Müge ATEŞ, Mustafa Sinan KAYNAK, Selma ŞAHİN

İntestinal Absorpsiyonu Artırmak Amacıyla Kullanılan Permeasyon Artırıcı Ajanlar

Sistemik etki elde etmek amacıyla ilaçlar farklı yollarla uygulanmaktadır. Bu uygulama yolları arasında en yaygın olarak kullanılanı oral yoldur. Oral yolla verilen bir ilaç etki edeceği bölgeye ulaşana kadar çeşitli biyolojik membranlardan geçmek zorundadır. Bu membranların en önemlilerinden biri de barsak epitelidir. Barsak epitelinden absorpsiyon başlıca iki mekanizma ile gerçekleşmektedir. Bunlar epitel hücre membranlarından absorpsiyon transselüler yol ve epitel hücreler arasındaki sıkı kavşaklar tight junction ’dan absorpsiyondur. Moleküllerin hücreler arasındaki sıkı kavşaklardan geçmesi paraselüler interselüler transport olarak adlandırılmaktadır. Paraselüler permeabilitenin düzenlenerek ilaç absorpsiyonunu artırmak için en etkili yol sıkı kavşakların yapısal olarak düzenlenmesidir. Polimer ve yüzey etkin özellikteki bazı maddelerin membranlardan paraselüler yolla geçen ilaçların absorpsiyonunu çeşitli mekanizmalarla artırdığı belitilmiştir. Bu maddeler permeasyon artırıcılar olarak da bilinmektedir. Bu derlemede, permeasyon artırıcıların fizikokimyasal özellikleri ve intestinal absorpsiyonu artırma mekanizmalarından bahsedilmektedir. Ayrıca permeasyon artırıcılara çeşitli örnekler verilerek, ve bu maddelerle yapılmış çalışmalar değerlendirilmiştir.

Anahtar Kelimeler:

Permeasyon artırıcılar, Paraselüler absorpsiyon, Permeabilite

Permeability enhancers used to increase intestinal absorption

Drugs are administered through various routes to obtain systemic effect. Of these, the most commonly used route of administration is the oral route. Following oral administration, the drug has to pass through several biological membranes until it reaches the site of effect. The most important one among these membranes is the intestinal epithelium. Absorption through the intestinal epithelium occurs mainly by two mechanisms. These mechanisms are absorption through the epithelial cell membranes transcellular route and absorption through the tight junctions between epithelial cells. Transport of molecules through the tight junctions is called as paracellular intercellular transport. The most effective way to improve drug absorption by regulating paracellular permeability is the structural organization of tight junctions. It is reported that some substances such as polymers, surfactants increase the absorption of paracellulary transported drugs across membranes by means of various mechanisms. These substances are also known as permeation enhancers. In this review, physicochemical peroperties of permeability enhancers and their mechanism of effect to increase intestinal absorption were discussed. Also various examples were given for these permeability enhancers and the studies counducted using these substances were evaluated.

Keywords:

