結(jié)論

據(jù)我們所知，這是第一個全面的研究，清楚地顯示了類藥物化合物的內(nèi)在表面性質(zhì)對生物相關(guān)介質(zhì)中溶解度增強(qiáng)的影響，而不是在水介質(zhì)中。這項(xiàng)研究表明，臨界膠束濃度（描述化合物在膠束中自締合的內(nèi)在能力）比公認(rèn)的親脂性更好地預(yù)測FaSSIF中的溶解度增強(qiáng)。我們的研究表明，考慮到化合物在膠束中結(jié)合的趨勢，藥物優(yōu)化策略將潛在地受益，作為增加腸道吸收的一種方式。

作者信息

通訊作者

*電話：+41616881941。傳真：+41616882908。電子郵件：魯本。阿爾瓦雷斯_ sanchez roche.com.

筆記

作者聲明沒有相互競爭的經(jīng)濟(jì)利益。

致謝

作者要感謝比約恩·瓦格納、維吉尼·米卡列夫、伊莎貝爾·帕里拉和薩賓·皮塔提供的技術(shù)援助，以及弗蘭茲·舒勒、薩拉·貝利和喬恩·凱爾·博德納爾對手稿的修訂和寶貴意見。

縮寫

FaSSIF，禁食狀態(tài)模擬腸液；FeSSIF，喂食狀態(tài)模擬腸液；臨界膠束濃度；生物制藥分類系統(tǒng)；SE，溶解度增強(qiáng)；logd，辛醇/水分配系數(shù)；電離常數(shù)

參考資料

(1)Amidon,G.L.;Lennernas,H.;Shah,V.P.;Crison,J.R.A theoretical basis for a biopharmaceutic drug classification:the correlation of in vitro drug product dissolution and in vivo bioavailability.Pharm.Res.1995,12(3),413?20.

(2)Tsume,Y.;Mudie,D.M.;Langguth,P.;Amidon,G.E.;Amidon,G.L.The Biopharmaceutics Classification System:Subclasses for in vivo predictive dissolution(IPD)methodology and IVIVC.Eur.J.Pharm.Sci.2014,57,152?63.

(3)Jones,H.M.;Parrott,N.;Ohlenbusch,G.;Lave,T.Predicting pharmacokinetic food effects using biorelevant solubility media and physiologically based modelling.Clin Pharmacokinetics 2006,45(12),1213?26.

(4)Galia,E.;Nicolaides,E.;Horter,D.;Lobenberg,R.;Reppas,C.;Dressman,J.B.Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs.Pharm.Res.1998,15(5),698?705.

(5)Andrieux,K.;Forte,L.;Lesieur,S.;Paternostre,M.;Ollivon,M.;Grabielle-Madelmont,C.Insertion and partition of sodium taurocholate into egg phosphatidylcholine vesicles.Pharm.Res.2004,21(8),1505?16.

(6)Nawroth,T.;Buch,P.;Buch,K.;Langguth,P.;Schweins,R.Liposome formation from bile salt-lipid micelles in the digestion and drug delivery model FaSSIF(mod)estimated by combined timeresolved neutron and dynamic light scattering.Mol.Pharmaceutics 2011,8(6),2162?72.

(7)Mithani,S.D.;Bakatselou,V.;TenHoor,C.N.;Dressman,J.B.Estimation of the increase in solubility of drugs as a function of bile salt concentration.Pharm.Res.1996,13(1),163?7.

(8)Ottaviani,G.;Gosling,D.J.;Patissier,C.;Rodde,S.;Zhou,L.;Faller,B.What is modulating solubility in simulated intestinal fluids?Eur.J.Pharm.Sci.2010,41(3?4),452?7.

(9)Fagerberg,J.H.;Karlsson,E.;Ulander,J.;Hanisch,G.;Bergstrom,C.A.Computational prediction of drug solubility in fasted simulated and aspirated human intestinal fluid.Pharm.Res.2014,32,578?89.

