgery Despite Optimization of Vitamin D Status. J Bone Miner Res. 2015, Aug;30(8):1377-85).
Giuliano A. R., & Wood R.J. (‘Vitamin D-regulated calcium transport in Caco-2 cells: unique in vitro model’, Am. J. Physiol. 260 (Gastrointest. Liver Physiol. 23): G207-G212,1991).
Goldenberg D et al., Thyroidectomy in patients who have undergone gastric bypass surgery. Head Neck. 2018 Jun;40(6):1237-1244.
Claims (13)
- 胆汁酸であるグリココール酸(GCA)又はその塩と、酪酸、又はその塩、オレイン酸、又はそれらの塩からなる群から選択される少なくとも1種の脂肪酸とを含む、カルシウム吸収欠乏に関係する疾患の治療及び/又は予防における使用のための組成物。
- 前記疾患が、哺乳動物における、骨粗鬆症、吸収不良状態、又は骨障害である、請求項1に記載の使用のための組成物。
- 前記疾患が骨粗鬆症であり、前記カルシウム吸収欠乏が骨ミネラル密度(BMD)の損失である、請求項2に記載の使用のための組成物。
- 前記哺乳動物が、骨ミネラル密度(BMD)が損失している、ルーワイ胃バイパス術(RYGB)又はスリーブ状胃切除術(SG)のヒト患者である、請求項2又は3に記載の組成物。
- 前記組成物がビタミンDをさらに含み、好ましくは前記ビタミンDがビタミンD3から主としてなる、請求項1~4のいずれか一項に記載の使用のための組成物。
- 前記組成物がカルシウムをさらに含み、好ましくは前記カルシウムが、炭酸カルシウム、クエン酸カルシウム、若しくはリン酸カルシウム、又はそれらの混合物として存在する、請求項1~5のいずれか一項に記載の使用のための組成物。
- 前記組成物中のカルシウム及びビタミンDの量が、1日当たりの推奨摂取量(RDI)以下として存在する、請求項5又は6に記載の使用のための組成物。
- 前記組成物が、ビヒクル、賦形剤、滑沢剤、香味剤、甘味剤、結合剤、及び崩壊剤のうち少なくとも1種を含む、請求項1~7のいずれか一項に記載の使用のための組成物。
- 前記組成物が、経口送達用、非経口送達用、静脈内注入用、又は注射用に製剤化される、請求項1~8のいずれか一項に記載の使用のための組成物。
- 前記組成物が、液体形態である、請求項1~8のいずれか一項に記載の使用のための組成物。
- 前記組成物が、固体形態である、請求項1~8のいずれか一項に記載の使用のための組成物。
- 前記組成物が、咀嚼錠、発泡錠、散剤、丸剤、錠剤、又はカプセル剤として製剤化される、請求項10又は11に記載の使用のための組成物。
- 前記組成物が栄養補助食品又は健康補助食品である、請求項1~12のいずれか一項に記載の使用のための組成物。
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CA2033725C (en) * | 1990-01-24 | 2001-05-29 | Folker Pittrof | Pharmaceutical and cosmetic compositions containing a salt of cholanic acid |
ITMI20011321A1 (it) | 2001-06-22 | 2002-12-22 | Chiesi Farma Spa | Composizione farmaceutica in forma di microemulsione atta alla somministrazione per via transdermale di apomorfina utile nel trattamento del |
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SI2343982T1 (sl) | 2008-09-17 | 2017-08-31 | Chiasma Inc. | Farmacevtski sestavki in metode povezane z dostavo |
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GB2478849A (en) * | 2010-03-16 | 2011-09-21 | Chiasma Inc | Improved pharmecutical compositions and methods of delivery |
US11154559B2 (en) | 2011-09-29 | 2021-10-26 | Ethicon Endo-Surgery, Inc. | Methods and compositions of bile acids |
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EP3768274B1 (en) | 2023-11-15 |
EP3768274A1 (en) | 2021-01-27 |
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ES2974199T3 (es) | 2024-06-26 |
BR112020018980A2 (pt) | 2020-12-29 |
CN112074274B (zh) | 2024-03-26 |
CN112074274A (zh) | 2020-12-11 |
JP2021517578A (ja) | 2021-07-26 |
EP3768274C0 (en) | 2023-11-15 |
US11679124B2 (en) | 2023-06-20 |
WO2019182501A1 (en) | 2019-09-26 |
PL3768274T3 (pl) | 2024-06-17 |
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