Permeation enhancers, Paracellular absorption, Permeability,

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Kayaalp, S.O. (1987). Rasyonel Tedavi Yönünden Tıbbi Farmakoloji (Fourth bs.): Tora- man ve Ulucan Matbaası, Ankara.
Martinez, M.N., Amidon, G.L.: A mechanistic approach to understanding the factors af- fecting drug absorption: a review of fundamentals. J Clin Pharmacol, 42 (6), 620 (2002).
Shargel, L.Y., A.B.C. (1993). Applied Biopharmaceutics and Pharmacokinetics (Third bs.): Prentice-Hall International Editions, London.
Bajaj, H., Bisht, S., Yadav, M., Singh, V.: Bioavailability Enhancement: A Review. Int J Pharm Bio Sci, 2 (2), 202 (2011).
Cano-Cebrian, M.J., Zornoza, T., Granero, L., Polache, A.: Intestinal absorption en- hancement via the paracellular route by fatty acids, chitosans and others: a target for drug delivery. Curr Drug Deliv, 2 (1), 9 (2005).
Lobenberg, R., Amidon, G.L.: Modern bioavailability, bioequivalence and biopharma- ceutics classification system. New scientific approaches to international regulatory standards. Eur J Pharm Biopharm, 50 (1), 3 (2000).
Hillgren, K.M., Kato, A., Borchardt, R.T.: In vitro systems for studying intestinal drug absorption. Med Res Rev, 15 (2), 83 (1995).
Kararli, T.T.: Gastrointestinal absorption of drugs. Crit Rev Ther Drug Carrier Syst, 6 (1), 39 (1989).
Hunter, J., Hirst, B.H.: Intestinal secretion of drugs. The role of P-glycoprotein and re- lated drug efflux systems in limiting oral drug absorption. Adv Drug Deliv Rev, 25 (2-3), 129 (1997).
Cox, D.S., Raje, S., Gao, H.L., Salama, N.N., Eddington, N.D.: Enhanced permeability of molecular weight markers and poorly bioavailable compounds across Caco-2 cell monolayers using the absorption enhancer, zonula occludens toxin. Pharm Res, 19 (11), 1680 (2002).
Aungst, B.J.: Intestinal permeation enhancers. J Pharm Sci, 89 (4), 429 (2000).
Shepherd, R., Reader, S., Falshaw, A.: Chitosan functional properties. Glycoconj J, 14 (4), 535 (1997).
Di Colo, G., Zambito, Y., Zaino, C.: Polymeric enhancers of mucosal epithelia perme- ability: synthesis, transepithelial penetration-enhancing properties, mechanism of ac- tion, safety issues. J Pharm Sci, 97 (5), 1652 (2008).
Williams, A.C., Barry, B.W.: Penetration enhancers. Adv Drug Deliv Rev, 56 (5), 603 (2004).
Junginger, H.E., Verhoef, J.C.: Macromolecules as safe penetration enhancers for hy- drophilic drugs - a fiction?. Pharm Sci Technolo Today, 1 (9), 370 (1998).
Dodane, V., Vilivalam, V.D.: Pharmaceutical applications of chitosan. Pharm Sci Tech- nol Today, 1 (6), 246 (1998).
Thanou, M., Verhoef, J.C., Junginger, H.E.: Oral drug absorption enhancement by chi- tosan and its derivatives. Adv Drug Deliv Rev, 52 (2), 117 (2001).
Dutta, P.K., Dutta, J., Tripathi, V.S.: Chitin and chitosan: Chemistry, properties and applications. J Sci Ind Res, 63 (1), 20 (2004).
Borchard, G., Luessen, H.L., deBoer, A.G., Verhoef, J.C., Lehr, C.M., Junginger, H.E.: The potential of mucoadhesive polymers in enhancing intestinal peptide drug absorp- tion .3. Effects of chitosan-glutamate and carbomer on epithelial tight junctions in vitro. J Control Release, 39 (2-3), 131 (1996).
Schipper, N.G.M., Varum, K.M., Artursson, P.: Chitosans as absorption enhancers for poorly absorbable drugs .1. Influence of molecular weight and degree of acetylation on drug transport across human intestinal epithelial (Caco-2) cells. Pharm Res, 13 (11), 1686 (1996).
Kotze, A.F., Thanou, M.M., Lueben, H.L., de Boer, A.G., Verhoef, J.C., Junginger, H.E.: Enhancement of paracellular drug transport with highly quaternized N-trimethyl chi- tosan chloride in neutral environments: In vitro evaluation in intestinal epithelial cells (Caco-2). J Pharm Sci, 88 (2), 253 (1999).
Artursson, P., Lindmark, T., Davis, S.S., Illum, L.: Effect of Chitosan on the Permeabil- ity of Monolayers of Intestinal Epithelial-Cells (Caco-2). Pharm Res, 11 (9), 1358 (1994).
Schipper, N.G.M., Olsson, S., Hoogstraate, J.A., deBoer, A.G., Varum, K.M., Artursson, P.: Chitosans as absorption enhancers for poorly absorbable drugs .2. Mechanism of absorption enhancement. Pharm Res, 14 (7), 923 (1997).
Bernkop-Schnurch, A., Guggi, D., Pinter, Y.: Thiolated chitosans: development and in vitro evaluation of a mucoadhesive, permeation enhancing oral drug delivery system. J Control Release, 94 (1), 177 (2004).