(10)Persson,L.C.;Porter,C.J.;Charman,W.N.;Bergstrom,C.A.Computational prediction of drug solubility in lipid based formulation excipients.Pharm.Res.2013,30(12),3225?37.

(11)Casartelli,A.;Bonato,M.;Cristofori,P.;Crivellente,F.;Dal Negro,G.;Masotto,I.;Mutinelli,C.;Valko,K.;Bonfante,V.A cellbased approach for the early assessment of the phospholipidogenic potential in pharmaceutical research and drug development.Cell Biol.Toxicol 2003,19(3),161?76.

(12)Fischer,H.;Atzpodien,E.A.;Csato,M.;Doessegger,L.;Lenz,B.;Schmitt,G.;Singer,T.In silico assay for assessing phospholipidosis potential of small druglike molecules:training,validation,and refinement using several data sets.J.Med.Chem.2012,55(1),126?39.

(13)Seelig,A.;Gottschlich,R.;Devant,R.M.A method to determine the ability of drugs to diffuse through the blood-brain barrier.Proc.Natl.Acad.Sci.U.S.A.1994,91(1),68?72.

(14)Peresypkin,A.;Kwei,G.;Ellison,M.;Lynn,K.;Zhang,D.;Rhodes,T.;Remenar,J.Supramolecular behavior of the amphiphilic drug(2R)-2-ethylchromane-2-carboxylic acid arginine salt(a novel PPARalpha/gamma dual agonist).Pharm.Res.2005,22(9),1438?44.

(15)Kloefer,B.;van Hoogevest,P.;Moloney,R.;Kuentz,M.;Leigh,M.L.S.;Dressman,J.Study of a standardized taurocholate-lecithin powder for preparing the biorelevant media FeSSIF and FaSSIF.Dissolution Technol.2010,17(3),6?13.

(16)Milletti,F.;Storchi,L.;Sforna,G.;Cruciani,G.New and original pKa prediction method using grid molecular interaction fields.J.Chem.Inf.Model.2007,47(6),2172?81.

(17)Mannhold,R.;Poda,G.I.;Ostermann,C.;Tetko,I.V.Calculation of molecular lipophilicity:State-of-the-art and comparison of log P methods on more than 96,000 compounds.J.Pharm.Sci.2009,98(3),861?93.

(18)Pagliara,A.;Carrupt,P.A.;Caron,G.;Gaillard,P.;Testa,B.Lipophilicity profiles of ampholytes.Chem.Rev.1997,97(8),3385?3400.

(19)Vertzoni,M.;Fotaki,N.;Kostewicz,E.;Stippler,E.;Leuner,C.;Nicolaides,E.;Dressman,J.;Reppas,C.Dissolution media simulating the intralumenal composition of the small intestine:physiological issues and practical aspects.J.Pharm.Pharmacol.2004,56(4),453?62.

(20)Kerns,E.H.;Di,L.;Carter,G.T.In vitro solubility assays in drug discovery.Curr.Drug Metab.2008,9(9),879?85.

(21)Lehto,P.;Kortejarvi,H.;Liimatainen,A.;Ojala,K.;Kangas,H.;Hirvonen,J.;Tanninen,V.P.;Peltonen,L.Use of conventional surfactant media as surrogates for FaSSIF in simulating in vivo dissolution of BCS class II drugs.Eur.J.Pharm.Biopharm.2011,78(3),531?8.

(22)Fagerberg,J.H.;Tsinman,O.;Sun,N.;Tsinman,K.;Avdeef,A.;Bergstrom,C.A.Dissolution rate and apparent solubility of poorly soluble drugs in biorelevant dissolution media.Mol.Pharmaceutics 2010,7(5),1419?30.

(23)Box,K.J.;Comer,J.E.Using measured pKa,LogP and solubility to investigate supersaturation and predict BCS class.Curr.Drug Metab.2008,9(9),869?78.

(24)Avdeef,A.Absorption and Drug Development:Solubility,Permeability,and Charge State,2nd ed.;John Wiley&Sons:Hoboken,NJ,2012;Vol.xli,p 698.