Sandri, G., Bonferoni, M.C., Rossi, S., Ferrari, F., Gibin, S., Zambito, Y., Di Colo, G., Caramella, C.: Nanoparticles based on N-trimethylchitosan: Evaluation of absorption properties using in vitro (Caco-2 cells) and ex vivo (excised rat jejunum) models. Eur J Pharm Biopharm, 65 (1), 68 (2007).
Guo, J., Ping, Q., Jiang, G., Dong, J., Qi, S., Feng, L., Li, Z., Li, C.: Transport of leupro- lide across rat intestine, rabbit intestine and Caco-2 cell monolayer. Int J Pharm, 278 (2), 415 (2004).
Kowapradit, J., Opanasopit, P., Ngawhirunpat, T., Apirakaramwong, A., Rojanarata, T., Ruktanonchai, U., Sajomsang, W.: In vitro permeability enhancement in intestinal epithelial cells (Caco-2) monolayer of water soluble quaternary ammonium chitosan derivatives. AAPS PharmSciTech, 11 (2), 497 (2010).
Bach, A.C., Babayan, V.K.: Medium-Chain Triglycerides - an Update. Am J Clin Nut, 36 (5), 950 (1982).
Lindmark, T., Nikkila, T., Artursson, P.: Mechanisms of absorption enhancement by medium chain fatty acids in intestinal epithelial Caco-2 cell monolayers. J Pharmacol Exp Ther, 275 (2), 958 (1995).
Sakai, M., Imai, T., Ohtake, H., Azuma, H., Otagiri, M.: Effects of absorption enhancers on the transport of model compounds in Caco-2 cell monolayers: Assessment by confo- cal laser scanning microscopy. J Pharm Sci, 86 (7), 779 (1997).
Lo, Y.L., Huang, J.D.: Effects of sodium deoxycholate and sodium caprate on the trans- port of epirubicin in human intestinal epithelial Caco-2 cell layers and everted gut sacs of rats. Biochem Pharmacol, 59 (6), 665 (2000).
Chao, A.C., Nguyen, J.V., Broughall, M., Griffin, A., Fix, J.A., Daddona, P.E.: In vitro and in vivo evaluation of effects of sodium caprate on enteral peptide absorption and on mucosal morphology. Int J Pharm, 191 (1), 15 (1999).
Anderberg, E.K., Lindmark, T., Artursson, P.: Sodium caprate elicits dilatations in hu- man intestinal tight junctions and enhances drug absorption by the paracellular route. Pharm Res, 10 (6), 857 (1993).
Tomita, M., Sawada, T., Ogawa, T., Ouchi, H., Hayashi, M., Awazu, S.: Differences in the enhancing effects of sodium caprate on colonic and jejunal drug absorption. Pharm Res, 9 (5), 648 (1992).
Tomita, M., Hayashi, M., Awazu, S.: Absorption-enhancing mechanism of EDTA, cap- rate, and decanoylcarnitine in Caco-2 cells. J Pharm Sci, 85 (6), 608 (1996).
Dos Santos, I., Fawaz, F., Lagueny, A.M., Bonini, F.: Improvement of norfloxacin oral bioavailability by EDTA and sodium caprate. Int J Pharm, 260 (1), 1 (2003).
Sakai, M., Imai, T., Ohtake, H., Otagiri, M.: Cytotoxicity of absorption enhancers in Caco-2 cell monolayers. J Pharm Pharmacol, 50 (10), 1101 (1998).
Watson, C.J., Rowland, M., Warhurst, G.: Functional modeling of tight junctions in in- testinal cell monolayers using polyethylene glycol oligomers. Am J Physiol Cell Physiol, 281 (2), C388 (2001).
Maher, S., Leonard, T.W., Jacobsen, J., Brayden, D.J.: Safety and efficacy of sodium caprate in promoting oral drug absorption: From in vitro to the clinic. Adv Drug Deliv Rev, 61 (15), 1427 (2009).
Anderberg, E.K., Nystrom, C., Artursson, P.: Epithelial transport of drugs in cell cul- ture. VII: Effects of pharmaceutical surfactant excipients and bile acids on transepithe- lial permeability in monolayers of human intestinal epithelial (Caco-2) cells. J Pharm Sci, 81 (9), 879 (1992).
Sharma, P., Varma, M.V., Chawla, H.P., Panchagnula, R.: Relationship between lipo- philicity of BCS class III and IV drugs and the functional activity of peroral absorption enhancers. Farmaco, 60 (11-12), 870 (2005).
Sasaki, K., Yonebayashi, S., Yoshida, M., Shimizu, K., Aotsuka, T., Takayama, K.: Im- provement in the bioavailability of poorly absorbed glycyrrhizin via various non-vascu- lar administration routes in rats. Int J Pharm, 265 (1-2), 95 (2003).
Raoof, A.A., Ramtoola, Z., McKenna, B., Yu, R.Z., Hardee, G., Geary, R.S.: Effect of sodium caprate on the intestinal absorption of two modified antisense oligonucleotides in pigs. Eur J Pharm Sci, 17 (3), 131 (2002).
Shin, S.C., Cho, C.W., Oh, I.J.: Effects of non-ionic surfactants as permeation enhanc- ers towards piroxicam from the poloxamer gel through rat skins. Int J Pharm, 222 (2), 199 (2001).
Fricker, G., Fahr, A., Beglinger, C., Kissel, T., Reiter, G., Drewe, J.: Permeation en- hancement of octreotide by specific bile salts in rats and human subjects: In vitro, in vivo correlations. Br J Pharmacol, 117 (1), 217 (1996).
Meaney, C.M., O’Driscoll, C.M.: A comparison of the permeation enhancement poten- tial of simple bile salt and mixed bile salt : fatty acid micellar systems using the CaCo-2 cell culture model. Int J Pharm, 207 (1-2), 21 (2000).
Dias, R., Sakhare, S., Mali, K.: In-vitro Absorption Studies of Mucoadhesive Tablets of Acyclovir. Indian J Pharm Educ Res, 44 (2), 183 (2010).
Rege, B.D., Yu, L.X., Husain, A.S., Polli, J.E.: Effect of common excipients on Caco-2 transport of low-permeability drugs. J Pharm Sci, 90 (11), 1776 (2001).
Shah, P., Jogani, V., Mishra, P., Mishra, A.K., Bagchi, T., Misra, A.: In vitro assessment of acyclovir permeation across cell monolayers in the presence of absorption enhancers. Drug Dev Ind Pharm, 34 (3), 279 (2008).
http://en.wikipedia.org/wiki/Cyclodextrin. Ağ Stella, V.J., Rajewski, R.A.: Cyclodextrins: Their future in drug formulation and deliv- ery. Pharm Res, 14 (5), 556 (1997).
Loftsson, T., Brewster, M.E.: Pharmaceutical applications of cyclodextrins .1. Drug solubilization and stabilization. J Pharm Sci, 85 (10), 1017 (1996).
Rajewski, R.A., Stella, V.J.: Pharmaceutical applications of cyclodextrins .2. In vivo drug delivery. J Pharm Sci, 85 (11), 1142 (1996).
Shaker, D.S., Ghanem, A.H., Li, S.K., Warner, K.S., Hashem, F.M., Higuchi, W.I.: Mech- anistic studies of the effect of hydroxypropyl-beta-cyclodextrin on in vitro transdermal permeation of corticosterone through hairless mouse skin. Int J Pharm, 253 (1-2), 1 (2003).
Marttin, E., Verhoef, J.C., Cullander, C., Romeijn, S.G., Nagelkerke, J.F., Merkus, F.W.H.M.: Confocal laser scanning microscopic visualization of the transport of dex- trans after nasal administration to rats: Effects of absorption enhancers. Pharm Res, 14 (5), 631 (1997).
Hovgaard, L.: Drug-delivery studies in Caco-2 monolayers IV: Absorption enhancer ef- fects of cyclodextrins. Pharm Res, 12 (9), 1328 (1995).
Chavanpatil, M., Vavia, P.R.: Enhancement of nasal absorption of acyclovir via cyclo- dextrins. J Inclusion Phenom Macrocyclic Chem, 44 (1-4), 137 (2002).
Anilkumar, P., Badarinath, A.V., Naveen, N., Prasad, K., Reddy, B.R.S., Hyndhavi, M., Nirosha, M.: A rationalized description on study of ıntestinal barrier, drug permeability and permeation enhancers. J Global Trends Pharm Sci, 2 (4), 431 (2011).
Kang, M.J., Cho, J.Y., Shim, B.H., Kim, D.K., Lee, J.: Bioavailability enhancing activi- ties of natural compounds from medicinal plants. J Med Plants Res, 3 (13), 1204 (2009).
Coleman, I.P.L., Blair, J.A., Hilburn, M.E.: Effect of dietary and synthetic chelating- agents on the ıntestinal-absorption of lead. Int J Environ Stud, 18 (3-4), 187 (1982).
Thanou, M., Verhoef, J.C., Nihot, M.T., Verheijden, J.H.M., Junginger, H.E.: Enhance- ment of the intestinal absorption of low molecular weight heparin (LMWH) in rats and pigs using Carbopol (R) 934P. Pharm Res, 18 (11), 1638 (2001).
Silva, C.M., Veiga, F., Ribeiro, A.J., Zerrouk, N., Arnaud, P.: Effect of chitosan-coated alginate microspheres on the permeability of Caco-2 cell monolayers. Drug Dev Ind Pharm, 32 (9), 1079 (2006).
Chen, F., Zhang, Z.R., Yuan, F., Qin, X., Wang, M.T., Huang, Y.: In vitro and in vivo study of N-trimethyl chitosan nanoparticles for oral protein delivery. Int J Pharm, 349 (1-2), 226 (2008).
Thanou, M., Verhoef, J.C., Marbach, P., Junginger, H.E.: Intestinal absorption of oc- treotide: N-trimethyl chitosan chloride (TMC) ameliorates the permeability and absorp- tion properties of the somatostatin analogue in vitro and in vivo. J Pharm Sci, 89 (7), 951 (2000).
Guggi, D., Kast, C.E., Bernkop-Schnurch, A.: In vivo evaluation of an oral salmon calcitonin-delivery system based on a thiolated chitosan carrier matrix. Pharm Res, 20 (12), 1989 (2003).
Krauland, A.H., Guggi, D., Bernkop-Schnurch, A.: Oral insulin delivery: The potential of thiolated chitosan-insulin tablets on non-diabetic rats. J Control Release, 95 (3), 547 (2004).
Hamman, J.H., Schultz, C.M., Kotze, A.F.: N-trimethyl chitosan chloride: Optimum degree of quaternization for drug absorption enhancement across epithelial cells. Drug Dev Ind Pharm, 29 (2), 161 (2003).